CN110922507A - Production process of low-molecular-weight heparin sodium with good quality and high yield - Google Patents
Production process of low-molecular-weight heparin sodium with good quality and high yield Download PDFInfo
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- 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
- C08B37/0075—Heparin; Heparan sulfate; Derivatives thereof, e.g. heparosan; Purification or extraction methods thereof
- C08B37/0078—Degradation products
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- C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
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Abstract
The invention relates to a production process of low molecular weight heparin sodium with good quality and high yield, which comprises the following steps: degrading, reducing and oxidizing heparin sodium, collecting an oxidizing solution, adjusting the oxidizing solution to be weakly acidic, adding dichloromethane, uniformly mixing, and filtering; collecting filtrate, adding sodium chloride, mixing, precipitating with ethanol, ultraviolet irradiating, grading molecular weight, and lyophilizing. Can effectively improve the purity and the yield of the low molecular weight heparin sodium. The method has the advantages of low preparation cost, simple and easy operation, less time consumption, high efficiency, good stability, environmental friendliness, good repeatability, and easy universality and large-scale production.
Description
Technical Field
The invention belongs to the field of production and preparation of low-molecular-weight heparin sodium, and particularly relates to a production process of low-molecular-weight heparin sodium with good quality and high yield.
Background
The information in this background section is only for enhancement of understanding of the general background of the invention and is not necessarily to be construed as an admission or any form of suggestion that this information forms the prior art already known to a person of ordinary skill in the art.
Heparin sodium (Heparin sodium) can interfere with many links of the blood coagulation process and has the function of anticoagulation in vivo and in vitro. The mechanism of action is complex, and the inhibition of activated blood coagulation factors II, IX, X, XI and XII by the latter is enhanced mainly by binding to antithrombin III (AT-III), which later involves preventing platelet aggregation and destruction, preventing the formation of thromboplastin, preventing prothrombin from becoming thrombin, inhibiting thrombin, thereby preventing fibrinogen from becoming fibrin, and thus exerting anticoagulation.
Compared with the common heparin sodium, the low molecular heparin sodium has the following obvious advantages: the weight average molecular weight is lower (5600-. Therefore, the preparation process of the low molecular weight heparin sodium is widely concerned in the field.
However, the inventor finds that: the existing preparation process of low molecular weight heparin sodium is greatly influenced by the quality of the raw material heparin sodium, and the quality of the product still needs to be improved.
Disclosure of Invention
In order to overcome the problems, the invention provides a production process of low molecular weight heparin sodium with good quality and high yield. Can effectively improve the purity and the yield of the low molecular weight heparin sodium. The method has the advantages of low preparation cost, simple and easy operation, less time consumption, high efficiency, good stability, environmental friendliness, good repeatability, and easy universality and large-scale production.
In order to achieve the technical purpose, the technical scheme adopted by the invention is as follows:
a production process of low molecular weight heparin sodium with good quality and high yield comprises the following steps:
degrading, reducing and oxidizing heparin sodium, collecting an oxidizing solution, adjusting the oxidizing solution to be weakly acidic, adding dichloromethane, uniformly mixing, and filtering;
collecting filtrate, adding sodium chloride, mixing, precipitating with ethanol, ultraviolet irradiating, grading molecular weight, and lyophilizing.
The research of the application finds that: the purity and the yield of the low molecular weight heparin sodium can be effectively improved by adding a certain amount of dichloromethane into the oxidation solution containing the heparin sodium.
In some embodiments, the dichloromethane is added in an amount of 0.1 to 5% by volume of the filtrate.
In some embodiments, the mildly acidic pH is 6.20 ± 0.02.
In some embodiments, the weakly acidic conditioning employs a strong or weak base salt.
In some embodiments, the weakly acidic conditioning is performed by using sodium hydroxide with the concentration of 18.0-22.0% W/V.
In some embodiments, the lyophilization process is preceded by vacuum spin drying.
In some embodiments, the vacuum spin drying comprises the following specific steps: the final filtrate was vacuum rotary dried to 1/3 volumes of filtrate to be collected, and then water was added to the original volume.
In some embodiments, the temperature of the vacuum spin drying is 45 ℃ or less.
The invention also provides the low molecular weight heparin sodium prepared by any one of the methods.
The invention also provides the application of the low molecular weight heparin sodium in preparing antithrombotic, anticoagulant, anti-inflammatory or antitumor drugs.
The invention has the beneficial effects that:
(1) the invention can effectively improve the purity and yield of the low molecular weight heparin sodium. The method has the advantages of low preparation cost, simple and easy operation, less time consumption, high efficiency, good stability, environmental friendliness, good repeatability, and easy universality and large-scale production.
(2) The operation method is simple, low in cost, universal and easy for large-scale production.
Detailed Description
It should be noted that the following detailed description is exemplary and is intended to provide further explanation of the disclosure. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs.
It is noted that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of example embodiments according to the present application. As used herein, the singular is intended to include the plural unless the context clearly dictates otherwise, and it should be further understood that the terms "comprises" and/or "comprising," when used in this specification, specify the presence of features, steps, operations, devices, components, and/or combinations thereof.
As introduced in the background art, the method aims at the problems of low purity and low yield of the low molecular weight heparin sodium. Therefore, the invention provides a production process of low molecular weight heparin sodium with good quality and high yield. Can effectively improve the purity and the yield of the low molecular weight heparin sodium. The method has the advantages of low preparation cost, simple and easy operation, less time consumption, high efficiency, good stability, environmental friendliness, good repeatability, and easy universality and large-scale production.
The present invention is described in further detail below with reference to specific examples, which are intended to be illustrative of the invention and not limiting.
Example 1:
1. dissolution
Precisely weighing refined heparin sodium, and dissolving with purified water to obtain 10% (W/V) solution.
2. Degradation of
Precisely weighing sodium nitrite solid with the mass being 2.5% (W/W) of the mass of the heparin sodium, pouring the solid into a small beaker, measuring a proper amount of purified water, adding the purified water into the beaker to completely dissolve the sodium nitrite, and preparing a 25% (W/V) test solution for later use. And after the heparin sodium is completely dissolved, adjusting the pH value of the feed liquid to 2.6. After the pH adjustment is finished, the prepared sodium nitrite solution is poured into the reaction system. After the system reacts for half an hour, taking the feed liquid every ten minutes to mix with a starch potassium iodide test solution (which can be used within the configured period of validity and can be replaced by a starch potassium iodide test paper), and finishing the degradation reaction if the starch potassium iodide test solution does not turn blue within 3 s.
3. Reduction of
After the degradation reaction is finished, the pH value of the feed liquid is measured by a pH meter, and 20.0% (W/V) sodium hydroxide solution is added dropwise to adjust the pH value of the feed liquid to 10.0, and the operation is finished within 10 min. Precisely weighing sodium borohydride solid with 1% (w/w) of the weight of the heparin sodium, pouring the sodium borohydride solid into the feed liquid, and maintaining low-speed stirring (the stirring speed is determined according to the condition that bubbles are released from the liquid surface, and preferably no bubbles or few bubbles are released) to react with the pH value for 12 hours. After the reduction reaction is finished, measuring the pH value, dropwise adding 6mol/L hydrochloric acid solution to adjust the pH value of the liquid medicine to 4.0, and maintaining the reaction for 30 min.
4. Oxidation by oxygen
After the reduction, sodium hydroxide (20% (W/V)) was added to adjust the pH of the solution to 10, hydrogen peroxide (30%, V/V) was added to 1.0%, the solution was adjusted to a pH of 10 every 2 hours to maintain stability, and the solution was allowed to stand and oxidize for 12 hours.
5. Ultraviolet light
Filtering after oxidation, adding 20.0% (W/V) sodium hydroxide solution dropwise to adjust pH of the medicinal liquid to 6.20, adding dichloromethane (2.5% (V/V) of the medicinal liquid volume), stirring for more than 30min, and filtering. Sodium chloride solids, 1.5% (w/v) of the feed volume, were weighed into the filtrate and dissolved. Measuring ethanol (95% ethanol needs to be filtered) with a volume 1 time of that of the feed liquid by using a measuring cylinder, pouring the measured ethanol into a beaker while stirring, properly stirring for 20min after the ethanol is added, and standing for 9 hours. (the time is determined by precipitation, the clearer the supernatant is. After the precipitation is finished, the supernatant is poured off, and the precipitate is left. An appropriate amount of purified water was poured into a beaker to a dissolution concentration of 8% (w/v), and the precipitate was dissolved by stirring. After the precipitate is completely dissolved, adjusting the pH value of the liquid medicine to 6.20 by using 6mol/L hydrochloric acid solution, completely transferring the liquid medicine into an ultraviolet irradiation instrument, and starting the ultraviolet irradiation instrument for 1 h.
6 molecular weight fractionation
Filtering after irradiation, measuring the volume of the filtrate, weighing 1.5% sodium chloride solid in the feed liquid, adding into the feed liquid, and stirring to dissolve. The measuring cylinder measures ethanol (95% ethanol) with the volume 0.9 times that of the feed liquid, the ethanol is poured into the feed liquid while stirring, and the feed liquid is kept stand for 9 hours after the pouring is finished. And pouring the supernatant after the standing is finished, and reserving the precipitate.
The precipitate was dissolved with purified water to give an 8% (w/v) solution. Taking 2ml of feed liquid, checking molecular weight, adjusting pH of the liquid medicine to 6.20 with 6mol/L hydrochloric acid solution, and filtering (same as above). Taking ethanol (95% ethanol) with the volume of 0.9 times of the filtrate volume, pouring the ethanol into the feed liquid while stirring, and standing for 9 hours after pouring. And pouring the supernatant after the standing is finished, and reserving the precipitate. The precipitate was dissolved in purified water to give a 10% solution, and a sample was taken to measure the molecular weight. And (5) if the molecular weight is unqualified, repeating the step 6 until the molecular weight is qualified, and then carrying out the next step.
7. Freeze-drying
And (3) putting the final filtrate obtained in the step (6) into a rotary dryer, carrying out vacuum spin drying under the condition of 40 ℃, pulling vacuum, stopping vacuum drying after liquid is collected to be 1/3 of the volume of the filtrate, supplementing water to the filtrate to be in the original volume, and directly feeding the filtered filtrate into a freeze dryer for freeze drying.
Example 2:
1. dissolution
Precisely weighing refined heparin sodium, and dissolving with purified water to obtain 5% (W/V) solution.
2. Degradation of
Precisely weighing sodium nitrite solid with the mass being 2.2 percent (W/W) of the mass of the heparin sodium, pouring the solid into a small beaker, measuring a proper amount of purified water, adding the purified water into the beaker to completely dissolve the sodium nitrite, and preparing a 25 percent (W/V) test solution for later use. And after the heparin sodium is completely dissolved, adjusting the pH value of the feed liquid to 2.3. After the pH adjustment is finished, the prepared sodium nitrite solution is poured into the reaction system. After the system reacts for half an hour, taking the feed liquid every ten minutes to mix with a starch potassium iodide test solution (which can be used within the configured period of validity and can be replaced by a starch potassium iodide test paper), and finishing the degradation reaction if the starch potassium iodide test solution does not turn blue within 3 s.
3. Reduction of
After the degradation reaction is finished, the pH value of the feed liquid is measured by a pH meter, and 20.0% (W/V) sodium hydroxide solution is added dropwise to adjust the pH value of the feed liquid to 10.0, and the operation is finished within 10 min. Precisely weighing sodium borohydride solid with 1% (w/w) of the weight of the heparin sodium, pouring the sodium borohydride solid into the feed liquid, and maintaining low-speed stirring (the stirring speed is determined according to the condition that bubbles are released from the liquid surface, and preferably no bubbles or few bubbles are released) to react with the pH value for 12 hours. After the reduction reaction is finished, measuring the pH value, dropwise adding 6mol/L hydrochloric acid solution to adjust the pH value of the liquid medicine to 4.0, and maintaining the reaction for 30 min.
4. Oxidation by oxygen
After the reduction, sodium hydroxide (20% (W/V)) was added to adjust the pH of the solution to 10, hydrogen peroxide (30%, V/V) was added to 1.0%, the solution was adjusted to a pH of 10 every 2 hours to maintain stability, and the solution was allowed to stand and oxidize for 12 hours.
5. Ultraviolet irradiation
Filtering after oxidation, adding 20.0% (W/V) sodium hydroxide solution dropwise to adjust pH of the medicinal liquid to 6.20, adding dichloromethane (0.1% (V/V) of the medicinal liquid volume), stirring for more than 30min, and filtering. Sodium chloride solids, 1.5% (w/v) of the feed volume, were weighed into the filtrate and dissolved. Measuring ethanol (95% ethanol needs to be filtered) with a volume 1 time of that of the feed liquid by using a measuring cylinder, pouring the measured ethanol into a beaker while stirring, properly stirring for 20min after the ethanol is added, and standing for 12 hours. (the time is determined by precipitation, the clearer the supernatant is. After the precipitation is finished, the supernatant is poured off, and the precipitate is left. An appropriate amount of purified water was poured into a beaker to a dissolution concentration of 5% (w/v), and the precipitate was dissolved by stirring. After the precipitate is completely dissolved, adjusting the pH value of the liquid medicine to 6.20 by using a 6mol/L hydrochloric acid solution, completely transferring the liquid medicine into an ultraviolet irradiation instrument, and starting the ultraviolet irradiation instrument for 2 hours.
6 molecular weight fractionation
Filtering after irradiation, measuring the volume of the filtrate, weighing 1.5% sodium chloride solid in the feed liquid, adding into the feed liquid, and stirring to dissolve. The measuring cylinder measures ethanol (95% ethanol) with the volume 0.7 times that of the feed liquid, the ethanol is poured into the feed liquid while stirring, and the feed liquid is kept stand for 12 hours after the pouring is finished. And pouring the supernatant after the standing is finished, and reserving the precipitate.
The precipitate was dissolved with purified water to give a 5% (w/v) solution. Taking 2ml of feed liquid, checking molecular weight, adjusting pH of the liquid medicine to 6.20 with 6mol/L hydrochloric acid solution, and filtering (same as above). Taking ethanol (95% ethanol) with the volume of 0.7 times of the filtrate volume, pouring the ethanol into the feed liquid while stirring, and standing for 12 hours after pouring. And pouring the supernatant after the standing is finished, and reserving the precipitate. The precipitate was dissolved in purified water to give a 5% solution, and a sample was taken to determine the molecular weight. And (5) if the molecular weight is unqualified, repeating the step (6) until the molecular weight is qualified, and then carrying out the next step.
7. Freeze-drying
And (3) putting the final filtrate obtained in the step (6) into a rotary dryer, performing vacuum spin drying under the condition of 40 ℃, stopping vacuum drying after 1/3 of the volume of the filtrate is collected, supplementing water to the filtrate to the original volume, and directly feeding the filtered filtrate into a freeze dryer for freeze drying.
Example 3:
1. dissolution
Precisely weighing refined heparin sodium, and dissolving into 15% (W/V) solution with purified water.
2. Degradation of
Precisely weighing sodium nitrite solid with the mass being 2.9% (W/W) of the mass of the heparin sodium, pouring the solid into a small beaker, measuring a proper amount of purified water, adding the purified water into the beaker to completely dissolve the sodium nitrite, and preparing a 25% (W/V) test solution for later use. And after the heparin sodium is completely dissolved, adjusting the pH value of the feed liquid to 2.9. After the pH adjustment is finished, the prepared sodium nitrite solution is poured into the reaction system. After the system reacts for half an hour, taking the feed liquid every ten minutes to mix with a starch potassium iodide test solution (which can be used within the configured period of validity and can be replaced by a starch potassium iodide test paper), and finishing the degradation reaction if the starch potassium iodide test solution does not turn blue within 3 s.
3. Reduction of
After the degradation reaction is finished, the pH value of the feed liquid is measured by a pH meter, and 20.0% (W/V) sodium hydroxide solution is added dropwise to adjust the pH value of the feed liquid to 10.0, and the operation is finished within 10 min. Precisely weighing sodium borohydride solid with 1% (w/w) of the weight of the heparin sodium, pouring the sodium borohydride solid into the feed liquid, and maintaining low-speed stirring (the stirring speed is determined according to the condition that bubbles are released from the liquid surface, and preferably no bubbles or few bubbles are released) to react with the pH value for 12 hours. After the reduction reaction is finished, measuring the pH value, dropwise adding 6mol/L hydrochloric acid solution to adjust the pH value of the liquid medicine to 4.0, and maintaining the reaction for 30 min.
4. Oxidation by oxygen
After the reduction, sodium hydroxide (20% (W/V)) was added to adjust the pH of the solution to 10, hydrogen peroxide (30%, V/V) was added to 1.0%, the solution was adjusted to a pH of 10 every 2 hours to maintain stability, and the solution was allowed to stand and oxidize for 12 hours.
5. Ultraviolet irradiation
After the oxidation, the mixture was filtered, and after the filtration was completed, a 20.0% (W/V) sodium hydroxide solution was added dropwise to adjust the pH of the liquid medicine to 6.20, a small amount of methylene chloride (5% (V/V) of the volume of the liquid medicine) was added thereto, and the mixture was stirred for 30 minutes or more, followed by filtration. Sodium chloride solids, 1.5% (w/v) of the feed volume, were weighed into the filtrate and dissolved. Measuring ethanol (95% ethanol needs to be filtered) with a volume 1 time of that of the feed liquid by using a measuring cylinder, pouring the measured ethanol into a beaker while stirring, properly stirring for 20min after the ethanol is added, and standing for 6 hours. (the time is determined by precipitation, the clearer the supernatant is. After the precipitation is finished, the supernatant is poured off, and the precipitate is left. An appropriate amount of purified water was poured into a beaker to a dissolution concentration of 10% (w/v), and the precipitate was dissolved by stirring. After the precipitate is completely dissolved, adjusting the pH of the liquid medicine to 6.20 with 6mol/L hydrochloric acid solution, transferring the liquid medicine into an ultraviolet irradiation instrument, and starting the ultraviolet irradiation instrument for 10 min.
6 molecular weight fractionation
Filtering after irradiation, measuring the volume of the filtrate, weighing 1.5% sodium chloride solid in the feed liquid, adding into the feed liquid, and stirring to dissolve. The measuring cylinder measures ethanol (95% ethanol) with the volume 1.0 time of that of the feed liquid, the ethanol is poured into the feed liquid while stirring, and the feed liquid is kept stand for 6 hours after the pouring is finished. And pouring the supernatant after the standing is finished, and reserving the precipitate.
The precipitate was dissolved with purified water to give a 10% (w/v) solution. Taking 2ml of feed liquid, checking molecular weight, adjusting pH of the liquid medicine to 6.20 with 6mol/L hydrochloric acid solution, and filtering (same as above). Taking ethanol (95% ethanol) with the volume of 1.0 volume of the filtrate, pouring the ethanol into the feed liquid while stirring, and standing for 6 hours after pouring. And pouring the supernatant after the standing is finished, and reserving the precipitate. The precipitate was dissolved in purified water to give a 15% solution, and a sample was taken to measure the molecular weight. And (5) if the molecular weight is unqualified, repeating the step 6 until the molecular weight is qualified, and then carrying out the next step.
7. Freeze-drying
And (3) putting the final filtrate obtained in the step (6) into a rotary dryer, performing vacuum spin drying under the condition of 45 ℃, stopping vacuum drying after 1/3 of the volume of the filtrate is collected, supplementing water to the filtrate to the original volume, and directly feeding the filtered filtrate into a freeze dryer for freeze drying.
Comparative example 1
The difference from example 1 is that: in step 5, no dichloromethane was added.
Comparative example 2
The difference from example 1 is that: in step 5, trichloroacetic acid was added instead of dichloromethane.
Comparative example 3
The difference from example 1 is that: in step 5, trifluorotrichloroethane was added in place of dichloromethane.
Comparative example 3
The difference from example 1 is that: in step 5, vinyl acetate was added instead of dichloromethane.
Experimental testing
Two methods are adopted in the experimental process to judge whether the residues of the protein and the nucleic acid in the low molecular heparin sodium meet the specification: one is clarity, and the clarity is less than 0.5 according to quality standards; one is to detect ultraviolet absorption at 260nm and 280nm, the quality standard specifies that the ultraviolet absorption of heparin sodium at 260nm and 280nm should be less than 0.1, and the specific detection method is as follows: taking the product, adding water to make into solution containing 2mg per 1ml, and measuring by ultraviolet spectrophotometry (appendix IV A), wherein the absorbance at 260nm wavelength is not more than 0.10; at the wavelength of 280nm, the absorbance of the solution is not more than 0.10;
TABLE 1 detection results of low molecular weight heparin sodium
From the above experimental data, it can be seen that, in the experiment in which dichloromethane is added in step 5, compared with the experiment in which dichloromethane is not added, trichloroacetic acid, trifluorotrichloroethane and vinyl acetate are added, the clarity of the product meets the standard requirement, and the ultraviolet absorption values at 260nm and 280nm are lower than those of other comparative experiments, which indicates that the impurity content of protein in the product is very low, so that the quality of the low-molecular heparin sodium product is better due to the addition of dichloromethane.
It should be noted that the above-mentioned embodiments are only preferred embodiments of the present invention, and the present invention is not limited thereto, and although the present invention is described in detail with reference to the foregoing embodiments, it will be apparent to those skilled in the art that modifications and equivalents can be made in the technical solutions described in the foregoing embodiments, or equivalents thereof. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention. Although the embodiments of the present invention have been described above, it should be understood by those skilled in the art that various modifications and variations can be made without inventive step on the basis of the technical solution of the present invention.
Claims (10)
1. A production process of low molecular weight heparin sodium with good quality and high yield is characterized by comprising the following steps:
degrading, reducing and oxidizing heparin sodium, collecting an oxidizing solution, adjusting the oxidizing solution to be weakly acidic, adding dichloromethane, uniformly mixing, and filtering;
collecting filtrate, adding sodium chloride, mixing, precipitating with ethanol, ultraviolet irradiating, grading molecular weight, and lyophilizing.
2. The process for producing high-quality and high-yield low-molecular-weight heparin sodium according to claim 1, wherein the addition amount of dichloromethane is 0.1-5% of the volume of the filtrate.
3. The process for producing heparin sodium with low molecular weight according to claim 1, wherein the pH value with weak acidity is 6.20 ± 0.02.
4. The process for producing heparin sodium with low molecular weight according to claim 1, wherein the weak acidity is adjusted by using a strong alkali or a weak alkali salt.
5. The production process of the low molecular weight heparin sodium with good quality and high yield as claimed in claim 1, wherein sodium hydroxide with concentration of 18.0-22.0% W/V is adopted for the weak acidity adjustment.
6. The process for producing high-quality and high-yield low-molecular-weight heparin sodium according to claim 1, wherein vacuum rotary drying is performed before the freeze-drying treatment.
7. The production process of the low molecular weight heparin sodium with good quality and high yield according to claim 1, wherein the vacuum rotary drying comprises the following specific steps: the final filtrate was vacuum rotary dried to 1/3 volumes of filtrate to be collected, and then water was added to the original volume.
8. The process for producing high-quality and high-yield low-molecular-weight heparin sodium according to claim 1, wherein the temperature of the vacuum rotary drying is below 45 ℃.
9. Low molecular weight heparin sodium prepared according to the method of any one of claims 1 to 8.
10. Use of the low molecular weight heparin sodium of claim 9 in the preparation of an antithrombotic, anticoagulant, anti-inflammatory or antitumor medicament.
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