CN105294885A - Preparation method of novel source of low molecular weight heparin from nitrous acid degradation - Google Patents
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Abstract
The invention relates to a preparation method of a novel source of low molecular weight heparin from nitrous acid degradation. The steps are as follows: (I) completely dissolving raw materials in water, adding sodium nitrite to prepare a reaction solution A; (II), adding sodium borohydride, and reacting to prepare a reaction solution B; (III) adding an alcohol solution, conducting solid-liquid separation, drying to prepare a solid A, and then dissolving the solid A in water to prepare a reaction solution C; (IV) replacing sodium ions with calcium ions by cation resin exchange to prepare a reaction solution D; and (V) adding alcohol solution to the reaction solution D, fully mixing, conducting solid-liquid separation, purifying, and drying to prepare the low molecular weight heparin. The invention can fundamentally promote the diversification of species sources for low molecular heparin, expand the supply of raw materials for heparin drugs, and achieve a higher degree of stabilization of the market of heparin and low molecular weight heparin drugs.
Description
Technical field
The present invention relates to the preparation method of a kind of new source nitrous acid degraded Low molecular heparin, utilize Niu Laiyuan (ox lung, Roll) and sheep source (sheep intestines) heparin to prepare the method for Low molecular heparin by nitrous acid degraded in particular to one, belong to bulk drug preparing technical field.
Background technology
Heparin belongs to a kind of anticoagulation clinical medicine, can extract, within 1916, being first found in the liver of dog, again source mainly being turned to ox and pig afterwards for obtaining high yield from various mammiferous mucosal tissue.But " mad cow disease " and " scrapie " of Europe outburst is transmitted to the mankind and lethal by Niu Yuyang due to last century Mo, so ox and sheep source heparin disabled, cause current heparin class medicine material to be only limitted to pig and originate.Low molecular heparin is mainly prepared from through depolymerized heparin, have higher than heparin biological activity, the clinical treatment advantage that transformation period longer and side effect is less, belongs to a kind of efficient antithrombotic reagent, and has heparin more than 60% every year for the preparation of Low molecular heparin.Current European Pharmacopoeia includes at least five kinds of Low molecular heparin, but these Low molecular heparin be all restricted to pig source heparin be raw material preparation, result in formation of the industrial chain that Low molecular heparin raw material sources are single.The market structure that this raw material sources are single threatens the stable of heparin class pharmaceutical market potentially." mad cow disease " and " scrapie " is effectively controlled at present, and the heparin in its source can ensure safety through existing various purification technique.
According to the number of animals raised of ox and sheep in Food and Argriculture OrganizationFAO's data presentation global range always higher than swine rearing amount, and pig source heparin also cannot meet the medical requirement in current aging epoch.Ox and sheep have been inevitable by being currently being developed to the new source of species of Low molecular heparin class medicine.
Summary of the invention
The present invention is directed to the monistic problem of nitrous acid degraded class Low molecular heparin medicine source of species, the heparin utilizing new species to originate prepares Low molecular heparin by nitrous acid degraded.
Summary of the invention
The present invention utilizes the heparin extracted in ox, sheep body to prepare two class Low molecular heparin through nitrous acid degradation method: nadroparin calcium and dalteparin sodium, and by carrying out comparing of structure and anticoagulating active respectively with EP standard substance, thus tentatively determine the clinical value of above Low molecular heparin class medicine.
Detailed Description Of The Invention
Technical solution of the present invention is as follows:
The preparation method of nadroparin calcium, step is as follows:
I the heparin sodium prepared by raw material ox lung, Roll and/or sheep intestines is dissolved in the water by () completely, add Sodium Nitrite, and heparin sodium is 10 ~ 30 times of Sodium Nitrite quality, pH is adjusted to be 2 ~ 5, react 80 ~ 120 minutes, then adjust pH to 9 ~ 12, obtained reaction solution A;
(ii) in the obtained reaction solution A of step (i), add sodium borohydride, sodium borohydride is 1 ~ 3% of heparin sodium quality, reacts 4 ~ 8 hours, and hydrochloric acid adjusts pH to 2 ~ 5, mixes, then is adjusted to neutrality with sodium hydroxide, obtained reaction solution B;
(iii) in the obtained reaction solution B of step (ii), the alcohol of 3 ~ 5 times of volumes is added, solid-liquid separation, drying, obtained solid A, then by soluble in water for solid A, the mass volume ratio of solid A and water is 1:(5 ~ 10), unit g/mL, obtained reaction liquid C;
(iv) by reaction liquid C obtained for step (iii), by Zeo-karb, sodium ion is replaced into calcium ion, obtained reaction solution D;
V () adds the alcohol of 3 ~ 5 times of volumes in the obtained reaction solution D of step (iv), fully after mixing, and solid-liquid separation, purified, dry, obtained Low molecular heparin.
Preferred according to the present invention, in described step (i), the acidic ph modifier adjusting pH is hydrochloric acid, and alkaline pH adjusting agent is sodium hydroxide.
Preferred according to the present invention, the alcohol in described step (iii), (v) is methyl alcohol or ethanol.
Preferred according to the present invention, in described step (iii), (v), solid-liquid separation is filtration or centrifugal.
Preferred according to the present invention, the purifying in described step (v) is dialysis membrane dialysis or alcohol precipitation; Preferred according to the present invention, in described step (v), drying is-50 ~-60 DEG C of freeze-drying.
The preparation method of dalteparin sodium, step is as follows:
(1) be dissolved in the water completely by the heparin sodium prepared by raw material ox lung, Roll and/or sheep intestines, add Sodium Nitrite, heparin sodium is 30 ~ 60 times of Sodium Nitrite quality, pH is adjusted to be 2 ~ 5, react 50 ~ 120 minutes, then adjust pH to 9 ~ 12, obtained reaction solution a;
(2) in the obtained reaction solution a of step (1), add sodium borohydride, sodium borohydride is 1 ~ 2% of heparin sodium quality, and react 6 ~ 12 hours, sodium hydroxide is adjusted to neutrality, obtains reaction solution b;
(3) in the obtained reaction solution b of step (2), the alcohol of 3 ~ 5 times of volumes is added, solid-liquid separation, drying, obtained solid a, then by soluble in water for solid a, the mass volume ratio of solid a and water is 1:(5 ~ 10), unit g/mL, obtained reaction solution c;
(4) by the reaction solution c that step (3) is obtained, the hydrogen peroxide that volume percent is 0.8 ~ 1.5% is added, through 25 ~ 30 DEG C of oxidations 10 ~ 20 hours, obtained reaction solution d;
(5) in the obtained reaction solution d of step (4), add the alcohol of 3 ~ 5 times of volumes, fully after mixing, solid-liquid separation, purified, dry, obtained Low molecular heparin.
Preferred according to the present invention, in described step (1), the acidic ph modifier adjusting pH is hydrochloric acid, and alkaline pH adjusting agent is sodium hydroxide.
Preferred according to the present invention, the alcoholic solution of described step (3), (5) is methyl alcohol or ethanol.
Preferred according to the present invention, in described step (3), (5), solid-liquid separation is filtration or centrifugal.
Preferred according to the present invention, the ultra-filtration membrane that the purifying in described step (5) selects dialysis membrane to be respectively molecular weight cut-off value 3000 and 8000 carries out ultrafiltration purification.
Preferred according to the present invention, in described step (5), drying is-50 ~-60 DEG C of freeze-drying.
Beneficial effect
1, the present invention utilizes new species heparin of originating to prepare Low molecular heparin by nitrous acid edman degradation Edman, by analyzing the clinical pharmaceutical use that structure and energy difference tentatively determines ox, sheep originates Low molecular heparin of Low molecular heparin on the Low molecular heparin in new species source and market.The present invention fundamentally can promote the source of species variation of Low molecular heparin, expands the supply of heparin class medicine material, stablize the object of heparin class and Low molecular heparin class pharmaceutical market with reaching higher degree.
2, the present invention adopts ox lung, Roll and/or sheep intestines can prepare the less Low molecular heparin of molecular weight as raw material, and thus biological activity is higher.
Embodiment
Below in conjunction with embodiment, technical scheme of the present invention is described further, but institute of the present invention protection domain is not limited thereto.
Embodiment and the raw material ox lung described in comparative example, Roll, heparin sodium prepared by sheep intestines, can see described method in " the heparin sodium technical study " of Qingyuan Wang (" Chinese Journal of Pharmaceuticals " 05 phase in 1991) by prior art purification, obtained heparin sodium.
Embodiment 1
Ox lung source heparin sodium prepares nadroparin calcium sample, and step is as follows:
I ox lung source heparin sodium is dissolved in the water by () completely, add Sodium Nitrite, heparin sodium is 30 times of Sodium Nitrite quality, adjusts pH to be 2.5, reacts 80 minutes, then adjusts pH to 10, obtained reaction solution A;
(ii) in the obtained reaction solution A of step (i), add sodium borohydride, the mass percent of sodium borohydride and heparin sodium is 1%, reacts 6 hours, and hydrochloric acid adjusts pH to 3, mixes, then is adjusted to neutrality with sodium hydroxide, obtained reaction solution B;
(iii) in the obtained reaction solution B of step (ii), the ethanol of 4 times of volumes is added, solid-liquid separation, dry, obtained solid A, then by soluble in water for solid A, the mass volume ratio of solid A and water is 1:10, unit g/mL, obtains reaction liquid C;
(iv) by reaction liquid C obtained for step (iii), by Zeo-karb, sodium salt sample displacement is calcium salt sample and retains to collect liquid, obtained reaction solution D;
V () adds the ethanol of 5 times of volumes in the obtained reaction solution D of step (iv), fully after mixing, solid-liquid separation, by the dialysis of alcohol precipitation sample dialysis membrane or ultrafiltration 10 minutes or obtain nadroparin calcium fine work solution through secondary alcohol precipitation.-60 DEG C of freeze-drying, obtained ox lung nadroparin calcium.
Embodiment 2
Roll source heparin sodium prepares nadroparin calcium sample, and step is as follows:
I () heparin sodium of being originated by Roll is dissolved in the water completely, add Sodium Nitrite, heparin sodium is 15 times of Sodium Nitrite quality, adjusts pH to be 3, react 110 minutes, then adjusts pH to 10, obtains reaction solution A;
(ii) in the obtained reaction solution A of step (i), add sodium borohydride, the mass percent of sodium borohydride and heparin sodium is 3%, reacts 4 hours, and hydrochloric acid adjusts pH to 3, mixes, then is adjusted to neutrality with sodium hydroxide, obtained reaction solution B;
(iii) in the obtained reaction solution B of step (ii), the ethanol of 4 times of volumes is added, solid-liquid separation, dry, obtained solid A, then by soluble in water for solid A, the mass volume ratio of solid A and water is 1:8, unit g/mL, obtains reaction liquid C;
(iv) by reaction liquid C obtained for step (iii), by Zeo-karb, sodium salt sample displacement is calcium salt sample and retains to collect liquid, obtained reaction solution D;
V () adds the ethanol of 3 times of volumes in the obtained reaction solution D of step (iv), fully after mixing, solid-liquid separation, by the dialysis of alcohol precipitation sample dialysis membrane or ultrafiltration 10 minutes or obtain nadroparin calcium fine work solution through secondary alcohol precipitation.-60 DEG C of freeze-drying, obtained Roll nadroparin calcium.
Embodiment 3
Sheep intestines source heparin sodium prepares nadroparin calcium sample, and step is as follows:
I sheep intestines source heparin sodium is dissolved in the water by () completely, add Sodium Nitrite, heparin sodium is 10 times of Sodium Nitrite quality, adjusts pH to be 4, reacts 100 minutes, then adjusts pH to 10, obtained reaction solution A;
(ii) in the obtained reaction solution A of step (i), add sodium borohydride, the mass percent of sodium borohydride and heparin sodium is 2%, reacts 5 hours, and hydrochloric acid adjusts pH to 4, mixes, then is adjusted to neutrality with sodium hydroxide, obtained reaction solution B;
(iii) in the obtained reaction solution B of step (ii), the ethanol of 3 times of volumes is added, solid-liquid separation, dry, obtained solid A, then by soluble in water for solid A, the mass volume ratio of solid A and water is 1:6, unit g/mL, obtains reaction liquid C;
(iv) by reaction liquid C obtained for step (iii), by Zeo-karb, sodium salt sample displacement is calcium salt sample and retains to collect liquid, obtained reaction solution D;
V () adds the ethanol of 4 times of volumes in the obtained reaction solution D of step (iv), fully after mixing, solid-liquid separation, by the dialysis of alcohol precipitation sample dialysis membrane or ultrafiltration 10 minutes or obtain nadroparin calcium fine work solution through secondary alcohol precipitation.-60 DEG C of freeze-drying, obtained sheep intestines nadroparin calcium.
Experimental example
1. molecular weight distribution detects
The three kinds of source nadroparin calciums prepared by embodiment 1-3 and nadroparin calcium EP standard substance are calculated molecular weight distribution by GPC method and corresponding software and are contrasted.
Moving phase: 0.1M ammonium acetate
Chromatographic column: pre-column TSKgelguardcolumnSWXL (6mm × 40mm)
TSK4000SWXL，7.8mm×300mm
TSK3000SWXL，7.8mm×300mm
Detector: Composition distribution
Flow velocity: 0.6mL/min
Sample concentration: 20 μ g/ μ L
Sample size: 10 μ L
2. Activity determination: (method is with reference to EP)
By three kinds of source nadroparin calciums by anti-IIa/Xa Activity determination, and compare with nadroparin calcium EP standard substance.
Nadroparin calcium test result is as follows:
Interpretation of result:
Above different genera source heparin obtains the sample of the quality standard meeting EP dalteparin sodium through different technical parameters.Wherein, pig lung nadroparin calcium differs greatly.Because ox lung heparin has the molecular weight lower than the heparin in other sources, and then the molecular weight of the dalteparin sodium causing ox lung to be originated and activity on the low side, but the active relative ratio of ox lung nadroparin calcium and ox lung heparin sodium is higher than the relative ratio of standard substance (chitling is originated).Ox lung and sheep intestines heparin degree higher, so and then in conjunction with more calcium ion.
Embodiment 4
Ox lung source heparin sodium prepares dalteparin sodium, and step is as follows:
(1) be dissolved in the water completely by ox lung source heparin sodium, add Sodium Nitrite, heparin sodium is 40 times of Sodium Nitrite quality, adjusts pH to be 2.5, reacts 100 minutes, then adjusts pH to 10, obtained reaction solution A;
(2) in the obtained reaction solution A of step (1), add sodium borohydride, sodium borohydride is 2% of heparin sodium quality, react 6 hours, and hydrochloric acid adjusts pH to 3, mixes, then is adjusted to neutrality with sodium hydroxide, obtains reaction solution B;
(3) in the obtained reaction solution B of step (2), the ethanol of 4 times of volumes is added, solid-liquid separation, dry, obtained solid A, then by soluble in water for solid A, the mass volume ratio of solid A and water is 1:5, unit g/mL, obtains reaction liquid C;
(4) by the reaction liquid C that step (3) is obtained, the hydrogen peroxide that volume percent is 1.5% is added, through 25 DEG C of oxidations 10 hours, obtained reaction solution D;
(5) in the obtained reaction solution D of step (4), add the ethanol of 3 times of volumes, after abundant mixing, alcohol precipitation sample dialysis membrane is the ultra-filtration membrane purifying of molecular weight cut-off value 3000 and 8000 by solid-liquid separation,-60 DEG C of freeze-drying, obtained ox lung dalteparin sodium.
Embodiment 5
Roll source heparin sodium prepares dalteparin sodium, and step is as follows:
(1) heparin sodium of being originated by Roll is dissolved in the water completely, adds Sodium Nitrite, and heparin sodium is 50 times of Sodium Nitrite quality, adjusts pH to be 2.5, reacts 80 minutes, then adjusts pH to 10, obtained reaction solution A;
(2) in the obtained reaction solution A of step (1), add sodium borohydride, sodium borohydride is 1% of heparin sodium quality, react 11 hours, and hydrochloric acid adjusts pH to 3, mixes, then is adjusted to neutrality with sodium hydroxide, obtains reaction solution B;
(3) in the obtained reaction solution B of step (2), the ethanol of 4 times of volumes is added, solid-liquid separation, dry, obtained solid A, then by soluble in water for solid A, the mass volume ratio of solid A and water is 1:10, unit g/mL, obtains reaction liquid C;
(4) by the reaction liquid C that step (3) is obtained, the hydrogen peroxide that volume percent is 0.8% is added, through 28 DEG C of oxidations 15 hours, obtained reaction solution D;
(5) in the obtained reaction solution D of step (4), add the ethanol of 4 times of volumes, after abundant mixing, alcohol precipitation sample dialysis membrane is the ultra-filtration membrane purifying of molecular weight cut-off value 3000 and 8000 by solid-liquid separation,-60 DEG C of freeze-drying, obtained Roll dalteparin sodium.
Embodiment 6
Sheep intestines source heparin sodium prepares dalteparin sodium, and step is as follows:
(1) be dissolved in the water completely by sheep intestines source heparin sodium, add Sodium Nitrite, heparin sodium is 60 times of Sodium Nitrite quality, adjusts pH to be 2.5, reacts 50 minutes, then adjusts pH to 10, obtained reaction solution A;
(2) in the obtained reaction solution A of step (1), add sodium borohydride, sodium borohydride is 1.5% of heparin sodium quality, react 9 hours, and hydrochloric acid adjusts pH to 3, mixes, then is adjusted to neutrality with sodium hydroxide, obtains reaction solution B;
(3) in the obtained reaction solution B of step (2), the ethanol of 3 times of volumes is added, solid-liquid separation, dry, obtained solid A, then by soluble in water for solid A, the mass volume ratio of solid A and water is 1:10, unit g/mL, obtains reaction liquid C;
(4) by the reaction liquid C that step (3) is obtained, the hydrogen peroxide that volume percent is 1% is added, through 30 DEG C of oxidations 12 hours, obtained reaction solution D;
(5) in the obtained reaction solution D of step (4), add the ethanol of 2 ~ 5 times of volumes, after abundant mixing, alcohol precipitation sample dialysis membrane is the ultra-filtration membrane purifying of molecular weight cut-off value 3000 and 8000 by solid-liquid separation,-60 DEG C of freeze-drying, obtained sheep intestines dalteparin sodium.
Experimental example:
1. molecular weight distribution detects
Dalteparin sodium and the dalteparin sodium EP standard substance in the three kinds of sources obtained by embodiment 4-6 are analyzed by GPC-MALLS, and calculate the molecular weight of each DALT of contrast.
Detector: WyattDAWNHELEOSII multiple angle laser light scattering instrument
WyattOptilabrEX Composition distribution
Moving phase: 0.2MNaNO
3, 0.2g/LNaN
3
Sample concentration: 20 μ g/ μ L
Sample size: 100 μ L
Flow velocity: 0.5mL/min
Chromatographic column: ShodexOHpakSB-803HQ (6 μm, 8 × 300mm
2)
Determined wavelength: 658nm
2. Activity determination: (method is with reference to EP)
Just three kinds of source dalteparin sodiums are by anti-IIa/Xa Activity determination, and compare with dalteparin sodium EP standard substance.
Dalteparin sodium detected result is as follows:
Interpretation of result:
Above different sources heparin process variations is determined by respective starting raw material, and different heparin sources has different molecular weight distribution and activity.Each source heparin all can be met the molecular weight of EP dalteparin sodium and active mass range under different technical parameters.
Claims (10)
1. a preparation method for nadroparin calcium, is characterized in that, step is as follows:
I the heparin sodium prepared by raw material ox lung, Roll and/or sheep intestines is dissolved in the water by () completely, add Sodium Nitrite, and heparin sodium is 10 ~ 30 times of Sodium Nitrite quality, pH is adjusted to be 2 ~ 5, react 80 ~ 120 minutes, then adjust pH to 9 ~ 12, obtained reaction solution A;
(ii) in the obtained reaction solution A of step (i), add sodium borohydride, sodium borohydride is 1 ~ 3% of heparin sodium quality, reacts 4 ~ 8 hours, and hydrochloric acid adjusts pH to 2 ~ 5, mixes, then is adjusted to neutrality with sodium hydroxide, obtained reaction solution B;
(iii) in the obtained reaction solution B of step (ii), the alcoholic solution of 3 ~ 5 times of volumes is added, solid-liquid separation, drying, obtained solid A, then by soluble in water for solid A, the mass volume ratio of solid A and water is 1:(5 ~ 10), unit g/mL, obtained reaction liquid C;
(iv) by reaction liquid C obtained for step (iii), by Zeo-karb, sodium ion is replaced into calcium ion, obtained reaction solution D;
V () adds the alcoholic solution of 3 ~ 5 times of volumes in the obtained reaction solution D of step (iv), fully after mixing, and solid-liquid separation, purified, dry, obtained Low molecular heparin.
2. preparation method as claimed in claim 1, is characterized in that, in described step (i), the acidic ph modifier adjusting pH is hydrochloric acid, and alkaline pH adjusting agent is sodium hydroxide.
3. preparation method as claimed in claim 1, it is characterized in that, the alcoholic solution in described step (iii), (v) is methyl alcohol or ethanol.
4. preparation method as claimed in claim 1, is characterized in that, in described step (iii), (v), solid-liquid separation is filtration or centrifugal.
5. preparation method as claimed in claim 1, is characterized in that, the purifying in described step (v) is dialysis membrane dialysis or alcohol precipitation; Preferred according to the present invention, in described step (v), drying is-50 ~-60 DEG C of freeze-drying.
6. a preparation method for dalteparin sodium, step is as follows:
(1) be dissolved in the water completely by the heparin sodium prepared by raw material ox lung, Roll and/or sheep intestines, add Sodium Nitrite, heparin sodium is 30 ~ 60 times of Sodium Nitrite quality, pH is adjusted to be 2 ~ 5, react 50 ~ 120 minutes, then adjust pH to 9 ~ 12, obtained reaction solution a;
(2) in the obtained reaction solution a of step (1), add sodium borohydride, sodium borohydride is 1 ~ 2% of heparin sodium quality, and react 6 ~ 12 hours, sodium hydroxide is adjusted to neutrality, obtains reaction solution b;
(3) in the obtained reaction solution b of step (2), the alcoholic solution of 3 ~ 5 times of volumes is added, solid-liquid separation, drying, obtained solid a, then by soluble in water for solid a, the mass volume ratio of solid a and water is 1:(5 ~ 10), unit g/mL, obtained reaction solution c;
(4) by the reaction solution c that step (3) is obtained, the hydrogen peroxide that volume percent is 0.8 ~ 1.5% is added, through 25 ~ 30 DEG C of oxidations 10 ~ 20 hours, obtained reaction solution d;
(5) in the obtained reaction solution d of step (4), add the alcoholic solution of 3 ~ 5 times of volumes, fully after mixing, solid-liquid separation, purified, dry, obtained Low molecular heparin.
7. preparation method as claimed in claim 6, is characterized in that, in described step (1), the acidic ph modifier adjusting pH is hydrochloric acid, and alkaline pH adjusting agent is sodium hydroxide.
8. preparation method as claimed in claim 6, it is characterized in that, the alcoholic solution of described step (3), (5) is methyl alcohol or ethanol.
9. preparation method as claimed in claim 6, is characterized in that, in described step (3), (5), solid-liquid separation is filtration or centrifugal.
10. preparation method as claimed in claim 6, is characterized in that, the ultra-filtration membrane that the purifying in described step (5) selects dialysis membrane to be respectively molecular weight cut-off value 3000 and 8000 carries out ultrafiltration purification; Preferred according to the present invention, in described step (5), drying is-50 ~-60 DEG C of freeze-drying.
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2018032502A1 (en) * | 2016-08-19 | 2018-02-22 | 苏州融析生物科技有限公司 | Sheep-derived low molecular weight heparin, preparation method therefor and application thereof |
| CN107759712A (en) * | 2016-08-19 | 2018-03-06 | 苏州融析生物科技有限公司 | The LMWHs in sheep source and preparation method and application |
| CN110885386A (en) * | 2019-12-23 | 2020-03-17 | 天津生物化学制药有限公司 | Method for extracting ultra-low molecular weight heparin sodium by using nadroparin calcium waste |
| CN111019014A (en) * | 2019-11-22 | 2020-04-17 | 苏州二叶制药有限公司 | Preparation process of nadroparin calcium |
| CN112005110A (en) * | 2018-07-24 | 2020-11-27 | 深圳市海普瑞药业集团股份有限公司 | Analysis method and application of dalteparin sodium nitrite degradation product |
| RU2753678C1 (en) * | 2020-09-25 | 2021-08-19 | Алексей Георгиевич Александров | Method for obtaining nadroparin calcium |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2018032502A1 (en) * | 2016-08-19 | 2018-02-22 | 苏州融析生物科技有限公司 | Sheep-derived low molecular weight heparin, preparation method therefor and application thereof |
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| CN112005110A (en) * | 2018-07-24 | 2020-11-27 | 深圳市海普瑞药业集团股份有限公司 | Analysis method and application of dalteparin sodium nitrite degradation product |
| CN112005110B (en) * | 2018-07-24 | 2022-11-29 | 深圳市海普瑞药业集团股份有限公司 | Analysis method and application of dalteparin sodium nitrite degradation product |
| CN111019014A (en) * | 2019-11-22 | 2020-04-17 | 苏州二叶制药有限公司 | Preparation process of nadroparin calcium |
| CN110885386A (en) * | 2019-12-23 | 2020-03-17 | 天津生物化学制药有限公司 | Method for extracting ultra-low molecular weight heparin sodium by using nadroparin calcium waste |
| RU2753678C1 (en) * | 2020-09-25 | 2021-08-19 | Алексей Георгиевич Александров | Method for obtaining nadroparin calcium |
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