CN1157415C - Alginate having low molecular weight, method of manufacturing it and its use - Google Patents
Alginate having low molecular weight, method of manufacturing it and its use Download PDFInfo
- Publication number
- CN1157415C CN1157415C CNB998169315A CN99816931A CN1157415C CN 1157415 C CN1157415 C CN 1157415C CN B998169315 A CNB998169315 A CN B998169315A CN 99816931 A CN99816931 A CN 99816931A CN 1157415 C CN1157415 C CN 1157415C
- Authority
- CN
- China
- Prior art keywords
- molecular weight
- alginates
- molecular
- dalton
- weight
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- 229920000615 alginic acid Polymers 0.000 title claims abstract description 122
- 235000010443 alginic acid Nutrition 0.000 title claims abstract description 121
- 229940072056 alginate Drugs 0.000 title abstract description 37
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 title abstract description 36
- 238000004519 manufacturing process Methods 0.000 title description 2
- 238000000034 method Methods 0.000 claims abstract description 48
- 239000002994 raw material Substances 0.000 claims abstract description 27
- 230000015556 catabolic process Effects 0.000 claims abstract description 19
- 238000006731 degradation reaction Methods 0.000 claims abstract description 19
- 206010020772 Hypertension Diseases 0.000 claims abstract description 17
- 238000002360 preparation method Methods 0.000 claims abstract description 13
- 210000004369 blood Anatomy 0.000 claims abstract description 11
- 239000008280 blood Substances 0.000 claims abstract description 11
- 230000002265 prevention Effects 0.000 claims abstract description 9
- 208000016998 Conn syndrome Diseases 0.000 claims abstract description 4
- 208000013846 primary aldosteronism Diseases 0.000 claims abstract description 4
- 241001474374 Blennius Species 0.000 claims description 35
- 239000012528 membrane Substances 0.000 claims description 31
- 238000001728 nano-filtration Methods 0.000 claims description 22
- 150000003839 salts Chemical class 0.000 claims description 22
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 22
- 239000002253 acid Substances 0.000 claims description 21
- 238000002525 ultrasonication Methods 0.000 claims description 9
- 239000003814 drug Substances 0.000 claims description 8
- 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 claims description 7
- 238000013019 agitation Methods 0.000 claims description 7
- 239000008103 glucose Substances 0.000 claims description 7
- 150000002500 ions Chemical class 0.000 claims description 7
- 108010093096 Immobilized Enzymes Proteins 0.000 claims description 5
- 238000001311 chemical methods and process Methods 0.000 claims description 5
- 239000007800 oxidant agent Substances 0.000 claims description 5
- 238000000053 physical method Methods 0.000 claims description 5
- 239000012670 alkaline solution Substances 0.000 claims description 4
- 239000012736 aqueous medium Substances 0.000 claims description 4
- BFGKITSFLPAWGI-UHFFFAOYSA-N chromium(3+) Chemical compound [Cr+3] BFGKITSFLPAWGI-UHFFFAOYSA-N 0.000 claims description 4
- 238000000746 purification Methods 0.000 claims description 4
- 150000001768 cations Chemical class 0.000 claims description 3
- 230000003287 optical effect Effects 0.000 claims description 3
- 238000012545 processing Methods 0.000 claims description 3
- 230000005855 radiation Effects 0.000 claims description 3
- 238000006555 catalytic reaction Methods 0.000 claims description 2
- 238000000926 separation method Methods 0.000 claims description 2
- 239000011260 aqueous acid Substances 0.000 claims 1
- 239000000783 alginic acid Substances 0.000 abstract description 9
- 229960001126 alginic acid Drugs 0.000 abstract description 9
- 150000004781 alginic acids Chemical class 0.000 abstract description 9
- 201000009395 primary hyperaldosteronism Diseases 0.000 abstract 1
- 239000000047 product Substances 0.000 description 30
- MZYRDLHIWXQJCQ-YZOKENDUSA-L potassium alginate Chemical compound [K+].[K+].O1[C@@H](C([O-])=O)[C@@H](OC)[C@H](O)[C@H](O)[C@@H]1O[C@@H]1[C@@H](C([O-])=O)O[C@@H](O)[C@@H](O)[C@H]1O MZYRDLHIWXQJCQ-YZOKENDUSA-L 0.000 description 27
- 235000010408 potassium alginate Nutrition 0.000 description 26
- 239000000737 potassium alginate Substances 0.000 description 26
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 22
- 230000000694 effects Effects 0.000 description 15
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 14
- 230000003203 everyday effect Effects 0.000 description 14
- 239000000243 solution Substances 0.000 description 14
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 11
- 239000011591 potassium Substances 0.000 description 11
- 229910052700 potassium Inorganic materials 0.000 description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 10
- XXQBEVHPUKOQEO-UHFFFAOYSA-N potassium superoxide Chemical compound [K+].[K+].[O-][O-] XXQBEVHPUKOQEO-UHFFFAOYSA-N 0.000 description 10
- 238000000108 ultra-filtration Methods 0.000 description 10
- 229920002307 Dextran Polymers 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 9
- 238000001914 filtration Methods 0.000 description 8
- 208000007530 Essential hypertension Diseases 0.000 description 7
- 238000006243 chemical reaction Methods 0.000 description 7
- 238000004440 column chromatography Methods 0.000 description 7
- 239000012153 distilled water Substances 0.000 description 7
- 238000009826 distribution Methods 0.000 description 7
- 238000001035 drying Methods 0.000 description 7
- 238000007254 oxidation reaction Methods 0.000 description 7
- PQSUYGKTWSAVDQ-ZVIOFETBSA-N Aldosterone Chemical compound C([C@@]1([C@@H](C(=O)CO)CC[C@H]1[C@@H]1CC2)C=O)[C@H](O)[C@@H]1[C@]1(C)C2=CC(=O)CC1 PQSUYGKTWSAVDQ-ZVIOFETBSA-N 0.000 description 6
- PQSUYGKTWSAVDQ-UHFFFAOYSA-N Aldosterone Natural products C1CC2C3CCC(C(=O)CO)C3(C=O)CC(O)C2C2(C)C1=CC(=O)CC2 PQSUYGKTWSAVDQ-UHFFFAOYSA-N 0.000 description 6
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 6
- VYZAMTAEIAYCRO-UHFFFAOYSA-N Chromium Chemical compound [Cr] VYZAMTAEIAYCRO-UHFFFAOYSA-N 0.000 description 6
- 229960002478 aldosterone Drugs 0.000 description 6
- 239000011575 calcium Substances 0.000 description 6
- 239000002775 capsule Substances 0.000 description 6
- 229910052804 chromium Inorganic materials 0.000 description 6
- 239000011651 chromium Substances 0.000 description 6
- 239000000284 extract Substances 0.000 description 6
- 230000003647 oxidation Effects 0.000 description 6
- 241000196324 Embryophyta Species 0.000 description 5
- 206010020571 Hyperaldosteronism Diseases 0.000 description 5
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 5
- 229910052791 calcium Inorganic materials 0.000 description 5
- 239000012510 hollow fiber Substances 0.000 description 5
- 230000001631 hypertensive effect Effects 0.000 description 5
- 238000011160 research Methods 0.000 description 5
- 238000004062 sedimentation Methods 0.000 description 5
- 229910052708 sodium Inorganic materials 0.000 description 5
- 239000011734 sodium Substances 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 238000005303 weighing Methods 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- 101000925662 Enterobacteria phage PRD1 Endolysin Proteins 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 4
- 230000003276 anti-hypertensive effect Effects 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 235000013305 food Nutrition 0.000 description 4
- 239000007789 gas Substances 0.000 description 4
- 239000011521 glass Substances 0.000 description 4
- 210000002381 plasma Anatomy 0.000 description 4
- 229910001414 potassium ion Inorganic materials 0.000 description 4
- 235000011121 sodium hydroxide Nutrition 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- 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 3
- 241000512259 Ascophyllum nodosum Species 0.000 description 3
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 3
- NPYPAHLBTDXSSS-UHFFFAOYSA-N Potassium ion Chemical compound [K+] NPYPAHLBTDXSSS-UHFFFAOYSA-N 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 239000008187 granular material Substances 0.000 description 3
- 210000004347 intestinal mucosa Anatomy 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 210000004379 membrane Anatomy 0.000 description 3
- 238000005502 peroxidation Methods 0.000 description 3
- 239000001103 potassium chloride Substances 0.000 description 3
- 235000011164 potassium chloride Nutrition 0.000 description 3
- 235000010413 sodium alginate Nutrition 0.000 description 3
- 239000000661 sodium alginate Substances 0.000 description 3
- 229940005550 sodium alginate Drugs 0.000 description 3
- 238000001228 spectrum Methods 0.000 description 3
- ZYECOAILUNWEAL-NUDFZHEQSA-N (4z)-4-[[2-methoxy-5-(phenylcarbamoyl)phenyl]hydrazinylidene]-n-(3-nitrophenyl)-3-oxonaphthalene-2-carboxamide Chemical compound COC1=CC=C(C(=O)NC=2C=CC=CC=2)C=C1N\N=C(C1=CC=CC=C1C=1)/C(=O)C=1C(=O)NC1=CC=CC([N+]([O-])=O)=C1 ZYECOAILUNWEAL-NUDFZHEQSA-N 0.000 description 2
- QPFMBZIOSGYJDE-UHFFFAOYSA-N 1,1,2,2-tetrachloroethane Chemical compound ClC(Cl)C(Cl)Cl QPFMBZIOSGYJDE-UHFFFAOYSA-N 0.000 description 2
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- 208000008589 Obesity Diseases 0.000 description 2
- KFSLWBXXFJQRDL-UHFFFAOYSA-N Peracetic acid Chemical compound CC(=O)OO KFSLWBXXFJQRDL-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 238000000862 absorption spectrum Methods 0.000 description 2
- -1 alginate oligosaccharide compound Chemical class 0.000 description 2
- 239000011324 bead Substances 0.000 description 2
- QNBLWPGKPNANOY-UHFFFAOYSA-N benzene-1,3,5-triol;hydrochloride Chemical compound Cl.OC1=CC(O)=CC(O)=C1 QNBLWPGKPNANOY-UHFFFAOYSA-N 0.000 description 2
- 230000036772 blood pressure Effects 0.000 description 2
- 230000018044 dehydration Effects 0.000 description 2
- 238000006297 dehydration reaction Methods 0.000 description 2
- 206010012601 diabetes mellitus Diseases 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 150000004676 glycans Chemical class 0.000 description 2
- 230000002218 hypoglycaemic effect Effects 0.000 description 2
- 230000031891 intestinal absorption Effects 0.000 description 2
- 238000005342 ion exchange Methods 0.000 description 2
- 238000005374 membrane filtration Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 235000020824 obesity Nutrition 0.000 description 2
- 229920001542 oligosaccharide Polymers 0.000 description 2
- 239000004033 plastic Substances 0.000 description 2
- 238000006116 polymerization reaction Methods 0.000 description 2
- 229920001282 polysaccharide Polymers 0.000 description 2
- 239000005017 polysaccharide Substances 0.000 description 2
- 150000004804 polysaccharides Chemical class 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 235000015320 potassium carbonate Nutrition 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 238000003127 radioimmunoassay Methods 0.000 description 2
- 239000013558 reference substance Substances 0.000 description 2
- 230000029865 regulation of blood pressure Effects 0.000 description 2
- OGIDPMRJRNCKJF-UHFFFAOYSA-N titanium oxide Inorganic materials [Ti]=O OGIDPMRJRNCKJF-UHFFFAOYSA-N 0.000 description 2
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 239000004160 Ammonium persulphate Substances 0.000 description 1
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 1
- 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 description 1
- 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 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 description 1
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 1
- IAJILQKETJEXLJ-UHFFFAOYSA-N Galacturonsaeure Natural products O=CC(O)C(O)C(O)C(O)C(O)=O IAJILQKETJEXLJ-UHFFFAOYSA-N 0.000 description 1
- 239000001828 Gelatine Substances 0.000 description 1
- 208000001953 Hypotension Diseases 0.000 description 1
- PWHULOQIROXLJO-UHFFFAOYSA-N Manganese Chemical compound [Mn] PWHULOQIROXLJO-UHFFFAOYSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- FKNQFGJONOIPTF-UHFFFAOYSA-N Sodium cation Chemical compound [Na+] FKNQFGJONOIPTF-UHFFFAOYSA-N 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 206010000059 abdominal discomfort Diseases 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- ROOXNKNUYICQNP-UHFFFAOYSA-N ammonium persulfate Chemical compound [NH4+].[NH4+].[O-]S(=O)(=O)OOS([O-])(=O)=O ROOXNKNUYICQNP-UHFFFAOYSA-N 0.000 description 1
- 235000019395 ammonium persulphate Nutrition 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000000578 anorexic effect Effects 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 229910052728 basic metal Inorganic materials 0.000 description 1
- 150000003818 basic metals Chemical class 0.000 description 1
- 239000003637 basic solution Substances 0.000 description 1
- AEMOLEFTQBMNLQ-UHFFFAOYSA-N beta-D-galactopyranuronic acid Natural products OC1OC(C(O)=O)C(O)C(O)C1O AEMOLEFTQBMNLQ-UHFFFAOYSA-N 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- 229910001424 calcium ion Inorganic materials 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000002144 chemical decomposition reaction Methods 0.000 description 1
- QSWDMMVNRMROPK-UHFFFAOYSA-K chromium(3+) trichloride Chemical class [Cl-].[Cl-].[Cl-].[Cr+3] QSWDMMVNRMROPK-UHFFFAOYSA-K 0.000 description 1
- 239000004927 clay Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 239000000428 dust Substances 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 229910001651 emery Inorganic materials 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 229920000140 heteropolymer Polymers 0.000 description 1
- 229910000040 hydrogen fluoride Inorganic materials 0.000 description 1
- 239000000413 hydrolysate Substances 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 208000021822 hypotensive Diseases 0.000 description 1
- 230000001077 hypotensive effect Effects 0.000 description 1
- 238000007654 immersion Methods 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000009413 insulation Methods 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 238000005304 joining Methods 0.000 description 1
- 229920002521 macromolecule Polymers 0.000 description 1
- 229910052748 manganese Inorganic materials 0.000 description 1
- 239000011572 manganese Substances 0.000 description 1
- 235000012054 meals Nutrition 0.000 description 1
- 239000011268 mixed slurry Substances 0.000 description 1
- 230000012666 negative regulation of transcription by glucose Effects 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 150000002482 oligosaccharides Chemical class 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 238000012856 packing Methods 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- BITYAPCSNKJESK-UHFFFAOYSA-N potassiosodium Chemical compound [Na].[K] BITYAPCSNKJESK-UHFFFAOYSA-N 0.000 description 1
- 239000012286 potassium permanganate Substances 0.000 description 1
- VISKNDGJUCDNMS-UHFFFAOYSA-M potassium;chlorite Chemical compound [K+].[O-]Cl=O VISKNDGJUCDNMS-UHFFFAOYSA-M 0.000 description 1
- HDMGAZBPFLDBCX-UHFFFAOYSA-M potassium;sulfooxy sulfate Chemical compound [K+].OS(=O)(=O)OOS([O-])(=O)=O HDMGAZBPFLDBCX-UHFFFAOYSA-M 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000003825 pressing Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 238000002791 soaking Methods 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- UKLNMMHNWFDKNT-UHFFFAOYSA-M sodium chlorite Chemical compound [Na+].[O-]Cl=O UKLNMMHNWFDKNT-UHFFFAOYSA-M 0.000 description 1
- 229910001415 sodium ion Inorganic materials 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 239000004408 titanium dioxide Substances 0.000 description 1
- 238000009281 ultraviolet germicidal irradiation Methods 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Images
Landscapes
- Polysaccharides And Polysaccharide Derivatives (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
The present invention relates to alginate obtained by using alginic acid as a raw material via a degradation method, the average molecular weight of the alginate is between about 5, 000 to 20, 000 daltons, the intrinsic viscosity of the alginate is between 1 and 20 measured by the Ubbelohde viscometer, and the molecular weight of most of molecules of the alginate is between 1, 000 to 30, 000 daltons. The present invention also relates to a preparation method of the low-molecular weight alginate and uses of the low-molecular weight alginate for the prevention and the treatment of hypertension and primary hyperaldosteronism (ALD) and for the reduction of blood sugar.
Description
Technical field
The present invention relates to low-molecular-weight alginate, more particularly, the molecular-weight average that the present invention relates to obtain as raw material, by degradation method with Lalgine is greatly about 5000-20, alginate between 000 dalton, its Ubbelohde viscosity characteristics viscosity number is between 1-20, the molecular weight of this alginate molecule of the overwhelming majority is in 1, and 000-30 is between 000 dalton.The invention still further relates to preparation method and its purposes aspect prevention and treatment hypertension and primary aldosterone (ALD) increase disease and lowering blood glucose of this lower molecular weight alginate.
Background technology
Natural seaweed acid (alginic acid) is a kind of very common material that can extract from marine plant such as sea-tangle, kelp, brown alga, bulk kelp, purposes is very extensive, natural seaweed acid and derivative thereof as bring high blood pressure down and the medicine of disease such as preventing hypertension on the books already in the literature.
Sea-tangle is to compare rich in natural resources in the ocean, has on the shoreline in many places widely and cultures.In the custom of the useful Radix Laminariae alleviating hypertension symptom in coastal area of china area, 12 grams of ingesting every day, to one or the second stage of essential hypertension certain curative effect is arranged.People use it in the various application extract Lalgine or its salt from plants such as sea-tangle after, and for example, the adult takes more than sodium alginate gram every days 20, and of short duration antihypertensive effect is arranged.Also there is the human potassium alginate to do the experiment of SHR spontaneous hypertensive rat, find that experimentation on animals is effective, but for the people, curative effect was not remarkable after the hyperpietic took the big potassium alginate of molecular weight.But take the too little alginates of molecular weight and also do not have long antihypertensive effect, for example, Japanese kokai publication hei 6-237783 discloses and has utilized Lalgine sick and Lalgine oligose of health-care effect and preparation method thereof arranged to preventing hypertension for prepared a kind of of raw material, they utilize the lytic enzyme of degradable polysaccharide from the potassium alginate that belong to oligosaccharides of the natural seaweed acid preparation polymerization degree for 2-5, but, the purposes of product is just to prevention (inhibition) hypertension, does not relate to hypertensive result of treatment.
A kind of marine alga food for decreasing fat is disclosed in CN1097307, it is to obtain by the following method: commercially available medicinal alginic acid is added water logging do not have immersion to make its expansion, add 6-7N hydrochloric acid again, allow alginic acid degraded become oligopolymer, the water depickling adds the saturated ethanolic soln of potassium hydroxide then, make it change into oligomeric Potassium polyalginate, last PH is stabilized in 8, and drying is pulverized and obtained Powdered brown alga anoretic.But in this patent, do not describe the molecular weight of product and the effect that brings high blood pressure down particularly, do not emphasize to treat the effect of hypertension and aldosteronism yet.
SU1821470 discloses a kind of method of extracting glycan from waterplant, it comprises at elevated temperatures extracts from pretreated waterplant in basic solution, add hydrochloric acid or sulfuric acid, the alginate that are separated hydrolysis under 80-100 ℃ and PH=0-1, cooling is by caustic soda neutralization, purifying mixture, the alginate of depolymerization are precipitated to get off, and hydrolysate is dried to the viscosity of 1.5-4.0cPs.Do not mention that wherein this product treats hypertensive purposes.
WO9320826 A1 discloses a kind of pharmaceutical composition based on alginate, and it is used for prevention and treatment gastrointestinal upset disease.
US5460957 discloses and has a kind ofly contained calcium, potassium ion but do not contain the novel alginate oligosaccharide compound of sodium, and it is as the hypotensive additive in the food.This alginate oligose (I) is to handle sodiun alginate or potassium alginate (II) by (1) with glycan lytic enzyme (III), and (2) replace sodium (or sodium and potassium) ion with calcium or potassium ion then, and/or introduces calcium and other potassium ion.The product of this patent has the polymerization degree of 2-5, and molecular weight is very low.
KR9200242 discloses the method for preparing the lower molecular weight alginate, only is to use ultrasonication that main polymer chain is decomposed, but the molecular weight of product is generally more than 35,000, and ultrasonication also can only reach more than 20,000 or 20,000 repeatedly.In this patent, do not point out prevention and treat hypertensive effect.
Disclose the method for extracting sodiun alginate from brown alga among the KR9105768, the molecular weight of product is 60, and 000-300 is between 000.
Disclose among the US5283076 and contained the Foods or drinks that molecular weight is the sodiun alginate of 10000-150000, be used for prevention of obesity (obesity) and diabetes (diabetic).
JP3273002 discloses the decomposed substance of alginic acid, and its molecular weight is 1000-1500, as the stablizer of food or medicine.
US4104460 discloses the method for extracting alginic acid from marine alga, and it is included in adds peroxide compound in the Lalgine, use processing such as alkali such as yellow soda ash, volatile salt, sodium hydroxide then, but do not mention the purposes as medicine in the document.
The alginates derivative that prior art obtains can only work in the short period of time, mainly suppresses the rising of blood pressure, but general readily good therapeutic effect.
Summary of the invention
The purpose of this invention is to provide a kind of Lalgine (salt) derivative, require the effect of its prevention and treatment hypertension and aldosteronism relatively more outstanding and effective drug duration is long, lowering blood glucose effect in addition simultaneously.
The inventor finds through years of researches, by methods such as oxidation, enzymolysis natural seaweed acid (salt) is degraded to a certain degree, be molecular-weight average in a certain specified range, the Lalgine of this moment and salt pair treatment hypertension thereof and aldosteronism are very effective, but and lowering blood glucose.
Research work of the present invention divides three phases, and the molecular-weight average of the alginates of producing at first is 6.8 * 10
4The molecular weight of the alginates molecule of the overwhelming majority is in 2000-100, between 000, with molecular weight 50, after the separating more than 000, residuum is through Xiyuan Hospital, Chinese Medicine Academy of China's clinical observation, take the 5-8 gram every day primary hypertension patient is had significant curative effect, total effective rate reaches 83.3%, and we use molecular weight greater than 30 through range of molecular weight distributions is investigated, 000 and molecular weight mainly distribute mainly 30,000-100, the alginates in 000 scope carries out clinical observation to the hyperpietic, does not find tangible antihypertensive effect.Subordinate phase, we have produced low-molecular-weight alginates, and its molecular-weight average is 3.5 * 10
4And the molecular weight of alginates molecule of the overwhelming majority is between 2,000 to 58,000, takes the 4-7 gram every day total effective rate of primary hypertension patient is reached 85%.In the phase III, we have produced more low-molecular-weight alginates, and its molecular-weight average is at 5000-20, between 000; Preferably at 7000-12, between 000 and especially more preferably at 6000-10000, most preferably between 7000-9000.Preferably, the molecular weight of alginates molecule of the overwhelming majority is in 1,000-30, and between 000 and more fortunately 1,600-20, between 000, especially at 1600-12,000 and especially 1,600-10,000 and most preferably at 1800-10, between 000.The Ubbelohde viscosity characteristics viscosity number of alginates product is between the 1-20 and preferably between 3-14.Particularly, when alginates have molecular-weight average between 6000-9000 and the molecular weight of alginates molecule of the overwhelming majority be in 1600-10, in the time of in 000 scope, dose 0.5-3 restrained this alginates the total effective rate of primary hypertension patient was reached more than 88% every day, and cut out after taking a week continuously, patient's blood pressure is stabilized in normal level in 2～3 days time.Therefore, in the phase III, finished the present invention.
The invention provides a kind of low-molecular-weight alginate, more particularly, the invention provides with Lalgine as raw material, combine the molecular-weight average that obtains greatly about 5000-20 by degradation method and membrane separation technique, between 000, preferably at 7000-12, between 000 and particularly preferably in the alginate between the 7500-8500.Preferably, the molecular weight of this alginate molecule of the overwhelming majority is in 1,000-30, and between 000 and goodly be in 1,600-20, between 000 and most preferably be in 1,600-10 is between 000.The Ubbelohde viscosity characteristics viscosity number of alginates product is acceptable positively charged ion or a trivalent chromic ion on the pharmacology at the salt-forming cation of this alginates between the 1-20 and wherein.
The present invention also provides preparation method and its purposes aspect prevention and treatment hypertension and primary aldosteronism and lowering blood glucose of this lower molecular weight alginate.
In above-mentioned preparation method, degradation step comprises physical method, photochemical method, immobilized enzyme method or chemical process.
Physical method comprises ultrasonication or high speed shear processing; Photochemical method is to utilize optical radiation and catalysis to handle; Be to use strong acid, highly basic and inorganic or organic oxidizing agent to handle with chemical process.
For oxidation degradation method, need to use oxygenant, these oxygenants comprise organic oxidizing agent and inorganic oxidizer.It comprises hydrogen peroxide, Peracetic Acid, and Potassium peroxide, peroxidation salt of wormwood, potassium per(oxy)borate (sodium), potassium permanganate, ammonium persulphate, potassium hydrogen persulfate double salt, Textone, potassium chlorite, or the like.
After the Lalgine degraded, need to adopt ultra-filtration membrane and nanofiltration membrane to hold back technology to obtain the product of desired molecule weight range.The present invention adopts DHFM series ZBS1 type that Dalian Inst of Chemicophysics, Chinese Academy of Sciences produces and ZBS3 type hollow fiber ultrafiltration membrane molecular weight cut off 10,000 and 30,000 respectively, cuts out molecular weight respectively greater than 10,000 or 30,000 alginates.Then, but use trade mark that film engineering center of Dalian Chemical Physics Research Institute produces to be the NF4040 type nanofiltration membrane filtering molecular weight of Bai Te alginate less than 1000 or 1200 (pressing a little).
Here " overwhelming majority " in the phrase " molecular weight of Lalgine (salt) molecule of the overwhelming majority " made explanations: because the pore size of ultra-filtration membrane and nanofiltration membrane is not uniformly absolute, there is a spot of filter opening bigger than normal slightly or less than normal slightly, and the aperture can change under different pressures, therefore can modify with " overwhelming majority " for molecular weight cut-off.When for example using nanofiltration membrane to filter, originally 1000 molecule is held back in design, but since filter opening be not strict evenly and filter opening change with the variation of pressure, the small number of molecules of molecular weight a little higher than 1000 (for example 1200 molecular weight) also can be missed.
The invention provides a kind of method for preparing the low molecular weight seaweed hydrochlorate, it comprises: (1) degradation step: the degraded of high molecular Lalgine raw material to the molecular-weight average that arrives more than 20000 below about 80000 dalton, is added alkaline solution and makes it dissolving; (2) utilize hyperfiltration process, cut out the above molecule of molecular weight 30000 dalton, stay molecular weight less than 30000 daltonian alginates molecules, (3) utilize nanofiltration membrane, cut out molecular weight less than 1000 daltonian alginates molecules, obtain molecular-weight average between 5000-20000 dalton and the molecular weight of this alginates molecule of the overwhelming majority be in 1000-3, in 0000 dalton's scope, in addition dry at last.
A kind of method for preparing the low molecular weight seaweed hydrochlorate, it comprises: (1) degradation step: with high molecular Lalgine raw material degraded to more than 20000 to the molecular weight below 80000 dalton; (2) degraded product is made the salt of solubility with alkaline purification, (3) under agitation add water or aqueous medium, add oxygenant then product further is degraded into more low-molecular-weight alginates, (4) utilize hyperfiltration process to cut out the above molecule of molecular weight 30000 dalton, stay molecular weight less than 30000 daltonian alginates molecules, (5) utilize nanofiltration membrane to cut out molecular weight less than 1000 daltonian alginates molecules, obtain molecular-weight average between 5000-20000 dalton and the molecular weight of this alginates molecule of the overwhelming majority be in the 1000-30000 dalton scope, in addition dry at last.
A kind of method for preparing low molecular weight seaweed acid, it comprises: (1) degradation step: the degraded of high molecular Lalgine raw material is made it dissolving to adding alkaline solution to the molecular-weight average below about 70000 dalton more than 10000; (2) utilize hyperfiltration process, cut out the above molecule of molecular weight 10000 dalton, stay molecular weight less than 10000 daltonian Lalgine molecules, (3) utilize nanofiltration membrane, cut out molecular weight less than 1200 daltonian Lalgine molecules, obtain molecular-weight average between 5000-8000 dalton and the molecular weight of this alginates molecule of the overwhelming majority be in 1200-1, in 0000 dalton's scope, in addition dry at last.
A kind of method for preparing the low molecular weight seaweed hydrochlorate, it comprises: (1) degradation step: with high molecular Lalgine raw material degraded to more than 10000 to the molecular weight below 70000 dalton; (2) degraded product is made the salt of solubility with alkaline purification, (3) under agitation add water or aqueous medium, add oxygenant then product further is degraded into more low-molecular-weight alginates, (4) utilize hyperfiltration process to cut out the above molecule of molecular weight 10000 dalton, stay molecular weight less than 10000 daltonian alginates molecules, (5) utilize nanofiltration membrane to cut out molecular weight less than 1200 daltonian alginates molecules, obtain molecular-weight average between 5000-7000 dalton and the molecular weight of this alginates molecule of the overwhelming majority be in the 1200-10000 dalton scope, in addition dry at last.
Degradation step in these preparation methods comprises mechanical degradation, photochemical degradation and methods such as chemical degradation, immobilized enzyme.
Physical method comprises ultrasonication and high speed shear; Photochemical method is to utilize optical radiation and catalytic treatment; Be to use strong acid, highly basic and inorganic or organic oxidizing agent to handle with chemical process.
The small molecules alginates that can absorb intravasation by intestinal mucosa is the main functional component that plays the step-down effect in the alginates, also be to the effective main component of primary aldosteronism, molecular weight is greater than 12,000 alginates just reduces by intestinal mucosa and by the amount of intestinal absorption, increase along with molecular weight, fewer and feweri by the alginates that intestinal mucosa absorbs, the alginates that molecular weight is big has only potassic alginates that certain effect is just arranged, and this moment alginates the blood pressure regulation effect only be because the combining of Lalgine and sodium ion in the enteron aisle come blood pressure regulation by sodium potassium ion exchange interaction.That is to say that if will bring into play bigger effect, alginates must be by intestinal absorption, so the size of molecular weight is crucial.What deserves to be mentioned is, the molecular weight of alginates too little (for example being lower than 900), though absorb easily, demonstrate antihypertensive effect, but the time of keeping is shorter.
The alginates that contains chromium has the effect of lowering blood glucose, and the content of chromium generally accounts for the 0.01%-0.05% of alginates gross weight in alginates, takes the alginates 6-8g that contains chromium every day and has tangible hypoglycemic effect.
Employed in the present invention Lalgine extracts from marine plant, especially extracts from sea-tangle, kelp, brown alga, and wherein sea-tangle is abundant and cheap resource.In order to obtain the alginate with specific molecular-weight average of the present invention, we use the high molecular Lalgine sold on the market or its salt as raw material, perhaps use the Lalgine that extracts according to usual way or its salt as raw material, the molecular-weight average of this class Lalgine or its salt generally is 30,000-300,000.For the method for the Lalgine of from marine plant, producing this family macromolecule amount or its salt without any restriction, as long as molecular weight and molecular weight distribution are greatly in above specified scope.
Salt of the present invention can be pharmaceutically useful any salt, i.e. acceptable salt on the pharmacology.Salifiable positively charged ion for example comprises basic metal, alkaline-earth metal, iron, zinc, chromium (III), the positively charged ion of manganese etc., and ammonium ion.Wherein the solubility alginate are preferred, and sylvite is most preferred." alginic acid " has identical meaning with " Lalgine " in this article, and same " alginate " also have identical meaning with " alginates ".
" molecular weight " used herein measured with column chromatography: HL-2 type constant flow pump and the automatic Fraction Collector of BSZ-100 type that the instrument of use has Shanghai Hu Xi instrument plant to produce, the 222 type spectrophotometers that also have Shanghai analytical instrument factory to produce; Because of Lalgine or its salt are polysaccharide, the dextran Dextran that selects different molecular weight for use is thing in contrast, the molecular-weight average of Dextran T4-6 is 5,000, the molecular-weight average of Dextran T8-12 is 10200, the molecular-weight average of Dextran T60-90 is 68300, the molecular-weight average of Dextran T100 is 100,000, the molecular-weight average of Dextran200-300 is 266,000, this a series of Dextran (for trade mark) is the product of Sweden Pharmacia company, is provided by Hong Kong Farco Chemical Supplies; The column chromatography filler is Sephacryls-300; Condition determination: amount to 50ml, elutriant is the sodium chloride solution of 0.1 volumetric molar concentration, and flow velocity 1ml/min collects: the 1ml/ pipe; Detection method: the about 10mg of sample thief, add 1ml water and make it dissolving, add the Phloroglucinol hydrochloric acid soln, heated and boiled, promptly show red-violet colour, this product is the sylvite bonded heteropolymer of mannuronic acid and guluronic acid, can generate the red-violet colour compound with the Phloroglucinol hydrochloric acid soln; Detect by means of spectrophotometer then, perhaps detect the absorption value of alginate under 230nm with Tianjin, island spectrophotometer.
Precision weighing Dextran T4-6, T8-12, T60-90, T100, each 5mg of T200-300 is dissolved in respectively in the 0.5ml elutriant, and the difference upper prop is with this condition, with low molecular weight seaweed hydrochlorate precision weighing 5mg, be dissolved in the 0.5ml elutriant, with preparation reference substance working curve the same terms upper prop wash-out.Describe the wash-out working curve of Dextran reference substance and the wash-out working curve of sample of the present invention,, determine the molecular-weight average of low molecular weight seaweed hydrochlorate by contrast.Should be noted that, insoluble alginates is to change into soluble salt (as sodium salt or sylvite) by ion-exchange just to measure its molecular weight afterwards, for example alginate calcium is at first to add hydrochloric acid to change into the Lalgine throw out, handles just changing into water miscible sodium alginate then with aqueous sodium hydroxide solution.
Ubbelohde viscosity characteristics viscosity number is according to two appendix VI of Chinese Pharmacopoeia nineteen ninety-five version G: the viscosity test method, measure with the marine alga salt concn of 0.2wt%.
Summary of drawings
Fig. 1 is the infrared absorption spectrum of the low molecule potassium alginate of embodiment 1;
Fig. 2 is the infrared absorption spectrum of high molecular Lalgine raw material;
Fig. 3 is the low molecule potassium alginate of embodiment 1
1The H-NMR spectrum;
Fig. 4 is a high molecular Lalgine raw material
1The H-NMR spectrum.
Preferred forms of the present invention
Embodiment 1: the ultrasonic degradation method
Take by weighing Lalgine (the pharmaceutical grade Lalgine through state approval that DaLian, China seaweed industry company produces) 100g, its molecular-weight average is 200,000, and range of molecular weight distributions approximately is 35,000-300,000.In Lalgine, add entry and make Lalgine account for about 10% of total amount, stir.Adopt U.S. Sonic ﹠amp; Materials 1500 types, total power 1500W uses operating frequency 20KHz, Lalgine suspension was carried out ultrasonication 2 hours, in ultrasonication, add potassium hydroxide solution PH is remained between the 5-9, obtain molecular-weight average and be 35,000 marine alga salt brine solution.Then, DHFM series ZBS 3 type hollow fiber ultrafiltration membrane (the adopting 0.15Mpa pressure) molecular weight cut off 30,000 that uses Dalian Inst of Chemicophysics, Chinese Academy of Sciences to produce, cut out molecular weight greater than 30,000 potassium alginate obtains the solution of molecular weight less than 30,000 potassium alginate.Then, the trade mark that uses film engineering center of Dalian Chemical Physics Research Institute to produce dewater as the NF4040 type nanofiltration membrane (pressurization 0.15MPa) of Bai Te and the filtering molecular weight less than 1200 alginate, after twice filtration, obtaining range of molecular weight distributions is 1,200-30,000 product.95% ethanol sedimentation that adds the long-pending amount of diploid in product goes out low molecular weight seaweed acid potassium, and with drying precipitate, recording its molecular-weight average through column chromatography is 16,000.
With the molecular weight that cuts out greater than 30,000 potassium alginate as part of raw materials, restock a certain amount of initial (original) be purchased the Lalgine raw material, aforesaid operations is carried out in circulation.
With the low molecular weight seaweed potassium of this embodiment carry out infrared analysis and
1The test of H-NMR spectrum compares with the raw material Lalgine, the INFRARED SPECTRUM contrast of Fig. 1 and Fig. 2, Fig. 3 and Fig. 4's
1H-NMR composes contrast, and molecular structure did not change substantially before and after the result showed degraded.
Embodiment 2: the hydrogen peroxide degraded
Fs: take by weighing Lalgine (the pharmaceutical grade Lalgine that DaLian, China seaweed industry company produces) 500g through state approval.Lalgine is added distilled water, stir, make Lalgine account for 9% of water inventory, be heated to 40 ℃ (temperature of reaction), splash into hydrogen peroxide while stirring and (contain H
2O
230%), make concentration of hydrogen peroxide final in the system (be called for short final H
2O
2Concentration) be to account for 1% of gross weight, under agitation reacted 2 hours, be warming up to more than 80 ℃ and remove unreacted hydrogen peroxide by decomposition, under agitation drip 30% potassium hydroxide solution then in the Lalgine of handling through hydrogen peroxide, adding an amount of distilled water fully dissolves product, the pH value of system is remained between the 6-7, and this moment, the molecular-weight average of product was 65000.The Ubbelohde viscosity characteristics viscosity number of product is listed in the table 1.
Subordinate phase: use DHFM series ZBS1 type hollow fiber ultrafiltration membrane (adopting 0.15Mpa pressure) molecular weight cut off 10,000, cut out molecular weight, obtain the solution of molecular weight less than 10,000 potassium alginate greater than 10,000 potassium alginate.Then, use Bai Te board NF4040 type nanofiltration membrane to carry out (adopting the pressure of 0.11Mpa) dehydration and filtering molecular weight less than 1000 alginate, after twice filtration, obtaining range of molecular weight distributions is 1,000-10,000 product.Dry then, recording its molecular-weight average through column chromatography is 7500.
With the molecular weight that cuts out greater than 10,000 potassium alginate as part of raw materials, a certain amount of initial Lalgine raw material that is purchased of restock, aforesaid operations is carried out in circulation.
Embodiment 3-10:
Repeat the schedule of operation of embodiment 2, just temperature of reaction and final concentration of hydrogen peroxide are as shown in following table 1.
Table 1: experimental result
| Embodiment | Temperature of reaction | Final H 2O 2Concentration | The potassium alginate intrinsic viscosity |
| ?2 | ?40℃ | ?1％ | 15-19 |
| ?3 | ?40℃ | ?2％ | 13-17 |
| ?4 | ?40℃ | ?3％ | 12-16 |
| ?5 | ?60℃ | ?1％ | 12-16 |
| ?6 | ?60℃ | ?2％ | 11-15 |
| ?7 | ?60℃ | ?3％ | 10-14 |
| ?8 | ?80℃ | ?1％ | 9-13 |
| ?9 | ?80℃ | ?2％ | 8-12 |
| ?10 | ?80℃ | ?3％ | 7-11 |
Embodiment 11: hydrogen peroxide and ultrasonic wave combine
At first carry out fs identical operations program with embodiment 2.
Then product (was used U.S. Sonic ﹠amp in 1 hour with ultrasonication down at 40 ℃; Materials 1500 types, total power 1500W uses operating frequency 20KHz), in ultrasonication, drip 30% potassium hydroxide solution, finally after reaching about 7.3, PH stops to add potassium hydroxide solution.
Use DHFM series ZBS1 type hollow fiber ultrafiltration membrane molecular weight cut off 10,000, cut out molecular weight, obtain the solution of molecular weight less than 10,000 potassium alginate greater than 10,000 potassium alginate.Then, use Bai Te board NF4040 type nanofiltration membrane dewater and the filtering molecular weight less than 1000 alginate, after twice filtration, obtaining range of molecular weight distributions is 1,000-10,000 product.95% ethanol sedimentation that adds the long-pending amount of diploid in product goes out low molecular weight seaweed acid potassium, and with drying precipitate, recording its molecular-weight average through column chromatography is 7000, and recording intrinsic viscosity is 3.
With the molecular weight that cuts out greater than 10,000 potassium alginate as part of raw materials, a certain amount of initial Lalgine raw material that is purchased of restock, aforesaid operations is carried out in circulation.
Embodiment 12: Potassium peroxide (K
2O
2) oxidation style:
Parallelly carry out 9 experiments, each experiment takes by weighing the 100g Lalgine, adds distilled water 400ml, soaks into it.Adopted three kinds of different temperature of reaction respectively: 40 ℃, 60 ℃ and 80 ℃, under agitation add the 20% Potassium peroxide aqueous solution, further select three kinds of different final K for each temperature of reaction
2O
2Concentration: 2%, 4% and 6%.After Potassium peroxide adds, continue to stir and reacted 2.5 hours.Generating gluey product is oligomeric potassium alginate, continue to add distilled water, regulating PH with 20% potassium hydroxide aqueous solution is 7.0, making potassium alginate concentration is 0.8%, use DHFM series ZBS1 type hollow fiber ultrafiltration membrane molecular weight cut off 10,000, then, use Bai Te board NF4040 type nanofiltration membrane filtering molecular weight to be condensed into 5% slip less than 1000 alginate and dehydration, 95% ethanol that adds the long-pending amount of diploid be equivalent to himself volume carries out sedimentation, drying obtains the potassium alginate of molecular-weight average 8,000.
With the molecular weight that cuts out greater than 10,000 potassium alginate as part of raw materials, a certain amount of initial Lalgine raw material that is purchased of restock, aforesaid operations is carried out in circulation.
Experimental result
| Temperature of reaction | K 2O 2Concentration | The potassium alginate intrinsic viscosity |
| 40℃ | ?2％ | 12-16 |
| ?4％ | 10-14 | |
| ?6％ | 8-12 | |
| 60℃ | ?2％ | 8-10 |
| ?4％ | 7-9 | |
| ?6％ | 6-8 | |
| 80℃ | ?2％ | 5-8 |
| ?4％ | 4-7 | |
| ?6％ | 3-6 |
Wherein using 80 ℃ temperature of reaction and using the resulting product of 6% concentration to record molecular-weight average through column chromatography is 6,000.
Embodiment 13: with the method for oxidation of peroxidation salt of wormwood
Similar among employed schedule of operation and the embodiment 12, just the 20% Potassium peroxide aqueous solution replaces with 30% peroxidation wet chemical.
The result of the intrinsic viscosity of product and embodiment 12 is very approaching.
Embodiment 14: the hydrogen fluoride trealment method
The 100g Lalgine is pulverized and vacuum-drying, sent into then in the reactor, be evacuated to 5mmHg, add HF gas and make reacting kettle inner pressure reach normal pressure, allow Lalgine absorb the HF of the 32-40% of its weight, stirred 1 hour down at 10-20 ℃.Utilize then the rare gas element tetrachloroethane under 80-100 ℃ from reactor desorb HF gas, obtain oligomeric Lalgine.The HF gas that desorbs is recovered repeated use.
Oligomeric Lalgine is neutralized to about PH=7.3 with 10% potassium hydroxide solution, adds suitable quantity of water and make potassium alginate solution, use ZBS1 and NF4040 nanofiltration membrane to repeat ultrafiltration and the nanofiltration membrane operation of front embodiment, filter fluorine-containing impurity.With 95% long-pending ethanol sedimentation of the diploid that is equivalent to the product volume, drying, obtain having the potassium alginate of molecular-weight average 7000.
Embodiment 15: the immobilized enzyme degradation method
The immobilized enzyme degradation technique can improve the rate of utilization of enzyme, utilizes EMERY, and the achievement in research of A.N. (Chem Eng., 71,1972) is improved, and adopts porous soda glass ball, its capillary aperture 600-800 dust, sphere diameter 1mm.Porous soda glass ball is used 5%TiCl under 45 ℃
4Solution soaking 24 hours, there is not absorbed titanium tetrachloride with the distilled water flush away then, then, the sintered glass ball that soaks titanium tetrachloride is placed the 2% concentration solution of alginic acid lytic enzyme (referring to Japanese patent application JP 6-237783), soaked 18 hours down at 2 ℃, the sintered glass ball that soaked the alginic acid lytic enzyme is packed in the column chromatography test filled column, insulation is under 40-55 ℃, the potassium alginate solution of adding 0.8% keeps PH7.0-7.3 in filled column, from the joining day to the elution time, need 6 hours, can obtain low molecular weight seaweed acid potassium solution, molecular weight distribution width 800-35,000.
Embodiment 16: the photochemical degradation method
Titanium dioxide powder is sticked to the surface of potter's clay ball, under 1250 ℃, sinter the titanium oxide bead of diameter 2mm into, mix with the Lalgine that contains 25% water, pack in the sealed vessel, aerating oxygen, with visible light or UV-irradiation 20 hours, obtain oligomeric Lalgine, add 10% potassium hydroxide aqueous solution and be neutralized to about PH=7.3, add suitable quantity of water and make potassium alginate solution, use ZBS1 and NF4040 nanofiltration membrane to repeat ultrafiltration and the nanofiltration membrane operation of front embodiment, with 95% long-pending ethanol sedimentation of the diploid that is equivalent to the product volume, drying obtains having the potassium alginate of molecular-weight average 7000, and the titanium oxide bead can reclaim repeated use.
Embodiment 17: the method for making of low molecular weight seaweed acid calcium adopts and the similar method of front embodiment, with the Lalgine raw material through the hydrogen peroxide oxidation degradation treatment, the addition of hydrogen peroxide should make hydrogen peroxide account for the 1%-3% of the mixed slurry weight of Lalgine and water, Heating temperature is reacted to 40-80 ℃, oxidization time 2 hours, add 30% sodium hydroxide solution in the Lalgine after oxidation, change into low molecular weight seaweed acid sodium, ultrafiltration and the nanofiltration membrane of using ZBS1 and NF4040 nanofiltration membrane to repeat front embodiment are operated, and obtain having the sodium alginate of molecular-weight average 8000.Add 5% calcium chloride water then, obtain insoluble alginate calcium throw out, use distilled water wash, remove the hydrochloric acid that is generated, make PH near neutral, drying.
Embodiment 18: the preparation method who contains the alginate of chromium:
Repeat the schedule of operation of embodiment 17, just calcium chloride solution replaces with trivalent chromic ion solution such as chromium trichlorides.
The preparation method of embodiment 19. low molecular weight seaweed acid
The low molecular weight seaweed hydrochlorate of 100g embodiment 2 is handled with 10%HCl, obtained the low molecular weight seaweed acid deposit, use distilled water wash, dry then.
The preparation method of pharmaceutical preparation is as follows:
Capsule:
Get the alginates product of 8000 molecular weight, the gelatine capsule of packing into is made capsule, and every 0.5g of capsule takes about 4 every day.
Use the low molecular weight seaweed acid of embodiment 19, incapsulate, every 0.5g of capsule takes about 4 every day.
Granule:
Pack in the plastic pouch alginates of molecular-weight average 8000, every bag of 1g takes 1 to 2 bag every day.
The alginates of molecular-weight average 18,000 if pack in plastic pouch, every bag of 2g takes 1 to 2 bag every day.
Tablet:
With the alginates of the common medical starch sold on the market and molecular-weight average 8000 mixed with 1: 3, compressing tablet on tablet machine makes every heavy 0.7g, takes 4 every day.
The suggestion capsule, granule, tablet is one after each meal.
It is as follows that alginates is used for the treatment of hypertensive effect:
Xiyuan Hospital, Chinese Medicine Academy of China's 30 case primary hypertension patients are taken low molecular weight seaweed acid potassium (5,000-30,000), take the 4-7 gram every day, essential hypertension are had definite curative effect, total effective rate about 85%.
Cardiovascular specialist's usefulness of Dalian Medical Univ more low molecular weight seaweed acid potassium (1,000-10,000) is observed nearly 30 routine hyperpietics, takes the 1-4 gram every day, and primary hypertension patient is had definite curative effect, and total effective rate surpasses 88%.
The effect of treatment aldosteronism is as follows:
Low molecular weight seaweed acid potassium can treat hypertension with aldosteronism.
10 experimenters now are provided, use the radioimmunity test kit, measure these 10 experimenters and take low molecular weight seaweed acid potassium front and back plasma aldosterone level.Full diet, the blood drawing check of upright position.Oral this alginates granule 6-8 gram divides secondary to take every day, take 15 days continuously after, take aldosterone level in the blood plasma of front and back with radioimmunoassay (RIA) test.
Table 1: upright position aldosterone level
| The experimenter | A | B | C | D | E | F | G | H | I | J |
| Before taking | 265 | 250 | 225 | 195 | 185 | 205 | 300 | 290 | 250 | 185 |
| After taking | 200 | 125 | 180 | 195 | 130 | 145 | 180 | 200 | 180 | 185 |
Learn by statistics and handle, calculate 10 experimenters' plasma aldosterone level.Average A LD level=235ng/L before the treatment, treatment back average A LD level=172ng/L has on average reduced 63ng/L.
Hypoglycemic effect is as follows:
30 hyperpietics are attended by higher blood sugar concentration, average blood sugar concentration is 7.0mmol/L blood plasma, take the alginates that contains chromium (content of chromium account for alginates gross weight 0.01%) of 6-8g every day, through after taking 15 days, glucose level on average is reduced to 4.7mmol/L.
Claims (12)
1, a kind of low-molecular-weight alginates, it combines as raw material, by degradation method and membrane separation technique with Lalgine and obtains, the molecular-weight average that it is characterized in that this alginates is at 5000-20, between 000 dalton, be in 1000-30 with the molecular weight of this alginates molecule of the overwhelming majority, in 000 dalton's scope, its Ubbelohde viscosity characteristics viscosity number is between 3-14, and wherein the salt-forming cation of this alginates is an acceptable positively charged ion on the pharmacology.
2, according to the low molecular weight seaweed hydrochlorate of claim 1, its molecular-weight average is at 7000-12, between 000 dalton, wherein the molecular weight of Jue Dabufen this alginates molecule is in 1600-20, between 000 dalton, its Ubbelohde viscosity characteristics viscosity number is between 3-14, and wherein the salt-forming cation of this alginates is an acceptable positively charged ion on the pharmacology.
3, according to the low molecular weight seaweed hydrochlorate of claim 1 or 2, acceptable positively charged ion is a trivalent chromic ion on the wherein said pharmacology.
4, a kind of method for preparing the described low molecular weight seaweed hydrochlorate of claim 1, it comprises: (1) with high molecular Lalgine raw material degraded to 20000 or more to the molecular-weight average below 80000 dalton, add alkaline solution and make it to dissolve; (2) utilize hyperfiltration process, cut out the above molecule of molecular weight 30000 dalton, stay molecular weight less than 30000 daltonian alginates molecules, (3) utilize nanofiltration membrane, cut out molecular weight less than 1000 daltonian alginates molecules, obtain molecular-weight average between 5000-20000 dalton and the molecular weight of this alginates molecule of the overwhelming majority be in 1000-3, the alginates in 0000 dalton's scope, in addition dry at last.
5, a kind of method for preparing the described low molecular weight seaweed hydrochlorate of claim 1, it comprises: (1) with high molecular Lalgine raw material degraded to more than 20000 to the molecular weight below 80000 dalton; (2) degraded product is made the salt of solubility with alkaline purification, (3) under agitation add water or aqueous medium, add oxygenant then product further is degraded into more low-molecular-weight alginates, (4) utilize hyperfiltration process to cut out the above molecule of molecular weight 30000 dalton, stay molecular weight less than 30000 daltonian alginates molecules, (5) utilize nanofiltration membrane to cut out molecular weight less than 1000 daltonian alginates molecules, obtain molecular-weight average between 5000-20000 dalton and the molecular weight of this alginates molecule of the overwhelming majority be in alginates in the 1000-30000 dalton scope, in addition dry at last.
6, a kind of method for preparing the described low molecular weight seaweed hydrochlorate of claim 1, it comprises: (1) with high molecular Lalgine raw material degraded to 10000 or more to the molecular-weight average below 70000 dalton, add alkaline solution and make it to dissolve; (2) utilize hyperfiltration process, cut out the above molecule of molecular weight 10000 dalton, stay molecular weight less than 10000 daltonian alginates molecules, (3) utilize nanofiltration membrane, cut out molecular weight less than 1200 daltonian alginates molecules, obtain molecular-weight average between 5000-8000 dalton and the molecular weight of this alginates molecule of the overwhelming majority be in 1200-1, the alginates in 0000 dalton's scope, in addition dry at last.
7, a kind of method for preparing the described low molecular weight seaweed hydrochlorate of claim 1, it comprises: (1) with high molecular Lalgine raw material degraded to more than 10000 to the molecular weight below 70000 dalton; (2) degraded product is made the salt of solubility with alkaline purification, (3) under agitation add water or aqueous medium, add oxygenant then product further is degraded into more low-molecular-weight alginates, (4) utilize hyperfiltration process to cut out the above molecule of molecular weight 10000 dalton, stay molecular weight less than 10000 daltonian alginates molecules, (5) utilize nanofiltration membrane to cut out molecular weight less than 1200 daltonian alginates molecules, obtain molecular-weight average between 5000-7000 dalton and the molecular weight of this alginates molecule of the overwhelming majority be in alginates in the 1200-10000 dalton scope, in addition dry at last.
8, according to any one method among the claim 4-7, wherein degradation step comprises physical method, photochemical method, immobilized enzyme method or chemical process.
9, method according to Claim 8, wherein physical method comprises ultrasonication or high speed shear processing; Photochemical method is to utilize optical radiation and catalysis to handle; Be to use strong acid, highly basic and inorganic or organic oxidizing agent to handle with chemical process.
10, a kind of method for preparing low molecular weight seaweed acid is handled the resulting low molecular weight seaweed hydrochlorate of the method product of any one among the claim 4-7 with aqueous acid, obtain low-molecular-weight Lalgine throw out, washes disacidify with water, and is dry then.
11, according to claim 1,2 or 3 described low molecular weight seaweed hydrochlorates in the application aspect the medicine of preparation prevention and treatment hypertension and primary aldosteronism and lowering blood glucose.
12, use the application of medicine for lowering blood glucose in preparation according to claim 1,2 or 3 described low-molecular-weight alginatess.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB998169315A CN1157415C (en) | 1999-11-30 | 1999-11-30 | Alginate having low molecular weight, method of manufacturing it and its use |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB998169315A CN1157415C (en) | 1999-11-30 | 1999-11-30 | Alginate having low molecular weight, method of manufacturing it and its use |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1380885A CN1380885A (en) | 2002-11-20 |
| CN1157415C true CN1157415C (en) | 2004-07-14 |
Family
ID=34171085
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB998169315A Expired - Fee Related CN1157415C (en) | 1999-11-30 | 1999-11-30 | Alginate having low molecular weight, method of manufacturing it and its use |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1157415C (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009086685A1 (en) * | 2007-12-29 | 2009-07-16 | Dalian Yaweite Bioengineering Co., Ltd. | An alginic acid with low molecular weight, its salts, uses, preparative methods, pharmaceutical compositions and foods |
| CN104311696A (en) * | 2014-09-26 | 2015-01-28 | 大连雅威特生物技术股份有限公司 | Application of oligomeric sodium alginate in preparation of medicines, health products and salt products |
| CN104961843A (en) * | 2015-07-21 | 2015-10-07 | 青岛大学 | Preparation method of low-viscosity sodium alginate |
Families Citing this family (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2938638B8 (en) * | 2012-12-28 | 2018-12-26 | DuPont Nutrition Biosciences ApS | Depolymerisation of alginic acid |
| CN103830281A (en) * | 2013-04-25 | 2014-06-04 | 郭宏昌 | Preparation and application of marine algae drug derivative for promoting growth of bone cells |
| CN104222999B (en) * | 2014-09-26 | 2016-06-01 | 大连雅威特生物技术股份有限公司 | The composition of a kind of Novel low-sodium salt, preparation and purposes |
| CN107149132A (en) * | 2017-04-29 | 2017-09-12 | 深圳震乾坤生物科技有限公司 | Low potassium Kelp Powder row's sodium salt and preparation method and application |
| CN111204713A (en) * | 2020-03-03 | 2020-05-29 | 金溯源(北京)科技有限公司 | Preparation method and formula of food-grade chlorine dioxide |
| CN113603808B (en) * | 2021-08-10 | 2023-03-31 | 山东省科学院生物研究所 | Modified algin, preparation method and application thereof in preparation of medicine for promoting gastrointestinal peristalsis |
| CN114957511B (en) * | 2022-05-19 | 2024-01-05 | 青岛海洋生物医药研究院股份有限公司 | Algin oligosaccharide zinc and preparation method and application thereof |
-
1999
- 1999-11-30 CN CNB998169315A patent/CN1157415C/en not_active Expired - Fee Related
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009086685A1 (en) * | 2007-12-29 | 2009-07-16 | Dalian Yaweite Bioengineering Co., Ltd. | An alginic acid with low molecular weight, its salts, uses, preparative methods, pharmaceutical compositions and foods |
| CN101889027B (en) * | 2007-12-29 | 2013-05-01 | 于传兴 | Alginic acid with low molecular weight, its salts, uses, preparative methods, pharmaceutical compositions and foods |
| US8686053B2 (en) | 2007-12-29 | 2014-04-01 | Chuanxing YU | Alginic acid with low molecular weight, its salts, uses, preparative methods, pharmaceutical compositions and foods |
| CN104311696A (en) * | 2014-09-26 | 2015-01-28 | 大连雅威特生物技术股份有限公司 | Application of oligomeric sodium alginate in preparation of medicines, health products and salt products |
| CN104961843A (en) * | 2015-07-21 | 2015-10-07 | 青岛大学 | Preparation method of low-viscosity sodium alginate |
| CN104961843B (en) * | 2015-07-21 | 2017-04-26 | 青岛大学 | Preparation method of low-viscosity sodium alginate |
Also Published As
| Publication number | Publication date |
|---|---|
| CN1380885A (en) | 2002-11-20 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP4330839B2 (en) | Method for producing glucose and / or water-soluble cellooligosaccharide | |
| CN1241932C (en) | Novel oligosaccharides, preparation method and pharmaceutical composition containing same | |
| CN1157415C (en) | Alginate having low molecular weight, method of manufacturing it and its use | |
| EP0037319B1 (en) | Mucopolysaccharides having biological properties; their preparation and use as medicines | |
| IL236842A (en) | Process for preparation of beta-glucan and compositions comprising it | |
| JP6432709B2 (en) | Method for producing polysulfate pentosan | |
| CN1580079A (en) | Method for extracting edible tree fungi polysaccharide | |
| JP7220670B2 (en) | Method for decomposing polysaccharides using ozone | |
| CN1200952C (en) | Homogeneous chemical modification of hemicellulose of stalks | |
| CN1245108C (en) | Novel method for producing inulin using heliangine or cicheriin as raw material | |
| CN1559647A (en) | Preparation method of seaweed antioxidation active component | |
| CN1254496C (en) | Method of preparing branched polyethylene glycol | |
| WO2001040315A9 (en) | The alginate having low molecular weight, methods of manufacturing it and its use | |
| CN1488364A (en) | Method for treating aloe gel, aloe leaf gel and aloe hide glue and aloe polyaccharide obtained thereof | |
| JP2012121963A (en) | Method for producing polyguluronic acid, method for producing polymannuronic acid, polyguluronic acid, and polymannuronic acid | |
| WO2019054344A1 (en) | Pentosan polysulfate and method for producing pentosan polysulfate | |
| CN1671744A (en) | Low molecular weight oversulfated polysaccharide | |
| CN1273494C (en) | Production of K-kala glue | |
| CN1289533C (en) | Method for preparaing water-soluble free amine chitosan | |
| CN1765923A (en) | Method for extracting and separating protein from the root of kudzu vine | |
| CN1640395A (en) | Supermolecular intercalation-structure slow-release captopril and its preparing method | |
| CN1281629C (en) | Polysaccharide of selenic acid and preparation method | |
| CN102408458A (en) | Production process for refining glucosamine hydrochloride through membrane separation | |
| CN1543876A (en) | Novel monascin oral liquid and method for producing the same | |
| CN112079938A (en) | Highland barley polysaccharide extraction method, highland barley polysaccharide extract and application thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| C56 | Change in the name or address of the patentee |
Owner name: DALIAN YAWEITE BIOTECHNOLOGY CO., LTD. Free format text: FORMER NAME: DALIAN YAWEITE BIOLOGY ENGINEERING CO., LTD. |
|
| CP03 | Change of name, title or address |
Address after: 13 No. 537, No. 116023, Huangpu Road, Dalian hi tech Industrial Park, Liaoning, China 16 Patentee after: DALIAN AVITAL BIOTECHNOLOGY CO., LTD. Address before: 116023 No. 190-1, Southwest Road, Dalian, Liaoning, China Patentee before: Dalian Yaweite Biology Engineering Co., Ltd. |
|
| PE01 | Entry into force of the registration of the contract for pledge of patent right |
Denomination of invention: Alginate having low molecular weight, method of manufacturing it and its use Effective date of registration: 20170112 Granted publication date: 20040714 Pledgee: Industrial Bank Limited by Share Ltd Dalian branch Pledgor: DALIAN AVITAL BIOTECHNOLOGY CO., LTD. Registration number: 2017990000033 |
|
| PLDC | Enforcement, change and cancellation of contracts on pledge of patent right or utility model | ||
| CF01 | Termination of patent right due to non-payment of annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20040714 Termination date: 20171130 |
|
| PC01 | Cancellation of the registration of the contract for pledge of patent right | ||
| PC01 | Cancellation of the registration of the contract for pledge of patent right |
Date of cancellation: 20190201 Granted publication date: 20040714 Pledgee: Industrial Bank Limited by Share Ltd Dalian branch Pledgor: DALIAN AVITAL BIOTECHNOLOGY CO., LTD. Registration number: 2017990000033 |