WO2020001632A1 - 褐藻胶寡糖二酸的组合物 - Google Patents
褐藻胶寡糖二酸的组合物 Download PDFInfo
- Publication number
- WO2020001632A1 WO2020001632A1 PCT/CN2019/093778 CN2019093778W WO2020001632A1 WO 2020001632 A1 WO2020001632 A1 WO 2020001632A1 CN 2019093778 W CN2019093778 W CN 2019093778W WO 2020001632 A1 WO2020001632 A1 WO 2020001632A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- alginate oligosaccharide
- acid
- diacid
- total weight
- composition according
- Prior art date
Links
- 229920001542 oligosaccharide Polymers 0.000 title claims abstract description 139
- 239000000203 mixture Substances 0.000 title claims abstract description 125
- 235000010443 alginic acid Nutrition 0.000 title claims abstract description 100
- 229920000615 alginic acid Polymers 0.000 title claims abstract description 100
- -1 alginate oligosaccharide Chemical class 0.000 title claims abstract description 86
- 229940072056 alginate Drugs 0.000 title claims abstract description 84
- AEMOLEFTQBMNLQ-UHFFFAOYSA-N beta-D-galactopyranuronic acid Natural products OC1OC(C(O)=O)C(O)C(O)C1O AEMOLEFTQBMNLQ-UHFFFAOYSA-N 0.000 claims abstract description 74
- AEMOLEFTQBMNLQ-BZINKQHNSA-N D-Guluronic Acid Chemical compound OC1O[C@H](C(O)=O)[C@H](O)[C@@H](O)[C@H]1O AEMOLEFTQBMNLQ-BZINKQHNSA-N 0.000 claims abstract description 73
- 150000003839 salts Chemical class 0.000 claims abstract description 7
- AEMOLEFTQBMNLQ-VANFPWTGSA-N D-mannopyranuronic acid Chemical compound OC1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@@H]1O AEMOLEFTQBMNLQ-VANFPWTGSA-N 0.000 claims description 103
- IAJILQKETJEXLJ-UHFFFAOYSA-N Galacturonsaeure Natural products O=CC(O)C(O)C(O)C(O)C(O)=O IAJILQKETJEXLJ-UHFFFAOYSA-N 0.000 claims description 103
- 238000000034 method Methods 0.000 claims description 41
- 208000002193 Pain Diseases 0.000 claims description 31
- 230000036407 pain Effects 0.000 claims description 30
- 235000000346 sugar Nutrition 0.000 claims description 28
- 238000002360 preparation method Methods 0.000 claims description 22
- 201000004810 Vascular dementia Diseases 0.000 claims description 21
- 239000003814 drug Substances 0.000 claims description 17
- 208000024827 Alzheimer disease Diseases 0.000 claims description 15
- 208000018737 Parkinson disease Diseases 0.000 claims description 14
- 206010012601 diabetes mellitus Diseases 0.000 claims description 14
- 150000008163 sugars Chemical class 0.000 claims description 14
- 206010061218 Inflammation Diseases 0.000 claims description 13
- 230000004054 inflammatory process Effects 0.000 claims description 13
- 201000010099 disease Diseases 0.000 claims description 12
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 12
- 206010039966 Senile dementia Diseases 0.000 claims description 7
- 150000002016 disaccharides Chemical class 0.000 claims description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- 150000004044 tetrasaccharides Chemical class 0.000 claims description 5
- 150000004043 trisaccharides Chemical class 0.000 claims description 5
- 230000036541 health Effects 0.000 claims description 4
- 159000000000 sodium salts Chemical group 0.000 claims description 4
- ZEPAXLPHESYSJU-UHFFFAOYSA-N 2,3,4,5,6,7,8-heptahydroxyoctanal Chemical compound OCC(O)C(O)C(O)C(O)C(O)C(O)C=O ZEPAXLPHESYSJU-UHFFFAOYSA-N 0.000 claims description 3
- PZUPAGRIHCRVKN-UHFFFAOYSA-N 5-[5-[3,4-dihydroxy-6-[(3,4,5-trihydroxyoxan-2-yl)oxymethyl]-5-[3,4,5-trihydroxy-6-[(3,4,5-trihydroxyoxan-2-yl)oxymethyl]oxan-2-yl]oxyoxan-2-yl]oxy-3,4-dihydroxy-6-[(3,4,5-trihydroxyoxan-2-yl)oxymethyl]oxan-2-yl]oxy-6-(hydroxymethyl)oxane-2,3,4-triol Chemical compound OCC1OC(O)C(O)C(O)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(COC4C(C(O)C(O)CO4)O)O3)O)C(COC3C(C(O)C(O)CO3)O)O2)O)C(COC2C(C(O)C(O)CO2)O)O1 PZUPAGRIHCRVKN-UHFFFAOYSA-N 0.000 claims description 2
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 claims description 2
- 239000000047 product Substances 0.000 description 102
- 230000000694 effects Effects 0.000 description 65
- 238000002474 experimental method Methods 0.000 description 63
- 150000002482 oligosaccharides Chemical class 0.000 description 60
- 241000699670 Mus sp. Species 0.000 description 55
- 239000002253 acid Substances 0.000 description 42
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 39
- 241001465754 Metazoa Species 0.000 description 38
- 241000700159 Rattus Species 0.000 description 30
- 238000006243 chemical reaction Methods 0.000 description 29
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 27
- 239000000243 solution Substances 0.000 description 27
- 230000002829 reductive effect Effects 0.000 description 25
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 21
- 230000000144 pharmacologic effect Effects 0.000 description 21
- 241000699666 Mus <mouse, genus> Species 0.000 description 20
- CBENFWSGALASAD-UHFFFAOYSA-N Ozone Chemical compound [O-][O+]=O CBENFWSGALASAD-UHFFFAOYSA-N 0.000 description 20
- 238000010171 animal model Methods 0.000 description 19
- 208000019695 Migraine disease Diseases 0.000 description 18
- 238000012347 Morris Water Maze Methods 0.000 description 18
- 238000006116 polymerization reaction Methods 0.000 description 18
- 238000011156 evaluation Methods 0.000 description 17
- 239000000126 substance Substances 0.000 description 17
- 238000012360 testing method Methods 0.000 description 17
- 206010027599 migraine Diseases 0.000 description 16
- 206010015150 Erythema Diseases 0.000 description 14
- 229940079593 drug Drugs 0.000 description 14
- 229920001282 polysaccharide Polymers 0.000 description 14
- 239000005017 polysaccharide Substances 0.000 description 14
- 150000004804 polysaccharides Chemical class 0.000 description 14
- 238000011534 incubation Methods 0.000 description 13
- 239000007788 liquid Substances 0.000 description 13
- 230000000638 stimulation Effects 0.000 description 13
- 210000004027 cell Anatomy 0.000 description 12
- 238000005481 NMR spectroscopy Methods 0.000 description 11
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 11
- 150000001875 compounds Chemical class 0.000 description 11
- 239000012153 distilled water Substances 0.000 description 11
- 239000001257 hydrogen Substances 0.000 description 11
- 229910052739 hydrogen Inorganic materials 0.000 description 11
- XLYOFNOQVPJJNP-ZSJDYOACSA-N Heavy water Chemical compound [2H]O[2H] XLYOFNOQVPJJNP-ZSJDYOACSA-N 0.000 description 10
- 102000007568 Proto-Oncogene Proteins c-fos Human genes 0.000 description 10
- 108010071563 Proto-Oncogene Proteins c-fos Proteins 0.000 description 10
- 210000001168 carotid artery common Anatomy 0.000 description 10
- 238000010525 oxidative degradation reaction Methods 0.000 description 10
- 239000000523 sample Substances 0.000 description 10
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 9
- 239000000783 alginic acid Substances 0.000 description 9
- 229960001126 alginic acid Drugs 0.000 description 9
- 150000004781 alginic acids Chemical class 0.000 description 9
- 230000002146 bilateral effect Effects 0.000 description 9
- 210000004556 brain Anatomy 0.000 description 9
- 239000007924 injection Substances 0.000 description 9
- 238000002347 injection Methods 0.000 description 9
- 239000012528 membrane Substances 0.000 description 9
- 239000000543 intermediate Substances 0.000 description 8
- 238000004519 manufacturing process Methods 0.000 description 8
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 8
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 8
- 230000008961 swelling Effects 0.000 description 8
- 238000005303 weighing Methods 0.000 description 8
- SNIOPGDIGTZGOP-UHFFFAOYSA-N Nitroglycerin Chemical compound [O-][N+](=O)OCC(O[N+]([O-])=O)CO[N+]([O-])=O SNIOPGDIGTZGOP-UHFFFAOYSA-N 0.000 description 7
- 239000000006 Nitroglycerin Substances 0.000 description 7
- 206010003246 arthritis Diseases 0.000 description 7
- 229910052799 carbon Inorganic materials 0.000 description 7
- 239000002552 dosage form Substances 0.000 description 7
- 239000012634 fragment Substances 0.000 description 7
- 229960003711 glyceryl trinitrate Drugs 0.000 description 7
- 239000000843 powder Substances 0.000 description 7
- 230000009182 swimming Effects 0.000 description 7
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 6
- 239000002775 capsule Substances 0.000 description 6
- 229920003045 dextran sodium sulfate Polymers 0.000 description 6
- 210000003128 head Anatomy 0.000 description 6
- 238000001819 mass spectrum Methods 0.000 description 6
- 230000004044 response Effects 0.000 description 6
- 239000011780 sodium chloride Substances 0.000 description 6
- 239000003826 tablet Substances 0.000 description 6
- PLRACCBDVIHHLZ-UHFFFAOYSA-N 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine Chemical compound C1N(C)CCC(C=2C=CC=CC=2)=C1 PLRACCBDVIHHLZ-UHFFFAOYSA-N 0.000 description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 5
- 101001135571 Mus musculus Tyrosine-protein phosphatase non-receptor type 2 Proteins 0.000 description 5
- 239000004480 active ingredient Substances 0.000 description 5
- 230000007131 anti Alzheimer effect Effects 0.000 description 5
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 5
- 210000004369 blood Anatomy 0.000 description 5
- 239000008280 blood Substances 0.000 description 5
- 230000015556 catabolic process Effects 0.000 description 5
- 238000006731 degradation reaction Methods 0.000 description 5
- 230000007087 memory ability Effects 0.000 description 5
- 201000006417 multiple sclerosis Diseases 0.000 description 5
- 239000001301 oxygen Substances 0.000 description 5
- 229910052760 oxygen Inorganic materials 0.000 description 5
- 230000002035 prolonged effect Effects 0.000 description 5
- 238000011552 rat model Methods 0.000 description 5
- 210000003491 skin Anatomy 0.000 description 5
- 238000001228 spectrum Methods 0.000 description 5
- 208000024891 symptom Diseases 0.000 description 5
- 210000000427 trigeminal ganglion Anatomy 0.000 description 5
- 238000000108 ultra-filtration Methods 0.000 description 5
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 4
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical group O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 description 4
- 102000004506 Blood Proteins Human genes 0.000 description 4
- 108010017384 Blood Proteins Proteins 0.000 description 4
- 208000034628 Celiac artery compression syndrome Diseases 0.000 description 4
- 229920000855 Fucoidan Polymers 0.000 description 4
- 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 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 208000022559 Inflammatory bowel disease Diseases 0.000 description 4
- 206010033799 Paralysis Diseases 0.000 description 4
- 239000012505 Superdex™ Substances 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 4
- 210000003423 ankle Anatomy 0.000 description 4
- BBWBEZAMXFGUGK-UHFFFAOYSA-N bis(dodecylsulfanyl)-methylarsane Chemical compound CCCCCCCCCCCCS[As](C)SCCCCCCCCCCCC BBWBEZAMXFGUGK-UHFFFAOYSA-N 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 230000009194 climbing Effects 0.000 description 4
- 210000001072 colon Anatomy 0.000 description 4
- 239000012141 concentrate Substances 0.000 description 4
- 239000007857 degradation product Substances 0.000 description 4
- 231100000321 erythema Toxicity 0.000 description 4
- 238000013210 evaluation model Methods 0.000 description 4
- 238000002270 exclusion chromatography Methods 0.000 description 4
- 239000007789 gas Substances 0.000 description 4
- 239000008103 glucose Substances 0.000 description 4
- 210000003141 lower extremity Anatomy 0.000 description 4
- 210000001165 lymph node Anatomy 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 210000003657 middle cerebral artery Anatomy 0.000 description 4
- 238000010172 mouse model Methods 0.000 description 4
- 238000000569 multi-angle light scattering Methods 0.000 description 4
- 231100000252 nontoxic Toxicity 0.000 description 4
- 230000003000 nontoxic effect Effects 0.000 description 4
- 230000001590 oxidative effect Effects 0.000 description 4
- 239000000546 pharmaceutical excipient Substances 0.000 description 4
- 108090000765 processed proteins & peptides Proteins 0.000 description 4
- 238000012545 processing Methods 0.000 description 4
- 108090000623 proteins and genes Proteins 0.000 description 4
- 239000000661 sodium alginate Substances 0.000 description 4
- 235000010413 sodium alginate Nutrition 0.000 description 4
- 229940005550 sodium alginate Drugs 0.000 description 4
- 238000001356 surgical procedure Methods 0.000 description 4
- 108010087765 Antipain Proteins 0.000 description 3
- 201000006474 Brain Ischemia Diseases 0.000 description 3
- 206010008120 Cerebral ischaemia Diseases 0.000 description 3
- 206010061818 Disease progression Diseases 0.000 description 3
- 108010010803 Gelatin Proteins 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 241000699660 Mus musculus Species 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 239000002671 adjuvant Substances 0.000 description 3
- 230000003178 anti-diabetic effect Effects 0.000 description 3
- 230000002137 anti-vascular effect Effects 0.000 description 3
- SDNYTAYICBFYFH-TUFLPTIASA-N antipain Chemical compound NC(N)=NCCC[C@@H](C=O)NC(=O)[C@H](C(C)C)NC(=O)[C@H](CCCN=C(N)N)NC(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 SDNYTAYICBFYFH-TUFLPTIASA-N 0.000 description 3
- 230000006399 behavior Effects 0.000 description 3
- 230000004071 biological effect Effects 0.000 description 3
- 210000004204 blood vessel Anatomy 0.000 description 3
- 210000005013 brain tissue Anatomy 0.000 description 3
- 150000001720 carbohydrates Chemical class 0.000 description 3
- 239000000969 carrier Substances 0.000 description 3
- 206010008118 cerebral infarction Diseases 0.000 description 3
- 229940000425 combination drug Drugs 0.000 description 3
- 238000013480 data collection Methods 0.000 description 3
- 230000003111 delayed effect Effects 0.000 description 3
- 230000005750 disease progression Effects 0.000 description 3
- 239000002270 dispersing agent Substances 0.000 description 3
- 239000003937 drug carrier Substances 0.000 description 3
- 210000001951 dura mater Anatomy 0.000 description 3
- 239000002158 endotoxin Substances 0.000 description 3
- 210000003414 extremity Anatomy 0.000 description 3
- 238000003304 gavage Methods 0.000 description 3
- 229920000159 gelatin Polymers 0.000 description 3
- 239000008273 gelatin Substances 0.000 description 3
- 235000019322 gelatine Nutrition 0.000 description 3
- 235000011852 gelatine desserts Nutrition 0.000 description 3
- 230000000971 hippocampal effect Effects 0.000 description 3
- 238000009396 hybridization Methods 0.000 description 3
- 239000007928 intraperitoneal injection Substances 0.000 description 3
- 150000002500 ions Chemical class 0.000 description 3
- 229920006008 lipopolysaccharide Polymers 0.000 description 3
- 150000003272 mannan oligosaccharides Chemical class 0.000 description 3
- 238000000691 measurement method Methods 0.000 description 3
- 210000004379 membrane Anatomy 0.000 description 3
- 230000006386 memory function Effects 0.000 description 3
- 210000002569 neuron Anatomy 0.000 description 3
- 239000007800 oxidant agent Substances 0.000 description 3
- 229920001223 polyethylene glycol Polymers 0.000 description 3
- 230000000291 postprandial effect Effects 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 206010039073 rheumatoid arthritis Diseases 0.000 description 3
- 239000004094 surface-active agent Substances 0.000 description 3
- 230000004083 survival effect Effects 0.000 description 3
- 201000000596 systemic lupus erythematosus Diseases 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- 210000003371 toe Anatomy 0.000 description 3
- 238000011830 transgenic mouse model Methods 0.000 description 3
- 210000003901 trigeminal nerve Anatomy 0.000 description 3
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 3
- 206010002091 Anaesthesia Diseases 0.000 description 2
- 229920002261 Corn starch Polymers 0.000 description 2
- 201000004624 Dermatitis Diseases 0.000 description 2
- 206010015866 Extravasation Diseases 0.000 description 2
- 229930091371 Fructose Natural products 0.000 description 2
- 239000005715 Fructose Substances 0.000 description 2
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- 208000036110 Neuroinflammatory disease Diseases 0.000 description 2
- 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 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- 201000004681 Psoriasis Diseases 0.000 description 2
- 241000700157 Rattus norvegicus Species 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- 208000002847 Surgical Wound Diseases 0.000 description 2
- 210000001015 abdomen Anatomy 0.000 description 2
- 210000000683 abdominal cavity Anatomy 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 238000009825 accumulation Methods 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 125000003172 aldehyde group Chemical group 0.000 description 2
- 230000037005 anaesthesia Effects 0.000 description 2
- 230000003110 anti-inflammatory effect Effects 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 238000009227 behaviour therapy Methods 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 210000000988 bone and bone Anatomy 0.000 description 2
- 239000007958 cherry flavor Substances 0.000 description 2
- RNFNDJAIBTYOQL-UHFFFAOYSA-N chloral hydrate Chemical compound OC(O)C(Cl)(Cl)Cl RNFNDJAIBTYOQL-UHFFFAOYSA-N 0.000 description 2
- 229960002327 chloral hydrate Drugs 0.000 description 2
- OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 description 2
- 230000001684 chronic effect Effects 0.000 description 2
- 206010009887 colitis Diseases 0.000 description 2
- 229920001436 collagen Polymers 0.000 description 2
- 239000010949 copper Substances 0.000 description 2
- 239000008120 corn starch Substances 0.000 description 2
- 230000002354 daily effect Effects 0.000 description 2
- 230000003247 decreasing effect Effects 0.000 description 2
- 235000014113 dietary fatty acids Nutrition 0.000 description 2
- 235000015872 dietary supplement Nutrition 0.000 description 2
- 238000009297 electrocoagulation Methods 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 230000036251 extravasation Effects 0.000 description 2
- 239000000194 fatty acid Substances 0.000 description 2
- 229930195729 fatty acid Natural products 0.000 description 2
- 239000000835 fiber Substances 0.000 description 2
- 239000000796 flavoring agent Substances 0.000 description 2
- 235000013355 food flavoring agent Nutrition 0.000 description 2
- 235000003599 food sweetener Nutrition 0.000 description 2
- 238000007429 general method Methods 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 210000001320 hippocampus Anatomy 0.000 description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 2
- 230000002055 immunohistochemical effect Effects 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 230000028709 inflammatory response Effects 0.000 description 2
- 238000001802 infusion Methods 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 230000000968 intestinal effect Effects 0.000 description 2
- 208000027905 limb weakness Diseases 0.000 description 2
- 231100000861 limb weakness Toxicity 0.000 description 2
- 230000000670 limiting effect Effects 0.000 description 2
- 239000002502 liposome Substances 0.000 description 2
- 239000007937 lozenge Substances 0.000 description 2
- 206010025135 lupus erythematosus Diseases 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 108020004999 messenger RNA Proteins 0.000 description 2
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 2
- 244000005700 microbiome Species 0.000 description 2
- 230000031990 negative regulation of inflammatory response Effects 0.000 description 2
- 208000004296 neuralgia Diseases 0.000 description 2
- 230000003959 neuroinflammation Effects 0.000 description 2
- 238000001208 nuclear magnetic resonance pulse sequence Methods 0.000 description 2
- 229960001412 pentobarbital Drugs 0.000 description 2
- 230000010412 perfusion Effects 0.000 description 2
- 239000006187 pill Substances 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- 230000002335 preservative effect Effects 0.000 description 2
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 210000003625 skull Anatomy 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 230000003595 spectral effect Effects 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 239000003765 sweetening agent Substances 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- 239000012085 test solution Substances 0.000 description 2
- LITQZINTSYBKIU-UHFFFAOYSA-F tetracopper;hexahydroxide;sulfate Chemical group [OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[Cu+2].[Cu+2].[Cu+2].[Cu+2].[O-]S([O-])(=O)=O LITQZINTSYBKIU-UHFFFAOYSA-F 0.000 description 2
- 238000012549 training Methods 0.000 description 2
- 238000012546 transfer Methods 0.000 description 2
- URAYPUMNDPQOKB-UHFFFAOYSA-N triacetin Chemical compound CC(=O)OCC(OC(C)=O)COC(C)=O URAYPUMNDPQOKB-UHFFFAOYSA-N 0.000 description 2
- 230000002792 vascular Effects 0.000 description 2
- 235000015112 vegetable and seed oil Nutrition 0.000 description 2
- 239000008158 vegetable oil Substances 0.000 description 2
- 210000000707 wrist Anatomy 0.000 description 2
- GSCHIGXDTVYEEM-UHFFFAOYSA-N 2-[2-[[3-[6-[[4,5-dihydroxy-3-[3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxyoxan-2-yl]oxymethyl]-3,4-dihydroxy-5-[3,4,5-trihydroxy-6-[(3,4,5-trihydroxyoxan-2-yl)oxymethyl]oxan-2-yl]oxyoxan-2-yl]oxy-4,5-dihydroxy-6-[4,5,6-trihydroxy-2-(hydroxymethyl)oxan Chemical compound OC1C(O)C(O)C(CO)OC1OC1C(OCC2C(C(O)C(O)C(OC3C(OC(O)C(O)C3O)CO)O2)OC2C(C(O)C(OC3C(C(O)C(O)C(COC4C(C(O)C(O)CO4)O)O3)O)C(COC3C(C(O)C(O)CO3)OC3C(C(O)C(O)C(CO)O3)O)O2)O)OCC(O)C1O GSCHIGXDTVYEEM-UHFFFAOYSA-N 0.000 description 1
- 206010049589 Afterbirth pain 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
- 108010090849 Amyloid beta-Peptides Proteins 0.000 description 1
- 102000013455 Amyloid beta-Peptides Human genes 0.000 description 1
- 206010002383 Angina Pectoris Diseases 0.000 description 1
- 206010002556 Ankylosing Spondylitis Diseases 0.000 description 1
- 208000006820 Arthralgia Diseases 0.000 description 1
- 108010011485 Aspartame Proteins 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- 206010006002 Bone pain Diseases 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 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 1
- 206010048964 Carotid artery occlusion Diseases 0.000 description 1
- 208000000094 Chronic Pain Diseases 0.000 description 1
- 208000006561 Cluster Headache Diseases 0.000 description 1
- 206010009900 Colitis ulcerative Diseases 0.000 description 1
- 102000008186 Collagen Human genes 0.000 description 1
- 108010035532 Collagen Proteins 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 208000011231 Crohn disease Diseases 0.000 description 1
- WQZGKKKJIJFFOK-CBPJZXOFSA-N D-Gulose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@H](O)[C@H]1O WQZGKKKJIJFFOK-CBPJZXOFSA-N 0.000 description 1
- WQZGKKKJIJFFOK-QTVWNMPRSA-N D-mannopyranose Chemical compound OC[C@H]1OC(O)[C@@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-QTVWNMPRSA-N 0.000 description 1
- 206010012289 Dementia Diseases 0.000 description 1
- 206010012438 Dermatitis atopic Diseases 0.000 description 1
- 206010056340 Diabetic ulcer Diseases 0.000 description 1
- 235000019739 Dicalciumphosphate Nutrition 0.000 description 1
- 241001269524 Dura Species 0.000 description 1
- 206010016228 Fasciitis Diseases 0.000 description 1
- 244000182067 Fraxinus ornus Species 0.000 description 1
- 235000002917 Fraxinus ornus Nutrition 0.000 description 1
- 240000001238 Gaultheria procumbens Species 0.000 description 1
- 235000007297 Gaultheria procumbens Nutrition 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 206010020852 Hypertonia Diseases 0.000 description 1
- XQFRJNBWHJMXHO-RRKCRQDMSA-N IDUR Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(I)=C1 XQFRJNBWHJMXHO-RRKCRQDMSA-N 0.000 description 1
- 206010065390 Inflammatory pain Diseases 0.000 description 1
- 206010049949 Intercostal neuralgia Diseases 0.000 description 1
- 108010041872 Islet Amyloid Polypeptide Proteins 0.000 description 1
- 102000036770 Islet Amyloid Polypeptide Human genes 0.000 description 1
- 238000012449 Kunming mouse Methods 0.000 description 1
- IAJILQKETJEXLJ-SQOUGZDYSA-N L-guluronic acid Chemical compound O=C[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O IAJILQKETJEXLJ-SQOUGZDYSA-N 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
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- 240000007472 Leucaena leucocephala Species 0.000 description 1
- 208000008930 Low Back Pain Diseases 0.000 description 1
- 208000008771 Lymphadenopathy Diseases 0.000 description 1
- 229920000057 Mannan Polymers 0.000 description 1
- 235000006679 Mentha X verticillata Nutrition 0.000 description 1
- 235000002899 Mentha suaveolens Nutrition 0.000 description 1
- 235000001636 Mentha x rotundifolia Nutrition 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 206010027603 Migraine headaches Diseases 0.000 description 1
- 241000238367 Mya arenaria Species 0.000 description 1
- 208000000112 Myalgia Diseases 0.000 description 1
- 108010083674 Myelin Proteins Proteins 0.000 description 1
- 102000006386 Myelin Proteins Human genes 0.000 description 1
- 208000007920 Neurogenic Inflammation Diseases 0.000 description 1
- 108010081690 Pertussis Toxin Proteins 0.000 description 1
- 208000004983 Phantom Limb Diseases 0.000 description 1
- 206010056238 Phantom pain Diseases 0.000 description 1
- 208000004550 Postoperative Pain Diseases 0.000 description 1
- 206010071390 Resting tremor Diseases 0.000 description 1
- 206010039361 Sacroiliitis Diseases 0.000 description 1
- 229920001800 Shellac Polymers 0.000 description 1
- 206010061363 Skeletal injury Diseases 0.000 description 1
- 239000005708 Sodium hypochlorite Substances 0.000 description 1
- ZSJLQEPLLKMAKR-UHFFFAOYSA-N Streptozotocin Natural products O=NN(C)C(=O)NC1C(O)OC(CO)C(O)C1O ZSJLQEPLLKMAKR-UHFFFAOYSA-N 0.000 description 1
- 206010042496 Sunburn Diseases 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- 206010044565 Tremor Diseases 0.000 description 1
- 201000006704 Ulcerative Colitis Diseases 0.000 description 1
- LEHOTFFKMJEONL-UHFFFAOYSA-N Uric Acid Chemical compound N1C(=O)NC(=O)C2=C1NC(=O)N2 LEHOTFFKMJEONL-UHFFFAOYSA-N 0.000 description 1
- TVWHNULVHGKJHS-UHFFFAOYSA-N Uric acid Natural products N1C(=O)NC(=O)C2NC(=O)NC21 TVWHNULVHGKJHS-UHFFFAOYSA-N 0.000 description 1
- 208000035868 Vascular inflammations Diseases 0.000 description 1
- 206010047095 Vascular pain Diseases 0.000 description 1
- 206010052428 Wound Diseases 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 238000005903 acid hydrolysis reaction Methods 0.000 description 1
- 238000003916 acid precipitation Methods 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 208000038016 acute inflammation Diseases 0.000 description 1
- 230000006022 acute inflammation Effects 0.000 description 1
- 208000005298 acute pain Diseases 0.000 description 1
- IAJILQKETJEXLJ-QTBDOELSSA-N aldehydo-D-glucuronic acid Chemical compound O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)C(O)=O IAJILQKETJEXLJ-QTBDOELSSA-N 0.000 description 1
- 229920000180 alkyd Polymers 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 239000003472 antidiabetic agent Substances 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 239000003429 antifungal agent Substances 0.000 description 1
- 239000004599 antimicrobial Substances 0.000 description 1
- 210000001367 artery Anatomy 0.000 description 1
- 210000000544 articulatio talocruralis Anatomy 0.000 description 1
- 239000000605 aspartame Substances 0.000 description 1
- IAOZJIPTCAWIRG-QWRGUYRKSA-N aspartame Chemical compound OC(=O)C[C@H](N)C(=O)N[C@H](C(=O)OC)CC1=CC=CC=C1 IAOZJIPTCAWIRG-QWRGUYRKSA-N 0.000 description 1
- 229960003438 aspartame Drugs 0.000 description 1
- 235000010357 aspartame Nutrition 0.000 description 1
- 201000008937 atopic dermatitis Diseases 0.000 description 1
- 208000010668 atopic eczema Diseases 0.000 description 1
- 210000000227 basophil cell of anterior lobe of hypophysis Anatomy 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 210000000133 brain stem Anatomy 0.000 description 1
- 239000011449 brick Substances 0.000 description 1
- 239000006189 buccal tablet Substances 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 210000005252 bulbus oculi Anatomy 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 208000037887 cell injury Diseases 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 230000009990 central nervous inflammation Effects 0.000 description 1
- 208000037977 central nervous inflammation Diseases 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 230000035606 childbirth Effects 0.000 description 1
- 229960004926 chlorobutanol Drugs 0.000 description 1
- 208000037976 chronic inflammation Diseases 0.000 description 1
- 230000006020 chronic inflammation Effects 0.000 description 1
- 239000004927 clay Substances 0.000 description 1
- 208000018912 cluster headache syndrome Diseases 0.000 description 1
- 230000000112 colonic effect Effects 0.000 description 1
- 239000013256 coordination polymer Substances 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 229910000365 copper sulfate Inorganic materials 0.000 description 1
- BERDEBHAJNAUOM-UHFFFAOYSA-N copper(I) oxide Inorganic materials [Cu]O[Cu] BERDEBHAJNAUOM-UHFFFAOYSA-N 0.000 description 1
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 description 1
- 238000007428 craniotomy Methods 0.000 description 1
- KRFJLUBVMFXRPN-UHFFFAOYSA-N cuprous oxide Chemical compound [O-2].[Cu+].[Cu+] KRFJLUBVMFXRPN-UHFFFAOYSA-N 0.000 description 1
- 229940112669 cuprous oxide Drugs 0.000 description 1
- 201000003146 cystitis Diseases 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- AEMOLEFTQBMNLQ-YBSDWZGDSA-N d-mannuronic acid Chemical compound O[C@@H]1O[C@@H](C(O)=O)[C@H](O)[C@@H](O)[C@H]1O AEMOLEFTQBMNLQ-YBSDWZGDSA-N 0.000 description 1
- 238000006114 decarboxylation reaction Methods 0.000 description 1
- 239000008367 deionised water Substances 0.000 description 1
- 229910021641 deionized water Inorganic materials 0.000 description 1
- 239000003405 delayed action preparation Substances 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- NEFBYIFKOOEVPA-UHFFFAOYSA-K dicalcium phosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])([O-])=O NEFBYIFKOOEVPA-UHFFFAOYSA-K 0.000 description 1
- 229940038472 dicalcium phosphate Drugs 0.000 description 1
- 229910000390 dicalcium phosphate Inorganic materials 0.000 description 1
- UGMCXQCYOVCMTB-UHFFFAOYSA-K dihydroxy(stearato)aluminium Chemical compound CCCCCCCCCCCCCCCCCC(=O)O[Al](O)O UGMCXQCYOVCMTB-UHFFFAOYSA-K 0.000 description 1
- 230000000916 dilatatory effect Effects 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 239000002612 dispersion medium Substances 0.000 description 1
- 210000005064 dopaminergic neuron Anatomy 0.000 description 1
- 239000003651 drinking water Substances 0.000 description 1
- 235000020188 drinking water Nutrition 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 210000000883 ear external Anatomy 0.000 description 1
- 238000004070 electrodeposition Methods 0.000 description 1
- 201000002491 encephalomyelitis Diseases 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 1
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 1
- 229960003699 evans blue Drugs 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 210000001508 eye Anatomy 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 150000002191 fatty alcohols Chemical class 0.000 description 1
- 210000003191 femoral vein Anatomy 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 210000005224 forefinger Anatomy 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 239000013505 freshwater Substances 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 229940097043 glucuronic acid Drugs 0.000 description 1
- 125000005456 glyceride group Chemical group 0.000 description 1
- 239000001087 glyceryl triacetate Substances 0.000 description 1
- 235000013773 glyceryl triacetate Nutrition 0.000 description 1
- 125000005613 guluronic acid group Chemical group 0.000 description 1
- 238000007490 hematoxylin and eosin (H&E) staining Methods 0.000 description 1
- 150000002386 heptoses Chemical class 0.000 description 1
- 229920006158 high molecular weight polymer Polymers 0.000 description 1
- 210000003630 histaminocyte Anatomy 0.000 description 1
- BHEPBYXIRTUNPN-UHFFFAOYSA-N hydridophosphorus(.) (triplet) Chemical compound [PH] BHEPBYXIRTUNPN-UHFFFAOYSA-N 0.000 description 1
- 206010020718 hyperplasia Diseases 0.000 description 1
- 230000009610 hypersensitivity Effects 0.000 description 1
- 210000003016 hypothalamus Anatomy 0.000 description 1
- 230000003053 immunization Effects 0.000 description 1
- 238000002649 immunization Methods 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 239000003701 inert diluent Substances 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 239000007972 injectable composition Substances 0.000 description 1
- 229910010272 inorganic material Inorganic materials 0.000 description 1
- 239000011147 inorganic material Substances 0.000 description 1
- 238000003780 insertion Methods 0.000 description 1
- 230000037431 insertion Effects 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 238000007914 intraventricular administration Methods 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- XMGQYMWWDOXHJM-UHFFFAOYSA-N limonene Chemical compound CC(=C)C1CCC(C)=CC1 XMGQYMWWDOXHJM-UHFFFAOYSA-N 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- 230000004807 localization Effects 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 208000018555 lymphatic system disease Diseases 0.000 description 1
- 210000003563 lymphoid tissue Anatomy 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 210000004373 mandible Anatomy 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 206010027175 memory impairment Diseases 0.000 description 1
- 210000002418 meninge Anatomy 0.000 description 1
- 210000000713 mesentery Anatomy 0.000 description 1
- 210000001872 metatarsal bone Anatomy 0.000 description 1
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- OSWPMRLSEDHDFF-UHFFFAOYSA-N methyl salicylate Chemical compound COC(=O)C1=CC=CC=C1O OSWPMRLSEDHDFF-UHFFFAOYSA-N 0.000 description 1
- 229960002216 methylparaben Drugs 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 235000013336 milk Nutrition 0.000 description 1
- 239000008267 milk Substances 0.000 description 1
- 210000004080 milk Anatomy 0.000 description 1
- 210000003470 mitochondria Anatomy 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 150000002772 monosaccharides Chemical class 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 208000013465 muscle pain Diseases 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- 210000005012 myelin Anatomy 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 230000007230 neural mechanism Effects 0.000 description 1
- 230000000926 neurological effect Effects 0.000 description 1
- 230000003955 neuronal function Effects 0.000 description 1
- 208000021722 neuropathic pain Diseases 0.000 description 1
- 239000002858 neurotransmitter agent Substances 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 229940114655 nitroglycerin 10 mg Drugs 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 210000004248 oligodendroglia Anatomy 0.000 description 1
- 239000007968 orange flavor Substances 0.000 description 1
- 201000008482 osteoarthritis Diseases 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 230000004792 oxidative damage Effects 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000006072 paste Substances 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 230000003950 pathogenic mechanism Effects 0.000 description 1
- 231100000915 pathological change Toxicity 0.000 description 1
- 230000036285 pathological change Effects 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 210000004303 peritoneum Anatomy 0.000 description 1
- 239000008024 pharmaceutical diluent Substances 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 229960003742 phenol Drugs 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
- 230000002980 postoperative effect Effects 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- 229960003415 propylparaben Drugs 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 210000001609 raphe nuclei Anatomy 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000007665 sagging Methods 0.000 description 1
- 239000012488 sample solution Substances 0.000 description 1
- 238000006748 scratching Methods 0.000 description 1
- 230000002393 scratching effect Effects 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 229940076279 serotonin Drugs 0.000 description 1
- 239000004208 shellac Substances 0.000 description 1
- 229940113147 shellac Drugs 0.000 description 1
- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 description 1
- 235000013874 shellac Nutrition 0.000 description 1
- 238000004904 shortening Methods 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 239000000344 soap Substances 0.000 description 1
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 description 1
- MSXHSNHNTORCAW-WTFUTCKNSA-M sodium;(2s,3s,4s,5s,6r)-3,4,5,6-tetrahydroxyoxane-2-carboxylate Chemical compound [Na+].O[C@@H]1O[C@H](C([O-])=O)[C@@H](O)[C@H](O)[C@@H]1O MSXHSNHNTORCAW-WTFUTCKNSA-M 0.000 description 1
- 239000007892 solid unit dosage form Substances 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 238000002798 spectrophotometry method Methods 0.000 description 1
- 210000000278 spinal cord Anatomy 0.000 description 1
- 238000010186 staining Methods 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
- ZSJLQEPLLKMAKR-GKHCUFPYSA-N streptozocin Chemical compound O=NN(C)C(=O)N[C@H]1[C@@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O ZSJLQEPLLKMAKR-GKHCUFPYSA-N 0.000 description 1
- 229960001052 streptozocin Drugs 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 210000003523 substantia nigra Anatomy 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 229920001059 synthetic polymer Polymers 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 239000013076 target substance Substances 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- RTKIYNMVFMVABJ-UHFFFAOYSA-L thimerosal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 description 1
- 229940033663 thimerosal Drugs 0.000 description 1
- 229940098465 tincture Drugs 0.000 description 1
- 208000004371 toothache Diseases 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 229960002622 triacetin Drugs 0.000 description 1
- 206010044652 trigeminal neuralgia Diseases 0.000 description 1
- 229940116269 uric acid Drugs 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 230000002227 vasoactive effect Effects 0.000 description 1
- 230000024883 vasodilation Effects 0.000 description 1
- 230000002861 ventricular Effects 0.000 description 1
- 208000009935 visceral pain Diseases 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 210000003857 wrist joint Anatomy 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
- A61K31/7032—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a polyol, i.e. compounds having two or more free or esterified hydroxy groups, including the hydroxy group involved in the glycosidic linkage, e.g. monoglucosyldiacylglycerides, lactobionic acid, gangliosides
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
- A23L33/125—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives containing carbohydrate syrups; containing sugars; containing sugar alcohols; containing starch hydrolysates
-
- 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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7012—Compounds having a free or esterified carboxyl group attached, directly or through a carbon chain, to a carbon atom of the saccharide radical, e.g. glucuronic acid, neuraminic acid
-
- 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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/702—Oligosaccharides, i.e. having three to five saccharide radicals attached to each other by glycosidic linkages
-
- 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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- 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
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2200/00—Function of food ingredients
- A23V2200/30—Foods, ingredients or supplements having a functional effect on health
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2200/00—Function of food ingredients
- A23V2200/30—Foods, ingredients or supplements having a functional effect on health
- A23V2200/322—Foods, ingredients or supplements having a functional effect on health having an effect on the health of the nervous system or on mental function
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2200/00—Function of food ingredients
- A23V2200/30—Foods, ingredients or supplements having a functional effect on health
- A23V2200/328—Foods, ingredients or supplements having a functional effect on health having effect on glycaemic control and diabetes
Definitions
- the invention relates to an optimal composition of alginate oligosaccharide diacid obtained by a biological activity screening method.
- the method uses an animal model of senile dementia to evaluate the effect of different degrees of polymerization of alginate oligosaccharide and its ratio on biological activity.
- the composition with the best biological activity is screened and the desired target substance is prepared by means of ultrafiltration membrane separation.
- Fucoidan oligosaccharides have received widespread attention due to their potential medicinal value. Fucoidan oligosaccharides are usually prepared by alginic acid through several steps.
- alginate oligosaccharide molecules there are M segments formed by the connection of mannuronic acid (D-mannuronic acid) through ⁇ -1,4-glycosidic bonds, and the guluronic acid (L-guluronic acid) through ⁇ -1 , G segment formed by 4-glycosidic linkage, and MG segment formed by hybridization of these two sugars.
- the structural formulas of mannuronic acid and guluronic acid are as shown in formulas (I) and (II):
- M and G sections can be separated from the raw alginic acid.
- the general method can be simply described as: after the initial degradation of alginic acid, a mixed polysaccharide of polymannuronic acid and polyguluronic acid is obtained. After the mixed polysaccharide is precipitated by the acid method, a certain amount of polygulose can be removed. Alkyd. For example, see the methods disclosed in Chinese Patent Application No. 99866637.8 and CN02823707.2.
- the method for preparing oligomannuronic acid is as follows: the M-stage intermediate obtained above is heated under acidic conditions and further acidolyzed to obtain small fragments of mannuronic acid polymers in a desired molecular weight range.
- the reducing terminal can be oxidized to a ring-opened sugar diacid.
- Patent Documents 1 and 2 are hereinafter collectively referred to as prior patents, which are all incorporated herein by reference.
- reaction process of the mannuronic acid disclosed in the prior patent can be expressed by the following reaction equation (V), that is, the mannuronic acid C1-position aldehyde group at the reducing end of the oligomannuronic polysaccharide is oxidized to a carboxyl group.
- a common oxidant is a basic copper sulfate solution, that is, a film reagent.
- This oxidation method was adopted in a prior patent. Specifically, under alkaline conditions, the reaction substrate is polymannuronic acid, namely The above M-stage intermediate is added to the copper sulfate solution and reacted in a boiling water bath for 15 minutes to 2 hours. This method uses Cu 2+ ions as oxidant to oxidize aldehyde groups. Brick red cuprous oxide precipitates during the reaction. This reaction is often used to identify reducing sugars.
- mannan-oligosaccharic acid has anti-Alzheimer's disease (AD) and anti-diabetic effects, and the mannan-oligosaccharic acid having a polymerization degree of 6 has the best activity.
- the pathogenesis of Alzheimer's disease and type 2 diabetes is closely related to amyloid ( ⁇ -amyloid and amylin). After the amyloid aggregates, protein oligomers are produced, which further aggregate to form fibers. These protein aggregates are cytotoxic, induce oxidative damage to mitochondria in the cells, and trigger a cascade of inflammatory responses, causing a large number of neurons and ⁇ -cell damage, eventually leading to Alzheimer's disease and type 2 diabetes. Mannan oligosaccharic acid targets amyloid and antagonizes its cascade response, thereby preventing and treating Alzheimer's disease and type 2 diabetes.
- the guluronic acid in the alginic acid needs to be removed, and the content of the guluronic acid in the alginic acid is usually Above 30%, up to about 70%, so in order to obtain high-purity mannan oligosaccharide diacid, the actual production cost is very high.
- a first aspect of the invention relates to a composition of alginate oligosaccharic acid comprising a mannuronic acid and / or a guluronic acid or a pharmaceutically acceptable salt thereof having the formula (IV):
- n is an integer selected from 1-9
- m is selected from 0, 1 or 2
- m ' is selected from 0 or 1
- Another aspect of the present invention relates to a pharmaceutical composition or a health supplement, which comprises a composition of alginate oligosaccharide diacid as described above.
- Another aspect of the present invention also relates to the use of a composition of alginate oligosaccharic acid in the treatment of a disease selected from the group consisting of senile dementia, Parkinson's disease, inflammation, pain, diabetes, or vascular dementia.
- the alginate oligosaccharide diacid composition of the present invention is a mixture of mannuronic acid and guluronic acid with different degrees of polymerization, and its main component is that mannuronic acid passes through a ⁇ -1,4-glycosidic bond
- the most active sugars are 5-8 sugars, especially 6 sugars.
- a mixture of mannuronic acid and guluronic acid oligosaccharic acid having a degree of polymerization of 2 to 10 also has pharmacological activity against Alzheimer's disease and anti-diabetes, provided that The content of guluronic acid is controlled within a certain range. That is, the alginate oligosaccharide diacid composition of the present invention can be prepared at a greatly reduced production cost, which is easier to achieve in actual production, and easier to realize industrialized large-scale production.
- Figure 2 is a mass spectrum of a disaccharide, a trisaccharide, and a tetrasaccharide in Product A.
- FIG. 3 is a mass spectrum of pentasaccharide, hexasaccharide and heptose in product A.
- Figure 4 is a mass spectrum of octaose, nonasaccharide, and decasaccharide in product A.
- Figure 5 shows the NMR spectrum of Product A.
- Figure 6 shows the NMR spectrum of Product B.
- Figure 7 shows the NMR spectrum of product C.
- Figure 8 shows the NMR spectrum of product D.
- Figure 9 shows the effect of different oligosaccharide compositions and mannuronic acid hexasaccharides on the number of times AD animals cross the platform; the numbers corresponding to the numbers on the horizontal axis in the figure are: i: control group; ii: model group; iii: product A; iv: product B; v: product C; vi: product D; vii: mannuronic acid hexaose.
- FIG. 10 shows the effects of different oligosaccharide compositions and mannuronic acid hexasaccharides on the swimming distance of AD animals; the abscissa reference numerals are the same as those in FIG. 9.
- FIG. 11 shows the effect of different oligosaccharide compositions and mannuronic acid hexaose on the climbing time of PD animals on the 11th day; the abscissa reference numerals are the same as those in FIG. 9.
- FIG. 12 shows the effects of different oligosaccharide compositions and mannuronic acid hexaose on the incubation period of the 11th day of PD animals; wherein the abscissa reference numerals are the same as those in FIG. 9.
- Figures 13a and 13b show the therapeutic effect of different oligosaccharide compositions and mannuronic acid hexaose on inflammatory bowel disease in mice; the abscissa in the figure is the same as that in Figure 9.
- FIG. 14 shows the effect of different oligosaccharide compositions and mannuronic acid hexaose on postprandial blood glucose in diabetic mice; the abscissa in the figure is the same as that in FIG. 9.
- Figure 15 shows the effect of oligosaccharide composition and mannuronic acid hexaose on the latency of mouse writhing response induced by acetic acid; the numbers on the abscissa in the figure correspond to the samples: i: model group; ii: product A ; Iii: product B; iv: product C; v: product D; vi: mannuronic acid hexaose.
- FIG. 16 shows the effects of different oligosaccharide compositions and mannuronic acid hexaose on the number of writhing reactions in mice induced by acetic acid; wherein the abscissa reference numerals are the same as those in FIG. 15.
- FIG. 17 shows the effect of different oligosaccharide compositions and mannuronic acid hexaose on the number of scratches in migraine rats induced by nitroglycerin; the abscissa reference numerals are the same as those in FIG. 9.
- FIG. 18 shows the effect of different oligosaccharide compositions and mannuronic acid hexaose on the number of c-fos positive cells in the caudal side of the nucleus of the trigeminal spinal tract induced by trigeminal ganglion induced by electrical stimulation;
- Figure 9 shows the effect of different oligosaccharide compositions and mannuronic acid hexaose on the number of c-fos positive cells in the caudal side of the nucleus of the trigeminal spinal tract induced by trigeminal ganglion induced by electrical stimulation
- FIG. 19 shows the effects of different oligosaccharide compositions and mannuronic acid hexaose on the latency of the dark avoidance experiment in vascular dementia mice induced by bilateral common carotid artery ligation; the abscissas are the same as those in FIG. 9.
- FIG. 20 shows the effect of different oligosaccharide compositions and mannuronic acid hexaose on the number of errors in dark avoidance experiments in vascular dementia mice induced by bilateral common carotid artery ligation; the abscissas are the same as those in FIG. 9.
- FIG. 21 shows the effect of different oligosaccharide compositions and mannuronic acid hexaose on the avoidance of the latency period of the water maze experiment of vascular dementia mice induced by bilateral common carotid artery ligation; the abscissas are the same as those in FIG.
- Fig. 22 shows the effect of different oligosaccharide compositions and mannuronic acid hexaose on the number of times of crossing the platform of mice with vascular dementia induced by bilateral common carotid artery ligation; wherein the abscissa reference numerals are the same as Fig. 9.
- a first aspect of the invention relates to a composition of alginate oligosaccharic acid comprising a mannuronic acid and / or a guluronic acid or a pharmaceutically acceptable salt thereof having the formula (IV):
- n is an integer selected from 1-9
- m is selected from 0, 1 or 2
- m ' is selected from 0 or 1
- the total weight of guluronic acid is less than 50% of the weight of the composition.
- the alginate oligosaccharide diacid composition of the present invention is a mixture of mannuronic acid and guluronic acid with different degrees of polymerization, and its main component is formed by the connection of mannuronic acid through ⁇ -1,4-glycosidic bonds
- mannanedioic acid has pharmacological activity against Alzheimer's disease and anti-diabetes, among which the most active sugar is 5-8 sugars, especially 6 sugars.
- a mixture of mannuronic acid and guluronic acid oligosaccharic acid having a degree of polymerization of 2 to 10 is also resistant to Alzheimer's disease and diabetes Pharmacological activity, but the content of guluronic acid needs to be controlled within a certain range.
- the content of guluronic acid in the product after the initial degradation of the alginic acid is usually above 30% and up to about 70%. If you apply according to the previous application in order to obtain highly active manna Glyuronic acid should be separated and removed as far as possible. However, based on the above findings of the inventors, it may not be necessary to separate and remove the guluronic acid from the degradation products. Further, the inventors have found that by controlling the conditions of the acid precipitation reaction, and controlling the ratio of guluronic acid to a certain range, the activity of the obtained composition can reach or even exceed that of the mannan oligosaccharides disclosed in the earlier application. Diacid 6 sugars.
- the yield of the product is theoretically significantly higher than the yield of the product disclosed in the previous application, which greatly reduces production costs and reduces waste emissions, which is easier to achieve in actual production. It is easier to realize large-scale industrial production.
- the proportion of the total weight of the diacid is between 1.0 and 3.5.
- the weight percent content of the alginic oligosaccharide diacid in each of the degrees of polymerization of the algin oligosaccharide diacid composition in the present invention is 5-25% of the disaccharide and 15 ⁇ 15 of the trisaccharide. 30%, tetrasaccharides 15-28%, pentasaccharides 10-25%, hexasaccharides 5-15%, heptasaccharides 3-10%, octose 2-5%, nonasaccharides 1-5%, decasaccharides 1-5 %.
- the weight percentage content of the oligosaccharides in the combination is: 10-20% disaccharides, 18-30% trisaccharides, 15-28% tetrasaccharides, 15-20% pentasaccharides, and 5 hexasaccharides. ⁇ 10%, heptasaccharide 3-5%, octose 2-3%, nonaose 1-3%, decasuose 1-3%.
- the total weight of guluronic acid in the alginate oligosaccharide diacid composition of the present invention accounts for 0.1-50%, preferably 1-30%, of the weight of the composition.
- the pharmaceutically acceptable salt is a sodium salt or a potassium salt.
- a mixed polysaccharide of polymannuronic acid and polyguluronic acid can be obtained, and the mixed polysaccharide can be precipitated by the acid method, and a certain amount of polyguluronic acid can be removed; during the acid method precipitation process
- the higher the pH control the higher the polyguluronic acid content in the obtained mixed polysaccharide.
- the mixed polysaccharides described above undergo oxidative degradation of sugar chains to obtain oxidized oligosaccharides with different degrees of polymerization.
- the oxidized oligosaccharides are characterized by mannuronic acid or guluronic acid at the reducing end of the oligosaccharide. It is oxidized to 3-6 carbon sugars.
- An oxidant particularly advantageous for the reaction of the present invention is ozone.
- the oxidative degradation reaction of sugar chains can occur by passing ozone into a solution containing mixed polysaccharides.
- the temperature at which the oxidative degradation step is performed is preferably 0-70 ° C, and more preferably 10-45 ° C.
- the oxidative degradation step is performed at a pH of 3-13, preferably 4-10, and more preferably 6-8.
- the oxidative degradation reaction using ozone in the present invention is similar to the oxidative degradation of basic copper sulfate (prior patent) or acid hydrolysis (Chinese patent application 01107952.5) in the presence of hydrogen peroxide and sodium hypochlorite used in the prior art in three ways. Both can degrade sugar chains, the difference is that the reducing end structure of the sugar chain of the degradation product is different, and the reducing end of the oxidative degradation product mannuronic acid or guluronic acid obtained in the present invention contains 3-6 carbon Acid structure.
- the process used in the oxidative degradation step of the present invention also has other advantages: 1. Mild reaction conditions without special reaction conditions; 2. The ozone used can be prepared at the reaction site, reducing transportation pressure in industrial production; 3. Ozone is automatically decomposed into oxygen after the reaction. There is no danger of reaction reagent residue, and it will not cause pollution to the environment.
- the reaction process is shown in the following equation (VI):
- the total weight of guluronic acid accounts for less than 50% of the weight of the composition, preferably 0.1-50%, and most preferably 1-30%.
- the method of the present invention includes the following steps:
- the mixed polysaccharides of the raw materials polymannuronic acid and polyguluronic acid used in the present invention can be prepared by methods known in the prior art. For example, the methods disclosed in Chinese Patent Application No.98806637.8 and CN02823707.2. The general method can be briefly described as: after the initial degradation of alginic acid, a mixed polysaccharide of polymannuronic acid and polyguluronic acid can be obtained. After the mixed polysaccharide is precipitated by the acid method, some of the polyguluronic acid can be adjusted. Acid content to obtain a mixed polysaccharide of polymannuronic acid and polyguluronic acid.
- the mixed polysaccharide was dissolved in an appropriate amount of water at room temperature or under heating conditions, stirred, and ozone was continuously introduced, and the reaction started.
- the reaction pH can be adjusted to between 3-13, preferably 4-10, more preferably 6-8, by adding dilute hydrochloric acid or dilute NaOH solution.
- the temperature is preferably 0-70 ° C, and more preferably 10-45 ° C.
- the reaction product obtained above was prepared into a solution having a concentration of about 10%, and was separated by a molecular cut-off membrane to remove degradation products below monosaccharides, and the impermeable liquid was collected.
- the molecular retention membrane MWCO used has a specification of 1000 Da to 3000 Da, preferably 2000 Da.
- the collected solution was concentrated on a rotary evaporator and dried under vacuum to obtain a mixture of oligofucoidan oligosaccharides. After analysis, it was found that these products are all disaccharide-decasaccharide oligosaccharides whose composition is in a certain ratio range. Examples 1-3 illustrate this method by way of example.
- the pharmacological activity of the oligosaccharide composition of the present invention was compared with that of the mannooligosaccharic acid hexaose in the earlier application at the same time. Sour hexaose. Without being bound by any theory, it is believed that when the proportion of di-hexasaccharide in the composition is higher than 60%, and the total weight of guluronic acid accounts for less than 50% of the weight of the composition, the activity of the composition is the highest; but When the ratio of guluronic acid exceeds 60%, the activity of the composition is also reduced.
- the invention also provides a medicament or health supplement comprising the alginate oligosaccharide combination as described above and optionally a pharmaceutically acceptable carrier or excipient.
- the pharmaceutical preparation of the present invention is manufactured by a known method, including a conventional mixing, dissolving or lyophilizing method.
- the pharmaceutical composition of the present invention is administered to a patient by various routes suitable for the selected mode of administration, such as oral or parenteral (by intravenous, intramuscular, topical or subcutaneous route).
- the combination drug of the present invention in combination with a pharmaceutically acceptable carrier can be administered systemically, for example, orally. They can be enclosed in hard or soft shell gelatin capsules and compressed into tablets.
- a pharmaceutically acceptable carrier such as an inert diluent or an edible carrier
- the active compounds of the present invention may be combined with one or more excipients and in swallowable tablets, buccal tablets, lozenges, capsules, elixirs, suspensions, syrups, discs And other forms.
- Such compositions and preparations should contain at least 0.1% of active compound.
- the ratio of such compositions and preparations may, of course, be varied and may comprise from about 1% to about 99% of the weight of a given unit dosage form.
- the amount of active compound enables an effective dose level to be obtained.
- Tablets, lozenges, pills, capsules, etc. may also contain: binders, such as tragacanth, acacia, corn starch or gelatin; excipients, such as dicalcium phosphate; disintegrants, such as corn starch, Potato starch, alginic acid, etc .; lubricants, such as magnesium stearate; and sweeteners, such as sucrose, fructose, lactose, or aspartame; or flavoring agents, such as mint, wintergreen, or cherry flavor.
- a liquid carrier such as a vegetable oil or polyethylene glycol.
- any material used to prepare any unit dosage form should be pharmaceutically acceptable and non-toxic in the amount used.
- the active compounds can be incorporated into sustained-release preparations and devices.
- the active compounds can also be administered intravenously or intraperitoneally by infusion or injection.
- Aqueous solutions of the active compounds or their salts, optionally miscible non-toxic surfactants, can be prepared.
- Dispersants in glycerol, liquid polyethylene glycols, triacetin and mixtures thereof, and oils can also be prepared. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
- compositions suitable for injection or infusion can include sterile aqueous solutions or dispersions containing the active ingredients (optionally encapsulated in liposomes) of an instant preparation suitable for sterile injectable or infusible solutions or dispersants.
- Agent or sterile powder In all cases, the final dosage form must be sterile, liquid and stable under the conditions of manufacture and storage.
- the liquid carrier can be a solvent or a liquid dispersion medium, including, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, liquid polyethylene glycol, and the like), vegetable oils, non-toxic glycerides, and suitable mixtures thereof.
- Appropriate fluidity can be maintained, for example, by the formation of liposomes, by maintaining the desired particle size in the case of dispersants, or by the use of surfactants.
- a variety of antibacterial and antifungal agents such as parabens, chlorobutanol, phenol, sorbic acid, thimerosal, etc. can be used to prevent microorganisms.
- isotonic agents for example, sugars, buffers or sodium chloride.
- Prolonged absorption of injectable compositions can be produced by using compositions that delay the absorption (eg, aluminum monostearate and gelatin).
- Sterile injectable solutions are prepared by combining the required amount of active compound in a suitable solvent with the various other ingredients listed above as needed, and then sterilizing by filtration.
- the preferred methods of preparation are vacuum drying and freeze-drying techniques, which results in a powder of the active ingredient plus any additional previously required ingredients present in the sterile filtered solution .
- Useful solid carriers include comminuted solids (such as talc, clay, microcrystalline cellulose, silica, alumina, etc.).
- Useful liquid carriers include water, ethanol or ethylene glycol or water-ethanol / ethylene glycol mixtures, and the combination drugs of the present invention can optionally be dissolved or dispersed in effective amounts with the help of non-toxic surfactants.
- Adjuvants such as fragrances
- additional antimicrobial agents can be added to optimize properties for a given use.
- Thickeners (such as synthetic polymers, fatty acids, fatty acid salts and esters, fatty alcohols, modified cellulose, or modified inorganic materials) can also be used with liquid carriers to form coatable pastes, gels, ointments , Soap, etc., directly on the user's skin.
- the therapeutic requirements of a compound or a mixture thereof depend not only on the compound itself, but also on the mode of administration, the nature of the disease to be treated, and the age and condition of the patient, and ultimately on the decision of the attending physician or clinician.
- the above-mentioned preparations may exist in a unit dosage form, which is a physically dispersed unit containing a unit dose and is suitable for administration to human bodies and other mammalian bodies.
- the unit dosage form can be a capsule or tablet, or many capsules or tablets.
- the amount of unit dosage of active ingredient may be varied or adjusted between about 0.1 to about 1000 milligrams or more, depending on the particular treatment involved.
- Another aspect of the present invention provides a pharmaceutical composition or a health product comprising the alginate oligosaccharide composition of the present invention and an appropriate carrier if necessary.
- Another aspect of the present invention provides the use of an alginate oligosaccharide composition for treating senile dementia.
- Yet another aspect of the present invention provides a method of treating a patient with senile dementia, which comprises administering to a patient in need thereof an effective amount of the alginate oligosaccharide composition of the present invention.
- Yet another aspect of the present invention provides the use of an alginate oligosaccharide composition for treating Parkinson's disease.
- Yet another aspect of the present invention provides a method of treating a patient with Parkinson's disease, which comprises administering to a patient in need thereof an effective amount of the alginate oligosaccharide composition of the present invention.
- Another aspect of the present invention provides the use of an alginate oligosaccharide composition for treating an inflammatory response.
- Yet another aspect of the present invention provides a method of treating a patient suffering from inflammation, comprising administering to a patient in need thereof an effective amount of the alginate oligosaccharide composition of the present invention.
- Yet another aspect of the present invention provides the use of an alginate oligosaccharide composition to treat a pain response.
- Yet another aspect of the present invention provides a method for treating a patient suffering from pain, comprising administering to a patient in need thereof an effective amount of the alginate oligosaccharide composition of the present invention.
- Another aspect of the present invention provides the use of alginate oligosaccharide composition for treating diabetes.
- Yet another aspect of the present invention provides a method of treating a patient suffering from diabetes, which comprises administering to a patient in need thereof an effective amount of the alginate oligosaccharide composition of the present invention.
- Another aspect of the present invention provides the use of an alginate oligosaccharide composition for treating vascular dementia.
- Yet another aspect of the present invention provides a method of treating a patient suffering from vascular dementia, which comprises administering to a patient in need thereof an effective amount of the alginate oligosaccharide composition of the present invention.
- the pain described in the present invention includes various pains, including but acute pain, chronic pain, neuropathic pain, postoperative pain, chronic lower back pain, cluster headache, herpes neuralgia, phantom limb pain, central pain, toothache, opioid Substance-resistant pain, visceral pain, surgical pain, bone injury pain, pain during labor and childbirth, pain due to burns including sunburn, postpartum pain, migraine, angina, and pain associated with the urogenital tract (including Cystitis), vascular pain, trigeminal neuralgia, intercostal neuralgia, surgical incision pain, chronic fasciitis pain, heel pain, muscle pain, bone pain, joint pain, cancerous pain, non-cancerous pain, etc.
- various pains including but acute pain, chronic pain, neuropathic pain, postoperative pain, chronic lower back pain, cluster headache, herpes neuralgia, phantom limb pain, central pain, toothache, opioid Substance-resistant pain, visceral pain, surgical pain, bone injury pain, pain during labor
- the inflammation in the present invention includes various inflammations, including but not limited to acute inflammation, chronic inflammation, vascular inflammation, neuroinflammation, central nervous inflammation (such as multiple sclerosis, including encephalomyelitis, etc.), peripheral neuroinflammation, arthritis ( (Such as osteoarthritis, sacroiliitis, etc., psoriasis arthritis, rheumatoid arthritis, rheumatoid arthritis, etc.), ankylosing spondylitis, inflammatory bowel disease (such as Crohn's disease and ulcerative colitis), Inflammatory diabetic ulcer, systemic lupus erythematosus, inflammatory skin diseases (such as psoriasis, atopic dermatitis, eczema), and the like.
- arthritis such as osteoarthritis, sacroiliitis, etc., psoriasis arthritis, rheumatoid arthritis, rheumatoid arthritis, etc.
- the alginate oligosaccharide composition of the present invention is prepared by using a method different from the prior art, and does not need to separate the M stage and the G stage, which greatly reduces the complexity of the production process, and also greatly reduces the production cost. Simple, high content of active ingredients, no residual reagents. It has been experimentally proven that the alginate oligosaccharide composition of the present invention has the potential to prevent and treat Alzheimer's disease, diabetes, Parkinson's disease, various inflammatory reactions, pain, and vascular dementia.
- AD model was induced by unilateral intraventricular injection of A ⁇ , and learning and memory behaviors of AD model rats were evaluated by Morris water maze.
- Rats were anesthetized by intraperitoneal injection of sodium pentobarbital (40mg / kg) and fixed on a brain stereotactic device, routine skin preparation and disinfection, incision of the skin, extremity exposure, hippocampal CA1 area refer to "Rat brain stereotactic atlas” (Bao Xinming, Shu Siyun, Beijing, People's Medical Publishing House, 1991, 28) "Anterior and posterior 3.0mm, 2.2mm next to the middle slit, 2.8mm subdural" for positioning.
- the model group and the administration group were injected into the right hippocampal CA1 area with a micro-injector, and then slowly injected with condensed A ⁇ (A ⁇ 1-40 was formulated in PBS solution to 1.4 mg / mL, and incubated in a 37 ° C incubator for 5 minutes. It was brought into an aggregated state) 5 ⁇ l at a flow rate of 1 ⁇ L / min. After the injection was completed, the needle was left for 5 minutes to fully disperse A ⁇ , and then the needle was slowly withdrawn. The surgical incision is sutured and the body is warmed up. The control group was injected with an equal amount of sterilized PBS, and the remaining steps were the same as before. The corresponding drugs were given 7 days before the operation and continued to the end of the experiment.
- the Morris water maze experiment was performed on the 11th day after the operation.
- Positioning and sailing experiment Each group of rats is trained once a day for 5 consecutive days, which is the positioning and sailing experiment, and the time it takes for the animal to find the platform (ie, the escape latency) is recorded. Those who did not find a platform in about 90s, guided them to swim in a straight direction toward the platform and stood on the platform for 30s to induce their learning and memory.
- mice were randomly divided into 8 groups: a blank control group, an MPTP model group, and an administration group, with 14 animals in each group. Animals were dosed on the same day. The blank control group and the MPTP model group were perfused with saline. The other groups were given the corresponding drugs, once a day for 17 consecutive days. From the 6th day, modeling drugs were given. The animals in the blank control group were subcutaneously given 10ml / kg of saline, and the remaining animals were given subcutaneously MPTP 25mg / kg once a day for five days.
- MPTP selectively destroys dopaminergic neurons in the brain substantia nigra.
- MPTP-induced PD animal model is the most classic animal model similar to the pathological changes and clinical characteristics of human Parkinson's disease.
- the main symptoms of PD are resting tremor, increased muscle tone, and decreased exercise.
- the head-turning time and climbing-down time of the pole climbing experiment can represent the overall activity coordination ability of mice.
- mice Male DBA / 1 mice, weighing 19-22 g, were randomly divided into blank control group, model group and administration group, with 8 mice in each group. Except for the blank control group, the remaining animals were subcutaneously injected with bovine type II collagen-complete Freund's adjuvant (CII-CFA) emulsion 10 mg / kg at the root of the tail on day 0. On day 23, lipopolysaccharide (LPS) was injected intraperitoneally. 1.5mg / kg. Administration was started on the 28th day, the blank control group and the model group were orally administered with normal saline, and the other groups were given the corresponding drugs, administered once a day for 14 consecutive days. After the LPS injection, the mice were observed daily for morbidity.
- CII-CFA bovine type II collagen-complete Freund's adjuvant
- LPS lipopolysaccharide
- the clinical score is based on a scale of 0-4 according to the degree of the disease (redness, swelling, joint deformation) to reflect the degree of disease progression.
- the degree of the disease redness, swelling, joint deformation
- 1 point is near the metatarsal bone or near the ankle joint or sacrum, with redness or mild swelling, 1 toe is red and swollen
- 2 points is ankle and sacrum with slight erythema and swelling, or more than two toes Redness and swelling
- the highest score for each limb is 4 points, and the highest score for each animal is 16 points ).
- mice Female C57BL / 6 mice, weighing 17-20 g, were randomly selected as blank control groups. The remaining animals were subcutaneously injected with myelin oligodendrocyte glycoprotein-complete Freund's adjuvant (MOG-CFA) emulsion on the 0th day to sensitize, MOG 10mg / kg, CFA 20mg / kg, and on the 0th day and On the second day, pertussis toxin was injected intraperitoneally at 10ug / kg. The administration was started on the first day. The blank control group and the model group were orally administered with normal saline. The other groups were given the corresponding drugs, which were administered once a day for 24 consecutive days.
- MOG-CFA myelin oligodendrocyte glycoprotein-complete Freund's adjuvant
- mice On the 12th day after immunization, the immunized mice will develop symptoms, and begin to observe and record the body weight and clinical scores every day (0-4 points indicate different degrees, 0 points are normal performance, and there are no obvious signs of disease; 1 points are drooping tails Weakness, unilateral weakness in the hind limbs; 2 points for sagging tail and weakness in both hind legs; 3 points for unilateral hind limb weakness and paralysis; 4 points for both hind limb weakness and paralysis) to reflect the degree of disease progression.
- MRL / lpr transgenic mice have homozygous mutations in the Faslpr gene, which can spontaneously form hyperplasia of lymphoid tissues. The mice begin to develop disease at about 10-14 weeks of age and develop systemic lupus erythematosus symptoms.
- Lymph node scores are performed once a week (0-6 points indicate different degrees, 0 points are normal; 1 point is less than 1cm in diameter on one side of the point; 2 points are less than 1cm in diameter on both sides of the point; 3 points In order to be less than 1cm in diameter on three sides, 4 points are larger than 1cm in diameter on one side, and the diameter is less than 1cm in two points; The diameter of the other two points is less than 1cm; 6 points are divided into three sides and the diameter is greater than 1cm).
- IBD Inflammatory bowel disease
- DSS distaln sodium sulfate
- mice Female C57 mice, 7-8 weeks old, weighing 18-20 g, were randomly divided into: blank control group, model group, administration group, 8 mice in each group.
- the mice in the model group and the administration group were given 2.5% high-molecular-weight polymer dextran sodium sulfate (DSS) for modeling on the 1st to 7th days by drinking water, and the administration was started on the 1st day, blank
- the control group and the model group were orally administered with normal saline, and the other groups were given the corresponding drugs, administered once a day for 30 consecutive days.
- the mice On day 31, the mice were sacrificed by cervical dislocation, the abdominal cavity was opened, and the mesentery was separated. Each mouse was taken from the beginning to the end of the anesthesia, and each group was sampled sequentially to measure the colon length.
- mice Male NIH mice were randomly selected into a normal control group, a model group, and an administration group, with 10 mice in each group. On the day of the test, all animals except the normal group were injected with streptozotocin 150 mg / kg intraperitoneally. The corresponding drugs were continuously administered for 10 days. On the 11th day, the eyeballs were removed to take blood, and the blood glucose concentration was measured.
- Kunming mice half male and half male, weighing 18-22 g, were randomly divided into blank control group, model group, and administration group, with 10 mice in each group. From the day of grouping, the blank control group was orally administered with 20 ml / kg of distilled water daily, and the remaining groups were orally administered with the corresponding drugs, once a day for 7 consecutive days. One hour after the last dose, mice in each group were intraperitoneally injected with 0.2 ml of a 0.6% acetic acid solution, and the writhing latency of the mice (i.e., the time from the injection of acetic acid to the occurrence of writhing response) and the writhing were recorded within 20 minutes after the acetic acid injection Body times.
- Injecting chemicals such as acetic acid solution into the abdominal cavity of mice can stimulate the peritoneum of the mouse and cause intermittent pain, which is manifested by the abdomen recession, the front wall of the abdomen close to the bottom of the cage, the hips twisted, and the hind legs extended.
- a special posture is called a writhing body response.
- the writhing incubation period (the time from the injection of acetic acid to the writhing response) and the number of writhing in a certain period of time can represent the severity of pain. The shorter the incubation period of writhing body, the more the number of writhing body, the more severe the pain.
- SD male rats weighing 180-220g, were randomly divided into: blank control group, model group, administration group, 8 rats in each group. Administration was started on the day of grouping. The blank control group and the model group were administered with distilled water by gavage. The remaining groups were given the corresponding drugs once a day for 28 consecutive days. 30 minutes after the last administration, the animals in the blank control group were given physiology. In addition to saline, the other groups were subcutaneously injected with nitroglycerin 10 mg / kg under the right shoulder for modeling. Observe the time and duration of ear redness after modeling, and the number of scratches in the period of 30-45 minutes after modeling. The content of 5-HT in brain tissue was measured by fluorescence spectrophotometry. Measured at the wavelength of Ex356nm / Em and 483nm, the results are expressed in ng / g brain weight.
- Migraine is a vascular and nerve dysfunction disease under the interaction of blood vessels and neural mechanisms.
- Nitroglycerin can cause the hypersensitivity of trigeminal nerve fibers and cause migraines by dilating meningeal blood vessels, forming neurogenic inflammation, and activating neuronal functions in the hypothalamus, brainstem, and spinal cord segments.
- the nitroglycerin model is an animal model established in 1995 and has now become a classic animal migraine model. According to the pathogenic mechanism of nitroglycerin, the ear redness time due to vasodilation, the number of scratching heads due to pain, and the serotonin (5-HT) content in the brain tissue can be evaluated to evaluate the severity of migraine. The longer the ear redness lasts, the more times the head is scratched, and the higher the 5-HT content, the more severe the migraine.
- the corresponding drugs were given orally in each group, while the blank control group, sham operation group, and model group received oral distilled water. After 10 days of continuous administration, except for the blank control group, all rats were anesthetized with intraperitoneal injection of chloral hydrate 350mg / kg, and then the rats were fixed on a stereotactic device, a midline incision was made on top of the head, and the skin and muscle were cut in layers. An opening in the middle of the sagittal suture of the brain exposes the skull.
- the parameters of the electrical stimulation are 200ms period, amplitude 10v, wave width 5ms, and stimulation for 10 minutes.
- the animals in the sham operation group were only inserted with electrodes and not stimulated.
- the right femoral vein was injected with 50 mg / kg of Evans blue 7 minutes before the stimulation, and the perfusion was fixed within 20 minutes after the stimulation.
- Activation of the trigeminal vascular system is a key link in the pain of migraine patients, and the occurrence of neurological inflammation of the meninges plays an important role in the generation and maintenance of migraine pain.
- the trigeminal nerve distributed in the dura mater When the trigeminal nerve distributed in the dura mater is stimulated, it releases vasoactive substances, which causes meningeal blood vessels to dilate, extravasation of plasma components, mast cell degranulation, and activation of platelets, resulting in migraine headaches.
- the neurotransmitter released after pain stimulation binds to the corresponding receptor on the cell membrane. Under the action of the second messenger, the C-fos mRNA gene is expressed, and the c-fos protein is translated and synthesized in the nucleus. effect.
- the degree of migraine can be reflected by measuring the dural serum protein exudation of migraine animals and the number of c-fos positive cells on the caudal side of the nucleus of the trigeminal spine. A lower number of cells indicates a less severe migraine.
- the bilateral common carotid artery ligation (BCCAo) model is a vascular dementia model commonly used in the art and established by global cerebral ischemia-reperfusion.
- mice Male C57BL / 6 mice, weighing 22 ⁇ 2g, were randomly divided into: sham operation group, 30 minutes bilateral common carotid artery occlusion (BCCAo) model group (referred to as 30min BCCAo group), administration group, There are 10 animals in each group. After the animals were divided into groups, mice in the sham operation group and the 30-minute BCCAo group were perfused with distilled water once a day. After 5 consecutive days of intragastric administration, BCCAo surgery was performed. The mice in the administration group were given the corresponding drugs by gavage. They were administered by gavage once a day. After 5 days of continuous administration, BCACo surgery was performed.
- BCCAo bilateral common carotid artery occlusion
- mice of each group are anesthetized with sodium pentobarbital; the common carotid arteries of the model group and the administration group are separated and ligated for 30 minutes, and then the ligature is removed and the neck wound is sutured; In the group, bilateral common carotid arteries were not ligated and the neck incisions were directly sutured. Twenty-four hours after BCCAo, the mice in each group continued to be orally administered with the corresponding drugs or distilled water according to the pre-operative dosing regimen, and each was continuously administered for 23 days.
- the dark avoidance test was performed on the 7th day after BCCAo, and the Morris water maze test was started on the 13th day to evaluate the improvement effect of mannuronic acid composition on the learning and memory ability of mice.
- the mice were sacrificed and the brain tissues were fixed.
- the staining of the hippocampal nerve cells after BCCAo and the protective effect of the mannuronic acid composition on the damaged neurons were evaluated by HE staining and other methods.
- the dark avoidance experiment is used to detect the spatial discrimination of learning and memory ability of mice.
- the memory impairment of spatial localization can only occur if the hippocampus or the area around the hippocampus is damaged.
- the dark-proof experiment box is a device designed by using the mouse's habit of darkening and avoiding light. Half of it is a dark room and half is a bright room. There is a small hole in the middle. The bottom of the dark room is covered with a copper grid that is energized. Animals are shocked when they enter the dark room. Escape to the bright room. After the animals are trained for 24 hours, the test is performed again. The time from when the animals are placed in the bright room to when they enter the dark room for the first time is the latency period of the dark avoidance experiment. The longer the incubation period of the dark avoidance experiment, the fewer the number of avoidance errors, indicating that the animal's memory is better.
- the Morris water maze (MWM) experiment is an experiment that forces experimental animals to swim and learn to find hidden platforms in the water. It is mainly used to test the experimental animals' learning and memory of spatial position and orientation (spatial positioning). ability.
- the mouse Morris water maze is mainly composed of a cylindrical pool with a diameter of 80cm and a height of 70cm and a movable platform with a diameter of 8cm. A digital camera is connected to the computer over the pool. Before the experiment, inject fresh water into the pool, the water depth is 15cm, and the water surface is 0.5cm higher than the platform surface. Add milk to make the pool water opaque, and keep the platform position unchanged during the experiment.
- Morris water maze behavior includes the following two test indicators.
- Place navigation experiments are used to measure the ability of mice to learn and memorize water mazes.
- the experiment started on the 13th day after BCCAo and lasted 4 days.
- the mice were trained once in the morning and afternoon in total, 8 times in total.
- the mouse enters the pool at 1/2 radian of the west quadrant, and heads into the pool wall. If the platform is not found within 120 seconds, the experimenter will guide them to the platform and leave it for 30 seconds to guide their learning and memory.
- the experimental observation and recording of the route map and the time required for the mice to find and climb onto the platform, that is, the escape latency and swimming speed of the Morris water maze experiment were recorded.
- the Morris water maze experiment avoidance latency refers to the time from when a mouse enters the water to when it finds a platform. The shorter the escape latency of the Morris water maze experiment, the better the animals' memory.
- a spatial search experiment (spatial probe test) is used to measure the ability of a mouse to retain the platform's spatial position memory after it learns to find a platform. After the positioning and navigation experiment was completed, the platform was removed at an interval of one day, and the mice were put into the water from the same water entry point, and the number of times they crossed the original platform was measured. Data acquisition and processing are performed by an automatic image monitoring and processing system.
- the middle cerebral artery ligation (MCAO) model is a vascular dementia model commonly used in the art established by focal cerebral ischemia.
- the rats in the other groups were anesthetized with intraperitoneal injection of chloral hydrate 350mg / kg, and the left side was fixed on the rat plate, and the outer ear canal and eyes were under the operating microscope.
- the pulse sequence is a 45 ° pulse, each acquisition is 4 seconds, the relaxation time is 1 second, and the accumulation is 20 times, and the spectral width is from -2 ppm to 10 ppm.
- One-dimensional hydrogen spectrum was obtained by Fourier transform after data collection, and the TSP methyl hydrogen signal was set to 0.00ppm.
- the intermediate contains a mannuronic acid fragment (M-block, chemical shift of 5.1 ppm) and a guluronic acid fragment (G-block, chemical shift of 5.5 ppm), and a mannuronic acid and gulose Uric acid mosaic fragment (MG-block, chemical shift 5.3 ppm).
- M-block mannuronic acid fragment
- G-block guluronic acid fragment
- MG-block mannuronic acid and gulose Uric acid mosaic fragment
- Step 2) Proportion and structure analysis of oligosaccharides of various polymerization degrees in alginate oligosaccharide diacid product A
- test results disaccharide-decaose are expressed as dp2-dp10, respectively, dp2 is 18%, dp3 is 24%, dp4 is 23%, dp5 is 14%, dp6 is 8%, dp7 is 7%, and dp8 is 2 %, Dp9 is 2%, and dp10 is 2%.
- Step 3) LC-MS analysis of the structure of oligosaccharides of various polymerization degrees in the alginate oligosaccharide diacid product A
- Mass spectrometry conditions Agilent 6540 QTOF; ion source: ESI collision voltage 120V; negative ion mode.
- the acquisition signal (m / z) width is 100-1000.
- Sample preparation Weigh 50mg sample to be dissolved in 0.5ml D2O, freeze-dry, add 0.5ml deuterated heavy water to dissolve, re-lyophilize, and finally dissolve the lyophilized sample powder with an appropriate amount of heavy water, and transfer it to the nuclear magnetic tube. A 100 mg / ml test solution was prepared, and 0.01% (w / v) deuterated TSP (trimethylsilylpropionic) sodium salt was added as an internal standard.
- TSP trimethylsilylpropionic
- a 400M Fourier transform nuclear magnetic resonance instrument collects one-dimensional hydrogen spectra at room temperature.
- the pulse sequence is a 45 ° pulse, each acquisition is 4 seconds, the relaxation time is 1 second, and the accumulation is 20 times, and the spectral width is from -2 ppm to 10 ppm.
- One-dimensional hydrogen spectrum was obtained by Fourier transform after data collection, and the TSP methyl hydrogen signal was set to 0.00ppm.
- the NMR spectrum of product A is shown in Figure 5.
- the multiple peak with a chemical shift of 4.6 ppm is the hydrogen signal at the C-1 position of mannuronic acid (M)
- 5.0 ppm is the hydrogen signal at the C-1 position of guronic acid (G)
- 4.9 ppm It is the C-1 hydrogen signal of mannuronic acid and guluronic acid chimeric fragment (MG).
- the formula for the content of guluronic acid is:
- I4.6, I5.0, and I4.9 are mannuronic acid (M), guluronic acid (G), mannuronic acid, and guluronic acid chimeric fragment (MG), respectively.
- M mannuronic acid
- G guluronic acid
- MG guluronic acid chimeric fragment
- a 400M Fourier transform nuclear magnetic resonance apparatus was used to determine the guluronic acid content in product B at 60 ° C at 50%.
- the determination method is the same as that in the relevant part of Example 1.
- the nuclear magnetic resonance hydrogen spectrum is shown in FIG. 6. It can be seen from the figure that the integrated area of mannuronic acid (M, chemical shift value of 4.6 ppm) and guluronic acid (G, chemical shift value of 5.0 ppm) is relatively close, while that of mannuronic acid and guluronic acid is The integrated area of the mosaic fragment (MG, chemical shift is 4.9 ppm) is small.
- Formula for calculating content of guluronic acid product (G) According to Example 1, the content of G is 50%.
- Example 1 Weigh 100g of the intermediate in Example 1. After adding water to suspension, add NaOH to adjust the pH value to alkaline, so that the powder is completely dissolved, and finally prepare a 1L solution, and then add HCl to adjust the pH value to 2.95. Partial white precipitation appears. The precipitate was removed by centrifugation, and the supernatant was collected and further diluted with distilled water to prepare a 1.5L volume solution. The pH was adjusted to 9.0 with NaOH, and the reaction was performed at 45 ° C in a water bath. The gas flow at the outlet of the oxygen cylinder and the power of the ozone generator were adjusted so that the ozone mass concentration flow reached 3 g / hr and passed into the reaction solution.
- a 400M Fourier transform nuclear magnetic resonance apparatus was used to determine the guluronic acid content in product C at 10 ° C at 10%. The determination method was the same as that in the relevant part of Example 1. The test results are shown in Figure 7.
- the mannuronic acid M, chemical shift value of 4.6 ppm
- G chemical shift value of 5.0 ppm
- Mannuronic acid and guluraldehyde The integrated area of the acid mosaic fragment (MG, chemical shift 4.9 ppm) is close to the integrated area of guluronic acid.
- Formula for calculating content of guluronic acid product (G) According to Example 1, the content of G is 10%.
- the product with high G content is prepared by referring to the preparation method of the foregoing Example 2.
- the raw material of sodium alginate is a high G content sample provided by Qingdao Haizhilin Biotechnology Development Co., Ltd.
- the preparation method is the same as that in Example 2. Specifically: 500 g of sodium alginate powder with high G content, mixed with distilled water, swelled, and prepared into a 5 L volume solution, adjusted the pH to 4.0 with NaOH, and reacted at room temperature at 25 ° C.
- the gas flow at the outlet of the oxygen cylinder and the power of the ozone generator were adjusted so that the ozone mass concentration flow reached 1 g / hr and passed into the reaction solution.
- a 400M Fourier transform nuclear magnetic resonance apparatus was used to determine the guluronic acid content in product D at 60 ° C, and the determination method was the same as in the relevant part of Example 1.
- the nuclear magnetic resonance spectrum is shown in FIG. 8. It can be seen from the figure that the integrated area of guluronic acid (G, chemical shift value of 5.0 ppm) is greater than the integrated area of mannuronic acid (M, chemical shift value of 4.6 ppm), while mannuronic acid and guluraldehyde The integrated area of the acid mosaic fragment (MG, chemical shift is 4.9 ppm) is small.
- the formula for calculating the content of guluronic acid (G) According to Example 1, the content of G is 60%.
- the swimming distance in the quadrant of the original platform in the model group decreased significantly as a percentage of the total distance, and the percentage of the swimming distance of the administration group in the quadrant in the original platform increased significantly in the total distance, see FIG. 10.
- the latency and climbing time of the former were significantly prolonged.
- the incubation period and climbing time of each administration group were shortened to different degrees.
- the product A, B, and C had better pharmacological activity than the previously expected single-polymerized mannanuronic acid hexaose with the highest activity, but the activity of product D was weaker than that of mannuronic acid hexaose.
- mice in the model group developed paralysis of paralysis in both hind limbs.
- the average clinical score of the model group reached 3 points, indicating that the multiple sclerosis model was successfully modeled.
- the inflammation progress of each administration group was alleviated to varying degrees.
- the clinical scores of products A, B, and C were lower than that of mannuronic acid hexaose throughout the experiment and at the end point, indicating that the pharmacological activity of products A, B, and C was better than that of mannuronic acid hexaose;
- the clinical score of Product D was slightly higher throughout the experiment and at the end point, reflecting that the anti-inflammatory activity of Product D was the weakest, indicating that the content of guluronic acid and the proportion of di-hexaose in the composition had an effect on the activity of the product. Significant effect, but when the content of guluronic acid is too high, the activity of the composition will be reduced.
- transgenic mice began to develop disease, and lymphadenopathy appeared, and the lymph node score continued to increase with time, indicating that the model group had successfully developed the disease and the disease progressed rapidly.
- the disease progression of each administration group was alleviated to varying degrees.
- the model group showed a significant shortening of the colon due to inflammation, and most of the mice lost significantly weight. Nearly half of the model group died later, indicating that the intestinal inflammation was very serious. Compared with the model group, the intestinal inflammation in each administration group was alleviated to varying degrees, which was reflected in the recovery of colon length and improved survival rate.
- products A, B, and C make the incubation latency of mice longer than mannuronic acid hexaose, and the number of twists is less than that of mannuronic acid hexaose, indicating that products A, B, and C have better pharmacological activity than Mannuronic acid hexaose;
- the twisting latency of product D is short, and the number of twists is slightly higher than that of mannuronic acid hexaose, reflecting that the activity of product D is weaker than that of mannuronic acid.
- the rats developed ear redness, which lasted for about 2.5 hours.
- the number of scratches in the model group was significantly higher than that of the blank control group in the 30-45 minute period.
- the ear redness of the rats in the administration group was significantly delayed, the duration of ear redness was shortened, and the number of scratches in the 30-45 minute period was reduced.
- products A, B, and C made the number of scratches of rats less than that of mannuronic acid hexaose, indicating that the pharmacological activity of products A, B, and C was better than that of mannuronic acid hexaose; but product D group of rats The number of scratches is slightly higher than that of mannuronic acid hexaose, reflecting that the activity of product D is weaker than that of mannuronic acid hexaose.
- the number of c-fos positive cells in products A, B, and C was less than that of mannuronic acid hexaose, indicating that the pharmacological activity of products A, B, and C was better than that of mannuronic acid hexaose; but product D
- the number of c-fos positive cells in the group was slightly higher than that of mannuronic acid hexaose, reflecting that the activity of product D was weaker than that of mannuronic acid hexaose.
- the latency period of the former dark avoidance experiment was significantly shortened, and the number of errors increased significantly, indicating that the memory ability of the model group mice was significantly reduced, and the evaluation model was successfully established.
- the incubation period of the avoidance experiment in each administration group was significantly increased, and the number of errors was significantly reduced.
- the incubation period of the mice in products A, B, and C was longer than that of mannuronic acid hexaose, and the number of errors was less than that of mannuronic acid hexaose, indicating that the pharmacological activity of products A, B, and C was better than that of mannaldehyde.
- Diacid hexaose Diacid hexaose; however, the incubation period of product D is slightly shorter than that of mannuronic acid hexaose, and the number of errors is slightly higher, reflecting that the activity of product D is weaker than that of mannuronic acid hexaose.
- the experimental results are consistent with the previous experiments, indicating that the content of guluronic acid and the proportion of di-hexaose in the composition have a significant effect on the activity of the product, but the combination will be reduced when the content of guluronic acid is too high ⁇ ⁇ ⁇ Activity. See Figures 19 and 20.
- the products A, B, and C group mice crossed the platform more times than the mannuronic acid hexaose, indicating that the product A, B, and C had better pharmacological activity than the mannuronic acid hexaose; but the product D group The number of times of crossing the platform is slightly lower than that of mannuronic acid hexaose, reflecting that the activity of product D is weaker than that of mannuronic acid hexaose. See Figure 22.
- the escape latency of the rats in group A, B, and C was shorter than that of mannuronic acid hexaose, indicating that the pharmacological activity of products A, B, and C was better than that of mannuronic acid hexaose; but group D of product escaped
- the incubation period is slightly longer than that of mannuronic acid hexaose, reflecting that Product D is less active than mannuronic acid hexaose.
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Biomedical Technology (AREA)
- Molecular Biology (AREA)
- Epidemiology (AREA)
- Diabetes (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Psychiatry (AREA)
- Hospice & Palliative Care (AREA)
- Nutrition Science (AREA)
- Mycology (AREA)
- Food Science & Technology (AREA)
- Emergency Medicine (AREA)
- Endocrinology (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Polymers & Plastics (AREA)
- Psychology (AREA)
- Physical Education & Sports Medicine (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Immunology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Polysaccharides And Polysaccharide Derivatives (AREA)
- Saccharide Compounds (AREA)
Abstract
Description
Claims (16)
- 根据权利要求1的褐藻胶寡糖二酸组合物,其中m+m’=1或2的褐藻胶寡糖二酸的重量总和不低于所述组合总重量的50%以上,优选60%-90%,更优选70%-90%。
- 根据权利要求2的褐藻胶寡糖二酸组合物,其中m+m’=1的褐藻胶寡糖二酸的重量总和不低于所述组合总重量的10%,优选30-40%。
- 根据权利要求1的褐藻胶寡糖二酸组合物,其中m+m’=2的褐藻胶寡糖二酸的重量总和不低于所述组合总重量的10%,优选30-50%。
- 根据权利要求1的褐藻胶寡糖二酸组合物,其中n=1-5的褐藻胶寡糖二酸的重量总和占所述组合总重量的80-95%。
- 根据权利要求1的褐藻胶寡糖二酸组合物,其中n=1-3的褐藻胶寡糖二酸的重量总和占所述组合总重量的20-70%。
- 根据权利要求1的褐藻胶寡糖二酸组合物,其中n=1-3的褐藻胶寡糖二酸的重量总和与n=4-7的褐藻胶寡糖二酸重量总和的比例在1.0-3.5之间。
- 根据权利要求7的褐藻胶寡糖二酸组合物,其中n=1-3的褐藻胶寡糖二酸的重量总和与n=4-7的褐藻胶寡糖二酸重量总和的比例在1.0-3.0之间。
- 根据权利要求1的褐藻胶寡糖二酸组合物,其中古罗糖醛酸的重量总和占所述组合物重量的0.1-50%,优选1-30%。
- 根据权利要求1-9任一项所述的褐藻胶寡糖二酸组合物,其中各聚合度褐藻胶寡糖二酸在所述组合中的重量百分含量为:二糖5~25%,三糖15~30%,四糖15~28%,五糖10~25%,六糖5~15%,七糖3~10%,八糖2~5%,九糖1~5%,十糖1~5%。
- 根据权利要求10所述的褐藻胶寡糖二酸组合物,其中各聚合度褐藻胶寡糖二酸在所述组合中的重量百分含量为:二糖10~20%,三糖18~30%,四糖15~28%,五糖15~20%,六糖5~10%,七糖3~5%,八糖2~3%,九糖1~3%,十糖1~3%。
- 根据权利要求1-11任一项所述的褐藻胶寡糖二酸组合物,其中所述药学上可接受的盐是钠盐或钾盐。
- 一种药物组合物或保健品,其包含有效量的权利要求1-12 任一项所述的褐藻胶寡糖二酸组合物和必要时适当的载体。
- 如权利要求1-12任一项所述的褐藻胶寡糖二酸组合物在制备用于治疗选自老年性痴呆、帕金森病、炎症、疼痛、糖尿病或血管性痴呆的药物或者保健品中的用途。
- 作为抗老年性痴呆、帕金森病、炎症、疼痛、糖尿病或血管性痴呆的药物或保健品的根据权利要求1-12任一项所述的褐藻胶寡糖二酸组合物。
- 一种治疗患有选自如下疾病的患者的方法:老年性痴呆、帕金森病、炎症、疼痛、糖尿病或血管性痴呆,该方法包括给予需要的患者有效量的根据权利要求1-12任一项所述的褐藻胶寡糖二酸组合物。
Priority Applications (10)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
KR1020217001852A KR20210041556A (ko) | 2018-06-29 | 2019-06-28 | 알긴산 올리고당 이산 조성물 |
JP2020572823A JP2021529197A (ja) | 2018-06-29 | 2019-06-28 | アルギン酸オリゴサッカリン二酸の組成物 |
CA3104959A CA3104959A1 (en) | 2018-06-29 | 2019-06-28 | Composition of alginic oligosaccharic diacids |
EP19825647.1A EP3815692A4 (en) | 2018-06-29 | 2019-06-28 | ALGINATE OLIGOSACCHARIDIC DIACID COMPOSITION |
EA202190080A EA202190080A1 (ru) | 2018-06-29 | 2019-06-28 | Композиция олигомерных сахарных дикислот, получаемых из альгиновой кислоты |
BR112020026849-6A BR112020026849A2 (pt) | 2018-06-29 | 2019-06-28 | Composição de diácidos oligossacáricos algínicos |
US17/256,853 US11464794B2 (en) | 2018-06-29 | 2019-06-28 | Composition of alginic oligosaccharic diacids |
AU2019296843A AU2019296843A1 (en) | 2018-06-29 | 2019-06-28 | Composition of alginate oligosaccharide diacid |
PH12020552287A PH12020552287A1 (en) | 2018-06-29 | 2020-12-29 | Composition of alginic oligosaccharic diacids |
ZA2021/00350A ZA202100350B (en) | 2018-06-29 | 2021-01-18 | Composition of alginic oligosaccharic diacids |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201810721327.6 | 2018-06-29 | ||
CN201810721327.6A CN110652517A (zh) | 2018-06-29 | 2018-06-29 | 褐藻胶寡糖二酸的组合物 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2020001632A1 true WO2020001632A1 (zh) | 2020-01-02 |
Family
ID=68984639
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/CN2019/093778 WO2020001632A1 (zh) | 2018-06-29 | 2019-06-28 | 褐藻胶寡糖二酸的组合物 |
Country Status (13)
Country | Link |
---|---|
US (1) | US11464794B2 (zh) |
EP (1) | EP3815692A4 (zh) |
JP (1) | JP2021529197A (zh) |
KR (1) | KR20210041556A (zh) |
CN (1) | CN110652517A (zh) |
AU (1) | AU2019296843A1 (zh) |
BR (1) | BR112020026849A2 (zh) |
CA (1) | CA3104959A1 (zh) |
EA (1) | EA202190080A1 (zh) |
MA (1) | MA53021A (zh) |
PH (1) | PH12020552287A1 (zh) |
WO (1) | WO2020001632A1 (zh) |
ZA (1) | ZA202100350B (zh) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2021023239A1 (zh) * | 2019-08-06 | 2021-02-11 | 上海绿谷制药有限公司 | 甘露糖醛酸寡糖治疗Th1主导相关疾病的用途 |
Families Citing this family (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN112741838A (zh) * | 2019-10-31 | 2021-05-04 | 上海绿谷制药有限公司 | 含有褐藻胶寡糖二酸的药用组合物 |
CN114588171A (zh) * | 2022-04-24 | 2022-06-07 | 中国海洋大学 | 褐藻胶低聚糖在制备预防和/或治疗炎症所致肠黏膜o-糖链结构异常疾病产品中的应用 |
CN114874351B (zh) * | 2022-05-19 | 2023-06-16 | 青岛海洋生物医药研究院股份有限公司 | 一种褐藻胶寡糖-纳米银配合物及其制方法和应用 |
CN115005447B (zh) * | 2022-06-16 | 2024-02-06 | 青岛海关技术中心 | 低聚古罗糖醛酸在制备抗疲劳产品中的应用 |
CN116688222B (zh) * | 2023-06-27 | 2024-05-07 | 暨南大学附属第一医院(广州华侨医院) | 一种基于乏氧外泌体的智能响应水凝胶敷料及其制备方法和应用 |
Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN100508985C (zh) * | 2004-03-24 | 2009-07-08 | 中国海洋大学 | 褐藻胶寡糖及其衍生物及其制备方法和用途 |
US8835403B2 (en) | 2004-03-24 | 2014-09-16 | Meiyu Geng | Algin oligosaccharides and the derivatives thereof as well as the manufacture and the use of the same |
CN106344593A (zh) * | 2015-07-17 | 2017-01-25 | 上海绿谷制药有限公司 | 褐藻胶寡糖及其衍生物在治疗血管性痴呆中的应用 |
CN106344595A (zh) * | 2015-07-17 | 2017-01-25 | 上海绿谷制药有限公司 | 褐藻胶寡糖及其衍生物在治疗疼痛中的应用 |
CN106344594A (zh) * | 2015-07-17 | 2017-01-25 | 上海绿谷制药有限公司 | 褐藻胶寡糖及其衍生物在治疗炎症中的应用 |
CN106344592A (zh) * | 2015-07-17 | 2017-01-25 | 上海绿谷制药有限公司 | 还原端1位为羧基的甘露糖醛酸寡糖及其衍生物在治疗帕金森氏症中的应用 |
Family Cites Families (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPWO2007069468A1 (ja) * | 2005-12-14 | 2009-05-21 | 国立大学法人 長崎大学 | サイトカイン分泌促進剤 |
JP2016108474A (ja) * | 2014-12-08 | 2016-06-20 | 栄治 松村 | オリゴ糖の製造方法およびオリゴ糖 |
CN104892792B (zh) | 2015-05-22 | 2018-08-24 | 上海绿谷制药有限公司 | 一种氧化型α-1,4-寡聚葡萄糖醛酸及其制备方法和用途 |
DE102016113018A1 (de) * | 2016-07-14 | 2018-01-18 | Abbas Mirshafiey | Pharmazeutische Verwendung von beta-D-Mannuronsäure |
KR20190046871A (ko) * | 2016-08-15 | 2019-05-07 | 상하이 그린벨리 파머수티컬 주식회사 | 올리고만누론 이산의 제조방법 |
EA201991615A1 (ru) * | 2016-12-30 | 2019-12-30 | Шанхай Грин Вэли Фармасьютикал Ко., Лтд. | Композиция маннуроновой дикислоты |
-
2018
- 2018-06-29 CN CN201810721327.6A patent/CN110652517A/zh active Pending
-
2019
- 2019-06-28 US US17/256,853 patent/US11464794B2/en active Active
- 2019-06-28 CA CA3104959A patent/CA3104959A1/en active Pending
- 2019-06-28 WO PCT/CN2019/093778 patent/WO2020001632A1/zh active Application Filing
- 2019-06-28 EA EA202190080A patent/EA202190080A1/ru unknown
- 2019-06-28 AU AU2019296843A patent/AU2019296843A1/en active Pending
- 2019-06-28 BR BR112020026849-6A patent/BR112020026849A2/pt unknown
- 2019-06-28 KR KR1020217001852A patent/KR20210041556A/ko not_active Application Discontinuation
- 2019-06-28 JP JP2020572823A patent/JP2021529197A/ja active Pending
- 2019-06-28 EP EP19825647.1A patent/EP3815692A4/en active Pending
- 2019-06-28 MA MA053021A patent/MA53021A/fr unknown
-
2020
- 2020-12-29 PH PH12020552287A patent/PH12020552287A1/en unknown
-
2021
- 2021-01-18 ZA ZA2021/00350A patent/ZA202100350B/en unknown
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN100508985C (zh) * | 2004-03-24 | 2009-07-08 | 中国海洋大学 | 褐藻胶寡糖及其衍生物及其制备方法和用途 |
US8835403B2 (en) | 2004-03-24 | 2014-09-16 | Meiyu Geng | Algin oligosaccharides and the derivatives thereof as well as the manufacture and the use of the same |
CN106344593A (zh) * | 2015-07-17 | 2017-01-25 | 上海绿谷制药有限公司 | 褐藻胶寡糖及其衍生物在治疗血管性痴呆中的应用 |
CN106344595A (zh) * | 2015-07-17 | 2017-01-25 | 上海绿谷制药有限公司 | 褐藻胶寡糖及其衍生物在治疗疼痛中的应用 |
CN106344594A (zh) * | 2015-07-17 | 2017-01-25 | 上海绿谷制药有限公司 | 褐藻胶寡糖及其衍生物在治疗炎症中的应用 |
CN106344592A (zh) * | 2015-07-17 | 2017-01-25 | 上海绿谷制药有限公司 | 还原端1位为羧基的甘露糖醛酸寡糖及其衍生物在治疗帕金森氏症中的应用 |
Non-Patent Citations (3)
Title |
---|
"Remington's Pharmaceutical Sciences", 1995, MACK PUBLISHING COMPANY |
BAO XINMINGSHU SIYUN: "Rat Brain Stereotactic Atlas", 1991, PEOPLE'S MEDICAL PRESS, pages: 28 |
CAS , no. 9005-38-3 |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2021023239A1 (zh) * | 2019-08-06 | 2021-02-11 | 上海绿谷制药有限公司 | 甘露糖醛酸寡糖治疗Th1主导相关疾病的用途 |
EP4011378A4 (en) * | 2019-08-06 | 2023-08-30 | Shanghai Green Valley Pharmaceutical Co., Ltd. | USE OF MANNURONIC ACID OLIGOSACCHARIDS OR COMPOSITION CONTAINING THEM FOR THE TREATMENT OF TH1 DOMINANT DISEASES |
Also Published As
Publication number | Publication date |
---|---|
JP2021529197A (ja) | 2021-10-28 |
ZA202100350B (en) | 2023-06-28 |
MA53021A (fr) | 2021-05-05 |
EP3815692A4 (en) | 2022-04-13 |
US11464794B2 (en) | 2022-10-11 |
US20210260085A1 (en) | 2021-08-26 |
CA3104959A1 (en) | 2020-01-02 |
EP3815692A1 (en) | 2021-05-05 |
AU2019296843A1 (en) | 2021-01-28 |
CN110652517A (zh) | 2020-01-07 |
BR112020026849A2 (pt) | 2021-04-06 |
PH12020552287A1 (en) | 2021-06-21 |
KR20210041556A (ko) | 2021-04-15 |
EA202190080A1 (ru) | 2021-07-20 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
WO2020001632A1 (zh) | 褐藻胶寡糖二酸的组合物 | |
KR102539060B1 (ko) | 만누론 이산의 조성물 | |
CN106344595B (zh) | 褐藻胶寡糖及其衍生物在制备治疗疼痛药物中的应用 | |
CN106344593B (zh) | 褐藻胶寡糖及其衍生物在制备治疗血管性痴呆药物中的应用 | |
CN114558007A (zh) | 吲哚-3-乳酸在制备抗结直肠癌药物中的应用 | |
JP6062065B2 (ja) | 過敏性腸症候群を治療するためのアルピニア種抽出物 | |
ES2404819T3 (es) | Aplicación de 3,5-dihidroxitolueno o derivados de este en la preparación de medicina y alimento funcional para tratar o prevenir la depresión | |
WO2023155936A2 (zh) | 脆弱拟杆菌两性离子荚膜多糖或/和改性的两性离子荚膜多糖的新应用 | |
CN114699422B (zh) | 脆弱拟杆菌的荚膜多糖提取物在制备防治阿尔茨海默病的药物中的应用 | |
WO2020001611A1 (zh) | 甘露糖醛二酸的组合物在治疗炎症中的应用 | |
WO2020001639A1 (zh) | 甘露糖醛二酸的组合物在治疗疼痛中的应用 | |
EA045761B1 (ru) | Композиция олигомерных сахарных дикислот, получаемых из альгиновой кислоты | |
WO2020001640A1 (zh) | 甘露糖醛二酸的组合物在治疗帕金森氏症中的应用 | |
WO2020001643A1 (zh) | 甘露糖醛二酸的组合物在治疗血管性痴呆症中的应用 | |
CN104876942B (zh) | 单硝酸异山梨酯半水化合物 | |
CN1033789C (zh) | 胶态酒石酸铋药物的制备方法 | |
KR101804849B1 (ko) | 타르타르산 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 퇴행성뇌질환 예방 또는 치료용 약학적 조성물 | |
EA041420B1 (ru) | Композиции маннуроновой дикислоты, способы ее получения и использования |
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: 19825647 Country of ref document: EP Kind code of ref document: A1 |
|
ENP | Entry into the national phase |
Ref document number: 3104959 Country of ref document: CA |
|
ENP | Entry into the national phase |
Ref document number: 2020572823 Country of ref document: JP Kind code of ref document: A |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
REG | Reference to national code |
Ref country code: BR Ref legal event code: B01A Ref document number: 112020026849 Country of ref document: BR |
|
ENP | Entry into the national phase |
Ref document number: 2019296843 Country of ref document: AU Date of ref document: 20190628 Kind code of ref document: A |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2019825647 Country of ref document: EP |
|
ENP | Entry into the national phase |
Ref document number: 112020026849 Country of ref document: BR Kind code of ref document: A2 Effective date: 20201228 |