CN104072637B - Preparation method for low-molecular-weight heparin calcium - Google Patents
Preparation method for low-molecular-weight heparin calcium Download PDFInfo
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- CN104072637B CN104072637B CN201410320475.9A CN201410320475A CN104072637B CN 104072637 B CN104072637 B CN 104072637B CN 201410320475 A CN201410320475 A CN 201410320475A CN 104072637 B CN104072637 B CN 104072637B
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Abstract
The invention relates to the field of medical synthesis, and discloses a preparation method for low-molecular-weight heparin calcium. The method disclosed by the invention comprises the following steps: preparing a low-molecular-weight heparin sodium solution by virtue of a sodium nitrite method at first, and then carrying out resin calcification on cation exchange resin by use of a calcium chloride solution, then carrying out calcium-sodium ion substitution on the calcified cation resin columns on the low-molecular-weight heparin sodium solution, and finally filtering, freeze-drying and crushing the substitution solution after the calcium-sodium ion substitution to obtain the low-molecular-weight heparin calcium. According to the preparation method disclosed by the invention, a step of preparing low-molecular-weight heparin with the extremely low pH value is avoided; the low-molecular-weight heparin calcium is obtained by resin one-time moderate substitution for the low-molecular-weight heparin sodium, so that the loss of anti-Xa factor titer in severe environments is avoided, the anti-Xa/anti-IIa ratio is increased, and the production steps are simplified.
Description
Technical field
The present invention relates to medical synthesis field is and in particular to a kind of preparation method of low molecular weight calcium heparin.
Background technology
Heparin is a kind of mixture being made up of oligosaccharide such as alduronic acid and glucamine, has anticoagulating active, from discovery
So far have the history in more than 80 years, its product can be substituted completely still without a kind of at present, be still important biochemical drug.Liver
Element is prevention Post operation thrombosiss and treats venothrombotic choice drug.But substantial amounts of use can cause bleeding and induce blood
The side effect such as platelet minimizing, limit its substantial amounts of use.
Low molecular weight heparin is heparin fractionated or the bglii fragment of the molecular weight obtaining of degrading, and its weight average molecular weight exists
3000-8000, has the Anti-Xa factor effect suitable with heparin, and antithrombase (IIa) activity substantially reduces, its antithrombotic effect
Blood coagulation system is affected less, bleeding tendency is less, it is little also to have a molecule, easily absorb, bioavailability is high, Half-life in vivo is long
The features such as, its effectiveness and safety, due to heparin, have become the focus of anticoagulant class drug research at present.
Low molecular weight calcium heparin is the calcium salt of low molecular weight heparin, and compared with sodium salt, calcium salt slowly spreads after injection, no
The calcium colloid of blood capillary between local cells can be reduced, also will not change vascular permeability, almost sodium-free salt subcutaneous injection can
The side effect of the local hemorrhage that can cause, therefore calcium salt is more suitable for Clinical practice.
The standard weighing the quality of low molecular heparin calcium has two, and one is Anti-Xa factor potency, and another is exactly anti-Xa/
Anti- II a ratio, the value of this two standards is higher, and product quality is better.The Chinese patent of Publication No. CN1554671A discloses
" a kind of preparation method of the low molecular heparin calcium of low nitrite content ", it is based on nitrite method by low molecular weight heparin sodium
It is changed into low molecular weight calcium heparin through multiple acid-base reaction although it successfully reduces the content of nitrite, but preparation process
Middle pH value is relatively low, adds and subsequently turns the strong neutralization reaction of soda acid in calcium step, has certain loss to Anti-Xa factor potency, causes
Anti-Xa factor potency and anti-Xa/ resist the not high problem of II a ratio, affect product quality, this process operations is cumbersome simultaneously, can
Other reagent impurity can be introduced.
Content of the invention
In view of this, it is an object of the invention to provide a kind of preparation method of low molecular weight calcium heparin, make this preparation side
Method can improve the Anti-Xa factor potency of low molecular weight calcium heparin and anti-Xa/ resists II a ratio；
It is yet a further object of the present invention to provide a kind of preparation method of low molecular weight calcium heparin, enable this preparation method
Low molecular weight calcium heparin processing step is prepared in enough simplification.
For in existing low molecular weight calcium heparin preparation method (CN1554671A), Anti-Xa factor potency and anti-Xa/ resist II a
Ratio is relatively low, affects product quality, the cumbersome problem of process operations simultaneously, the present invention provides following solution：
A kind of preparation method of low molecular weight calcium heparin, comprises the following steps：
Step 1, prepare low molecular weight heparin sodium solution using sodium nitrite method；
Step 2, cation exchange resin carry out resin calcification with calcium chloride solution, the low molecule then prepared step 1
Cationic resin after calcification on amount heparin sodium aqua, carries out calcium sodium ion displacement；
Step 3, the displacement liquid filtration by after the displacement of step 2 calcium sodium ion, lyophilizing, pulverizing obtain low molecular weight calcium heparin.
Preferably, step 1 is：
Step 1.1, taking heparin sodium are dissolved in aqueous solution, with vinegar acid for adjusting pH value to 2-4, add sodium nitrite reaction 4-6h
Obtain degradation solution；
Step 1.2, add in described degradation solution 30% hydrogenperoxide steam generator oxidation 15min, be subsequently adding 25% hydrogen-oxygen
Change in sodium solution and pH value is to 6.5-7.0, obtain neutralizer；
Step 1.3, add in described neutralizer 95% ethanol carry out precipitate with ethanol and separate alcohol hypostasis, gained alcohol hypostasis note
Penetrate and obtain low molecular weight heparin sodium solution with water dissolution.
Wherein, the ratio of described heparin sodium, sodium nitrite and 30% hydrogen peroxide is preferably 2.5kg:70g-90g:
660mL, more preferably 2.5kg:80g-85g:660mL；Described each pH value all can from limit in the range of appoint take a point value, and
It is not limited to the endpoint value of scope, and above-mentioned preferred step 1 concrete scheme can be not limited to other parameters combination in any,
For example described with vinegar acid for adjusting pH value to 2-4, described pH value can take such as 2.01,2.02......3.98 in the range of this,
3.99 or 4.00 any one as pH value, and can with hydrogen peroxide, the concentration of sodium hydroxide and response time, oxidation when
Between parameter combination in any, other pH value with reference to this explain.
Preferably, described cation exchange resin is strongly acidic macroporous cation exchange resin, more preferably
D001 type strongly acidic macroporous cation exchange resin or JZD001X7-II type macropore strong acid polystyrene cation exchange tree
Fat.
Preferably, the weight average molecular weight of described low molecular weight heparin sodium is 3000-4500D.
Preferably, the weight average molecular weight of described low molecular weight calcium heparin is 3000-4500D.
Preferably, described resin calcification step is：
Calcium chloride solution on cation exchange resin, replace to lower column liquid pH value be in neutrality after, water for injection rinse sun from
Sub-exchange resin completes resin calcification.
Wherein, described calcium chloride solution concentration is preferably 0.5mol/L.
The present invention avoids the low molecular weight heparin step that pH value is less than 2 in preparation process, decreases low-molecular-weight liver
Decomposition under extremely low pH environment for the element, passes through low molecular weight heparin sodium carry out gentle with cation exchange resin simultaneously and puts
Change, it is to avoid using calcium hydroxide and low molecular weight heparin acid-base neutralization exothermic reaction it is ensured that low molecular weight calcium heparin
Stable, it is to avoid the loss of the Anti-Xa factor potency under intense environment.Through detection and analysis, the low-molecular-weight liver of present invention preparation
Plain calcium Anti-Xa factor potency is between 105-120IU/mg hence it is evident that being higher than the highest Anti-Xa factor potency described in CN1554671A
102IU/mg (embodiment 1), simultaneously anti-Xa/ resist II a highest ratios reach more than 4.4, higher than CN1554671A record highest
Ratio 4.2.
Additionally, this invention simplifies production stage, line replacement is once entered by resin, improve production efficiency, using sun
Ion exchange resin, the calcium ion in first selective absorption raw material, is then entered line replacement, reduces impurity with low molecular weight heparin sodium
Introducing, replaced the low molecular weight calcium heparin producing, most of for combined state calcium it is ensured that calcium content reliable and stable.
Specific embodiment
The invention discloses a kind of preparation method of low molecular weight calcium heparin, those skilled in the art can use for reference interior herein
Hold, be suitably modified technological parameter and realize.Specifically, all similar replacements and change are to those skilled in the art
For be it will be apparent that they are considered as including in the present invention.Preparation method of the present invention has passed through preferable enforcement
Example is described, related personnel substantially can in without departing from present invention, spirit and scope to method described herein and
Application is modified or suitably changes and combine, and to realize and to apply the technology of the present invention.
Just a kind of preparation method of low molecular weight calcium heparin provided by the present invention is described further below.
Embodiment 1：Prepare low molecular weight calcium heparin
Degraded：Take refined heparin sodium 2.5kg to be dissolved in aqueous solution, with vinegar acid for adjusting pH value to 2-4, add sodium nitrite
80.00g reaction 4-6h.
Oxidation：The degradation solution that upper step is obtained, adds 30% (mass percent, similarly hereinafter) hydrogenperoxide steam generator 660mL oxidation
15min.
Neutralization：Add in 25% sodium hydroxide solution and pH value is to 6.5-7.0.
Precipitate with ethanol：Neutralizer adds 95% ethanol precipitate with ethanol, and alcohol hypostasis is with, after water for injection dissolving, being that low molecular weight heparin sodium is molten
Liquid.
Calcification resin：The upper 0.5mol/L chlorination of JZD001X7-II type large hole strong acid styrene system cation exchange resin
Calcium solution, replaces after being in neutrality to lower column liquid pH value, water for injection rinses ion exchange resin.
Calcium is replaced：Cation exchange column on low molecular weight heparin sodium solution, carries out sodium calcium displacement.
Refined：Displacement liquid, after 0.22um filtration, obtains fine work solution.
Lyophilizing：Fine work solution is placed in freezer dryer lyophilizing, after pulverizing, obtains low molecular weight calcium heparin finished product 1858g.
Embodiment 2：Prepare low molecular weight calcium heparin
Degraded：Take refined heparin sodium 2.5kg to be dissolved in aqueous solution, with vinegar acid for adjusting pH value to 2-4, add sodium nitrite
81.25g reaction 4-6h.
Oxidation：The degradation solution that upper step is obtained, adds 30% hydrogenperoxide steam generator 660mL oxidation 15min.
Neutralization：Add in 25% sodium hydroxide solution and pH value is to 6.5-7.0.
Precipitate with ethanol：Neutralizer adds 95% ethanol precipitate with ethanol, and alcohol hypostasis is with, after water for injection dissolving, being that low molecular weight heparin sodium is molten
Liquid.
Calcification resin：The upper 0.5mol/L chlorination of JZD001X7-II type large hole strong acid styrene system cation exchange resin
Calcium solution, replaces after being in neutrality to lower column liquid pH value, water for injection rinses ion exchange resin.
Calcium is replaced：Cation exchange column on low molecular weight heparin sodium solution, carries out sodium calcium displacement.
Refined：Displacement liquid, after 0.22um filtration, obtains fine work solution.
Lyophilizing：Fine work solution is placed in freezer dryer lyophilizing, after pulverizing, obtains low molecular weight calcium heparin finished product 1932g.
Embodiment 3：Prepare low molecular weight calcium heparin
Degraded：Take refined heparin sodium 2.5kg to be dissolved in aqueous solution, with vinegar acid for adjusting pH value to 2-4, add sodium nitrite
82.5g reaction 4-6h.
Oxidation：The degradation solution that upper step is obtained, adds 30% hydrogenperoxide steam generator 660mL oxidation 15min.
Neutralization：Add in 25% sodium hydroxide solution and pH value is to 6.5-7.0.
Precipitate with ethanol：Neutralizer adds 95% ethanol precipitate with ethanol, and alcohol hypostasis is with, after water for injection dissolving, being that low molecular weight heparin sodium is molten
Liquid.
Calcification resin：0.5mol/L calcium chloride solution on D001 type strongly acidic macroporous cation exchange resin, replace under
After post liquid pH value is in neutrality, water for injection rinses ion exchange resin.
Calcium is replaced：Cation exchange column on low molecular weight heparin sodium solution, carries out sodium calcium displacement.
Refined：Displacement liquid, after 0.22um filtration, obtains fine work solution.
Lyophilizing：Fine work solution is placed in freezer dryer lyophilizing, after pulverizing, obtains low molecular weight calcium heparin finished product 2047g.
Embodiment 4：Prepare low molecular weight calcium heparin
Degraded：Take refined heparin sodium 2.5kg to be dissolved in aqueous solution, with vinegar acid for adjusting pH value to 2-4, add sodium nitrite
83.75g reaction 4-6h.
Oxidation：The degradation solution that upper step is obtained, adds 30% hydrogenperoxide steam generator 660mL oxidation 15min.
Neutralization：Add in 25% sodium hydroxide solution and pH value is to 6.5-7.0.
Precipitate with ethanol：Neutralizer adds 95% ethanol precipitate with ethanol, and alcohol hypostasis is with, after water for injection dissolving, being that low molecular weight heparin sodium is molten
Liquid.
Calcification resin：0.5mol/L calcium chloride solution on D001 type strongly acidic macroporous cation exchange resin, replace under
After post liquid pH value is in neutrality, water for injection rinses ion exchange resin.
Calcium is replaced：Cation exchange column on low molecular weight heparin sodium solution, carries out sodium calcium displacement.
Refined：Displacement liquid, after 0.22um filtration, obtains fine work solution.
Lyophilizing：Fine work solution is placed in freezer dryer lyophilizing, after pulverizing, obtains low molecular weight calcium heparin finished product 2195g.
Embodiment 5：Product checking
Low molecular weight calcium heparin prepared by embodiment 1- embodiment 4 is detected, contrast product is employing
The product of the method preparation that CN1554671A embodiment 1 is recorded, testing result such as following table：
Table 1 Product checking result
As shown in Table 1, the product of present invention preparation meets every quality standard of low molecular weight calcium heparin, and in anti-Xa
Factor potency, anti-Xa/ resist II a ratio and loss on drying ratio aspect to be significantly better than CN1554671A.
The above is only the preferred embodiment of the present invention it is noted that ordinary skill people for the art
For member, under the premise without departing from the principles of the invention, some improvements and modifications can also be made, these improvements and modifications also should
It is considered as protection scope of the present invention.
Claims (7)
1. a kind of preparation method of low molecular weight calcium heparin is it is characterised in that comprise the following steps：
Step 1, prepare low molecular weight heparin sodium solution using sodium nitrite method；
Step 2, cation exchange resin carry out resin calcification with calcium chloride solution, the low-molecular-weight liver then prepared step 1
Cationic resin column after calcification on plain sodium solution, carries out calcium sodium ion displacement；
Step 3, step 2 calcium sodium ion is replaced after displacement liquid through 0.22um filtrations, lyophilizing, pulverizing, acquisition low-molecular-weight liver
Plain calcium；
Described cation exchange resin is D001 type strongly acidic macroporous cation exchange resin or JZD001 × 7-II type macropore is strong
Acid styrene type cation exchange resin.
2. according to claim 1 preparation method it is characterised in that step 1 is：
Step 1.1, taking heparin sodium are dissolved in aqueous solution, with vinegar acid for adjusting pH value to 2-4, add sodium nitrite reaction 4-6h to obtain
Degradation solution；
Step 1.2, add in described degradation solution 30% hydrogenperoxide steam generator oxidation 15min, be subsequently adding 25% sodium hydroxide
With pH value to 6.5-7.0 in solution, obtain neutralizer；
Step 1.3, add in described neutralizer 95% ethanol carry out precipitate with ethanol and separate alcohol hypostasis, gained alcohol hypostasis injection
Water dissolution, obtains low molecular weight heparin sodium solution.
3. according to claim 2 preparation method it is characterised in that described heparin sodium, sodium nitrite and 30% hydrogen peroxide
Ratio be 2.5kg:70g-90g:660mL.
4. according to claim 1 preparation method it is characterised in that the weight average molecular weight of described low molecular weight heparin sodium is
3000-4500D.
5. according to claim 1 preparation method it is characterised in that the weight average molecular weight of described low molecular weight calcium heparin is
3000-4500D.
6. according to claim 1 preparation method it is characterised in that described resin calcification step is：
Calcium chloride solution on cation exchange resin, replaces after being in neutrality to lower column liquid pH value, water for injection rinses cation and hands over
Change resin and complete resin calcification.
7. according to claim 6 preparation method it is characterised in that described calcium chloride solution concentration be 0.5mol/L.
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| CN201410320475.9A CN104072637B (en) | 2014-07-07 | 2014-07-07 | Preparation method for low-molecular-weight heparin calcium |
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| CN104262510B (en) * | 2014-10-11 | 2016-08-17 | 山东万邦赛诺康生化制药股份有限公司 | A kind of preparation method of the low molecular weight heparin sodium of ultralow free sulphur acidic group |
| CN106986954B (en) * | 2017-04-19 | 2020-12-25 | 烟台东诚药业集团股份有限公司 | Joint preparation method of dalteparin sodium and nadroparin calcium |
| CN108409890A (en) * | 2018-03-16 | 2018-08-17 | 湖北亿诺瑞生物制药有限公司 | A method of producing calciparine from heparin sodium crude |
| CN109575156B (en) * | 2018-11-05 | 2021-02-23 | 上海宝维医药技术有限公司 | Purification method of low-molecular heparin |
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| FR2665163B1 (en) * | 1990-07-27 | 1992-10-16 | Sanofi Sa | PROCESS FOR THE PREPARATION OF CALCIUM HEPARINS. |
| CN1268650C (en) * | 2003-12-24 | 2006-08-09 | 兆科药业（合肥）有限公司 | Process for preparing low moledule heparin calcium of low nitrite content |
| CN101519459A (en) * | 2008-02-26 | 2009-09-02 | 苏州法思特生物制药科技有限公司 | Technique for producing ultra-low molecular heparin sodium (calcium) |
| CN103382232B (en) * | 2012-05-04 | 2015-11-18 | 常州泰康制药有限公司 | The preparation of nadroparin calcium and purifying process |
| CN103408676A (en) * | 2013-07-15 | 2013-11-27 | 河北常山生化药业股份有限公司 | Nadroparin calcium preparation technology |
| CN103315951B (en) * | 2013-07-17 | 2014-10-08 | 海南通用同盟药业有限公司 | Low-molecular-weight heparin calcium injection |
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