CN106188341B - Heparin sodium leftover bits and pieces prepares high-purity sulfuric acid dermatan technique - Google Patents
Heparin sodium leftover bits and pieces prepares high-purity sulfuric acid dermatan technique Download PDFInfo
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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 methods for preparing high-purity sulfuric acid dermatan using heparin sodium leftover bits and pieces, it is using the leftover bits and pieces for the heparin sodium output that produces choice goods as raw material, pass through ethanol precipitation, obtain heparan crude product and dermatan sulfate crude product, then heparan crude product is aoxidized by ethanol precipitation, hydrogen peroxide, obtains direct ratio rotation heparan and negative than rotation heparan；Dermatan sulfate crude product makes the heparin substance contained in crude product be degraded into low molecular weight heparin substance, then obtain purity up to 98% or more dermatan sulfate by ethanol precipitation, hydrogen peroxide oxidation by nitrite degradation.Solve the problems, such as that existing dermatan sulfate purity is not high in the market for a long time; realizing turns waste into wealth leftover bits and pieces process; biggish extra returns can be createed for enterprise; its processing step is simple; technical process is environmentally protective; poisonous and harmful substance is not generated, it is low in cost, it is easy to large-scale production.
Description
Technical field
The present invention relates to from preparation refined heparin sodium during output leftover bits and pieces in prepare high-purity sulfuric acid dermatan
Method belongs to glutinous polysaccharide biopharmaceutical technology.
Background technique
Dermatan sulfate (dermatan sulfate, abbreviation DS) is a kind of natural glycosaminoglycan, by duplicate disaccharides
Unit composition, disaccharides be acetylamino sulfuric acid galactolipin and iduronic acid, predominantly N- acetylgalactosamine 4- sulfuric acid and
The disaccharide chain structure that L- iduronic acid is constituted.Dermatan sulfate is distributed widely in animal tissue, has antithrombotic, water resistant
It is swollen, promote skin renewal, the excessive keratinization for preventing skin and acanthosis, skin care, the effect for keeping moisture, in recent years by
To the pay attention to day by day of domestic and international expert.The therapeutic effect of dermatan sulfate and its purity have direct relation, under normal circumstances sulfuric acid
The purity of dermatan is higher, and anticoagulant efficiency is lower, and activation heparin cofactor II activity is higher, the possibility that hemorrhage side effect occurs
Property it is smaller, it is more safe and reliable during being used for long-term treatment thrombus.
Dermatan sulfate is in addition to the therapeutic effect that itself has, moreover it can be used to prepare antithrombotic reagent Sulodexide.Shu Luo
Ground spy is grouped as by two kinds of groups of Heparan sulfate and dermatan sulfate, and two kinds of components, which can cooperate with, to play a role, Ke Yifa
Stronger antithrombotic effect is waved, and a possibility that it causes bleeding is small, is especially suitable for the long-term treatment of antithrombotic.Since the drug is good
Good therapeutic effect, thus there is the very big market demand, it uses in CN100384884C and passes through from heparin sodium by-product
The method of ethanol precipitation separating-purifying dermatan sulfate and low-numerator sulphuric acid heparan, although this method is heavy for being classified
Liquor strength, salt content and concentration of alcohol are studied when shallow lake, but not publicly influence medical fluid precipitation and separation effect it is important because
Plain pH value and precipitation temperature.Its dermatan sulfate testing result prepared is -55 °~-63 ° of specific rotation, anticoagulant efficiency≤
10USPu/mg, since its higher specific rotation of the purity of dermatan sulfate is lower, anticoagulant efficiency is lower, illustrates the sulfuric acid of its preparation
Dermatan purity is lower, thus can not play better therapeutic effect.
Summary of the invention
It provides the invention reside in prior art defect is improved and a kind of prepares high-purity sulfuric acid skin using heparin sodium leftover bits and pieces
The method of skin element.
The method that the present invention establishes, by ethanol precipitation, obtains dermatan sulfate mainly from heparin sodium leftover bits and pieces
Crude product；Using nitrite degradation dermatan sulfate crude product so that the depolymerized heparin contained in crude product at low molecular weight or it is single,
Disaccharide, and low molecular weight and single, double sugared heparin and a small amount of chondroitin sulfate are removed by ethanol precipitation, thus
To high-purity sulfuric acid dermatan.
Its concrete technology the following steps are included:
A. rough segmentation
2~10%w/v sodium chloride is added after purified water dissolution is added by 5~30%w/v of weight in wet base concentration in heparin sodium leftover bits and pieces,
After sodium chloride dissolution, ethyl alcohol is added after adjusting medical fluid pH4.0~6.5, when the concentration of ethyl alcohol in medical fluid is 30~38%v/v,
10~25 DEG C staticly settle, and precipitating, by sediment and supernatant separation, added second in isolated supernatant after 2~10 hours
Alcohol is staticly settled when the concentration of ethyl alcohol in medical fluid is 40~50%v/v at 10~25 DEG C, and it is heavy that precipitating is collected after 6~12 hours
Shallow lake obtains dermatan sulfate crude product；
B. it refines
After purified water dissolution is added by the concentration of 10~50%w/v of weight in wet base in above-mentioned dermatan sulfate crude product, regulating liquid medicine
PH2.0~2.5, then 0.6~3.0%(w/w is added into medical fluid) after sodium nitrite (in terms of dermatan sulfate crude product weight in wet base),
It is stirred to react under room temperature 2~5 hours, 1~6%(w/v is added after being then allowed to stand 24 hours) sodium chloride, adjustment medical fluid pH4.0~
After 6.5, ethyl alcohol is added, when concentration of alcohol is 37~45%(v/v in medical fluid) when, it is staticly settled at 10~25 DEG C, precipitating 8~24
Precipitating is collected after hour obtains the dermatan sulfate fine work of specific rotation≤- 65 °；
C. oxidative decoloration
After dermatan sulfate is dissolved by 10~50%(w/v of weight in wet base) plus purified water, medical fluid is adjusted at 25~35 DEG C
Behind pH9.0~12.0, hydrogen peroxide is added and is reacted, wherein concentration of the hydrogen peroxide in medical fluid is 0.5~4.0%v/v；
D. it precipitates
After above-mentioned reaction 8~36 hours, 1~6% sodium chloride, sodium chloride dissolution is added into medical fluid by mass volume ratio
Medical fluid pH4.0~6.5 are adjusted afterwards, are added the ethyl alcohol of 1.5~3.0 times of medicine liquid volumes, are then staticly settled at 10~25 DEG C,
Precipitating collects dermatan sulfate precipitating after 8~24 hours；
E. it is freeze-dried
Cool down after purified water dissolution is added by 30~45% concentration of weight in wet base in above-mentioned dermatan sulfate sediment, is cooled to -40
It vacuumizes at~-60 DEG C, is slowly heated after vacuum degree≤15Pa, kept the temperature after being heated to 50~55 DEG C, after heat preservation 3~5 hours
Dermatan sulfate target product is made.
Sampled detection, dermatan sulfate molecular weight are 8000~40000 dalton, and specific rotation is -65 °~-70 °, are resisted
Solidifying potency≤2uspu/mg, sulfate and carboxylic acid group's ratio are 0.8~1.2, purity >=98%.
The technological progress achieved by the present invention:
The present invention uses the leftover bits and pieces generated from crude heparin sodium into refined heparin sodium production process for raw material, from leftover bits and pieces
Further deep processing goes out high-purity sulfuric acid dermatan in material, realizes the process that leftover bits and pieces is turned waste into wealth, and can create for enterprise
Produce biggish extra returns.The present invention mainly uses sodium nitrite degradation and ethanol precipitation, dermatan sulfate obtained
The specific rotation of product is -65 °~-70 °, anticoagulant efficiency≤2USPu/mg, and molecular weight is 8000~40000 dalton, sulfate
It is 0.8~1.2 with carboxylic acid group's ratio, and through capillary electrophoresis analysis, uses dermatan sulfate standard items as control, measure preparation
Dermatan sulfate purity 98% or more.The dermatan sulfate clinic of high-purity can play better therapeutic effect, have more
The market competitiveness can bring bigger economic well-being of workers and staff for enterprise, and technique is environmentally protective, not generate poisonous and harmful substance, technique step
It is rapid simple, it is low in cost, it is easy to large-scale production.
Specific embodiment
The present invention is further explained in the light of specific embodiments.
Embodiment 1:a. rough segmentation
After taking the leftover bits and pieces wet product 2kg of production refined heparin sodium to add purified water to dissolve and be settled to 40L, 3.2kg chlorine is added
Change sodium ethyl alcohol is added after adjusting pH value of solution 6.0 with 3mol/L hydrochloric acid solution, makes the concentration of ethyl alcohol in solution after sodium chloride dissolution
It for 37.5%L/L, is then staticly settled at 15 ± 1 DEG C, sediment separate out and supernatant after precipitating 8 hours.Supernatant is collected, on
Ethyl alcohol is added in clear liquid, when making the concentration 49%L/L of ethyl alcohol in medical fluid, is staticly settled at 15 ± 1 DEG C, and precipitating is received after 8 hours
Collection precipitating obtains dermatan sulfate crude product 1.4kg；
B. the purification of dermatan sulfate
Add purified water to dissolve above-mentioned 1.4kg dermatan sulfate crude product and be settled to 10L, is adjusted with 3mol/L hydrochloric acid solution
11.2g sodium nitrite (in terms of dermatan sulfate crude product weight in wet base) is added into solution after medical fluid pH2.2, is dissolved in using sodium nitrite
It is after 45ml purified water plus into the liquid, it is stirred to react at normal temperature 2 hours, 500g chlorination is added after standing 24 hours in medical fluid
Sodium after stirring and dissolving, adjusts medical fluid pH6.2 with 3mol/L sodium hydroxide solution, ethyl alcohol is added, makes the concentration of ethyl alcohol in medical fluid
43%L/L is staticly settled at 15 ± 1 DEG C, and precipitating collects precipitating and obtains dermatan sulfate fine work 1.1kg, sample detection after 16 hours
Specific rotation is -66.0 °；
If sample detection if dermatan sulfate is not able to satisfy specific rotation≤- 65 °, must repeat above-mentioned precipitation process；Work as sulphur
After sour dermatan testing result meets the requirements, then following oxidative decoloration can be carried out；
C. dermatan sulfate oxidative decoloration
After adding purified water to dissolve the wet fine work of 1.1kg dermatan sulfate and water is added to be settled to 4L, used at 30 ± 1 DEG C
After 3mol/L sodium hydroxide solution adjusts medical fluid pH10.6, the hydrogen peroxide that 40ml 30% is added is reacted；
D. it is precipitated after aoxidizing
After above-mentioned reaction 10 hours, 140g sodium chloride is added into medical fluid, uses 3mol/L hydrochloric acid solution after sodium chloride dissolution
Medical fluid pH6.3 is adjusted, 8L ethyl alcohol is added, is then staticly settled at 15 ± 1 DEG C, precipitating collects dermatan sulfate after 10 hours heavy
It forms sediment；
E. dermatan sulfate is freeze-dried
After 2000ml purified water stirring and dissolving is added into dermatan sulfate precipitating, adds purified water and is settled to 3000ml,
Medical fluid is fitted into lyophilized plate to be put into freeze dryer, starts to cool down to medical fluid, after products temperature is down to -57 DEG C, to whole system
It vacuumizes, after vacuum degree is 14Pa in drying box, product is slowly heated, is kept the temperature after products temperature rises to 51 DEG C, kept the temperature
Dermatan sulfate 367g is made after 3.5 hours.
Sampled detection, dermatan sulfate specific rotation are -66.1 °, and anticoagulant efficiency is < 2USPU/mg, and molecular weight is
25163, sulfate and carboxylic acid group's ratio 1.0.It through Capillary Electrophoretic Determination, is compareed with dermatan sulfate standard items, measurement 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
After adding purified water to dissolve the leftover bits and pieces wet product 4kg for producing refined heparin sodium and be settled to 40L, 2.0kg chlorine is added
Change sodium ethyl alcohol is added after adjusting pH value of solution 5.8 with 3mol/L hydrochloric acid solution, makes the concentration of ethyl alcohol in solution after sodium chloride dissolution
It for 35.4%L/L, is then staticly settled at 11 ± 1 DEG C, sediment separate out and supernatant after precipitating 6 hours.In the supernatant of collection
In add ethyl alcohol, when making the concentration 45.0%L/L of ethyl alcohol in medical fluid, staticly settled at 11 ± 1 DEG C, precipitating 6 hours after collect
Precipitating obtains dermatan sulfate crude product 2.3kg；
B. the purification of dermatan sulfate
Add purified water to dissolve above-mentioned 2.3kg dermatan sulfate crude product and be settled to 10L, is adjusted with 3mol/L hydrochloric acid solution
46g sodium nitrite (in terms of dermatan sulfate crude product weight in wet base) is added into solution after medical fluid pH2.0, is dissolved in using sodium nitrite
It is after 230ml purified water plus into the liquid, it is stirred to react at normal temperature 3 hours, after standing 24 hours, 300g chlorine is added in medical fluid
Change sodium, after stirring and dissolving, adjusts medical fluid pH5.5 with 3mol/L sodium hydroxide solution, ethyl alcohol is added, makes the concentration of ethyl alcohol in medical fluid
It for 40%L/L, is staticly settled at 11 ± 1 DEG C, precipitating collects precipitating and obtains dermatan sulfate fine work 2.0kg, sampling inspection after 8 hours
Surveying specific rotation is -67.2 °；
If sample detection if dermatan sulfate is not able to satisfy specific rotation≤- 65 °, must repeat above-mentioned precipitation process；Work as sulphur
After sour dermatan testing result meets the requirements, then following oxidative decoloration can be carried out；
C. dermatan sulfate oxidative decoloration
After adding purified water to dissolve the wet fine work of 2.0kg dermatan sulfate and water is added to be settled to 8L, used at 26 ± 1 DEG C
After 3mol/L sodium hydroxide solution adjusts medical fluid pH11.5, the hydrogen peroxide that 240ml 30% is added is reacted；
D. it is precipitated after aoxidizing
After above-mentioned reaction 8 hours, 160g sodium chloride is added into medical fluid, uses 3mol/L hydrochloric acid solution tune after sodium chloride dissolution
Whole medical fluid pH5.2, adds 12L ethyl alcohol, then staticly settles at 11 ± 1 DEG C, and precipitating collects dermatan sulfate after 12 hours heavy
It forms sediment；
E. dermatan sulfate is freeze-dried
After 5000ml purified water stirring and dissolving is added into dermatan sulfate precipitating, adds purified water and is settled to 5500ml,
Medical fluid is fitted into lyophilized plate to be put into freeze dryer, starts to cool down to medical fluid, after products temperature is down to -51 DEG C, to whole system
It vacuumizes, after vacuum degree is 11Pa in drying box, product is slowly heated, is kept the temperature after products temperature rises to 54 DEG C, heat preservation 4
Dermatan sulfate 866g is made after hour；
Sampled detection, dermatan sulfate specific rotation are -67.5 °, and anticoagulant efficiency is < 2USPU/mg, and molecular weight is
28365, sulfate and carboxylic acid group's ratio 1.0.It through Capillary Electrophoretic Determination, is compareed with dermatan sulfate standard items, measurement system
The purity of the dermatan sulfate sample obtained is 98.5%.
Embodiment 3: the present embodiment and embodiment 1, embodiment 2 except that
A. rough segmentation
After adding purified water to dissolve the leftover bits and pieces wet product 10kg for producing refined heparin sodium and be settled to 40L, 0.8kg chlorine is added
Change sodium ethyl alcohol is added after adjusting pH value of solution 5.5 with 3mol/L hydrochloric acid solution, makes the concentration of ethyl alcohol in solution after sodium chloride dissolution
It for 32.3%L/L, is then staticly settled at 20 ± 1 DEG C, sediment separate out and supernatant after precipitating 3 hours.In the supernatant of collection
In add ethyl alcohol, when making the concentration 41.1%L/L of ethyl alcohol in medical fluid, staticly settled at 20 ± 1 DEG C, precipitating 10 hours after receive
Collection precipitating obtains dermatan sulfate crude product 5.8kg；
B. the purification of dermatan sulfate
Add purified water to dissolve above-mentioned 5.8kg dermatan sulfate crude product and be settled to 20L, is adjusted with 3mol/L hydrochloric acid solution
168g sodium nitrite (in terms of dermatan sulfate crude product weight in wet base) is added into solution after medical fluid pH2.5, is dissolved in using sodium nitrite
It is after 560ml purified water plus into the liquid, it is stirred to react at normal temperature 5 hours, after standing 24 hours, 1.0kg is added in medical fluid
Sodium chloride after stirring and dissolving, adjusts medical fluid pH6.3 with 3mol/L sodium hydroxide solution, ethyl alcohol is added, and makes the dense of ethyl alcohol in medical fluid
Degree is 41.2%L/L, is staticly settled at 20 ± 1 DEG C, and precipitating collects precipitating and obtains dermatan sulfate fine work 4.6kg after 24 hours, is taken
It is -68.6 ° that sample, which detects specific rotation,；
If sample detection if dermatan sulfate is not able to satisfy specific rotation≤- 65 °, must repeat above-mentioned precipitation process；Work as sulphur
After sour dermatan testing result meets the requirements, then following oxidative decoloration can be carried out；
C. dermatan sulfate oxidative decoloration
After adding purified water to dissolve the wet fine work of 4.6kg dermatan sulfate and water is added to be settled to 12L, used at 33 ± 1 DEG C
After 3mol/L sodium hydroxide solution adjusts medical fluid pH9.3, the hydrogen peroxide that 120ml 30% is added is reacted；
D. it is precipitated after aoxidizing
After above-mentioned reaction 20 hours, 480g sodium chloride is added into medical fluid, uses 3mol/L hydrochloric acid solution after sodium chloride dissolution
Medical fluid pH6.0 is adjusted, 36L ethyl alcohol is added, is then staticly settled at 20 ± 1 DEG C, precipitating collected dermatan sulfate after 22 hours
Precipitating；
E. dermatan sulfate is freeze-dried
After 10L purified water stirring and dissolving is added into dermatan sulfate precipitating, adds purified water and be settled to 12L, by medical fluid
It is fitted into lyophilized plate to be put into freeze dryer, starts to cool down to medical fluid, after products temperature is down to -52 DEG C, whole system is vacuumized,
After vacuum degree is 15Pa in drying box, product is slowly heated, is kept the temperature after products temperature rises to 55 DEG C, heat preservation is made after 5 hours
Obtain dermatan sulfate 1.9kg；
Sampled detection, dermatan sulfate specific rotation are -69.1 °, and anticoagulant efficiency is < 2USPU/mg, and molecular weight is
31254, sulfate and carboxylic acid group's ratio 1.0.It through Capillary Electrophoretic Determination, is compareed with dermatan sulfate standard items, measurement system
The purity of the dermatan sulfate sample obtained is 98.8%.
Claims (1)
1. a kind of heparin sodium leftover bits and pieces prepares high-purity sulfuric acid dermatan technique, feature the following steps are included:
A. rough segmentation
2~10%w/v sodium chloride, chlorination is added after purified water dissolution is added by 5~30%w/v of weight in wet base concentration in heparin sodium leftover bits and pieces
After sodium dissolution, ethyl alcohol is added after adjusting medical fluid pH4.0~6.5, when the concentration of ethyl alcohol in medical fluid is 30~38%v/v, 10~
25 DEG C staticly settle, and precipitating, by sediment and supernatant separation, added ethyl alcohol in isolated supernatant after 2~10 hours, when
It when the concentration of ethyl alcohol is 40~50%v/v in medical fluid, is staticly settled at 10~25 DEG C, precipitating is collected precipitating and obtained after 6~12 hours
Dermatan sulfate crude product；
B. it refines
After purified water dissolution is added by the concentration of 10~50%w/v of weight in wet base in above-mentioned dermatan sulfate crude product, regulating liquid medicine pH2.0
~2.5, then be stirred to react 2~5 hours, be then allowed to stand at normal temperature after 0.6~3.0% w/w sodium nitrite of addition into medical fluid
1~6%w/v sodium chloride is added after 24 hours, after adjusting medical fluid pH4.0~6.5, ethyl alcohol is added, when concentration of alcohol is 37 in medical fluid
It when~45% v/v, is staticly settled at 10~25 DEG C, precipitating collects precipitating and obtains the sulfuric acid of specific rotation≤- 65 ° after 8~24 hours
Dermatan fine work；
C. oxidative decoloration
By dermatan sulfate by 10~50% w/v of weight in wet base add purified water dissolve after, at 25~35 DEG C adjust medical fluid pH9.0~
After 12.0, hydrogen peroxide is added and is reacted, wherein concentration of the hydrogen peroxide in medical fluid is 0.5~4.0%v/v；
D. it precipitates
After above-mentioned reaction 8~36 hours, 1~6% sodium chloride is added into medical fluid by mass volume ratio, is adjusted after sodium chloride dissolution
Whole medical fluid pH4.0~6.5, add the ethyl alcohol of 1.5~3.0 times of medicine liquid volumes, then staticly settle at 10~25 DEG C, precipitating
Dermatan sulfate precipitating is collected after 8~24 hours；
E. it is freeze-dried
Cool down after purified water dissolution is added by 30~45% concentration of weight in wet base in above-mentioned dermatan sulfate sediment, it is cooled to -40~-
It vacuumizes at 60 DEG C, is slowly heated after vacuum degree≤15Pa, kept the temperature after being heated to 50~55 DEG C, is made after heat preservation 3~5 hours
Dermatan sulfate.
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| 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 |
| 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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| 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 |
| CN101885782A (en) * | 2009-05-11 | 2010-11-17 | 深圳市海普瑞药业股份有限公司 | Method for purifying dermatan sulfate from heparin byproduct |
| CN103804506A (en) * | 2014-02-11 | 2014-05-21 | 华中科技大学 | Method for extracting heparin and dermatan sulfate from small intestine lixivium |
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2016
- 2016-07-27 CN CN201610597994.9A patent/CN106188341B/en active Active
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN101885782A (en) * | 2009-05-11 | 2010-11-17 | 深圳市海普瑞药业股份有限公司 | Method for purifying dermatan sulfate from heparin byproduct |
| CN103804506A (en) * | 2014-02-11 | 2014-05-21 | 华中科技大学 | Method for extracting heparin and dermatan sulfate from small intestine lixivium |
Non-Patent Citations (1)
| Title |
|---|
| LOW MOLECULAR WEIGHT DERMATAN SULFATE AS AN ANTITHROMBOTIC AGENT;Robert J. Linhardt et al;《Biochemical Pharmacology》;19941231;第47卷(第7期);第1241-1252页 |
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