CN106188341A - High-purity sulfuric acid dermatan technique prepared by heparin sodium leftover bits and pieces - Google Patents
High-purity sulfuric acid dermatan technique prepared by heparin sodium leftover bits and pieces Download PDFInfo
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- CN106188341A CN106188341A CN201610597994.9A CN201610597994A CN106188341A CN 106188341 A CN106188341 A CN 106188341A CN 201610597994 A CN201610597994 A CN 201610597994A CN 106188341 A CN106188341 A CN 106188341A
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
- C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
- C08B37/006—Heteroglycans, i.e. polysaccharides having more than one sugar residue in the main chain in either alternating or less regular sequence; Gellans; Succinoglycans; Arabinogalactans; Tragacanth or gum tragacanth or traganth from Astragalus; Gum Karaya from Sterculia urens; Gum Ghatti from Anogeissus latifolia; Derivatives thereof
- C08B37/0063—Glycosaminoglycans or mucopolysaccharides, e.g. keratan sulfate; Derivatives thereof, e.g. fucoidan
- C08B37/0069—Chondroitin-4-sulfate, i.e. chondroitin sulfate A; Dermatan sulfate, i.e. chondroitin sulfate B or beta-heparin; Chondroitin-6-sulfate, i.e. chondroitin sulfate C; Derivatives thereof
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
- C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
- C08B37/0003—General processes for their isolation or fractionation, e.g. purification or extraction from biomass
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Abstract
The present invention relates to a kind of method utilizing heparin sodium leftover bits and pieces to prepare high-purity sulfuric acid dermatan, it is with the leftover bits and pieces of the heparin sodium output that produces choice goods as raw material, pass through ethanol precipitation, obtain heparinoid crude product and dermatan sulfate crude product, then heparinoid crude product is aoxidized by ethanol precipitation, hydrogen peroxide, obtains direct ratio rotation heparinoid and negative ratio revolves heparinoid；Dermatan sulfate crude product passes through nitrite degradation, makes the heparin class mass degradation contained in crude product become Low molecular heparin class material, then obtains purity by ethanol precipitation, hydrogen peroxide oxidation and reach the dermatan sulfate of more than 98%.Solve the problem that dermatan sulfate purity present on market for a long time is the highest; achieve the process that turned waste into wealth by leftover bits and pieces; can be that enterprise creates bigger extra returns; its processing step is simple; technical process environmental protection; do not produce poisonous and harmful substance, with low cost, it is easy to large-scale production.
Description
Technical field
The present invention relates to, during preparation refined heparin sodium, high-purity sulfuric acid dermatan prepared by the leftover bits and pieces of output
Method, belongs to mucopolysaccharide biological pharmacy technical field.
Background technology
Dermatan sulfate (dermatan sulfate is called for short DS), is a kind of natural glycosaminoglycans, by the disaccharide repeated
Unit form, its disaccharide be acetylamino sulphuric acid galactose and iduronic acid, predominantly N-acetylgalactosamine 4-sulphuric acid and
The disaccharidase chain structure that L-iduronic acid is constituted.Dermatan sulfate is distributed widely in animal tissue, has antithrombotic, water resistant
Swell, promote skin renewal, the excessive keratinization stoping skin and acanthosis, skin care, the effect of holding moisture, be subject in recent years
Pay attention to day by day to domestic and international expert.The therapeutic effect of dermatan sulfate and its purity have direct relation, generally sulphuric acid
The purity of dermatan is the highest, and its anticoagulant efficiency is the lowest, activates heparin cofactor II activity the highest, the possibility that hemorrhage side effect occurs
Property is the least, more safe and reliable during long-term treatment thrombosis.
Dermatan sulfate is in addition to the therapeutical effect that itself has, moreover it can be used to prepare antithrombotic reagent Sulodexide.Shu Luo
Ground spy is made up of Heparan sulfate and two kinds of components of dermatan sulfate, and two kinds of components can be worked in coordination with and be played a role, Ke Yifa
Wave stronger antithrombotic effect, and its probability caused bleeding is little, is especially suitable for antithrombotic long-term treatment.Owing to this medicine is good
Good therapeutic effect, thus there is the biggest market demand, CN100384884C have employed and pass through from heparin sodium by-product
Ethanol precipitation separating-purifying dermatan sulfate and the method for low-numerator sulphuric acid heparan, although the method is sunk for classification
During shallow lake, liquor strength, salt content and concentration of alcohol are all studied, but undisclosed affect medicinal liquid precipitate and separate effect important because of
Element pH value and precipitation temperature.The dermatan sulfate testing result that it is prepared is specific optical rotation-55 °～-63 °, anticoagulant efficiency≤
10USPu/mg, owing to the purity of dermatan sulfate its specific optical rotation the highest is the lowest, anticoagulant efficiency is the lowest, and its sulphuric acid prepared is described
Dermatan purity is relatively low, thus cannot play more preferable therapeutic effect.
Summary of the invention
The invention reside in improvement prior art defect and provide one to utilize heparin sodium leftover bits and pieces to prepare high-purity sulfuric acid skin
The method of skin element.
The method that the present invention sets up is mainly from heparin sodium leftover bits and pieces by ethanol precipitation, obtains dermatan sulfate
Crude product；Use nitrite degradation dermatan sulfate crude product so that the depolymerized heparin contained in crude product become low molecular weight or single,
Disaccharidase, and remove low molecular weight and single, double sugar heparin and a small amount of chondroitin sulfate by ethanol precipitation, thus obtain
To high-purity sulfuric acid dermatan.
Its concrete technology comprises the following steps:
A. rough segmentation
Heparin sodium leftover bits and pieces is added after purified water is dissolved by weight in wet base 5～30%w/v concentration and adds 2～10%w/v sodium chloride, chlorination
After sodium dissolves, adjust and add ethanol after medicinal liquid pH4.0～6.5, when in medicinal liquid, the concentration of ethanol is 30～38%v/v, 10～
25 DEG C staticly settle, and are separated with supernatant by precipitate after precipitating 2～10 hours, add ethanol in the supernatant separated, when
When the concentration of ethanol is 40～50%v/v in medicinal liquid, staticly settle at 10～25 DEG C, collect precipitation after precipitating 6～12 hours and obtain
Dermatan sulfate crude product；
B. refine
After above-mentioned dermatan sulfate crude product is added purified water dissolving by the concentration of weight in wet base 10～50%w/v, regulate medicinal liquid pH2.0
～2.5, then in medicinal liquid, add 0.6～3.0%(w/w) after sodium nitrite (in terms of dermatan sulfate crude product weight in wet base), at normal temperatures
Stirring reaction 2～5 hours, adds 1～6%(w/v after then standing 24 hours) sodium chloride, after adjusting medicinal liquid pH4.0～6.5, add
Enter ethanol, when in medicinal liquid, concentration of alcohol is 37～45%(v/v) time, staticly settle at 10～25 DEG C, receive after precipitating 8～24 hours
Collection precipitation obtains the dermatan sulfate fine work of specific optical rotation≤-65 °；
C. oxidative decoloration
By dermatan sulfate by weight in wet base 10～50%(w/v) add purified water dissolve after, at 25～35 DEG C adjust medicinal liquid pH9.0～
After 12.0, adding hydrogen peroxide and react, wherein hydrogen peroxide concentration in medicinal liquid is 0.5～4.0%v/v；
D. precipitate
Above-mentioned reaction 8～after 36 hours, is added the sodium chloride of 1～6% in medicinal liquid by mass volume ratio, and sodium chloride is adjusted after dissolving
Whole medicinal liquid pH4.0～6.5, adds the ethanol of 1.5～3.0 times of medicine liquid volumes, then staticly settles at 10～25 DEG C, precipitation
Dermatan sulfate precipitation is collected after 8～24 hours；
E. lyophilization
Above-mentioned dermatan sulfate precipitate is added after purified water is dissolved by weight in wet base 30～45% concentration and lowers the temperature, be cooled to-40～-
Evacuation when 60 DEG C, when being slowly heated after vacuum≤15Pa, is incubated after being heated to 50～55 DEG C, prepares after being incubated 3～5 hours
Dermatan sulfate target product.
Sampled detection, dermatan sulfate molecular weight is 8000～40000 dalton, and specific optical rotation is-65 °～-70 °, anti-
Solidifying titer≤2uspu/mg, sulfate and carboxylic acid group's ratio are 0.8～1.2, purity >=98%.
The technological progress that the present invention obtains:
The present invention uses the leftover bits and pieces produced from crude heparin sodium to refined heparin sodium production process to be raw material, from leftover bits and pieces
Deep processing goes out high-purity sulfuric acid dermatan further, it is achieved that the process turned waste into wealth by leftover bits and pieces, can be that enterprise creates
Bigger extra returns.The present invention mainly uses sodium nitrite degraded and ethanol precipitation, prepared dermatan sulfate product
Specific optical rotation be-65 °～-70 °, anticoagulant efficiency≤2USPu/mg, molecular weight is 8000～40000 dalton, sulfate and carboxylic
Acidic group ratio is 0.8～1.2, and through capillary electrophoresis analysis, with dermatan sulfate standard substance as comparison, records the sulfur of preparation
The purity of acid dermatan is more than 98%.Highly purified dermatan sulfate clinic can play more preferable therapeutic effect, has more market
Competitiveness, can be that enterprise brings bigger economic well-being of workers and staff, technique environmental protection, does not produce poisonous and harmful substance, processing step letter
Easily, with low cost, it is easy to large-scale production.
Detailed description of the invention
Below in conjunction with specific embodiment, the invention will be further described.
The rough segmentation of embodiment 1:a.
Take and produce leftover bits and pieces wet product 2kg of refined heparin sodium and add after purified water dissolves and be settled to 40L, addition 3.2kg sodium chloride,
After sodium chloride dissolves, adjust with 3mol/L hydrochloric acid solution and add ethanol after pH value of solution 6.0, make the concentration of ethanol in solution be
37.5%L/L, then staticly settles at 15 ± 1 DEG C, sediment separate out and supernatant after precipitating 8 hours.Collect supernatant, supernatant
Liquid is added ethanol, when making that in medicinal liquid, the concentration of ethanol is 49%L/L, staticly settles at 15 ± 1 DEG C, collect after precipitating 8 hours
Precipitation obtains dermatan sulfate crude product 1.4kg；
B. dermatan sulfate is refined
Above-mentioned 1.4kg dermatan sulfate crude product is added purified water dissolve and be settled to 10L, regulate medicinal liquid with 3mol/L hydrochloric acid solution
In solution, add 11.2g sodium nitrite (in terms of dermatan sulfate crude product weight in wet base) after pH2.2, use sodium nitrite to be dissolved in 45ml
Add into the liquid after purified water, stirring reaction at normal temperatures 2 hours, in medicinal liquid, add 500g sodium chloride after standing 24 hours,
After stirring and dissolving, adjusting medicinal liquid pH6.2 with 3mol/L sodium hydroxide solution, add ethanol, making the concentration of ethanol in medicinal liquid is 43%
L/L, staticly settles at 15 ± 1 DEG C, collects precipitation and obtain dermatan sulfate fine work 1.1kg, sampling detection ratio after precipitating 16 hours
Curl is-66.0 °；
Sampling detection can not meet specific optical rotation≤-65 ° if as dermatan sulfate, must repeat above-mentioned precipitation process；When sulphuric acid skin
After skin element testing result meets the requirements, then can carry out following oxidative decoloration；
C. dermatan sulfate oxidative decoloration
Wet for 1.1kg dermatan sulfate fine work is added after purified water dissolves and add water and be settled to 4L, at 30 ± 1 DEG C, use 3mol/L hydrogen
After sodium hydroxide solution adjusts medicinal liquid pH10.6, the hydrogen peroxide adding 40ml 30% reacts；
D. postprecipitation is aoxidized
After above-mentioned reaction 10 hours, adding 140g sodium chloride in medicinal liquid, sodium chloride adjusts with 3mol/L hydrochloric acid solution after dissolving
Medicinal liquid pH6.3, adds 8L ethanol, then staticly settles at 15 ± 1 DEG C, collects dermatan sulfate precipitation after precipitating 10 hours；
E. dermatan sulfate lyophilization
After adding 2000ml purified water stirring and dissolving in dermatan sulfate precipitates, add purified water and be settled to 3000ml, by medicine
Liquid loads lyophilized plate and puts in freeze dryer, starts to lower the temperature medicinal liquid, after products temperature is down to-57 DEG C, takes out whole system very
Goods, after in drying baker, vacuum is 14Pa, are slowly heated by sky, are incubated after products temperature rises to 51 DEG C, and insulation 3.5 is little
Dermatan sulfate 367g is prepared time after.
Sampled detection, dermatan sulfate specific optical rotation is-66.1 °, and anticoagulant efficiency is that < 2USPU/mg, molecular weight is
25163, sulfate and carboxylic acid group's ratio 1.0.Through Capillary Electrophoretic Determination, compare with dermatan sulfate standard substance, measure system
The purity of the dermatan sulfate sample obtained is 98.2%.
Embodiment 2: the present embodiment difference from Example 1 is,
A. rough segmentation
Leftover bits and pieces wet product 4kg producing refined heparin sodium is added after purified water dissolves and be settled to 40L, addition 2.0kg sodium chloride,
After sodium chloride dissolves, adjust with 3mol/L hydrochloric acid solution and add ethanol after pH value of solution 5.8, make the concentration of ethanol in solution be
35.4%L/L, then staticly settles at 11 ± 1 DEG C, sediment separate out and supernatant after precipitating 6 hours.In the supernatant collected
Adding ethanol, when making that in medicinal liquid, the concentration of ethanol is 45.0%L/L, staticly settle at 11 ± 1 DEG C, it is heavy to collect after precipitating 6 hours
Shallow lake obtains dermatan sulfate crude product 2.3kg；
B. dermatan sulfate is refined
Above-mentioned 2.3kg dermatan sulfate crude product is added purified water dissolve and be settled to 10L, regulate medicinal liquid with 3mol/L hydrochloric acid solution
In solution, add 46g sodium nitrite (in terms of dermatan sulfate crude product weight in wet base) after pH2.0, use sodium nitrite to be dissolved in 230ml
Add into the liquid after purified water, stirring reaction at normal temperatures 3 hours, after standing 24 hours, medicinal liquid adds 300g sodium chloride,
After stirring and dissolving, adjusting medicinal liquid pH5.5 with 3mol/L sodium hydroxide solution, add ethanol, making the concentration of ethanol in medicinal liquid is 40%
L/L, staticly settles at 11 ± 1 DEG C, collects precipitation and obtain dermatan sulfate fine work 2.0kg after precipitating 8 hours, and sampling detection is than rotation
Degree is for-67.2 °；
Sampling detection can not meet specific optical rotation≤-65 ° if as dermatan sulfate, must repeat above-mentioned precipitation process；When sulphuric acid skin
After skin element testing result meets the requirements, then can carry out following oxidative decoloration；
C. dermatan sulfate oxidative decoloration
Wet for 2.0kg dermatan sulfate fine work is added after purified water dissolves and add water and be settled to 8L, at 26 ± 1 DEG C, use 3mol/L hydrogen
After sodium hydroxide solution adjusts medicinal liquid pH11.5, the hydrogen peroxide adding 240ml 30% reacts；
D. postprecipitation is aoxidized
After above-mentioned reaction 8 hours, adding 160g sodium chloride in medicinal liquid, sodium chloride adjusts medicine with 3mol/L hydrochloric acid solution after dissolving
Liquid pH5.2, adds 12L ethanol, then staticly settles at 11 ± 1 DEG C, collects dermatan sulfate precipitation after precipitating 12 hours；
E. dermatan sulfate lyophilization
After adding 5000ml purified water stirring and dissolving in dermatan sulfate precipitates, add purified water and be settled to 5500ml, by medicine
Liquid loads lyophilized plate and puts in freeze dryer, starts to lower the temperature medicinal liquid, after products temperature is down to-51 DEG C, takes out whole system very
Goods, after in drying baker, vacuum is 11Pa, are slowly heated by sky, be incubated, be incubated 4 hours after products temperature rises to 54 DEG C
Rear prepared dermatan sulfate 866g；
Sampled detection, dermatan sulfate specific optical rotation is-67.5 °, and anticoagulant efficiency is that < 2USPU/mg, molecular weight is 28365, sulfur
Acidic group and carboxylic acid group's ratio 1.0.Through Capillary Electrophoretic Determination, compare with dermatan sulfate standard substance, measure the sulphuric acid prepared
The purity of dermatan sample is 98.5%.
Embodiment 3: the present embodiment is a difference in that with embodiment 1, embodiment 2,
A. rough segmentation
Leftover bits and pieces wet product 10kg producing refined heparin sodium is added after purified water dissolves and be settled to 40L, addition 0.8kg chlorination
Sodium, after sodium chloride dissolves, adjusts with 3mol/L hydrochloric acid solution and adds ethanol after pH value of solution 5.5, makes the concentration of ethanol in solution be
32.3%L/L, then staticly settles at 20 ± 1 DEG C, sediment separate out and supernatant after precipitating 3 hours.In the supernatant collected
Add ethanol, when making that in medicinal liquid, the concentration of ethanol is 41.1%L/L, staticly settle at 20 ± 1 DEG C, collect after precipitating 10 hours
Precipitation obtains dermatan sulfate crude product 5.8kg；
B. dermatan sulfate is refined
Above-mentioned 5.8kg dermatan sulfate crude product is added purified water dissolve and be settled to 20L, regulate medicinal liquid with 3mol/L hydrochloric acid solution
In solution, add 168g sodium nitrite (in terms of dermatan sulfate crude product weight in wet base) after pH2.5, use sodium nitrite to be dissolved in 560ml
Add into the liquid after purified water, stirring reaction at normal temperatures 5 hours, after standing 24 hours, medicinal liquid adds 1.0kg chlorination
Sodium, after stirring and dissolving, adjusts medicinal liquid pH6.3 with 3mol/L sodium hydroxide solution, adds ethanol, make the concentration of ethanol in medicinal liquid be
41.2%L/L, staticly settles at 20 ± 1 DEG C, collects precipitation and obtain dermatan sulfate fine work 4.6kg, sampling inspection after precipitating 24 hours
Survey specific optical rotation and be-68.6 °；
Sampling detection can not meet specific optical rotation≤-65 ° if as dermatan sulfate, must repeat above-mentioned precipitation process；When sulphuric acid skin
After skin element testing result meets the requirements, then can carry out following oxidative decoloration；
C. dermatan sulfate oxidative decoloration
Wet for 4.6kg dermatan sulfate fine work is added after purified water dissolves and add water and be settled to 12L, at 33 ± 1 DEG C, use 3mol/L
After sodium hydroxide solution adjusts medicinal liquid pH9.3, the hydrogen peroxide adding 120ml 30% reacts；
D. postprecipitation is aoxidized
After above-mentioned reaction 20 hours, adding 480g sodium chloride in medicinal liquid, sodium chloride adjusts with 3mol/L hydrochloric acid solution after dissolving
Medicinal liquid pH6.0, adds 36L ethanol, then staticly settles at 20 ± 1 DEG C, collects dermatan sulfate precipitation after precipitating 22 hours；
E. dermatan sulfate lyophilization
After adding 10L purified water stirring and dissolving in dermatan sulfate precipitates, add purified water and be settled to 12L, medicinal liquid is loaded
Lyophilized plate is put in freeze dryer, starts to lower the temperature medicinal liquid, after products temperature is down to-52 DEG C, to whole system evacuation, is dried
After vacuum is 15Pa in case, goods are slowly heated, are incubated after products temperature rises to 55 DEG C, after being incubated 5 hours, prepare sulfur
Acid dermatan 1.9kg；
Sampled detection, dermatan sulfate specific optical rotation is-69.1 °, and anticoagulant efficiency is that < 2USPU/mg, molecular weight is 31254, sulfur
Acidic group and carboxylic acid group's ratio 1.0.Through Capillary Electrophoretic Determination, compare with dermatan sulfate standard substance, measure the sulphuric acid prepared
The purity of dermatan sample is 98.8%.
Claims (1)
1. a high-purity sulfuric acid dermatan technique prepared by heparin sodium leftover bits and pieces, and its feature comprises the following steps:
A. rough segmentation
Heparin sodium leftover bits and pieces is added after purified water is dissolved by weight in wet base 5～30%w/v concentration and adds 2～10%w/v sodium chloride, chlorination
After sodium dissolves, adjust and add ethanol after medicinal liquid pH4.0～6.5, when in medicinal liquid, the concentration of ethanol is 30～38%v/v, 10～
25 DEG C staticly settle, and are separated with supernatant by precipitate after precipitating 2～10 hours, add ethanol in the supernatant separated, when
When the concentration of ethanol is 40～50%v/v in medicinal liquid, staticly settle at 10～25 DEG C, collect precipitation after precipitating 6～12 hours and obtain
Dermatan sulfate crude product；
B. refine
After above-mentioned dermatan sulfate crude product is added purified water dissolving by the concentration of weight in wet base 10～50%w/v, regulate medicinal liquid pH2.0
～2.5, then in medicinal liquid, add 0.6～3.0%(w/w) after sodium nitrite (in terms of dermatan sulfate crude product weight in wet base), at normal temperatures
Stirring reaction 2～5 hours, adds 1～6%(w/v after then standing 24 hours) sodium chloride, after adjusting medicinal liquid pH4.0～6.5, add
Enter ethanol, when in medicinal liquid, concentration of alcohol is 37～45%(v/v) time, staticly settle at 10～25 DEG C, receive after precipitating 8～24 hours
Collection precipitation obtains the dermatan sulfate fine work of specific optical rotation≤-65 °；
C. oxidative decoloration
By dermatan sulfate by weight in wet base 10～50%(w/v) add purified water dissolve after, at 25～35 DEG C adjust medicinal liquid pH9.0～
After 12.0, adding hydrogen peroxide and react, wherein hydrogen peroxide concentration in medicinal liquid is 0.5～4.0%v/v；
D. precipitate
Above-mentioned reaction 8～after 36 hours, is added the sodium chloride of 1～6% in medicinal liquid by mass volume ratio, and sodium chloride is adjusted after dissolving
Whole medicinal liquid pH4.0～6.5, adds the ethanol of 1.5～3.0 times of medicine liquid volumes, then staticly settles at 10～25 DEG C, precipitation
Dermatan sulfate precipitation is collected after 8～24 hours；
E. lyophilization
Above-mentioned dermatan sulfate precipitate is added after purified water is dissolved by weight in wet base 30～45% concentration and lowers the temperature, be cooled to-40～-
Evacuation when 60 DEG C, when being slowly heated after vacuum≤15Pa, is incubated after being heated to 50～55 DEG C, prepares after being incubated 3～5 hours
Dermatan sulfate.
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| CN201610597994.9A CN106188341B (en) | 2016-07-27 | 2016-07-27 | Heparin sodium leftover bits and pieces prepares high-purity sulfuric acid dermatan technique |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111040047A (en) * | 2019-12-11 | 2020-04-21 | 东营天东制药有限公司 | Process and application for refining low-molecular dermatan sulfate by enzyme-ultrafiltration method |
| CN113735994A (en) * | 2020-05-29 | 2021-12-03 | 江苏唯高生物科技有限公司 | Process for preparing sulodexide raw material |
| CN114478832A (en) * | 2022-02-14 | 2022-05-13 | 河北常山生化药业股份有限公司 | Method for purifying four polysaccharide products from heparin sodium by-product |
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| US5922690A (en) * | 1996-04-25 | 1999-07-13 | Van Gorp; Cornelius L. | Dermatan disulfate, an inhibitor of thrombin generation and activation |
| CN1445245A (en) * | 2003-04-18 | 2003-10-01 | 山东大学 | Dermatan sulfate with low molecule and its preparing method |
| CN1850864A (en) * | 2006-05-29 | 2006-10-25 | 南京健友生物化学制药有限公司 | Method for separating and purify dermatansulfate and low-molecular heparan sulfate from sodium heparan product |
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| ROBERT J. LINHARDT ET AL: "LOW MOLECULAR WEIGHT DERMATAN SULFATE AS AN ANTITHROMBOTIC AGENT", 《BIOCHEMICAL PHARMACOLOGY》 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111040047A (en) * | 2019-12-11 | 2020-04-21 | 东营天东制药有限公司 | Process and application for refining low-molecular dermatan sulfate by enzyme-ultrafiltration method |
| CN113735994A (en) * | 2020-05-29 | 2021-12-03 | 江苏唯高生物科技有限公司 | Process for preparing sulodexide raw material |
| CN114478832A (en) * | 2022-02-14 | 2022-05-13 | 河北常山生化药业股份有限公司 | Method for purifying four polysaccharide products from heparin sodium by-product |
| CN114478832B (en) * | 2022-02-14 | 2023-03-03 | 河北常山生化药业股份有限公司 | Method for purifying four polysaccharide products from heparin sodium by-product |
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| Publication number | Publication date |
|---|---|
| CN106188341B (en) | 2019-09-17 |
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