CN102816255A - Method for preparing ultra-low molecular weight heparin - Google Patents
Method for preparing ultra-low molecular weight heparin Download PDFInfo
- Publication number
- CN102816255A CN102816255A CN2011101551597A CN201110155159A CN102816255A CN 102816255 A CN102816255 A CN 102816255A CN 2011101551597 A CN2011101551597 A CN 2011101551597A CN 201110155159 A CN201110155159 A CN 201110155159A CN 102816255 A CN102816255 A CN 102816255A
- Authority
- CN
- China
- Prior art keywords
- low molecular
- heparin
- ultra
- sodium
- quaternary ammonium
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 239000003055 low molecular weight heparin Substances 0.000 title claims abstract description 42
- 238000000034 method Methods 0.000 title abstract description 10
- 229940127215 low-molecular weight heparin Drugs 0.000 title abstract description 7
- 229920000669 heparin Polymers 0.000 claims abstract description 65
- 229960002897 heparin Drugs 0.000 claims abstract description 26
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 claims abstract description 12
- 108090000935 Antithrombin III Proteins 0.000 claims abstract description 9
- 102100022977 Antithrombin-III Human genes 0.000 claims abstract description 9
- 239000003960 organic solvent Substances 0.000 claims abstract description 8
- 230000000694 effects Effects 0.000 claims abstract description 6
- 238000007068 beta-elimination reaction Methods 0.000 claims abstract description 5
- ZFGMDIBRIDKWMY-PASTXAENSA-N heparin Chemical compound CC(O)=N[C@@H]1[C@@H](O)[C@H](O)[C@@H](COS(O)(=O)=O)O[C@@H]1O[C@@H]1[C@@H](C(O)=O)O[C@@H](O[C@H]2[C@@H]([C@@H](OS(O)(=O)=O)[C@@H](O[C@@H]3[C@@H](OC(O)[C@H](OS(O)(=O)=O)[C@H]3O)C(O)=O)O[C@@H]2O)CS(O)(=O)=O)[C@H](O)[C@H]1O ZFGMDIBRIDKWMY-PASTXAENSA-N 0.000 claims description 35
- 229960001008 heparin sodium Drugs 0.000 claims description 26
- -1 heparin quaternary ammonium salt Chemical class 0.000 claims description 22
- 238000002360 preparation method Methods 0.000 claims description 19
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 15
- 150000003242 quaternary ammonium salts Chemical class 0.000 claims description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 8
- 239000007787 solid Substances 0.000 claims description 6
- 239000007864 aqueous solution Substances 0.000 claims description 5
- UREZNYTWGJKWBI-UHFFFAOYSA-M benzethonium chloride Chemical group [Cl-].C1=CC(C(C)(C)CC(C)(C)C)=CC=C1OCCOCC[N+](C)(C)CC1=CC=CC=C1 UREZNYTWGJKWBI-UHFFFAOYSA-M 0.000 claims description 3
- 229960001950 benzethonium chloride Drugs 0.000 claims description 3
- KCXMKQUNVWSEMD-UHFFFAOYSA-N benzyl chloride Chemical compound ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 claims description 3
- 229940073608 benzyl chloride Drugs 0.000 claims description 3
- NDKBVBUGCNGSJJ-UHFFFAOYSA-M benzyltrimethylammonium hydroxide Chemical compound [OH-].C[N+](C)(C)CC1=CC=CC=C1 NDKBVBUGCNGSJJ-UHFFFAOYSA-M 0.000 claims description 3
- 239000007857 degradation product Substances 0.000 claims description 2
- 150000007530 organic bases Chemical class 0.000 claims 2
- 229940079593 drug Drugs 0.000 claims 1
- 239000003814 drug Substances 0.000 claims 1
- 230000001590 oxidative effect Effects 0.000 claims 1
- 125000001453 quaternary ammonium group Chemical group 0.000 claims 1
- 230000009257 reactivity Effects 0.000 claims 1
- 229910052708 sodium Inorganic materials 0.000 claims 1
- 239000011734 sodium Substances 0.000 claims 1
- 159000000000 sodium salts Chemical class 0.000 claims 1
- 230000015556 catabolic process Effects 0.000 abstract description 7
- 238000006731 degradation reaction Methods 0.000 abstract description 7
- 239000012467 final product Substances 0.000 abstract description 2
- 229960005348 antithrombin iii Drugs 0.000 abstract 1
- 230000014508 negative regulation of coagulation Effects 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 36
- 239000000243 solution Substances 0.000 description 22
- 238000003756 stirring Methods 0.000 description 16
- DPDMMXDBJGCCQC-UHFFFAOYSA-N [Na].[Cl] Chemical compound [Na].[Cl] DPDMMXDBJGCCQC-UHFFFAOYSA-N 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 9
- 238000001291 vacuum drying Methods 0.000 description 9
- 238000005406 washing Methods 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- 238000003808 methanol extraction Methods 0.000 description 6
- 239000007983 Tris buffer Substances 0.000 description 5
- 238000004062 sedimentation Methods 0.000 description 5
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 239000008367 deionised water Substances 0.000 description 3
- 229910021641 deionized water Inorganic materials 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- 101000712605 Theromyzon tessulatum Theromin Proteins 0.000 description 2
- 229940122388 Thrombin inhibitor Drugs 0.000 description 2
- 208000007536 Thrombosis Diseases 0.000 description 2
- 230000002429 anti-coagulating effect Effects 0.000 description 2
- 229960003872 benzethonium Drugs 0.000 description 2
- 150000007942 carboxylates Chemical class 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- 239000000945 filler Substances 0.000 description 2
- 238000005374 membrane filtration Methods 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 239000001632 sodium acetate Substances 0.000 description 2
- 229960004249 sodium acetate Drugs 0.000 description 2
- 235000017281 sodium acetate Nutrition 0.000 description 2
- YRTWNFXASSUQEW-UHFFFAOYSA-M sodium;methanol;acetate Chemical compound [Na+].OC.CC([O-])=O YRTWNFXASSUQEW-UHFFFAOYSA-M 0.000 description 2
- 239000003868 thrombin inhibitor Substances 0.000 description 2
- 239000003643 water by type Substances 0.000 description 2
- 229920001817 Agar Polymers 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 208000032843 Hemorrhage Diseases 0.000 description 1
- 108010022901 Heparin Lyase Proteins 0.000 description 1
- 206010029164 Nephrotic syndrome Diseases 0.000 description 1
- IOVCWXUNBOPUCH-UHFFFAOYSA-N Nitrous acid Chemical compound ON=O IOVCWXUNBOPUCH-UHFFFAOYSA-N 0.000 description 1
- 206010047249 Venous thrombosis Diseases 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 230000002785 anti-thrombosis Effects 0.000 description 1
- 230000010100 anticoagulation Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 208000026106 cerebrovascular disease Diseases 0.000 description 1
- ATDGTVJJHBUTRL-UHFFFAOYSA-N cyanogen bromide Chemical class BrC#N ATDGTVJJHBUTRL-UHFFFAOYSA-N 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 201000005577 familial hyperlipidemia Diseases 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000002628 heparin derivative Substances 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 150000002978 peroxides Chemical class 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
Landscapes
- Polysaccharides And Polysaccharide Derivatives (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a method for preparing ultra-low molecular weight heparin. The method includes the steps of subjecting normal heparin to beta-elimination degradation in organic solvent to obtain low molecular weight heparin, isolating via ATIII (antithrombin III) filled column to obtain the ultra-low molecular weight heparin with high anti-FXa activity. The method for preparing the ultra-low molecular weight heparin is operable and mild in degradation condition, and can guarantee anticoagulant activity of a final product. The ultra-low molecular weight heparin prepared has titer of the anti-FXa activity ranging from 160-220IU/mg, the titer of the anti-FIIa activity ranging from 0.5-41U/mg, and average molecular weight ranging from 2000-3000Da.
Description
Technical field
The invention belongs to biomedicine field, be specifically related to a kind of ultra-low molecular heparin sodium (Ultra LowMolecular Weight Heparin, preparation method ULMWH).
Background technology
Low molecular heparin be from unfractionated heparin through the small molecules heparin product that degraded obtains, have advantages such as bioavailability height, plasma half-life be long, particularly its hemorrhage side effect that causes significantly reduces.Degradation method from the unfractionated heparin to the Low molecular heparin is more, and the degradation method that adopts at present mainly contains nitrous acid degraded, β-elimination edman degradation Edman, peroxide method and heparinase degraded.
The ultra-low molecular heparin is on the Low molecular heparin basis, to be further purified to separate the heparin derivative article that obtain, and its molecular-weight average is less than 3000Da.Compare with Low molecular heparin; Ultra-low molecular heparin tool anticoagulation safety; Its anti thrombotic action is strong, and subcutaneous injection is prone to absorb, and is mainly used in the prevention of thrombotic disease; Like nephrotic syndrome, the prevention of formation, old phlebothrombosis and the cardiovascular and cerebrovascular diseases of operation posterior vein thrombus and anti-curing hyperlipemia etc.
Summary of the invention
Technical problem to be solved by this invention provides a kind of preparation method of ultra-low molecular heparin sodium; This preparing method's degradation condition gentleness can reduce sulfonic group coming off from the heparin; Ultra-low molecular heparin sodium molecular-weight average through the preparation of this method has high anti-Fxa biological activity less than 3000Da.
The technical scheme that the present invention adopted is following:
A kind of preparation method of ultra-low molecular heparin sodium comprises the steps:
(1) get the elaboration heparin and be made into 10% the aqueous solution, add quaternary ammonium salt such as benzethonium chloride under the room temperature while stirring, stop after 1～2 hour stirring, sedimentation, topple over, washing precipitate, filter at last, drying, obtain white heparin quaternary ammonium salt solid;
(2) the heparin quaternary ammonium salt solid in (1) is dissolved in is made into 5%～10% solution in the organic solvent, add the Benzyl Chloride with heparin quaternary ammonium salt equivalent, under 30 ℃～35 ℃; Behind the stirring reaction 24 hours, be chilled to room temperature, add the 10% sodium-acetate/methanol solution of 2 times of volumes; Stir after 30 minutes, quiescent setting filters; Methanol wash, vacuum-drying under the room temperature obtains the carboxylate of heparin;
(3) the heparin carboxylate that (2) is obtained is dissolved in wiring solution-forming in 10 times the water; The benzethonium chloride of 2.3～2.5 times carboxylate amounts is dissolved in 10 times the water; After the dissolving, under room temperature, the vigorous stirring this solution is slowly joined in the aqueous solution of heparin carboxylate fully; After adding completion, continue to stir 1-2 hour, stop then stirring; After treating the white solid sedimentation, incline the upper strata stillness of night, add water washing, filter, washing again, obtains the quaternary ammonium salt of heparin carboxylate at dry (not being higher than 50 ℃) under the vacuum then;
The quaternary ammonium salt of the heparin carboxylate that (4) (3) is obtained is dissolved in 10 times the organic solvent; After waiting to dissolve; The alkali such as benzyltrimethylammonium hydroxide, DBU (diazabicylo) or the sodium methylate that add 0.05～0.2 volumetric molar concentration are that β-elimination degraded is carried out in reaction 4～24 hours (preferred 8～12 hours) under 0 ℃～50 ℃ (preferred 10 ℃～40) in temperature;
(5) with the degradation product after (4) reaction end; At room temperature add the methanol solution of 10% sodium-acetate of two volumes, stir after 1～2 hour, in 0 ℃～4 ℃ following sedimentations, filtration, methanol wash; 25 ℃～35 ℃ following vacuum-dryings, obtain the bullion of low molecular sodium heparin;
(6) the low molecular sodium heparin bullion in above-mentioned (5) is made into 10% solution, and 0 ℃～4 ℃ add sodium hydroxide solution down, transfer pH 9～10, and under this temperature, react 3 hours; Then with the neutralization of 1M hydrochloric acid, adding sodium-chlor to salinity is 8～10%, and with 3 times methanol extraction, throw out is used methanol wash, vacuum-drying;
(7) the low molecular sodium heparin bullion in above-mentioned (6) is made into 10% solution; The 1M sodium hydroxide solution; Adjust pH is 9～10, and the hydrogen peroxide of adding 30% stirred after 6 hours, and the hydrochloric acid that drips 1M is to neutral; Add 8～10% sodium-chlor then, use 2.5～3 times methanol extraction low molecular sodium heparin again; Filter, make the elaboration of low molecular sodium heparin with the methanol wash after drying;
(8) the elaboration Low molecular heparin that obtains in above-mentioned (7) is through containing the ATIII filled column, is eluent with sodium-chlor/0.05M Tris (Tutofusin tris) solution (pH=7.4) of 0.15M, flush away impurity and active low molecule; Sodium-chlor/0.05M Tris solution (pH=7.4) solution with 1.0M is eluent then; With ultra-low molecular heparin wash-out from the pillar, the elutriant that obtains filters with 3 times methanol extraction; Methanol wash, vacuum-drying;
(9) product that above-mentioned (8) is obtained is water-soluble be made into 10% solution after, adding sodium-chlor to concentration is 10%, with the methanol extraction of 3 times of volumes, filtration, methanol wash, vacuum-drying obtains ultra-low molecular heparin sodium elaboration;
(10) the elaboration ultra-low molecular heparin sodium that above-mentioned (9) is obtained is dissolved in deionized water and is made into 10% solution; Behind 0.2 micron membrane filtration; Lyophilize finally obtains the ultra-low molecular heparin sodium, and its anti-FXa tires at 160～220IU/mg; Anti-FIIa tires at 0.5～4IU/mg, and molecular-weight average is at 2000～3000Da.
Further improve as the present invention, the said organic solvent of step (4) is methylene dichloride or N among the above-mentioned ultra-low molecular heparin sodium preparation method.
Compared with prior art, the beneficial effect that has of the present invention is:
1, preparation method provided by the invention carries out β-elimination degraded with unfractionated heparin in organic solvent, has reduced sulfonic group and has come off from heparin, and the preparation method is feasible and degradation condition is gentle, thereby has guaranteed the anticoagulating active of final product.
2, the present invention carries out through containing the ATIII filled column that highly selective is separated, purifying obtains the higher ultra-low molecular heparin sodium of anticoagulating active with low molecular sodium heparin; Tire according to the anti-FXa of the ultra-low molecular heparin sodium of present method preparation and to tire at 0.5～4IU/mg at 160～220IU/mg, anti-FIIa, molecular-weight average is at 2000～3000Da.
Embodiment
Embodiment 1
The refined heparin sodium of getting 100 grams is dissolved in 1 premium on currency, then stir fast add down contain 270 restrain benzethonium chlorides 600 milliliters of the aqueous solution, react after 2 hours; Add 2 premium on currency, quiescent settling is toppled over the top stillness of night; Add water washing again, filter water washing then; Drying, obtain approximately 270 the gram the heparin quaternary ammonium salt;
Get in the methylene dichloride that heparin quaternary ammonium salt 100 grams that above-mentioned reaction obtains are dissolved in 500 milliliters; The Benzyl Chloride that adds 100 milliliters under the room temperature; After 24 hours, add 1.2 liters 10% sodium-acetate methanol solution in reaction under 30 ℃, stir after 20 minutes; Sedimentation, filtration, methanol wash, drying obtain heparin carboxylate 44 grams;
10 gram heparin carboxylates are dissolved in wiring solution-forming in 200 ml waters, and room temperature, the quick stirring add 100 milliliters the aqueous solution that contains 23 gram benzethonium chlorides down, react after 2 hours; Sedimentation; Use water washing, 50 ℃ of following vacuum-dryings obtain the quaternary ammonium salt of 22 gram heparin carboxylates;
The quaternary ammonium salt of 10 gram heparin carboxylates is dissolved in 100 milliliters of methylene dichloride, adds 17 milliliters benzyltrimethylammonium hydroxide and stirring reaction 24 hours under the room temperature.After reaction finishes, add 200 milliliters 10% sodium-acetate methanol solution, continue to stir 1 hour, quiescent settling filters, methanol wash, and room temperature vacuum-drying obtains 3.6 gram Low molecular heparin bullions;
The bullion low molecular sodium heparin that obtains 3 grams are dissolved in 30 ml waters, and 0 ℃ of sodium hydroxide that adds 1M is down transferred pH to 9.5, reacts after 3～4 hours; Hydrogen peroxide to the concentration of adding 30% is 0.05%; Stir under the room temperature after 6 hours, transfer solution to neutral, add sodium-chlor with the hydrochloric acid of 1M; Make that the concentration of sodium-chlor is 8%, with 100 milliliters methanol extraction.Filter, methanol wash, 45 ℃ of following vacuum-dryings obtain refined prod 2.6 grams;
Elaboration low molecular sodium heparin 1 gram is dissolved in 10 milliliters of 0.15M sodium-chlor/0.05M Tris (Tutofusin tris; Tromethane; Trometamol) solution (pH=7.4), on contain ATIII (Thrombin inhibitor) filled column (600 * 10mm), after 200 milliliters of 0.15M sodium-chlor/0.05M Tris solution (pH=7.4) drip washing; 1.0M sodium-chlor/0.05M Tris solution (pH=7.4) wash-out; Elutriant filters methanol wash with 3 times of methanol extractions; Vacuum-drying under the room temperature obtains 0.8 gram ultra-low molecular heparin sodium;
0.8 gram ultra-low molecular heparin sodium is dissolved in deionized water is made into 10% solution, with 0.2 micron membrane filtration, lyophilize finally obtains elaboration ultra-low molecular heparin sodium.
The molecular-weight average of above-mentioned ultra-low molecular heparin sodium is 2400Da, and (it is 193IU/mg that anticoagulin a) is worth to anti-FXa, and anti-FIIa (zymoplasm) value is 1.2IU/mg.
Embodiment 2
Contain the preparation of ATIII filler: 10 gram cyanogen bromides are dissolved in 100 ml deionized water become solution, at room temperature add 150 milliliters of agar syrup, transfer pH to 11.5 with sodium hydroxide under the ice bath, continue to stir after 10 minutes washing;
700 milligrams of ATIII (Thrombin inhibitor) are dissolved in the sodium hydrogen carbonate solution of 200 milliliters of 0.2M, then join in the gel of above-prepared, stir under the room temperature after 24 hours, with the buffered soln washing of pH7～9 and pH4～6, obtain containing the target filler of ATIII.
Claims (5)
1. the preparation method of a ultra-low molecular heparin sodium is characterized in that comprising the steps:
(1) gets the aqueous solution of elaboration heparin, add quaternary ammonium salt, obtain white heparin quaternary ammonium salt solid;
(2) the heparin quaternary ammonium salt solid in above-mentioned (1) is dissolved in the organic solvent, adds Benzyl Chloride and obtains the heparin carboxylate;
(3) the heparin carboxylate in above-mentioned (2) is water-soluble, adds quaternary ammonium salt, obtains white heparin carboxylate quaternary ammonium salt solid;
(4) quaternary ammonium salt of the heparin carboxylate in above-mentioned (3) is dissolved in the organic solvent, under the organic bases effect, carries out β-elimination degraded;
(5) degradation product in above-mentioned (4) is converted into sodium salt under the sodium hydroxide effect, obtains the bullion of ultra-low molecular heparin sodium;
(6) the ultra-low molecular heparin sodium is made with extra care, obtained to the ultra-low molecular heparin sodium crude through oxidative decoloration in above-mentioned (5);
(7) low molecular sodium heparin in above-mentioned (6) separates through containing the ATIII filled column, obtains high reactivity ultra-low molecular heparin sodium;
(8) the ultra-low molecular heparin sodium that obtains in above-mentioned (7) is through secondary filter, and lyophilize obtains medical ultra-low molecular heparin bulk drug.
2. according to the preparation method of the said a kind of ultra-low molecular heparin sodium of claim 1, it is characterized in that: quaternary ammonium salt is a benzethonium chloride described in the preparation process (1).
3. according to the preparation method of the said a kind of ultra-low molecular heparin sodium of claim 1, it is characterized in that: organic solvent is methylene dichloride or N described in the preparation process (4).
4. according to the preparation method of the said a kind of ultra-low molecular liquaemin of claim 1, it is characterized in that: organic base is quaternary ammonium base, DBU or sodium alkoxide such as benzyltrimethylammonium hydroxide described in the preparation process (4).
5. according to the preparation method of the said a kind of ultra-low molecular heparin sodium of claim 1; It is characterized in that: the ultra-low molecular heparin sodium that makes according to this preparation method is that anti-FXa tires at 160～220IU/mg; Anti-FIIa tires at 0.5～4IU/mg, and molecular-weight average is at 2000～3000Da.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201110155159.7A CN102816255B (en) | 2011-06-10 | 2011-06-10 | A kind of preparation method of ultra-low molecular heparin sodium |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201110155159.7A CN102816255B (en) | 2011-06-10 | 2011-06-10 | A kind of preparation method of ultra-low molecular heparin sodium |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102816255A true CN102816255A (en) | 2012-12-12 |
| CN102816255B CN102816255B (en) | 2015-11-25 |
Family
ID=47300730
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201110155159.7A Active CN102816255B (en) | 2011-06-10 | 2011-06-10 | A kind of preparation method of ultra-low molecular heparin sodium |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102816255B (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114072430A (en) * | 2020-04-27 | 2022-02-18 | 罗威制药股份有限公司 | Low molecular weight heparin obtaining procedure and low molecular weight heparin obtained thereby |
| CN116284499A (en) * | 2022-07-28 | 2023-06-23 | 河北常山生化药业股份有限公司 | Preparation method of sheep-derived low-molecular heparin sodium |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6384021B1 (en) * | 1999-07-23 | 2002-05-07 | Laboratorios Farmaceuticos Rovi | Heparin compositions of very low molecular weight |
| CN1852926A (en) * | 2003-07-24 | 2006-10-25 | 安万特医药股份有限公司 | Oligosaccharide mixture derived from heparin, its preparation method and pharmaceutical composition containing said mixture |
-
2011
- 2011-06-10 CN CN201110155159.7A patent/CN102816255B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6384021B1 (en) * | 1999-07-23 | 2002-05-07 | Laboratorios Farmaceuticos Rovi | Heparin compositions of very low molecular weight |
| CN1852926A (en) * | 2003-07-24 | 2006-10-25 | 安万特医药股份有限公司 | Oligosaccharide mixture derived from heparin, its preparation method and pharmaceutical composition containing said mixture |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114072430A (en) * | 2020-04-27 | 2022-02-18 | 罗威制药股份有限公司 | Low molecular weight heparin obtaining procedure and low molecular weight heparin obtained thereby |
| CN116284499A (en) * | 2022-07-28 | 2023-06-23 | 河北常山生化药业股份有限公司 | Preparation method of sheep-derived low-molecular heparin sodium |
Also Published As
| Publication number | Publication date |
|---|---|
| CN102816255B (en) | 2015-11-25 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| ES2668273T3 (en) | Use of chemically modified heparin derivatives in sickle cell disease | |
| EP0287477B1 (en) | Low molecular weight heparins with a regular structure, their preparation and biological uses | |
| AU2003300161B2 (en) | Heparin-derived polysaccharide mixtures, preparation thereof and pharmaceutical compositions containing same | |
| US9475888B2 (en) | Non anti-coagulative glycosaminoglycans comprising repeating disaccharide unit and their medical use | |
| US20110152509A1 (en) | Compositions of polysaccharides derived from heparin, their preparation and pharmaceutical compositions containing them | |
| CN103145868B (en) | A kind of lower molecular weight osamine polysaccharid derivative and pharmaceutical composition thereof and its preparation method and application | |
| WO2011054174A1 (en) | Depolymerized fucosylated glycosaminoglycan and preparation method thereof | |
| US9624315B2 (en) | Preparation of new intermediate of heparin pentasaccharide and preparation method thereof | |
| CN101636417A (en) | Low molecular weight heparins comprising at least one covalent bond with biotin or a biotin derivative, their manufacture and their use | |
| CN103601765B (en) | Fondaparinux sodium and intermediate thereof and preparation method | |
| CN102558392A (en) | Preparation method of high-FXa-resistant low-FIIa-resistant low-molecular heparin sodium | |
| CN102952202A (en) | Preparation method and use of ultralow-molecular weight heparin sodium | |
| WO2015103921A1 (en) | Fuc3s4s substituted oligoglycosaminoglycan and preparation method thereof | |
| CN102816255A (en) | Method for preparing ultra-low molecular weight heparin | |
| US12280072B2 (en) | Oligosaccharide compound for inhibiting intrinsic coagulation factor X-enzyme complex, and preparation method therefor and uses thereof | |
| JP6248179B2 (en) | Low molecular weight glycosaminoglycan derivative comprising terminal 2,5-dehydrated talose or a derivative thereof | |
| FR2548672A1 (en) | SULPHATE OLIGOSACCHARIDES AND THEIR USE AS MEDICAMENTS | |
| CN101711771A (en) | Heparin derivative polysaccharide mixture and preparation method and medicinal composition thereof | |
| CN108285498B (en) | Oligosaccharide compound for inhibiting endogenous coagulation factor X enzyme complex and preparation method and application thereof | |
| CN111423523B (en) | Oligosaccharide compound and pharmaceutically acceptable salt thereof, preparation method and application | |
| US20050090561A1 (en) | Oligosaccharide mixtures derived from heparin, preparation thereof and pharmaceutical compositions containing them | |
| CN116769069B (en) | Small-molecule non-anticoagulant heparin, preparation method thereof, and pharmaceutical composition and application thereof | |
| CN118459618A (en) | A novel galactosylated glycosaminoglycan and its preparation method and use | |
| CN112079942A (en) | Methylated heparin compound and preparation and application thereof | |
| Xu et al. | Design and synthesis of novel fucosylated chondroitin sulfate derivatives as intrinsic FXase inhibitors and evaluation of their antithrombotic activities |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| 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 | ||
| DD01 | Delivery of document by public notice |
Addressee: Wang Pi Document name: Notification to Pay the Fees |