CN1840547A - Method for preparing hydroxyethyl starch with different molecular weight and different substitution degree - Google Patents
Method for preparing hydroxyethyl starch with different molecular weight and different substitution degree Download PDFInfo
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- CN1840547A CN1840547A CN 200510136026 CN200510136026A CN1840547A CN 1840547 A CN1840547 A CN 1840547A CN 200510136026 CN200510136026 CN 200510136026 CN 200510136026 A CN200510136026 A CN 200510136026A CN 1840547 A CN1840547 A CN 1840547A
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Abstract
The preparation method for hydroxyethyl starch with different molecular weight and substitution degree comprises: adding proper corn starch into HCl with given concentration for hydrolysis at some temperature; adjusting pH value in 6.0-6.5, adding epoxyethane for hydroxyethylation on alkaline condition and low temperature; heating, filtering, ultrafiltering, and spray drying to obtain the product. This invention is environmental friend, low cost, and well quality.
Description
Technical field: the invention belongs to field of medicaments, it be specifically related to a kind of as plasma substitute different molecular weight and the preparation method of the hydroxyethylamyle of different substitution degrees.
Background technology: from the thirties in 20th century, since the gelatin gels plasma substitute comes out, existing so far nearly 80 years history.Invented the polyvinylpyrrolidone (PVP) of synthetic during the World War I, microorganism synthetic dextrorotation candy acid anhydride (Dextran) has appearred again in World War II, the mid-1970s U.S. develops hydroxyethylamyle (HydroxyethylStarch, HES), China is by China Concord Medical Science University, Chinese Academy of Medical Sciences's blood transfusion and Blood Research Institute, studied successful dextrorotation candy acid anhydride and hydroxyethylamyle respectively in 1958 and 1967, and form industrialization at home rapidly, this has brought into play significant role to China prevention and treatment Hypovolemia and shock patients, has saved millions of life.Clinically, the hydroxyethylamyle volume treatment of doing commonly used, behind the intravenously administrable, Q volume of blood can increase sharply, be usually used in treatment because of profuse bleeding, burn or other wounds shock or the hemorrhage that cause, can prevent each organic blood flow volume that cycle penalty that the backflow Q volume of blood causes causes, oxygen for the amount minimizing organ failure of appearance.Experimental study and the clinical application practice of decades show, really estimate from clinical application safety and blood plasma dilatation dose-effect, and hydroxyethylamyle has become first-use drug---the plasma substitute that common people are used for the treatment of the shock patient that losing blood property and a variety of causes cause.Abroad report in the period of 1978 to 1992 15, three kinds of plasma substitute quantity of clinical use gelatin, dextrorotation candy acid anhydride, hydroxyethylamyle relatively, to hydroxyethylamyle consumption in 1992 be that the first two plants more than 10 times; Aspect security, see with the anaphylaxis of clinical worry the most, also be that hydroxyethylamyle is minimum (0.054%), only be equivalent to 1/6 of gelatin, 1/4.7 of dextrorotation candy acid anhydride, even than also low one times of human albumin; Add raw material from natural corn, not only obtain easily but also good and cheap, and relatively letter of technology, be convenient to promote and produce.Because the chemical constitution and the similar of hydroxyethylamyle are former in the human body glycogen, be easy to metabolism at the blood vessel internal recycle in addition, the overwhelming majority is discharged from urine, thereby does not almost have savings in organ, and vast clinical position person is happy to adopt.
Abroad, the hydroxyethylamyle sodium chloride injection is at country variant, its selected clinically kind is different, the hydroxyethylamyle molecular-weight average is 480KD ten thousand on American market, mainly produced by du pont company (DuPont), commodity respectively are HESPan, and this product is widely used in the U.S., its Q volume of blood expands big, and is lasting and effective.6% (480/0.7) average out to 24h action time, the defective on the performance is that it is influential and poultry is long-pending in vivo to blood coagulation system, and the ($43/500ml 6%480/0.7 that costs an arm and a leg) thereby limited its application clinically.On the European market, Germany's Fresenius card has been succeeded in developing commodity He Si (HAES) 200/0.5 hydroxyethylamyle product by name than company (Fresenius kabi) in nineteen eighty-two, this product occupies the European market more than 70%, and entered Chinese market by standard in 1999, this product molecular-weight average 200KD, substitution value 0.43-0.55, be used for plasma substitute, dilatation intensity is big, it is 100% that the 6%HES dilatation is renderd a service, dilatation 4-8 working lipe hour, and the transformation period is 3-4 hour, irritated incidence is low, be the leading product on the European plasma substitute market, it is 130KD that nearest Fresenius card is released its molecular-weight average of hydroxyethylamyle product Voluven of new generation again than company, and substitution value is 0.4, they think a lower molecular weight and a low mole degree of exchange can further improve Product Safety and validity.By to studies show that of concerning between hydroxyethylamyle chemical structure characteristics and the physiological function, big more its dilatation intensity of hydroxyethylamyle molecular-weight average is big more, molecular weight size decision dilatation is renderd a service, transformation period length in its circulation of blood of degree of exchange size decision, make a general survey of the development of external hydroxyethylamyle as can be seen, hydroxyethylamyle just from the high mole of high molecular degree of exchange towards lower molecular weight and low degree of exchange production development. Homemade hydroxyethylamyle 40 or 20 products (706 plasma substitute), because molecular weight is lower, and degree of exchange higher (0.8-1.2), blood plasma dilatation effect is relatively poor, the transformation period is shorter in the circulation of blood, the anti-hemorrhagic shock function is lower, and clinical at home being mainly used in improved blood flow, treatment circulation or microcirculation disturbance patient.
The preparation hydroxyethylamyle will pass through hydrolysis and hydroxyethylation step usually, makes a general survey of domestic and international pertinent literature and patent, and hydrolysis and hydroxyethylation technology are not quite similar.With regard to hydrolysis, can be divided into substantially: acid hydrolysis, enzymic hydrolysis, methyl alcohol-acid hydrolysis.United States Patent (USP) once adopted acid hydrolysis (U.S.Pat.No.4,016,354), though its operation is simpler, the reaction times is longer, particularly the molecular weight distribution broad; Enzymic hydrolysis also has relevant patent (U.S.Pat.No.4,629,698), but because higher suitability for industrialized production and the enzyme itself of being unfavorable for of its cost is exactly a kind of sensitization source, so generally seldom adopt; Methyl alcohol-acid hydrolysis also has more report, ' 706 ' plasma substitute that our country produces adopts this method to be hydrolyzed exactly, similar patent (U.S.Pat.No.5 is abroad also arranged, 218,108), because methyl alcohol is a kind of inflammable, explosive, poisonous organic solvent, environmental pollution, production is difficult to guarantee safety again.For hydroxyethylation, a kind of is to be the dispersion medium (U.S.Pat.No.4,629,698, U.S.Pat.No.5,218,108) of ethoxyl etherification with water, and ' 706 ' plasma substitute that our country produces adopts this method to carry out hydroxyethylation exactly; Another kind is to be dispersion medium (U.S.Pat.No.4,016,354) with the organic solvent Virahol.Though starch disperses better in organic solvent, Virahol has also brought many defectives such as aftertreatment difficulty, long flow path, cost height accordingly, and it is not adapted at China and is used for suitability for industrialized production.
Can see that from above content the technology of preparation hydroxyethylamyle has multiple, but all be unable to do without with organic solvent as reaction medium or purified product.This patent is a brand-new preparation technology who develops at the problem that exists in the above-mentioned domestic and international technology about the preparation method of hydroxyethylamyle.
It is the acid hydrolysis medium that homemade hydroxyethylamyle (20/0.8,40/0.8) adopts methyl alcohol, has major hidden danger such as safety, environmental protection and complicated operation, long, the high shortcoming that is difficult to overcome of cost of technical process; Add and be limited to domestic technical qualification at that time, the goods molecular weight distribution also is difficult to control; Abroad in hydroxyethylation technology, the still employing with the Virahol is the suspension medium of ethoxyl etherification more, cause producing the back operation and will pass through acetone, ethanol, water etc. and repeatedly clean, cause and operate difficulty, long flow path, safety and environmental protection etc. and all be difficult to serious problems such as assurance.
Summary of the invention: the objective of the invention is for overcoming the great steady trouble of the safety and environmental protection that exists among the prior art hydroxyethylamyle preparation technology, the special this programme that proposes of technical process is long, cost is high, operation easier is big problem---be used for the preparation technology of the hydroxyethylamyle of different molecular weight and different substitution degrees, it is adopted new technology, avoided the dispersion medium of organic solvent, the cycle of having realized is short, cost is low and the product of better function, reaches the advanced level of international like product.
By as above design, the preparation technology's of the hydroxyethylamyle that is used for different molecular weight and different substitution degrees that this programme proposed feature is: the whole preparation process at it are to be dispersion medium with the pure water, and do not have any organic solvent; After hydrolysis, directly carry out ethoxyl etherification without centrifugal, explosion-proof drying operation; Be under low temperature environment, to add oxyethane in the hydroxylation process; In aftertreatment, adopt advanced ultra-filtration technique to regulate and control the molecular weight distribution of hydroxyethylamyle and residue and the by product of removing reaction.Its technological process comprises:
1. W-Gum concentration in pure water is 30～50% (W/V) in the acid hydrolysis, and concentration of hydrochloric acid is 2～3mol/L, and hydrolysis temperature is 50 ℃～60 ℃, and hydrolysis time was controlled at 1～4 hour by the goods molecular weight;
2. hydrolyzed starch concentration in pure water is 20～40% (W/V) in the hydroxyethylation, alkali concn is 0.5～1.0mol/L, determine that by goods mole substitution degree the oxyethane add-on is 20～50% (W/V), when reducing to 1～5 ℃, feed temperature adds oxyethane, be warming up to 35～45 ℃ after adding, reaction times is pressed goods mole substitution degree control 3～5 hours, and at room temperature places and spend the night;
3. behind hydroxyethylation, in the purifying process, after hydroxyethylamyle feed liquid process activated carbon decolorizing, the filtration, get hydroxyethylamyle with ultrafiltration, spraying drying means again.
In this programme, used W-Gum is the medical grade W-Gum in the preparation process.Gained hydroxyethylamyle feed liquid adds 1～3 times pure water under the condition of 50～60 ℃, 6～10% (W/V), carry out ultrafiltration with 8～100KD ultra-filtration membrane.Prepared hydroxyethylamyle average molecular weight range is 20KD～450KD, and mole substitution degree scope is 0.4～0.8.
Adopt this programme can embody following superiority: content 1. of the present invention promptly is the dispersion medium of full scale production technology with the pure water, need not any organic solvent, from root avoided the environmental pollution that methyl alcohol, Virahol, acetone, ether and ethanol etc. brought used the domestic and international existing production technique, produced dangerous, operating process length, the great problem that is difficult to overcome such as cost height; 2. in the hydroxyethylation process, controlled temperature is adding oxyethane below 5 ℃, and reacts in totally-enclosed reactor.Thereby avoided the volatilization of oxyethane to greatest extent, guaranteed to produce and personal security; 3. in the aftertreatment of product, adopted the ultra-filtration technique that is beneficial to suitability for industrialized production, make that residual ethylene oxide and other impurity all can be removed to bottom line in our goods, both guaranteed clinical safe in utilization, improve the product appearance quality again significantly, as homemade ' 706 ' goods long-term existence face light yellow complexions and slight opalescence phenomenon, we have reached water white transparency by the novel process product, and similar advanced goods with the world are on close level; 4. in the operation of prior art, there is by product to produce, in subsequent disposal, there is not a kind of good method to remove by product again, scrape off the yellow impurities of precipitation surface so will take much more after centrifugal, and when hydroxyethylation, hydrolyzed starch is made into suspension and gelatinization again again just can carry out ethoxyl etherification, the present invention directly carries out ethoxyl etherification after hydrolysis, thereby preparation time is shortened greatly, the also corresponding simplification of equipment used; 5. this shows the novel process of above-mentioned preparation hydroxyethylamyle of the present invention, characteristics (table 1) such as have environmental protection, safety, man-hour is short, cost is low.No matter the main physical and chemical index of quality of item or the biology pharmacodynamic experiment result that produce with this novel process all are better than domestic ' 706 ' goods (tables 2, Fig. 2,4), and it is suitable with external similar advanced goods comparison overall quality level, and animal dis motility rate in the test of antishock drug effect, our novel process product is higher than external product (table 2, Fig. 1,3).
Description of drawings:
Fig. 1 is HES200/0.5 and the reference substance HES200/0.5HPLC method molecular weight determination spectrogram that is made by the inventive method.
Fig. 2 is HES40/0.8 and homemade ' 706 ' (40/0.8) the HPLC method molecular weight determination spectrogram that is made by the inventive method.
Fig. 3 is compared by HES200/0.5 and reference substance HES200/0.5 antishock experimental animal survival rate that the inventive method makes.
Fig. 4 is compared by HES40/0.8 and reference substance HES40/0.8 antishock experimental animal survival rate that the inventive method makes.
Embodiment: followingly technology contents of the present invention is described by concrete example.
Example 1 (middle molecule is an example with HES 200/0.5)
Medical grade W-Gum 10Kg is joined in 50～55 ℃, the hydrochloric acid of 20L 2～3mol/L, abundant mixing, when treating that feed liquid rises to the regulation hydrolysis temperature, stirring reaction 2～2.5 hours picks up counting.After hydrolysis is finished, NaOH with 4mol/L in totally-enclosed interlayer reactor transfers reaction solution PH6.0～6.5, and NaOH to the NaOH final concentration that adds 4mol/L once more is 0.5～1.0mol/L, before adding oxyethane, earlier feed liquid is cooled to about 1～5 ℃, under the state that stirs, adds 20～30% oxyethane, after treating feed liquid and oxyethane mixing, reaction solution was warming up to 35～40 ℃ of stirring reactions 3～4 hours again.After hydroxyethylation is finished, stop to stir, leave standstill more than 12 hours.Before the aftertreatment, scrape off the white foam on reaction solution upper strata earlier, hydrochloric acid with 2～3mol/L is transferred reaction solution PH6.0～6.5, again by weight/amount of volume ratio 0.5～1.0% add medical sorbent material such as gac or white bole and thorough mixing evenly after, kept 0.5～2 hour in 90～100 ℃ of scopes, when treating that feed liquid is cooled to 60～80 ℃, use 1.0um respectively, 0.45um the titanium rod filters successively, the gained hydroxyethylamyle carries out ultrafiltration with the 10KD filter membrane under 6～10% condition, the purified water that is added is 1～3 times of feed liquid, temperature remains on 50～70 ℃ in the process, so that reach good ultrafiltration effect.Afterwards, if will be prepared into pulvis, can directly feed liquid be carried out spraying drying or vacuum-drying; If will be prepared into infusion solutions, should transfer earlier that PH4.0～7.0, hydroxyethylamyle concentration are 6.0～6.3%, Nacl content is 0.90～0.95%, again by weight/amount of volume ratio 0.2～0.5% add medical sorbent material such as gac or white bole and thorough mixing evenly after, kept 0.5～1 hour in 90～100 ℃ of scopes, when treating that feed liquid is cooled to 50～70 ℃, respectively with 0.45um, 0.22um titanium rod filter successively the finished product.By the HES 200/0.5 of foregoing invention method preparation and abroad as shown in Figure 1 with the HPLC collection of illustrative plates of based article molecular weight distribution.The anti-hemorrhagic shock results of pharmacodynamic test as shown in Figure 3.
Example 2 (low molecule is an example with HES 40/0.8)
Medical grade W-Gum 10Kg is joined in 55～60 ℃, the hydrochloric acid of 20L 2～3mol/L, abundant mixing, when treating that feed liquid rises to the regulation hydrolysis temperature, stirring reaction 1.5～2.0 hours picks up counting.After hydrolysis is finished, NaOH with 4mol/L in totally-enclosed interlayer reactor transfers reaction solution PH6.0～6.5, and NaOH to the NaOH final concentration that adds 4mol/L once more is 0.5～1.0mol/L, before adding oxyethane, earlier feed liquid is cooled to about 1～5 ℃, under the state that stirs, adds 40～50% oxyethane, after treating feed liquid and oxyethane mixing, reaction solution was warming up to 35～40 ℃ of stirring reactions 3～4 hours again.After hydroxyethylation is finished, stop to stir, leave standstill more than 12 hours.Before the aftertreatment, scrape off the white foam on reaction solution upper strata earlier, hydrochloric acid with 2～3mol/L is transferred reaction solution PH6.0～6.5, again by weight/amount of volume ratio 0.5～1.0% add medical sorbent material such as gac or white bole and thorough mixing evenly after, kept 0.5～2 hour in 90～100 ℃ of scopes, when treating that feed liquid is cooled to 60～80 ℃, use 1.0um respectively, 0.45um the titanium rod filters successively, the gained hydroxyethylamyle carries out ultrafiltration with the 10KD filter membrane under 6～10% condition, the purified water that is added is 1～2 times of feed liquid, temperature remains on 50～70 ℃ in the process, so that reach good ultrafiltration effect.Afterwards, if will be prepared into pulvis, can directly feed liquid be carried out spraying drying or vacuum-drying; If will be prepared into infusion solutions, should transfer earlier that PH4.0～7.0, hydroxyethylamyle concentration are 6.0～6.3%, Nacl content is 0.90～0.95%, again by weight/amount of volume ratio 0.2～0.5% add medical sorbent material such as gac or white bole and thorough mixing evenly after, kept 0.5～1 hour in 90～100 ℃ of scopes, when treating that feed liquid is cooled to 50～70 ℃, respectively with 0.45um, 0.22um titanium rod filter successively the finished product.By the HES 40/0.8 of foregoing invention method preparation and domestic HPLC collection of illustrative plates with the based article molecular weight distribution as shown in Figure 2.The anti-hemorrhagic shock results of pharmacodynamic test as shown in Figure 4.
| Content | Domestic former technology | External technology | This technology |
| Process time | 72 hours | Average 48 hours | 28 hours |
| * cost | 100％ | 200％ | 60％ |
| Safety | Dangerous | Hidden danger is arranged | Safety |
| Environment | Serious hidden danger | Pollution is arranged | Pollution-free |
The similar technology with other of table 1. technology of the present invention relatively
* annotate, the former technology of cost is 100%, and other is done relatively
| Test item | The inventive method resulting product (n=20) | * external HES 200/0.5 | * domestic ' 706 ' (40) goods | |
| 200/0.5 | 40/0.8 | |||
| Hydroxyethylamyle concentration | 5.7～6.3 ％ | 5.7～6.3％ | 5.7～6.3％ | 5.7～6.3％ |
| Molecular-weight average | 220～260KD (laser scattering method) | 22～25KD (HPLC method) | 220～260KD (laser scattering method) | 22～25KD (HPLC method) |
| Distribution coefficient (D) | 2.0～2.4 | 1.5～1.7 | 2.5～2.8 | 1.9～2.2 |
| The mole degree of exchange | 0.43～ 0.55 | 0.8～0.9 | 0.43～0.55 | 0.9～1.0 |
| Colourity (375nm) | 0.012～ 0.030 | 0.020～ 0.035 | 0.020～ 0.030 | 0.060～ 0.075 |
| Δ | 0 | 0 | 0 | Slight opalescence |
| PH value | 6.0～6.5 | 6.0～6.5 | 6.0～6.5 | 6.0～6.5 |
| Heavy metal | Qualified | Qualified | Qualified | Qualified |
The main physical and chemical quality of table 2 goods relatively
Annotate:
ΔPress the clear feelings degree of Chinese Pharmacopoeia (2000) regulation and check, 0 can not see opalescence substantially for naked eyes.* external and domestic ' 706 ' (40) reference substance n=3～5.
Claims (4)
1, a kind of preparation method who is used for the hydroxyethylamyle of different molecular weight and different substitution degrees is characterized in that in its whole preparation process with the pure water being dispersion medium, and does not have any organic solvent; After hydrolysis, directly carry out ethoxyl etherification without centrifugal, explosion-proof drying operation; Be under low temperature environment, to add oxyethane in the hydroxylation process; In aftertreatment, adopt advanced ultra-filtration technique to regulate and control the molecular weight distribution of hydroxyethylamyle and residue and the by product of removing reaction, its technological process comprises:
1. W-Gum concentration in pure water is 30～50% (W/V) in the acid hydrolysis, and concentration of hydrochloric acid is 2～3mol/L, and hydrolysis temperature is 50 ℃～60 ℃, and hydrolysis time was controlled at 1～4 hour by the goods molecular weight;
2. hydrolyzed starch concentration in pure water is 20～40% (W/V) in the hydroxyethylation, alkali concn is 0.5～1.0mol/L, determine that by goods mole substitution degree the oxyethane add-on is 20～50% (W/V), when reducing to 1～5 ℃, feed temperature adds oxyethane, be warming up to 35～45 ℃ after adding, reaction times is pressed goods mole substitution degree control 3～5 hours, and at room temperature places and spend the night;
3. behind hydroxyethylation, in the purifying process, after hydroxyethylamyle feed liquid process activated carbon decolorizing, the filtration, get hydroxyethylamyle with ultrafiltration, spraying drying means again.
2, preparation method as claimed in claim 1, it is characterized in that preparing used W-Gum is the medical grade W-Gum.
3, preparation method as claimed in claim 1 is characterized in that gained hydroxyethylamyle feed liquid adds 1～3 times pure water under the condition of 50～60 ℃, 6～10% (W/V), carry out ultrafiltration with 8～100KD ultra-filtration membrane.
4, preparation method as claimed in claim 1 is characterized in that prepared hydroxyethylamyle average molecular weight range is 20KD～450KD, and mole substitution degree scope is 0.4～0.8.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102167750A (en) * | 2011-01-19 | 2011-08-31 | 北京莱瑞森医药科技有限公司 | Preparation method of 130ethoxyl starch |
| CN102276742A (en) * | 2011-08-09 | 2011-12-14 | 武汉华科大生命科技有限公司 | Method for cleanly producing MMW (medium molecular weight) hydroxyethyl starches |
| CN102659953A (en) * | 2012-04-18 | 2012-09-12 | 高旭 | Preparation method of hydroxyethyl starch with molecular weight of 5,500,000 |
| CN104277126A (en) * | 2013-07-11 | 2015-01-14 | 北大方正集团有限公司 | Method for purifying hydroxyethyl starch |
| CN106589148A (en) * | 2016-12-27 | 2017-04-26 | 武汉华科大生命科技有限公司 | Preparation method of narrow-range hydroxyethyl starch |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2700011A1 (en) * | 1977-01-03 | 1978-07-06 | Hideo Omoto | Prodn. of hydroxyethyl starch for use as plasma substitute - from waxy starch by reaction with ethylene oxide then controlled acid hydrolysis |
| JPS5941441B2 (en) * | 1977-11-14 | 1984-10-06 | 杏林製薬株式会社 | Method for producing hydroxyethyl starch |
| DE3313600A1 (en) * | 1983-04-14 | 1984-10-18 | Laevosan-Gesellschaft mbH & Co. KG, Linz | PLASMA STRUCTURAL PRODUCTS BASED ON STARCH AND METHOD FOR THE PRODUCTION THEREOF |
| DE3919729C3 (en) * | 1989-06-16 | 1997-06-19 | Fresenius Ag | Hydroxyethyl starch as a plasma expander, process for their preparation and use as a colloidal plasma substitute |
| DE4310974C2 (en) * | 1993-04-03 | 1996-08-01 | Fresenius Ag | Use of hydroxyethyl starch to improve microcirculation |
| US7863260B2 (en) * | 2004-03-01 | 2011-01-04 | B. Braun Melsungen Ag | Hydroxyethylstarch |
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2005
- 2005-12-29 CN CNB200510136026XA patent/CN100453558C/en not_active Expired - Fee Related
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102167750A (en) * | 2011-01-19 | 2011-08-31 | 北京莱瑞森医药科技有限公司 | Preparation method of 130ethoxyl starch |
| CN102167750B (en) * | 2011-01-19 | 2012-07-25 | 北京莱瑞森医药科技有限公司 | Preparation method of 130ethoxyl starch |
| CN102276742A (en) * | 2011-08-09 | 2011-12-14 | 武汉华科大生命科技有限公司 | Method for cleanly producing MMW (medium molecular weight) hydroxyethyl starches |
| CN102659953A (en) * | 2012-04-18 | 2012-09-12 | 高旭 | Preparation method of hydroxyethyl starch with molecular weight of 5,500,000 |
| CN102659953B (en) * | 2012-04-18 | 2016-01-20 | 高旭 | A kind of molecular weight is the preparation method of the hydroxyethylamyle of 5,500,000 |
| CN104277126A (en) * | 2013-07-11 | 2015-01-14 | 北大方正集团有限公司 | Method for purifying hydroxyethyl starch |
| CN104277126B (en) * | 2013-07-11 | 2016-08-10 | 北大方正集团有限公司 | The method of purification of hetastarch |
| CN106589148A (en) * | 2016-12-27 | 2017-04-26 | 武汉华科大生命科技有限公司 | Preparation method of narrow-range hydroxyethyl starch |
| CN106589148B (en) * | 2016-12-27 | 2019-04-12 | 武汉华科大生命科技有限公司 | A kind of preparation method of narrow ditribution hydroxyethyl starch |
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| CN100453558C (en) | 2009-01-21 |
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