CN102633908A - Method for preparing high-quality LMW (low molecular weight) heparins - Google Patents
Method for preparing high-quality LMW (low molecular weight) heparins Download PDFInfo
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- CN102633908A CN102633908A CN2012101317306A CN201210131730A CN102633908A CN 102633908 A CN102633908 A CN 102633908A CN 2012101317306 A CN2012101317306 A CN 2012101317306A CN 201210131730 A CN201210131730 A CN 201210131730A CN 102633908 A CN102633908 A CN 102633908A
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Abstract
The invention discloses a method for preparing high-quality LMW (low molecular weight) heparins. Based on an improved beta-elimination and degradation method, through innovatively adding a heavy salinization method, a polyphosphazene alkaline hydrolysis method and a saponification method and the like, the key problems that in feed liquid, more macromolecular heparins exist, and micromolecular heparins are accumulated, and the like are solved, thereby preparing super small molecular fragments. The average molecular weight of ultralow molecular heparin sodium prepared by using the method above is 2000-3000, the molecular weight distribution of the heparin sodium is as follows: the proportion of the molecular weight less than 1600 is less than or equal to 40.0%; and the proportion of the molecular weight greater than 4500 is less than or equal to 11.0%; the rate of the resistant FXa/FIIa is greater than 30, wherein the valence of the resistant FXa is 145-180 IU/mg, and the valence of the resistant FIIa is less than 5.0 IU/mg. Compared with low molecular heparin sodium and ultralow molecular heparin sodium, the high-quality LMW heparin sodium has an extremely good antithrombotic activity, a smaller bleeding risk and a lower influence on platelets, therefore, the high-quality LMW heparin sodium is expected to be a new-generation heparin antithrombotic medicament.
Description
Technical field
The present invention relates to biomedicine field, particularly a kind of method for preparing high-quality ultra-low molecular weight heparin.
Background technology
Heparin (unfractionated heparin is a unfraction heparin) is the Sulfated TGSS C3 of a kind of height, with external blood coagulation resisting function is arranged all in vivo.Be mainly used in hemodialysis, thrombotic disease, operation on vessels of heart, cardia catheterization, extracorporeal circulation etc. clinically.Its maximum spinoff is to cause bleeding, and sometimes even can cause hemorrhagic dead, its hemorrhage incidence is up to 35% according to statistics.However, it is still the choice drug that prevents thrombosis, pulmonary infarction, disseminated intravascular coagulation and some thrombus bolt match property complication.Though people take the whole bag of tricks,, all can't tackle the problem at its root such as reducing dosage, local application etc. to reduce hemorrhage risk.The anticoagulant active of heparin is divided into anti-thrombus activity (FXa) and anti-freezing (FIIa) active two big classes; In antithrombotic process; Anti-FXa activity all is essential with the active effect of anti-FIIa, and the criterion of anti thrombotic action is with anti-FXa/FIIa value representation, and its value is big more; The expression anti thrombotic action is strong more, and bleeding tendency is more little.Low molecular heparin is by sodium salt or the calcium salt of unfraction heparin through chemical degradation or the preparation of enzyme liberating method, is a kind of upgrading products of unfractionated heparin, and its molecular-weight average is about 5000 Da.When the subcutaneous injection Low molecular heparin, the effect of its anti-FXa in vivo is more much better than than unfractionated heparin, and anti-FIIa activity a little less than, have also that the transformation period prolongs in the body, the bioavailability advantages of higher, be the medicine of the antithrombotic class of present main flow.Though a little less than the anti-FIIa activity of Low molecular heparin was compared relatively with unfraction heparin, it still had certain probability and causes bleeding and thrombocytopenia.
Ultra-low molecular weight heparin is the Heparin Oligosaccharides fragment that forms through degraded, and its main disaccharide structure and heparin are basic identical, i.e. α-L-IdoA-2-SO
4-β (I → 4)-α-D-GIrNSO
3-6-SO
4, molecular-weight average is about 2200 Da, and the distributed area of molecular weight is more concentrated than Low molecular heparin.It is compared with low molecule heparin product, and better antithrombotic acitivity is arranged, littler hemorrhage risk, and lower to hematoblastic influence.Research and development to the ultra-low molecular heparin have received increasing concern, become the focus of domestic and international heparin research gradually.Verified at present, behind the preventative use ultra-low molecular weight heparin, the incidence of VTE incident significantly reduces in multiple transitivity or local progressivity patients with solid tumor.The existing publication number of China is the patent of invention " a kind of method for preparing ultra-low molecular weight heparin " of CN101671711A and the patent of invention " a kind of preparation of ultra-low molecular weight heparin and purifying process " that publication number is CN102040671A.Wherein " a kind of method for preparing ultra-low molecular weight heparin " is with heparin in maltose binding protein-Heparinase I fusion rotein degraded substrate, obtains ultra-low molecular weight heparin; " a kind of preparation of ultra-low molecular weight heparin and purifying process " is to be the basis with β-elimination edman degradation Edman; The heparin quaternary ammonium salt that heparin and organic quaternary ammonium salt effect generate is affine to replace the heparin benzyl ester that the back generates; Alkaline condition descends to separating and obtains low-molecular-weight heparin fragment; Carry out separation and purification through inorganic ceramic ultrafiltration and Hollow Fiber Ultrafiltration bonded method, obtaining range of molecular weight distributions is the ultra-low molecular weight heparin sodium (calcium) of 2200 Da at 2000 ~ 2500D, molecular-weight average.Wherein, with enzyme liberating from the technology that heparin sodium extracts the ultra-low molecular heparin exist severe reaction conditions, cost is too high, impurity is too much, product is difficult to shortcomings such as purifying.And the ultra-low molecular heparin that adopts β-eliminations edman degradation Edman to prepare also have the anti-FXa factor tired low, anti-FIIa tire too high, have certain probability and cause problems such as hemorrhage; Mainly be that these all are the problems that present extraction process cann't be solved because factors such as sample purity is not enough, foreign matter content is too much, the accumulation of small molecules heparin cause.
Summary of the invention
Technical problem to be solved by this invention is exactly the deficiency to prior art, and a kind of low-cost preparation method of high-quality ultra-low molecular weight heparin is provided.
Application class of the present invention is similar to the action principle of chemosynthesis heparin pentasaccharides; Heparin to chitling mucous membrane source; β-elimination edman degradation Edman with improvement is the basis; Novelty ground adopts methods such as geavy saltization, phosphazene base depolymerization, saponification to solve key issues such as the macromole heparin in the feed liquid is too much, the accumulation of small molecules heparin, thereby prepares extra small molecule fragment.The ultra-low molecular heparin sodium molecular-weight average for preparing through this kind method is 2000～3000, MWD:＜1600 ratio≤40.0%;＞4500 ratio≤11.0%; Anti-FXa/FIIa＞30, anti-FXa tires: 145-180 IU/mg, anti-FIIa tires:＜5.0 IU/mg.Compare with the ultra-low molecular heparin sodium with low molecular sodium heparin; The high-quality ultra-low molecular weight heparin sodium of the present invention's preparation has extraordinary antithrombotic acitivity; Littler hemorrhage risk, and lower to hematoblastic influence, be expected to become neozoic heparin class antithrombotic reagent.
For realizing the object of the invention, ultra-low molecular weight heparin preparation method of the present invention may further comprise the steps:
1, heparin-benzethonium chloride salt is synthetic: the weight ratio by 1:2 ~ 3 takes by weighing heparin sodium and benzethonium chloride salt, is dissolved in respectively in the zero(ppm) water, will slowly join in the benzethonium chloride salts solution at heparin sodium aqua; Stir more than 2 hours; Standing demix removes supernatant, and the remaining suspension thing is centrifugal; Collecting precipitation thing heparin-benzethonium chloride salt, washing and dry then;
2, the heparin benzyl ester is synthetic: (1) gained heparin-benzethonium chloride salt is dissolved in N, adds Benzyl Chloride then, under 55 ~ 60 ℃, carried out esterification 25 ~ 30 hours;
3, the benzyl Calciparine/sodium salt is synthetic: prepare saturated sodium-acetate ethanolic soln, join in the feed liquid of (2) gained and stir, control feed temperature below 15 ℃, leave standstill more than 6 hours; Supernatant is removed in suction, and lower floor's suspension liquid is centrifugal, collecting precipitation thing benzyl Calciparine/sodium salt, washing then;
4, geavy saltization: take by weighing the benzethonium chloride salt and the benzyl heparin sodium of 2.5 times of weight of benzyl heparin sodium, stirring reaction more than 2 hours in the aqueous solution, then standing demix again; Remove supernatant; The remaining suspension thing is centrifugal, collecting precipitation thing heparin benzyl ester benzethonium chloride salt, and use distilled water wash;
5, depolymerization reaction: benzyl heparin benzyl rope ammonium salt is dissolved in the methylene dichloride, and adds phosphazene base as catalyzer, at room temperature stirring reaction is more than 24 hours; Then reaction solution is transferred in the saturated sodium-acetate methanol solution, post precipitation occurs, spinning, gained is the benzyl Calciparine/sodium salt that depolymerizes, methanol wash is also dry;
6, saponification: the benzyl Calciparine/sodium salt of depolymerization is dissolved in the zero(ppm) water; In below 10 ℃, add the sodium hydroxide reaction more than 2 hours, adding sodium-chlor again and using Hydrogen chloride adjustment pH is 6.5 ~ 7.5; The methanol extraction that in reaction solution, adds 2 ~ 3 times then is with washing of precipitate and dry;
7, alkali oxygen purifying: gained deposition in (6) is dissolved in the zero(ppm) water, and adjustment pH value to 9.0～11.0 add hydrogen peroxide stirring at room reaction 6～8 hours;
8, physical purification: feed liquid is transferred to the nanofiltration circulation tank carries out nanofiltration; Measure relative molecular-weight average of trapped fluid and MWD,, then carry out ultrafiltration with 1000 Da ultra-filtration membranes if relative molecular weight and MWD are undesirable; Between re-adjustment filtrating pH value to 6.5 ~ 7.4, filter through 0.22 μ m millipore filter;
9, freeze-drying: it is dry that filtrating is put into Freeze Drying Equipment.
As stated above, in heparin benzyl ester synthetic, the volume of the Benzyl Chloride that per kilogram heparin-benzethonium chloride salt adds is 1L.
As stated above, in the depolymerization reaction, the phosphazene base add-on is 1% of a benzyl heparin benzyl rope ammonium salt quality.
The present invention is according to similar chemosynthesis heparin pentasaccharides action principle; β-null method with improvement is the basis; Adopt steps such as geavy saltization, phosphazene base catalytic degradation, saponification through novelty ground, solved in the traditional technology of ultra-low molecular weight heparin preparation the macromole heparin too much, critical problem such as small molecules heparin accumulation.The present invention and other products following:
Come relatively from the effect of product; Prepared its anti-FXa of product of the present invention high, anti-FIIa far ultra other like products of the anti-FIIa ratio of extremely low, anti-FXa/ of tiring of tiring, and also have the bioavailability height, difference between individuals is little, the administration frequency is low, can not cause bleeding and advantage such as thrombopenia.Come relatively from the cost of technology, technology of the present invention is compared steps such as only having had more geavy saltization, phosphazene base catalytic degradation, saponification with traditional technology, and the cost that is produced thus is extremely low.
Embodiment
Embodiment 1: take by weighing 1 kg heparin sodium, 2.5 kg are subsequent use for benzethonium chloride salt.
1, in 9 liters of zero(ppm) water, progressively adds the heparin sodium that is taken by weighing, up to dissolving fully.
2, heparin benzethonium chloride salt is synthetic: with 2.5 kg benzethonium chloride salt, add zero(ppm) water and be stirred to dissolving fully.Then the adding of benzethonium chloride salts solution is under agitation slowly joined in the heparin sodium aqua, continue stirring and stop after 2 hours stirring, leave standstill for some time.Remove supernatant, and will remain the deposition suspended substance centrifugal, the collecting precipitation thing.
3, the pre-treatment of heparin benzethonium chloride salt: in centrifugal gained throw out, add 10 L zero(ppm) water and stir, soak, be no less than 1 hour.High speed centrifugation evenly is tiled in the throw out of final centrifugal gained in the Stainless Steel Disc, and every dish throw out thickness is no more than 2 cm, 60 ~ 70 ℃ of attemperation, heat-wind circulate drying 24-36 hour.
4, the heparin benzyl ester is synthetic: heparin-benzethonium chloride salt, add the 5L N, and stir and all dissolve until the visual inspection solid, continue again to stir 2 hours.The control feed temperature is 55 ~ 60 ℃, adds 3.5 L Benzyl Chlorides, carries out esterification, and the reaction times is 25 ~ 30 hours.
5, saturated acetic acid sodium ethanol alcohol precipitation: add saturated 95% ethanolic soln of 15 L sodium-acetates and stirring, the control feed temperature is below 15 ℃, and visual inspection stops to stir after the obvious sediment thing is arranged, and leaves standstill 6 hours.Supernatant is removed in suction, and lower floor's suspension liquid is centrifugal, collecting precipitation thing benzyl Calciparine/sodium salt.
6, the purifying of benzyl Calciparine/sodium salt: the benzyl Calciparine/sodium salt is dissolved in the sodium chloride aqueous solution, stirs down and mix, remove supernatant, the collecting precipitation thing with methyl alcohol.Gained is precipitated with after the methanol wash 3 times collecting precipitation.
7, geavy saltization: benzyl heparin sodium deposition is dissolved in the zero(ppm) water of about 6 times of amounts (w/v), and stirring is fully dissolved it.With 2.5 kg benzethonium chloride salt, add zero(ppm) water and be mixed with the benzethonium chloride salts solution then.The benzethonium chloride salts solution is under agitation added in the benzyl Calciparine/sodium salt aqueous solution, and stir about 2 hours then left standstill 2 hours again.Remove supernatant, will remain the deposition suspended substance centrifugal, the collecting precipitation thing.
8, the pre-treatment of heparin benzyl ester benzethonium chloride salt: the zero(ppm) water that centrifugal gained throw out is added 1 times of volume stirred washing by soaking 1 hour, and high speed centrifugation obtains deposition heparin benzyl ester benzethonium chloride salt.The zero(ppm) water that adds 1 times of volume stirs, and the visual inspection solid all continues to stir approximately 2 ~ 3 hours after the dissolving again.
9, depolymerization reaction: benzyl heparin benzyl rope ammonium salt is dissolved in the methylene dichloride, in this reaction solution, adds phosphazene base, and about 24 hours of stirring reaction at room temperature.Reaction solution is transferred in saturated 90% methanol solution of sodium-acetate, up to deposition occurring.High speed centrifugation 10 minutes, the separating obtained benzyl Calciparine/sodium salt that depolymerizes is used methanol wash.Final gained centrifugal sediment is evenly divided in Stainless Steel Disc, and every dish throw out thickness is no more than 2cm, vacuum-drying.
10, saponification: the benzyl Calciparine/sodium salt that depolymerizes is dissolved in the zero(ppm) water, control solution temperature below 10 ℃, and add sodium hydroxide and reacted about 2 hours, add Hydrogen chloride and sodium-chlor afterwards.The methyl alcohol that in reaction solution, adds 3 times of volumes, low temperature stir centrifugal acquisition deposition after 2 hours down.To precipitate with after the methanol wash 2 times and carry out drying.
11, alkali oxygen purifying: will regulate material liquid pH value to 9.0～11.0 with 20% sodium hydroxide solution.The 30wt% hydrogen peroxide that adds material liquid volume 0.1%～0.5% was stirring at room reaction 6～8 hours.
12, nanofiltration: feed liquid is transferred to the nanofiltration circulation tank and is diluted to certain volume with pump carry out nanofiltration, in debris, add zero(ppm) water then, carry out nanofiltration once more.
13, sample detection: adopt HPLC to detect relative molecular-weight average of above-mentioned sample and MWD with reference to the USP method.HPLC equipment is for wearing the subsidiary GPC module of peace U3000.Chromatographic column is TOSOH TSK-G2000SWXL, and moving phase is the Na of 28.40 g/L
2SO
4(pH is 5.0), flow velocity is 0.2 ml/min.Detector is a RI101 differential refraction detector of wearing peace UltiMate3000 UV-detector and Shodex.The result shows that gained sample sample average molecular weight is 2500 Da, and wherein the ratio of < 1600 ratio is 45%,>4500 Da is 5%, and MWD does not meet standard.
14, ultrafiltration: with 1000 Da ultra-filtration membranes above-mentioned sample is carried out ultrafiltration and obtain further refining sample; And detect with above-mentioned HPLC method; The result shows that the molecular-weight average of the refining sample of gained is at 2300 Da, and MWD: < ratio of 1600 Da is 25%; The ratio of 4500 Da is 5%, meets ultra-low molecular heparin standard.
15, smart filter: use pH meter to detect the pH value.The pH value is shown as 10.5, does not meet standard.The salt acid for adjusting pH value that uses 2 mol/L is 7.2.Last feed liquid is filtered through 0.22 μ m millipore filter.
The product detected result (with reference to the USP method) of tiring.Wherein anti-FXa tires: 153 IU/mg, anti-FIIa tires: 3.0 IU/mg, the anti-FIIa=51 of anti-FXa/.
Embodiment 2: present embodiment and embodiment 1 difference are that heparin sodium is 6 kg, and benzethonium chloride salt is 15 kg, and Benzyl Chloride is 20 L.
The product detected result: molecular-weight average is at 2200 Da, and MWD: the ratio of < ratio of 1600 Da is 20%,>4500 Da is 7%; Anti-FXa tires: 162 IU/mg, anti-FIIa tires: 3.0 IU/mg, the anti-FIIa=54 of anti-FXa/.
Claims (3)
1. the preparation method of a high-quality ultra-low molecular weight heparin sodium is characterized in that, may further comprise the steps:
1) heparin-benzethonium chloride salt is synthetic: the weight ratio by 1:2 ~ 3 takes by weighing heparin sodium and benzethonium chloride salt, is dissolved in respectively in the zero(ppm) water, will slowly join in the benzethonium chloride salts solution at heparin sodium aqua; Stir more than 2 hours; Standing demix removes supernatant, and the remaining suspension thing is centrifugal; Collecting precipitation thing heparin-benzethonium chloride salt, washing and dry then;
2) the heparin benzyl ester is synthetic: (1) gained heparin-benzethonium chloride salt is dissolved in N, adds Benzyl Chloride then, under 55 ~ 60 ℃, carried out esterification 25 ~ 30 hours;
3) the benzyl Calciparine/sodium salt is synthetic: prepare saturated sodium-acetate ethanolic soln, join in the feed liquid of (2) gained and stir, control feed temperature below 15 ℃; Leave standstill more than 6 hours, inhale and remove supernatant, lower floor's suspension liquid is centrifugal; Collecting precipitation thing benzyl Calciparine/sodium salt, washing then;
4) geavy saltization: benzethonium chloride salt and the benzyl heparin sodium that takes by weighing 2.5 times of weight of benzyl heparin sodium stirring reaction more than 2 hours in the aqueous solution, then standing demix again; Remove supernatant; The remaining suspension thing is centrifugal, collecting precipitation thing heparin benzyl ester benzethonium chloride salt, and use distilled water wash;
5) depolymerization reaction: benzyl heparin benzyl rope ammonium salt is dissolved in the methylene dichloride; And add phosphazene base as catalyzer, at room temperature stirring reaction is transferred to reaction solution in the saturated sodium-acetate methanol solution more than 24 hours then; Post precipitation appears; Spinning, gained are the benzyl Calciparine/sodium salt that depolymerizes, and methanol wash is also dry;
6) saponification: the benzyl Calciparine/sodium salt of depolymerization is dissolved in the zero(ppm) water; In below 10 ℃, add the sodium hydroxide reaction more than 2 hours, adding sodium-chlor again and using Hydrogen chloride adjustment pH is 6.5 ~ 7.5; The methanol extraction that in reaction solution, adds 2 ~ 3 times then is with washing of precipitate and dry;
7) alkali oxygen purifying: gained deposition in (6) is dissolved in the zero(ppm) water, and adjustment pH value to 9.0～11.0 add hydrogen peroxide stirring at room reaction 6～8 hours;
8) physical purification: feed liquid is transferred to the nanofiltration circulation tank carries out nanofiltration; Measure relative molecular-weight average of trapped fluid and MWD,, then carry out ultrafiltration with 1000 Da ultra-filtration membranes if relative molecular weight and MWD are undesirable; Between re-adjustment filtrating pH value to 6.5 ~ 7.4, filter through 0.22 μ m millipore filter;
9) freeze-drying: it is dry that filtrating is put into Freeze Drying Equipment.
2. method according to claim 1 is characterized in that, in heparin benzyl ester synthetic, the volume of the Benzyl Chloride that per kilogram heparin-benzethonium chloride salt adds is 1L.
3. method according to claim 1 and 2 is characterized in that, in the depolymerization reaction, the phosphazene base add-on is 1% of a benzyl heparin benzyl rope ammonium salt quality.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103145878A (en) * | 2012-12-08 | 2013-06-12 | 青岛九龙生物医药有限公司 | Ultralow heparin sodium technical study |
| CN103342761A (en) * | 2013-07-15 | 2013-10-09 | 河北常山生化药业股份有限公司 | Technology for preparing enoxaparin sodium by membrane separation |
| CN105985947A (en) * | 2015-02-28 | 2016-10-05 | 北京万达因生物医学技术有限责任公司 | Micromolecular heparin capable of selectively inhibiting amplification of primer dimer |
| CN108285498A (en) * | 2017-01-10 | 2018-07-17 | 九芝堂股份有限公司 | A kind of oligosaccharide compound and preparation method thereof and purposes inhibiting intrinsic coagulation factor X multienzyme complexes |
| 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 |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5389618A (en) * | 1990-06-26 | 1995-02-14 | Rhone-Poulenc Rorer S.A. | Mixtures of particular LMW heparinic polysaccharides for the prophylaxis/treatment of acute thrombotic events |
| CN101165071A (en) * | 2006-10-20 | 2008-04-23 | 江苏江山制药有限公司 | Clexane and preparation method thereof |
| CN101812190A (en) * | 2002-10-10 | 2010-08-25 | 安万特医药股份有限公司 | Heparin-derived polysaccharide mixtures, preparation thereof and pharmaceutical compositions containing same |
| CN102040671A (en) * | 2009-10-13 | 2011-05-04 | 北京贯虹科技有限公司 | Process for preparing and purifying ultra low molecular weight heparin |
-
2012
- 2012-05-02 CN CN2012101317306A patent/CN102633908A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5389618A (en) * | 1990-06-26 | 1995-02-14 | Rhone-Poulenc Rorer S.A. | Mixtures of particular LMW heparinic polysaccharides for the prophylaxis/treatment of acute thrombotic events |
| CN101812190A (en) * | 2002-10-10 | 2010-08-25 | 安万特医药股份有限公司 | Heparin-derived polysaccharide mixtures, preparation thereof and pharmaceutical compositions containing same |
| CN101165071A (en) * | 2006-10-20 | 2008-04-23 | 江苏江山制药有限公司 | Clexane and preparation method thereof |
| CN102040671A (en) * | 2009-10-13 | 2011-05-04 | 北京贯虹科技有限公司 | Process for preparing and purifying ultra low molecular weight heparin |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103145878A (en) * | 2012-12-08 | 2013-06-12 | 青岛九龙生物医药有限公司 | Ultralow heparin sodium technical study |
| CN103145878B (en) * | 2012-12-08 | 2016-04-13 | 青岛九龙生物医药有限公司 | A kind of ultralow point of heparin sodium technical study |
| CN103342761A (en) * | 2013-07-15 | 2013-10-09 | 河北常山生化药业股份有限公司 | Technology for preparing enoxaparin sodium by membrane separation |
| CN103342761B (en) * | 2013-07-15 | 2016-01-06 | 河北常山生化药业股份有限公司 | A kind of membrane sepn prepares Enoxaparin Sodium technique |
| CN105985947A (en) * | 2015-02-28 | 2016-10-05 | 北京万达因生物医学技术有限责任公司 | Micromolecular heparin capable of selectively inhibiting amplification of primer dimer |
| CN108285498A (en) * | 2017-01-10 | 2018-07-17 | 九芝堂股份有限公司 | A kind of oligosaccharide compound and preparation method thereof and purposes inhibiting intrinsic coagulation factor X multienzyme complexes |
| 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 |
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Application publication date: 20120815 |