CN110885386A - Method for extracting ultra-low molecular weight heparin sodium by using nadroparin calcium waste - Google Patents
Method for extracting ultra-low molecular weight heparin sodium by using nadroparin calcium waste Download PDFInfo
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Abstract
The invention discloses a method for extracting ultra-low molecular weight heparin sodium by using nadroparin calcium waste, which mainly comprises the steps of cracking, reducing, grading for 1-2 times, crystallizing, purifying, fine screening and the like. The nadroparin calcium belongs to one of low molecular weight heparin drugs, the nadroparin calcium waste is collected while producing nadroparin calcium, the waste is reprocessed to produce ultra-low molecular weight heparin, the utilization rate of the initial raw material common heparin sodium can be improved, the utilization rate of the initial raw material common heparin sodium can reach more than 90%, the Xa resistance titer is 32-35IU/mg, and the weight-average molecular weight is 1400-1600 daltons, so that the purposes of saving resources, reducing production cost and protecting ecological environment are achieved.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical production, and relates to a production method for producing ultra-low molecular weight heparin by reprocessing nadroparin calcium production waste.
Background
The ultra-low molecular weight heparin sodium is found to have the effects of protecting nerves, relieving asthma and the like in recent researches. The potency range is 10-50IU/mg, the molecular weight range is 1000-2000-plus-2000, and the efficacy of the ultra-low molecular weight heparin sodium is not possessed by the common heparin. The ultra-low molecular weight heparin sodium is a new medicament in the research and development stage, and the treatment efficacy of the ultra-low molecular weight heparin sodium is still in research and development.
At present, the ultra-low molecular weight heparin is directly produced by using common heparin sodium as a raw material (an enzymolysis method and a hydrogen peroxide method), and the problem of the prior art is that the utilization rate of the heparin sodium raw material is low, and partial heparin sodium is lost in the production process, so that the production cost is increased. The patent uses the waste material in the process of producing nadroparin calcium by using common heparin sodium, collects the waste material of nadroparin calcium, and reprocesses the waste material to produce the ultra-low molecular weight heparin, thereby improving the utilization rate of the common heparin sodium, reducing the production cost and saving resources.
The patent consumes the waste material in the process of producing nadroparin calcium by using common heparin sodium, thereby reducing the influence on the ecological environment caused by the environmental protection treatment or the discharge of the waste material.
Disclosure of Invention
The invention aims to provide a production method for producing ultra-low molecular weight heparin by reprocessing nadroparin calcium production waste, thereby achieving the purposes of saving resources and reducing production cost.
(1) Cracking: dissolving common heparin sodium serving as a raw material by using purified water, adjusting the pH value to 1.5-4.0, adding sodium nitrite (2% -4% of the mass of the heparin sodium), stirring and reacting for 0.5-1 hour, maintaining the pH value between 1.5-4.0 in the reaction period, judging and breaking the reaction end by using a starch-KI reagent, and when the starch-KI reagent is negative, finishing the cracking reaction to obtain a cracking liquid medicine;
(2) reduction: adjusting the pH value of the cracking liquid medicine to be neutral, adding sodium borohydride (1-3 percent of the weight of the heparin sodium), and stirring and reacting at the temperature of 20-40 ℃ for 20-24 hours; adjusting the pH value of the liquid medicine to 2.5-3.0, and stirring for 2 hours to obtain a reducing liquid medicine;
(3) 1, grading for 1 time: adding ethanol 3 times the volume of the reduction liquid medicine, adding ethanol, stirring uniformly to obtain precipitate, separating the supernatant from the precipitate, and discarding the separated supernatant;
(4) grading for 2 times: dissolving the precipitate with purified water, adjusting the pH value to 5.0-6.0, adding sodium chloride (30% -50% of the weight of heparin sodium), adding ethanol with the volume being 1 time of that of the liquid medicine, adding ethanol, stirring uniformly to obtain precipitate, separating the supernatant from the precipitate, collecting the precipitate and the supernatant, using the collected precipitate for nadroparin calcium production, and using the collected supernatant of 2-time grading waste for ultra-low molecular weight heparin production;
(5) and (3) crystallization: adding 0.5 times volume of ethanol into the collected waste supernatant, adding ethanol, stirring uniformly to obtain a precipitate, separating the supernatant from the precipitate, and collecting the precipitate;
(6) and (3) purification: dissolving the collected precipitate with purified water, adjusting the pH value to 7.0-8.0, adding sodium chloride (10% -20% of the weight of heparin sodium) and dissolving, adding ethanol in an amount which is 2 times that of the liquid medicine, adding ethanol and stirring uniformly to obtain a precipitate, separating the supernatant from the precipitate, and collecting the precipitate;
(7) fine screening: dissolving the precipitate with purified water, ultrafiltering with 1000D ultrafiltration membrane and plunger pump, precisely screening ultra-low molecular weight heparin sodium with molecular weight greater than 1000D, and collecting fine-screened medicinal liquid;
(8) and (3) drying: and (4) carrying out freeze vacuum drying on the fine-screened liquid medicine, and drying to obtain the ultra-low molecular weight heparin sodium.
The invention further discloses application of the method for extracting the ultra-low molecular weight heparin sodium by utilizing the nadroparin calcium waste material in improving the utilization rate of the initial raw material common heparin sodium. The production result shows that the ultra-low molecular weight heparin sodium produced by the invention has stable quality, meets the automatic control standard and meets the molecular weight standard in the literature of heparin product research summary.
The invention mainly solves the problem of waste material generated in the process of producing nadroparin calcium by using common heparin sodium, and the environment is inevitably polluted in the process of carrying out environment-friendly treatment on the waste material.
The invention mainly inspects whether the quality of the ultra-low molecular weight heparin sodium produced by the waste is stable. The main difficulty is to combine the production processes of two products skillfully, and the downstream products are produced by using the waste materials of the upstream products.
Compared with the prior art, the method for extracting the ultra-low molecular weight heparin sodium by utilizing the nadroparin calcium waste has the positive effects that:
(1) improves the utilization rate of the initial raw material of the common heparin sodium, the Xa resistance titer is between 32 and 35IU/mg, and the weight-average molecular weight is 1400-1600 dalton, thereby achieving the purposes of saving resources, reducing the production cost and protecting the ecological environment
(2) Solves the problem of waste treatment in the process of producing nadroparin calcium by using common heparin sodium.
(3) The waste material is utilized to produce the ultra-low molecular weight heparin sodium, so that the production cost of the medicine can be reduced.
(4) The production waste is recycled, and the influence of the waste on the ecological environment pollution can be reduced.
(5) According to the literature, "research summary of heparin products", it is known that the ultra-low molecular weight synthesis method and the enzymatic synthesis method exist at present, and both methods have the defects of high synthesis difficulty, high cost, high pollution, low yield and the like.
Detailed Description
The invention is described below by means of specific embodiments. Unless otherwise specified, the technical means used in the present invention are well known to those skilled in the art. In addition, the embodiments should be considered illustrative, and not restrictive, of the scope of the invention, which is defined solely by the claims. It will be apparent to those skilled in the art that various changes or modifications in the components and amounts of the materials used in these embodiments can be made without departing from the spirit and scope of the invention. The raw materials and reagents used in the present invention are commercially available. Among them, starch-KI reagent, heparin sodium, 1000D ultrafiltration membrane, etc. are commercially available.
Example 1
Cracking: weighing 1kg of heparin sodium, dissolving the heparin sodium by using purified water, adjusting the pH value to 1.5, adding 20g of sodium nitrite, stirring and reacting for 0.5 hour, maintaining the pH value between 1.5 in the reaction period, carrying out reaction endpoint judgment and fracture by using a starch-KI reagent, and finishing the cracking reaction when the starch-KI reagent is negative. Obtaining the lysis liquid medicine
Reduction: adjusting the pH value of the cracking liquid medicine to be neutral, adding 10g of sodium borohydride, and stirring and reacting for 20 hours at the temperature of 20 ℃; adjusting the pH value of the liquid medicine to 2.5, and stirring for 2 hours. To obtain the reduction liquid medicine.
1, grading for 1 time: adding 3 times of ethanol into the reduction liquid medicine, adding ethanol, stirring uniformly to obtain precipitate, separating the supernatant from the precipitate, and discarding the separated supernatant.
Grading for 2 times: the precipitate was dissolved with purified water, the pH was adjusted to 5.0, and 300g of sodium chloride was added and dissolved. Adding 1 time of ethanol into the medicinal liquid. Adding ethanol, stirring to obtain precipitate, separating the supernatant from the precipitate, and collecting the precipitate and the supernatant. The collected precipitate is used for producing nadroparin calcium, and the collected supernatant of 2-time grading waste is used for producing ultra-low molecular weight heparin.
And (3) crystallization: adding 0.5 times of ethanol into the collected waste supernatant, adding ethanol, stirring uniformly to obtain a precipitate, separating the supernatant from the precipitate, and collecting the precipitate. Testing the water content of the precipitate, and calculating the dry product weight yield of 28.3 percent according to the water content
And (3) purification: dissolving the collected precipitate with purified water, adjusting pH to 7.0, adding 100g sodium chloride, dissolving, adding 2 times of ethanol, adding ethanol, stirring to obtain precipitate, separating supernatant from precipitate, and collecting precipitate. Testing the water content of the precipitate, and calculating the weight yield of the dry product to be 25.1 percent according to the water content
Fine screening: dissolving the precipitate with purified water, ultrafiltering with 1000D ultrafiltration membrane and plunger pump for 5 hr or more, precisely screening ultra-low molecular weight heparin sodium with molecular weight greater than 1000D, and collecting the fine-screened medicinal liquid.
And (3) drying: freeze vacuum drying the fine-screened liquid medicine, rapidly cooling and freezing the liquid medicine, controlling the vacuum degree to be about 10Pa, slowly subliming water, and drying for 22h to obtain the ultra-low molecular weight heparin sodium with the weight yield of 21.7%.
Example 2
Cracking: weighing 1kg of heparin sodium, dissolving the heparin sodium by using purified water, adjusting the pH value to 3.0, adding 30g of sodium nitrite, stirring and reacting for 0.7 hour, maintaining the pH value between 3.0 in the reaction period, carrying out reaction endpoint judgment and fracture by using a starch-KI reagent, and finishing the cracking reaction when the starch-KI reagent is negative. Obtaining the lysis liquid medicine
Reduction: adjusting the pH value of the cracking liquid medicine to be neutral, adding 20g of sodium borohydride, and stirring and reacting at the temperature of 30 ℃ for 22 hours; adjusting the pH value of the liquid medicine to 2.8, and stirring for 2 hours. To obtain the reduction liquid medicine.
1, grading for 1 time: adding 3 times of ethanol into the reduction liquid medicine, adding ethanol, stirring uniformly to obtain precipitate, separating the supernatant from the precipitate, and discarding the separated supernatant.
Grading for 2 times: the precipitate was dissolved with purified water, the pH was adjusted to 5.5, and 400g of sodium chloride was added and dissolved. Adding 1 time of ethanol into the medicinal liquid. Adding ethanol, stirring to obtain precipitate, separating the supernatant from the precipitate, and collecting the precipitate and the supernatant. The collected precipitate is used for producing nadroparin calcium, and the collected supernatant of 2-time grading waste is used for producing ultra-low molecular weight heparin.
And (3) crystallization: adding 0.5 times of ethanol into the collected waste supernatant, adding ethanol, stirring uniformly to obtain a precipitate, separating the supernatant from the precipitate, and collecting the precipitate. Testing the water content of the precipitate, and calculating the weight yield of the dry product to be 27.9 percent according to the water content
And (3) purification: dissolving the collected precipitate with purified water, adjusting pH to 7.5, adding 150g of sodium chloride, dissolving, adding 2 times of ethanol, adding ethanol, stirring to obtain precipitate, separating supernatant from precipitate, and collecting precipitate. Testing the water content of the precipitate, and calculating the dry product weight yield of 24.2 percent according to the water content
Fine screening: dissolving the precipitate with purified water, ultrafiltering with 1000D ultrafiltration membrane and plunger pump for 5 hr or more, precisely screening ultra-low molecular weight heparin sodium with molecular weight greater than 1000D, and collecting the fine-screened medicinal liquid.
And (3) drying: freeze vacuum drying the fine-screened liquid medicine, rapidly cooling and freezing the liquid medicine, controlling the vacuum degree to be about 10Pa, slowly subliming water, and drying for 22h to obtain the ultra-low molecular weight heparin sodium with the weight yield of 20.4%.
Example 3
Cracking: weighing 1kg of heparin sodium, dissolving the heparin sodium by using purified water, adjusting the pH value to 4.0, adding 40g of sodium nitrite, stirring and reacting for 1.0 hour, maintaining the pH value between 4.0 in the reaction period, carrying out reaction endpoint judgment and fracture by using a starch-KI reagent, and finishing the cracking reaction when the starch-KI reagent is negative. Obtaining the lysis liquid medicine
Reduction: adjusting the pH value of the cracking liquid medicine to be neutral, adding 30g of sodium borohydride, and stirring and reacting for 24 hours at the temperature of 40 ℃; adjusting the pH value of the liquid medicine to 3.0, and stirring for 2 hours. To obtain the reduction liquid medicine.
1, grading for 1 time: adding 3 times of ethanol into the reduction liquid medicine, adding ethanol, stirring uniformly to obtain precipitate, separating the supernatant from the precipitate, and discarding the separated supernatant.
Grading for 2 times: the precipitate was dissolved with purified water, the pH was adjusted to 6.0, and 500g of sodium chloride was added and dissolved. Adding 1 time of ethanol into the medicinal liquid. Adding ethanol, stirring to obtain precipitate, separating the supernatant from the precipitate, and collecting the precipitate and the supernatant. The collected precipitate is used for producing nadroparin calcium, and the collected supernatant of 2-time grading waste is used for producing ultra-low molecular weight heparin.
And (3) crystallization: adding 0.5 times of ethanol into the collected waste supernatant, adding ethanol, stirring uniformly to obtain a precipitate, separating the supernatant from the precipitate, and collecting the precipitate. Testing the water content of the precipitate, and calculating the weight yield of the dry product to be 29.1 percent according to the water content
And (3) purification: dissolving the collected precipitate with purified water, adjusting pH to 8.0, adding sodium chloride 200g, dissolving, adding 2 times of ethanol, adding ethanol, stirring to obtain precipitate, separating supernatant from precipitate, and collecting precipitate. Testing the water content of the precipitate, and calculating the weight yield of the dry product to be 25.7 percent according to the water content
Fine screening: dissolving the precipitate with purified water, ultrafiltering with 1000D ultrafiltration membrane and plunger pump for 5 hr or more, precisely screening ultra-low molecular weight heparin sodium with molecular weight greater than 1000D, and collecting the fine-screened medicinal liquid.
And (3) drying: freeze vacuum drying the fine-screened liquid medicine, rapidly cooling and freezing the liquid medicine, controlling the vacuum degree to be about 10Pa, slowly subliming water, and drying for 22h to obtain the ultra-low molecular weight heparin sodium with the weight yield of 22.6%.
Ultra-low molecular weight heparin sodium quality data
The pH values in the above examples have been experimentally confirmed to produce acceptable ultra low molecular weight heparin.
Example 4
The method comprises the following steps:
the protective effect of ultra-low molecular weight heparin on different chemically induced injured cerebral cortical neurons was studied. The sodium-induced damage of cerebral cortical neurons in rats was used to observe the neuronal survival rate.
The method comprises the following steps:
1. separating fetal rat cerebral cortex in 16-18 days of pregnancy under aseptic condition, rapidly placing into high-sugar culture medium, removing pia mater and blood vessel, transferring brain tissue into another culture dish containing high-sugar culture medium, repeatedly blowing and dispersing into cell suspension by a thin-mouth suction pipe, filtering with 200-mesh metal net, adjusting cell number to 1 × 109L-1, inoculating into 96-hole culture plate or culture bottle treated with 0.01% L-polylysine overnight, culturing at 37 deg.C in 5% CO2 incubator, removing dead cells after cell adherence for 1 time, replacing liquid for 1 time every 2-3 days, culturing cells for 3-4 days, adding cytarabine (final concentration of 3-5 μmol. L-1) and culturing for 24h to inhibit non-neuron over-proliferation. The experiment was started after continuing the culture for 7 to 8 days.
2. The chemical injury model is prepared by firstly acting ultralow molecular weight heparin sodium (prepared by the method of the invention) with different concentrations on neurons for 24h, and then acting the ultralow molecular weight heparin sodium on the neurons for 4h by using a high-sugar culture medium containing 64 mmol.L-1 sodium azide. After the model is made, the culture is continued for 24h by replacing the conventional culture medium containing serum and high sugar, and various experimental indexes are measured.
As a result:
after 64 mmol.L-1 of sodium azide acts for 4 hours, the survival rate of neurons is obviously reduced, the activity of lactate dehydrogenase in a culture solution and cells [ Ca2+ ] i are obviously improved, and the sodium azide causes the neuron damage. Compared with the sodium azide group, the cell survival rate is increased by pre-administration of ultra-low molecular weight heparin sodium, and the lactate dehydrogenase activity and the cell [ Ca2+ ] i in the culture solution are reduced. The result shows that the ultra-low molecular weight heparin sodium (prepared by the method of the invention) has a certain protection effect on the neuron damage caused by sodium azide.
Claims (2)
1. A method for extracting ultra-low molecular weight heparin sodium by using nadroparin calcium waste is characterized by comprising the following steps:
(1) cracking: dissolving common heparin sodium serving as a raw material by using purified water, adjusting the pH to 1.5-4.0, adding sodium nitrite accounting for 2% -4% of the mass of the heparin sodium, stirring and reacting for 0.5-1 hour, maintaining the pH between 1.5-4.0 in the reaction period, judging a reaction end point by using a starch-KI reagent, and when the starch-KI reagent is negative, indicating that the cracking reaction is finished to obtain a cracking liquid medicine; 2M hydrochloric acid and 2M sodium hydroxide were used for pH adjustment;
(2) reduction: adjusting the pH value of the cracking liquid medicine to be neutral, adding sodium borohydride accounting for 1% -3% of the weight of the heparin sodium, and stirring and reacting for 20-24 hours at the temperature of 20-40 ℃; adjusting the pH value of the liquid medicine to 2.5-3.0, and stirring for 2 hours to obtain a reducing liquid medicine;
(3) 1, grading for 1 time: adding ethanol 3 times the volume of the reduction liquid medicine, adding ethanol, stirring uniformly to obtain precipitate, separating the supernatant from the precipitate, and discarding the separated supernatant;
(4) grading for 2 times: dissolving the precipitate with purified water, adjusting the pH value to 5.0-6.0, adding 30% -50% of sodium chloride based on the mass of heparin sodium, adding 1 time of ethanol in the volume of the liquid medicine, adding the ethanol, stirring uniformly to obtain a precipitate, separating the supernatant from the precipitate, collecting the precipitate and the supernatant, using the collected precipitate for nadroparin calcium production, and using the collected supernatant of 2-time grading waste for ultra-low molecular weight heparin production;
(5) and (3) crystallization: adding 0.5 times volume of ethanol into the collected waste supernatant, adding ethanol, stirring uniformly to obtain a precipitate, separating the supernatant from the precipitate, and collecting the precipitate;
(6) and (3) purification: dissolving the collected precipitate with purified water, adjusting the pH to 7.0-8.0, adding 10% -20% of sodium chloride based on the mass of heparin sodium, dissolving, adding 2 times of ethanol, adding ethanol, stirring uniformly to obtain precipitate, separating the supernatant from the precipitate, and collecting the precipitate;
(7) fine screening: dissolving the precipitate with purified water, ultrafiltering with 1000D ultrafiltration membrane and plunger pump, precisely screening ultra-low molecular weight heparin sodium with molecular weight greater than 1000D, and collecting fine-screened medicinal liquid;
(8) and (3) drying: and (4) carrying out freeze vacuum drying on the fine-screened liquid medicine, and drying to obtain the ultra-low molecular weight heparin sodium.
2. The use of the method of claim 1 for extracting ultra low molecular weight heparin sodium from nadroparin calcium waste to increase the utilization of the starting material, sodium heparin.
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Cited By (1)
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Application publication date: 20200317 |