A preparation process of heparin sodium

Abstract

The present invention discloses a preparation process of heparin sodium, which comprises the following steps: uniformly mixing minced porcine small intestinal mucosa with an aqueous sodium chloride solution, heating for denaturation and then cooling, adjusting the pH to alkaline, adding immobilized enzyme for treatment, centrifuging the enzymatic hydrolysate, heating and filtering the supernatant, subjecting the clarified filtrate to electroadsorption, then rinsing the heparin sodium enriched on the anode with pure aqueous solution, adding anhydrous ethanol to the pure aqueous solution of the enriched heparin sodium for precipitation to obtain a crude heparin sodium product, dissolving the crude heparin sodium product in pure aqueous solution, adjusting the pH to alkaline, heating and eluting through an adsorption column, adding anhydrous ethanol to the eluate for precipitation to obtain heparin sodium. The preparation process of the present invention can improve the extraction efficiency of heparin sodium, and at the same time improve the purity of heparin sodium and ensure the potency of heparin sodium.

Description

Technical Field

[0001] The invention relates to a preparation process of heparin sodium and belongs to the technical field of medicine. Background Art

[0002] Heparin sodium is a sodium salt of heparin, belonging to the class of mucopolysaccharide sulfate anticoagulants. Existing heparin sodium is mainly made from pig small intestinal mucosa, and its production method is generally to obtain crude heparin sodium by salt hydrolysis, enzymatic hydrolysis, ion exchange resin, and alcohol precipitation. However, crude heparin sodium is mixed with a large amount of nucleic acid, protein impurities, etc., and the efficiency of crude heparin sodium extraction is also low; in order to obtain high-purity heparin sodium, crude heparin sodium needs to be decolorized and impurity-removed, but hydrogen peroxide is generally used in the decolorization and impurity-removal process. Excessive use of hydrogen peroxide will damage heparin sodium and affect the potency of heparin sodium. Summary of the invention

[0003] In view of the problems existing in the above-mentioned prior art, the present invention provides a preparation process of heparin sodium, which can improve the extraction efficiency of heparin sodium, and at the same time improve the purity of heparin sodium, thereby ensuring the potency of heparin sodium.

[0004] In order to achieve the above object, the present invention adopts the following technical scheme: a preparation process of heparin sodium, comprising the following steps:

[0005] (1) The minced porcine small intestinal mucosa is uniformly mixed with a 1.76-2.12 (wt) % sodium chloride aqueous solution, and then heated to 85-80° C. for thermal denaturation for 10 min, and then rapidly cooled to 35-40° C., the pH is adjusted to alkaline, and an immobilized enzyme is added, and salt hydrolysis-enzyme hydrolysis synergistic treatment is performed for 90-120 min to obtain an enzymatic hydrolyzate;

[0006] (2) placing the enzymatic hydrolysate in a low-temperature centrifuge for centrifugation, taking the supernatant and heating it to 35-40° C., and then passing it through a microfiltration membrane while it is still hot to obtain a clarified filtrate;

[0007] (3) placing the clarified filtrate in an electric adsorption tank, applying power to conduct electric adsorption, and after the adsorption is completed, quickly taking out the anode enriched with heparin sodium, and washing the enriched heparin sodium on the anode with a pure water solution at a temperature of 35 to 40° C. to obtain a pure water solution enriched with heparin sodium;

[0008] (4) adding anhydrous ethanol to the pure aqueous solution enriched with sodium heparin, stirring and mixing for 10 minutes, and separating the solid after standing and settling to obtain crude sodium heparin;

[0009] (5) dissolving crude heparin sodium in a pure aqueous solution at 35 to 40° C., adjusting the pH to alkaline, heating to a temperature of 35 to 40° C., and eluting through an adsorption column loaded with alumina loaded with sodium permanganate to obtain an eluate;

[0010] (6) Add absolute ethanol to the eluent, stir and mix for 10 min, and after standing for precipitation, heparin sodium is obtained.

[0011] Preferably, in step (1), the weight of the ground porcine small intestinal mucosa is 35-40% of the weight of the 1.76-2.12 (wt)% sodium chloride aqueous solution.

[0012] Preferably, in step (1), the heating rate is 5 °C / min and the cooling rate is 10 °C / min.

[0013] Preferably, in steps (1) and (5), the pH is 8.3-8.7.

[0014] Preferably, in step (1), the immobilized enzyme is a trypsin cross-linked enzyme aggregate.

[0015] Preferably, in step (1), the weight of the immobilized enzyme is 0.6-1% of the weight of the ground porcine small intestinal mucosa.

[0016] Preferably, in step (2), the conditions of the low-temperature centrifuge are: the temperature is 4 °C, the rotation speed is 4500 r / min, and the centrifugation time is 10 min.

[0017] Preferably, in step (2), the pressure during microfiltration membrane filtration is 0.2 Mpa and the flow rate is 50 L / min.

[0018] Preferably, in step (3), the electroadsorption conditions are: the voltage is 8 V and the electrode is a carbon electrode.

[0019] Preferably, in step (3), the weight of the 35-40 °C pure aqueous solution is 1.75-2 times the weight of the ground porcine small intestinal mucosa in step (1).

[0020] Preferably, in step (4), the weight of the absolute ethanol is 1.5-2 times the weight of the 35-40 °C pure aqueous solution in step (3).

[0021] Preferably, in step (5), the weight of the 35-40 °C pure aqueous solution is 4-5 times the weight of the crude heparin sodium.

[0022] Preferably, in step (5), the adsorption column is obtained by wet-packing alumina loaded with sodium permanganate, zeolite molecular sieve, and activated carbon into a glass chromatography column and subjecting it to ultrasonic activation.

[0023] Preferably, in the adsorption column, calculated according to the following weight ratio, the alumina loaded with sodium permanganate is 21 parts, the zeolite molecular sieve is 7 parts, and the activated carbon is 6 parts.

[0024] Preferably, the sodium permanganate-loaded alumina is obtained by spraying an aqueous sodium permanganate solution on activated alumina, impregnating it evenly, and then drying it under vacuum.

[0025] Preferably, in step (5), elution is performed 2 to 3 times.

[0026] Preferably, in step (6), the weight of absolute ethanol is 5 to 7 times the weight of the crude heparin sodium.

[0027] Advantages of the present invention: In the preparation process of the present invention, during the preparation of crude heparin sodium, immobilized enzyme hydrolysis is adopted, and under suitable parameter conditions, combined with electroadsorption treatment, the yield and purity of crude heparin sodium can be improved; at the same time, the present invention uses electroadsorption instead of traditional resin adsorption, shortening the production time and improving the extraction efficiency of crude heparin sodium; in addition, the present invention uses an adsorption column filled with sodium permanganate-loaded alumina to elute the crude heparin sodium, achieving impurity removal and decolorization treatment at the same time, avoiding the use of hydrogen peroxide, reducing the damage to heparin sodium, further improving the purity of the refined heparin sodium, and also ensuring the potency of heparin sodium. Specific Embodiments

[0028] In order to more clearly and completely illustrate the present invention, the following specific examples are used to illustrate the present invention, but it is not a limitation to the invention.

[0029] Preparation Example 1 Immobilized Enzyme

[0030] The immobilized enzyme of the present invention is prepared according to CN201811618116.6.

[0031] The enzyme selected in the present invention is trypsin. According to the preparation process of Example 1 described in CN201811618116.6, a trypsin aggregate is obtained. The recovery rate of this trypsin aggregate is 96.4%. When this trypsin aggregate is in water at 40°C for 90 minutes, the enzyme activity retention rate is 91.4%.

[0032] Preparation Example 2 Adsorption Column

[0033] The adsorption column of the present invention is obtained by wet-packing sodium permanganate-loaded alumina, zeolite molecular sieve, and activated carbon into a glass chromatography column; specifically: first, spray an aqueous sodium permanganate solution with a concentration of 20 wt% and a temperature of 65 - 70°C on activated alumina, impregnate it and place it in a vacuum drying oven, dry it at 75 - 80°C for 8 hours, and the loading amount on the activated alumina is 5.8% to obtain sodium permanganate-loaded alumina; then, according to the weight ratio of 21 parts of sodium permanganate-loaded alumina, 7 parts of zeolite molecular sieve, and 6 parts of activated carbon, wet-pack them into a glass chromatography column, with a packing weight of 42.5 g, and then activate them at an ultrasonic frequency of 35 kHz and a temperature of 40 - 45°C for 30 minutes to obtain an adsorption column of sodium permanganate-loaded alumina.

[0034] The immobilized enzyme prepared in the above-mentioned Preparative Example 1 and the adsorption column prepared in the above-mentioned Preparative Example 2 are used in a preparation process of heparin sodium of the present invention, which involves the following preparation process:

[0035] (1) Mixing the minced porcine small intestinal mucosa and a 1.76-2.12 (wt) % sodium chloride aqueous solution uniformly, then heating the mixture to 85-80° C. at a rate of 5° C. / min for thermal denaturation for 10 min, then rapidly cooling the mixture to 35-40° C. at a rate of 10° C. / min, adjusting the pH to 8.3-8.7, adding a trypsin cross-linking enzyme polymer immobilized enzyme, and subjecting the mixture to a salt hydrolysis-enzyme hydrolysis synergistic treatment for 90-120 min to obtain an enzymatic hydrolyzate, wherein the weight of the minced porcine small intestinal mucosa is 35-40% of the weight of the 1.76-2.12 (wt) % sodium chloride aqueous solution, and the weight of the immobilized enzyme is 0.6-1% of the weight of the minced porcine small intestinal mucosa;

[0036] (2) The enzymatic hydrolyzate was centrifuged in a low-temperature centrifuge at a temperature of 4°C and a speed of 4500 r / min for 10 min, the supernatant was taken and heated to a temperature of 35-40°C, and then passed through a microfiltration membrane while hot at a pressure of 0.2 MPa and a flow rate of 50 L / min to obtain a clarified filtrate;

[0037] (3) placing the clarified filtrate in an electric adsorption tank, the electrode is a carbon electrode, and after power is turned on, the electric adsorption is carried out at a voltage of 8V. After the adsorption is completed, the anode enriched with heparin sodium is quickly taken out, and the enriched heparin sodium on the anode is rinsed clean with a pure water solution at a temperature of 35 to 40°C to obtain a pure water solution enriched with heparin sodium, wherein the weight of the pure water solution at a temperature of 35 to 40°C is 1.75 to 2 times the weight of the minced porcine small intestinal mucosa;

[0038] (4) adding anhydrous ethanol to the pure aqueous solution enriched with heparin sodium, stirring and mixing for 10 minutes, and separating the solid after standing and settling to obtain crude heparin sodium, wherein the weight of the anhydrous ethanol is 1.5 to 2 times the weight of the pure aqueous solution at 35 to 40° C.;

[0039] (5) dissolving the crude heparin sodium in a pure water solution at 35 to 40° C., adjusting the pH to 8.3 to 8.7, heating to 35 to 40° C., and eluting 2 to 3 times through an adsorption column loaded with alumina loaded with sodium permanganate to obtain an eluate, wherein the weight of the pure water solution at 35 to 40° C. is 4 to 5 times the weight of the crude heparin sodium;

[0040] (6) adding anhydrous ethanol to the eluate, stirring and mixing for 10 minutes, and allowing to stand for precipitation to obtain heparin sodium, wherein the weight of the anhydrous ethanol is 5 to 7 times the weight of the crude heparin sodium.

[0041] The specific implementation process is shown in the following Examples 1 to 8.

[0042] Example 1

[0043] A preparation process of heparin sodium, the specific operation steps are as follows:

[0044] (1) 5 kg of minced porcine small intestinal mucosa was mixed evenly with 14.3 kg of a 1.76 (wt)% sodium chloride aqueous solution, and then heated to 85-80° C. at a rate of 5° C. / min for thermal denaturation for 10 min, and then rapidly cooled to 35-40° C. at a rate of 10° C. / min, the pH was adjusted to 8.5, 30 g of a trypsin cross-linking enzyme polymer immobilized enzyme was added, and the mixture was subjected to a salt hydrolysis-enzyme hydrolysis synergistic treatment for 120 min to obtain an enzymatic solution;

[0045] (2) The enzymatic hydrolyzate was centrifuged in a low-temperature centrifuge at a temperature of 4°C and a speed of 4500 r / min for 10 min, the supernatant was taken and heated to a temperature of 35-40°C, and then passed through a microfiltration membrane while hot at a pressure of 0.2 MPa and a flow rate of 50 L / min to obtain a clarified filtrate;

[0046] (3) placing the clarified filtrate in an electric adsorption tank, the electrode is a carbon electrode, and after power is turned on, the electric adsorption is carried out at a voltage of 8V. After the adsorption is completed, the anode enriched with heparin sodium is quickly taken out, and 8.8 kg of pure water solution at a temperature of 35 to 40°C is used to rinse the enriched heparin sodium on the anode to obtain a pure water solution enriched with heparin sodium;

[0047] (4) Add 12.9 kg of anhydrous ethanol to the pure aqueous solution enriched with heparin sodium, stir and mix for 10 min, and separate the solid after standing to precipitate, to obtain 31.3 g of crude heparin sodium with a potency of 112 u / mg and a purity of 75.1%;

[0048] (5) dissolving crude heparin sodium in 125 g of a pure aqueous solution at 35 to 40° C., adjusting the pH to 8.5, heating to a temperature of 35 to 40° C., and eluting twice through an adsorption column loaded with alumina loaded with sodium permanganate to obtain an eluate;

[0049] (6) 155 g of anhydrous ethanol was added to the eluate, and the mixture was stirred for 10 min. After standing for precipitation, 28.6 g of heparin sodium concentrate was obtained, with a potency of 211 u / mg and a purity of 98.3%. The yield of the heparin sodium concentrate over the crude heparin sodium was 91.4%.

[0050] Example 2

[0051] On the basis of Example 1, this Example 2 changes the mass fraction of the sodium chloride aqueous solution in step (1) and selects a 1.88 (wt) % sodium chloride aqueous solution; the other steps are the same as those in Example 1.

[0052] In Example 2, 31.7 g of crude heparin sodium was obtained, with a potency of 110 u / mg and a purity of 75.3%; 29.1 g of fine heparin sodium was obtained, with a potency of 209 u / mg and a purity of 98.5%. The yield of the fine heparin sodium compared to the crude heparin sodium was 91.8%.

[0053] Example 3

[0054] Based on Example 1, in this Example 3, the mass fraction of the sodium chloride aqueous solution in step (1) was changed, and a 1.95 (wt)% sodium chloride aqueous solution was selected; other steps were the same as those in Example 1.

[0055] In Example 3, 31.2 g of crude heparin sodium was obtained, with a potency of 112 u / mg and a purity of 74.9%; 28.5 g of fine heparin sodium was obtained, with a potency of 213 u / mg and a purity of 98.1%. The yield of the fine heparin sodium compared to the crude heparin sodium was 91.3%.

[0056] Example 4

[0057] Based on Example 1, in this Example 4, the mass fraction of the sodium chloride aqueous solution in step (1) was changed, and a 2.12 (wt)% sodium chloride aqueous solution was selected; other steps were the same as those in Example 1.

[0058] In Example 4, 31 g of crude heparin sodium was obtained, with a potency of 113 u / mg and a purity of 74.8%; 28.3 g of fine heparin sodium was obtained, with a potency of 213 u / mg and a purity of 98.6%. The yield of the fine heparin sodium compared to the crude heparin sodium was 91.3%.

[0059] Example 5

[0060] Based on Example 2, in this Example 5, the addition amount of the 1.95 (wt)% sodium chloride aqueous solution in step (1) was changed to 13.5 kg; the addition amount of the trypsin cross-linked enzyme aggregate immobilized enzyme was 40 g.

[0061] In Example 5, 32.1 g of crude heparin sodium was obtained, with a potency of 111 u / mg and a purity of 75.9%; 29.5 g of fine heparin sodium was obtained, with a potency of 210 u / mg and a purity of 98.6%. The yield of the fine heparin sodium compared to the crude heparin sodium was 91.9%.

[0062] Example 6

[0063] Based on Example 2, in this Example 5, the addition amount of the 1.95 (wt)% sodium chloride aqueous solution in step (1) was changed to 12.5 kg; the addition amount of the trypsin cross-linked enzyme aggregate immobilized enzyme was 50 g.

[0064] In Example 5, 32.5 g of crude heparin sodium was obtained, with a potency of 113 u / mg and a purity of 76.2%; 29.9 g of fine heparin sodium was obtained, with a potency of 211 u / mg and a purity of 98.5%. The yield of the fine heparin sodium compared to the crude heparin sodium was 92.0%.

[0065] Example 7

[0066] Based on Example 5, in this Example 7, the pH values in steps (1) and (5) were changed to 8.3, and elution was performed 3 times in step (5).

[0067] In Example 7, 31.8 g of crude heparin sodium was obtained, with a potency of 111 u / mg and a purity of 75.5%; 29.2 g of fine heparin sodium was obtained, with a potency of 210 u / mg and a purity of 98.4%. The yield of the fine heparin sodium compared to the crude heparin sodium was 91.8%.

[0068] Example 8

[0069] Based on Example 5, in this Example 8, the pH values in steps (1) and (5) were changed to 8.3, and elution was performed 3 times in step (5).

[0070] In Example 8, 31.6 g of crude heparin sodium was obtained, with a potency of 112 u / mg and a purity of 75.6%; 29.0 g of fine heparin sodium was obtained, with a potency of 209 u / mg and a purity of 98.5%. The yield of the fine heparin sodium compared to the crude heparin sodium was 91.8%.

[0071] Comparative Example 1

[0072] Based on Example 1, in this Comparative Example 1, the mass fraction of the sodium chloride aqueous solution in step (1) was changed, and a 2.15 (wt)% sodium chloride aqueous solution was selected; other steps were the same as those in Example 1.

[0073] In Comparative Example 1, 25.6 g of crude heparin sodium was obtained, with a potency of 97 u / mg and a purity of 65.3%; 23.3 g of fine heparin sodium was obtained, with a potency of 192 u / mg and a purity of 95.4%. The yield of the fine heparin sodium compared to the crude heparin sodium was 91.0%.

[0074] Comparative Example 2

[0075] Based on Example 1, in this Comparative Example 2, the temperature was decreased to 45 - 50 °C in step (1), the supernatant was heated to 45 - 50 °C in step (2), and pure water was at 35 - 40 °C in steps (3) and (5); other steps were the same as those in Example 1.

[0076] In Comparative Example 2, 28.9 g of crude heparin sodium was obtained, with a potency of 95 u / mg and a purity of 62.5%; 26.2 g of fine heparin sodium was obtained, with a potency of 184 u / mg and a purity of 97.8%. The yield of the fine heparin sodium compared to the crude heparin sodium was 90.7%.

[0077] Comparative Example 3

[0078] Based on Example 1, in this Comparative Example 3, the temperature reduction to 25 - 30°C in step (1), the heating of the supernatant to a temperature of 25 - 30°C in step (2), and the pure water in steps (3) and (5) were changed to 25 - 30°C; other steps were the same as those in Example 1.

[0079] In Comparative Example 3, 33.7 g of crude heparin sodium was obtained, with a potency of 105 u / mg and a purity of 58.2%; 27.9 g of fine heparin sodium was obtained, with a potency of 199 u / mg and a purity of 96.8%. The yield of the fine heparin sodium compared to the crude heparin sodium was 82.7%.

[0080] Comparative Example 4

[0081] Based on Example 1, in this Comparative Example 4, steps (3) and (4) were changed. Step (3): Add the clarified filtrate to a special resin for adsorption for 8 h. After the adsorption is completed, collect the resin; wash the resin with a 1.76 (wt)% sodium chloride aqueous solution 3 times the volume of the resin, and then elute the heparin with a 1.76 (wt)% sodium chloride aqueous solution 3 times the volume of the resin, and adjust the pH value of the eluate to 8.5. Step (4): Then add anhydrous ethanol with a mass concentration 1.5 times the volume of the eluate, stir and mix for 10 min, let it stand for precipitation, and then separate the solid to obtain crude heparin sodium; other steps were the same as those in Example 1.

[0082] In Comparative Example 4, 18.3 g of crude heparin sodium was obtained, with a potency of 102 u / mg and a purity of 64.8%; 16.7 g of fine heparin sodium was obtained, with a potency of 212 u / mg and a purity of 97.6%. The yield of the fine heparin sodium compared to the crude heparin sodium was 91.2%.

[0083] Comparative Example 5

[0084] Based on Example 1, this Comparative Example 4 changed steps (5) and (6). Step (5): Dissolve the crude heparin sodium in a 1.76 (wt)% solution to obtain 25 L of a crude solution. Add 60 ml of hydrogen peroxide (30 - 35%) according to 0.2% by volume, mix, adjust the pH value to maintain at 8.5, and allow it to stand and oxidize in an environment with a temperature of 25 - 30°C. Then filter to obtain the filtrate. Step (6): Add anhydrous ethanol to the filtrate according to 0.6 times the volume of the filtrate, stir and mix for 10 min, and after standing and precipitation, obtain the high-quality heparin sodium. All other steps are the same as those in Example 1.

[0085] In Comparative Example 5, 31.1 g of crude heparin sodium was obtained, with a titer of 113 u / mg and a purity of 74.6%; 15.2 g of high-quality heparin sodium was obtained, with a titer of 201 u / mg and a purity of 96.9%. The yield of the high-quality heparin sodium compared to the crude heparin sodium was 48.8%.

[0086] In summary, in the preparation process of the present invention, under appropriate parameter conditions, assisted by immobilized enzymes for salting-out, combining immobilized enzymes and electroadsorption can improve the yield and purity of the crude heparin sodium, and also ensure the titer of the crude heparin sodium, and improve the extraction efficiency of the crude heparin sodium; in addition, in the preparation process of the present invention, under appropriate parameter conditions, combining immobilized enzymes and electroadsorption and cooperating with an adsorption column filled with alumina loaded with sodium permanganate can reduce the damage to heparin sodium, significantly improve the yield and purity of heparin sodium, and also ensure and improve the titer of heparin sodium.

[0087] Finally, it should be noted that the above examples are only used to illustrate rather than limit the technical solutions of the present invention. Although the present invention has been described in detail with reference to the above examples, those skilled in the art should understand that the present invention can still be modified or equivalently replaced. Any modification or partial replacement without departing from the spirit and scope of the present invention shall be covered by the scope of the claims of the present invention.

Claims

1. A preparation process of heparin sodium, characterized in that, it comprises the following steps: (1) Mix the minced porcine small intestine mucosa evenly with 1.76 - 2.12 (wt)% sodium chloride aqueous solution, then heat up to 85 - 80 °C for heat denaturation for 10 min, and then quickly cool down to 35 - 40 °C, adjust the pH to 8.3 - 8.7, add immobilized enzyme, and perform synergistic treatment of salting-out and enzymatic hydrolysis for 90 - 120 min to obtain an enzymatic hydrolysate; the immobilized enzyme is trypsin cross-linked enzyme aggregate; the heating rate is 5 °C / min, and the cooling rate is 10 °C / min; the weight of the minced porcine small intestine mucosa is 35 - 40% of the weight of the sodium chloride aqueous solution; the weight of the immobilized enzyme is 0.6 - 1% of the weight of the minced porcine small intestine mucosa; (2) Place the enzymatic hydrolysate in a low-temperature centrifuge for centrifugation, take the supernatant and heat it to 35 - 40 °C, and then filter it through a microfiltration membrane while it is hot to obtain a clarified filtrate; (3) Place the clarified filtrate in an electro-adsorption cell, use carbon electrodes, after electrifying, perform electro-adsorption at a voltage of 8 V. After the adsorption is completed, quickly take out the anode enriched with heparin sodium, and rinse the heparin sodium enriched on the anode with pure aqueous solution at 35 - 40 °C to obtain a pure aqueous solution enriched with heparin sodium; the weight of the pure aqueous solution at 35 - 40 °C is 1.75 - 2 times the weight of the minced porcine small intestine mucosa in step (1); (4) Add absolute ethanol to the pure aqueous solution enriched with heparin sodium, stir and mix for 10 min, let it stand for precipitation and then separate the solid to obtain a crude heparin sodium product; the weight of the absolute ethanol is 1.5 - 2 times the weight of the pure aqueous solution at 35 - 40 °C in step (3); (5) Dissolve the crude heparin sodium product in pure aqueous solution at 35 - 40 °C, adjust the pH to 8.3 - 8.7, heat it to 35 - 40 °C, and perform elution 2 - 3 times through an adsorption column filled with alumina loaded with sodium permanganate to obtain an eluate; the adsorption column is obtained by wet-packing alumina loaded with sodium permanganate, zeolite molecular sieve, and activated carbon into a glass chromatography column and subjecting it to ultrasonic activation; in the adsorption column, calculated according to the following weight ratio, alumina loaded with sodium permanganate is 21 parts, zeolite molecular sieve is 7 parts, and activated carbon is 6 parts, wherein the alumina loaded with sodium permanganate is obtained by spraying sodium permanganate aqueous solution on activated alumina, impregnating evenly, and then drying under vacuum; the weight of the pure aqueous solution at 35 - 40 °C is 4 - 5 times the weight of the crude heparin sodium product; (6) Add absolute ethanol to the eluate, stir and mix for 10 min, let it stand for precipitation, and then obtain heparin sodium; the weight of the absolute ethanol is 5 - 7 times the weight of the crude heparin sodium product.