CN114668746A - Preparation method of heparin sodium - Google Patents
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- CN114668746A CN114668746A CN202210504562.4A CN202210504562A CN114668746A CN 114668746 A CN114668746 A CN 114668746A CN 202210504562 A CN202210504562 A CN 202210504562A CN 114668746 A CN114668746 A CN 114668746A
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- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
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Abstract
The invention relates to the technical field of raw material medicine production, in particular to a preparation method of heparin sodium, which comprises the steps of preparing inferior-quality heparin sodium from crude heparin sodium, dissolving the inferior-quality heparin sodium by using a sodium chloride solution, adding ethanol, cooling, standing, filtering, drying solids, dissolving the inferior-quality heparin sodium, adding the dissolved inferior-quality heparin sodium into a calcium chloride solution, uniformly stirring and mixing the dissolved inferior-quality heparin sodium and the calcium chloride solution to obtain a solidification solution, dripping a sodium alginate solution into the solidification solution through a high-voltage electrostatic droplet generation device, centrifuging the solidification solution, transferring obtained solid microspheres into a modified chitosan solution, stirring, centrifuging and drying the modified chitosan solution.
Description
Technical Field
The invention relates to the technical field of production of raw material medicines, in particular to a preparation method of heparin sodium.
Background
Heparin sodium is a sodium salt of heparin, and the physicochemical properties of heparin sodium are basically the same as those of heparin. Heparin, named because it was originally obtained from the liver (Heparin), was an acidic mucopolysaccharide discovered in 1861 when Mclean was studied to challenge the blood mechanism. In 1939, Brinkhous et al demonstrated that heparin has anticoagulant activity, and since heparin has received much attention from various countries as a natural anticoagulant substance, there have been many reports on its clinical use, and heparin is mainly present in biological organs such as blood vessels, liver, skin, and lung.
At present, KMnO is mostly adopted in the refining process of heparin sodium4Or H2O2The oxidation process, however, the N-sulfate group of heparin sodium is sensitive, and the oxidizing agent may degrade heparin into acidic products, so that the refining yield is only about 80%, and the preparation method needs to be further optimized to improve the yield of heparin sodium.
Disclosure of Invention
The purpose of the invention is as follows: aiming at the technical problems, the invention provides a preparation method of heparin sodium.
The adopted technical scheme is as follows:
a preparation method of heparin sodium comprises the following steps:
s1: dissolving crude heparin sodium with sodium chloride solution, adjusting pH to 8.0-8.2 with sodium hydroxide solution, heating to 75-80 deg.C, stirring for 60-90min, adding oxidant, stirring for 3-5 hr, cooling, filtering, adjusting pH to 5.8-6.5 with hydrochloric acid, adding activated carbon, decolorizing and filtering again, adding ethanol, cooling to 5-10 deg.C, standing for 20-25 hr, and filtering to obtain sub-refined heparin sodium;
s2: dissolving hypo-fine heparin sodium with sodium chloride solution, adding ethanol, cooling to 5-10 deg.C, standing for 20-25 hr, filtering, washing the solid with ethanol, and drying to obtain fine heparin sodium;
s3: dissolving refined heparin sodium with a sodium chloride solution, adding the calcium chloride solution, stirring and mixing uniformly to obtain a solidification solution, dripping a sodium alginate solution into the solidification solution through a high-voltage electrostatic droplet generation device, centrifuging, transferring the obtained solid microspheres into a modified chitosan solution, stirring for 30-50min, centrifuging, and finally freeze-drying at a low temperature to obtain the finished product heparin sodium.
Further, the mass concentration of the sodium chloride solution is 1.5-3%;
the mass concentration of the sodium hydroxide solution is 5-10%;
the mass concentration of the calcium chloride solution is 1-2%.
Further, the oxidant is FeCl3/Al2O3An oxidizing agent.
Further, the FeCl3/Al2O3The preparation method of the oxidant comprises the following steps:
mixing Al2O3Grinding and sieving to obtain powder, adding FeCl into the powder3Stirring the aqueous solution for 2 to 4 hours, standing the solution for 20 to 25 hours, concentrating the solution under reduced pressure and evaporating the concentrated solution to dryness, and finally drying the dried solution in vacuum at the temperature of 150 ℃ and 160 ℃.
Further, the FeCl3The mass concentration of the aqueous solution is 10-20 percent, and Al2O3Powder and FeCl3The mass ratio of the aqueous solution is 1: 3-5.
Furthermore, the diameter of the pinhole of the high-voltage electrostatic droplet generation device is 200-400 μm, the distance between the needle head and the liquid level of the coagulating liquid is 1-1.4cm, the voltage is 5000V, and the flow rate is 4-6 mL/h.
Furthermore, the diameter of a pinhole of the high-voltage electrostatic droplet generating device is 250 micrometers, the distance between a needle head and a coagulation liquid surface is 1.2cm, the voltage is 5000V, and the flow rate is 5 mL/h.
Further, the modified chitosan solution is an aqueous solution of carboxymethyl chitosan.
Further, the preparation method of the carboxymethyl chitosan comprises the following steps:
adding chitosan into water, stirring to fully and uniformly disperse the chitosan, adding glyoxylic acid, reacting for 2-5h, adjusting the pH to 8-9 with NaOH, dropwise adding sodium borohydride solution repeatedly, continuously reacting for 2-5h, adjusting the pH to neutral with hydrochloric acid, adding ethanol to fully precipitate, centrifuging, washing the obtained solid with absolute ethanol, and freeze-drying at low temperature.
Further, the mass ratio of the chitosan to the glyoxylic acid is 1: 1.2-1.5.
The invention has the beneficial effects that:
the invention provides a preparation method of heparin sodium, which overcomes the defect of KMnO4Or H2O2The oxidizing agent may degrade heparinThe acidic product is formed, which causes the problem of lower refining yield of the heparin sodium, and the oxidizing agent and the corresponding parameters also have influence on the titer of the heparin sodium, and the FeCl in the invention3/Al2O3The oxidizing agent has good oxidizing effect and has positive effect on improving the refining yield and the titer of the heparin sodium, in addition, the inventor prepares the heparin sodium into finished microspheres, and as the composite encapsulation is adopted, the sodium alginate preformed microspheres are firstly formed and then encapsulated by the modified chitosan, the encapsulation rate and the drug-loading rate of the microspheres are improved, the sustained-release performance is good, the activity of the heparin sodium can be protected, and the adverse reaction to a human body can be reduced.
Detailed Description
The examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products available commercially.
Example 1:
a preparation method of heparin sodium comprises the following steps:
dissolving 20g of crude heparin sodium by 200mL of 2% sodium chloride solution, adjusting the pH to 8.2 by using 5% sodium hydroxide solution, heating to 80 ℃, stirring for 60min, and adding 5g of FeCl3/Al2O3Oxidizing agent, stirring for 5h, cooling and filtering, adjusting the pH of the filtrate to 6.0 by hydrochloric acid, adding 10% active carbon for decolorization and filtering again, adding 10 times of ethanol into the filtrate, cooling to 10 ℃, standing for 25h and filtering to obtain inferior refined heparin sodium, dissolving the inferior refined heparin sodium by using sodium chloride solution, adding ethanol and cooling to 10 ℃, standing for 25h, filtering, washing the solid by using ethanol and drying to obtain refined heparin sodium, dissolving the refined heparin sodium by using sodium chloride solution, adding the dissolved refined heparin sodium into calcium chloride solution with the same volume and mass concentration of 1%, stirring and mixing uniformly to obtain a solidification solution, dripping sodium alginate solution into the solidification solution by using a high-pressure electrostatic droplet generator (the diameter of a needle hole is 200 μm, the distance between the needle head and the liquid level of the solidification solution is 1.4cm, the voltage is 5000V, the flow rate is 4mL/h), centrifuging, transferring the obtained solid microspheres to a carboxymethyl chitosan aqueous solution with the mass concentration of 5%, stirring for 40min, centrifugingAnd then freeze-drying at low temperature to obtain the finished product heparin sodium.
Wherein FeCl3/Al2O3The preparation method of the oxidant comprises the following steps:
mixing Al2O3Grinding and sieving to obtain powder, adding FeCl with mass concentration of 15%3In aqueous solution, Al2O3Powder and FeCl3The mass ratio of the aqueous solution is 1: 3, stirring for 4 hours, standing for 20 hours, concentrating under reduced pressure, evaporating to dryness, and finally drying in vacuum at 150 ℃.
The preparation method of the carboxymethyl chitosan comprises the following steps:
adding chitosan into water, stirring to fully and uniformly disperse the chitosan and the water, and then adding glyoxylic acid, wherein the mass ratio of the chitosan to the glyoxylic acid is 1: 1.4, after reacting for 3 hours, adjusting the pH value to 9 by NaOH, slowly dripping sodium borohydride solution in times, continuously reacting for 5 hours, adjusting the pH value to be neutral by hydrochloric acid, adding ethanol for full precipitation, centrifuging, washing the obtained solid by absolute ethyl alcohol, and freeze-drying at low temperature.
Example 2:
a preparation method of heparin sodium comprises the following steps:
dissolving 20g of crude heparin sodium by 200mL of sodium chloride solution with the mass concentration of 3%, adjusting the pH to 8.2 by using sodium hydroxide solution with the mass concentration of 10%, heating to 80 ℃, stirring for 90min, and adding 5g of FeCl3/Al2O3Oxidizing agent, continuously stirring for 5h, cooling and filtering, adjusting the pH of the filtrate to 6.5 by hydrochloric acid, adding 10% active carbon for decolorization and filtering again, adding 10 times of ethanol into the filtrate, cooling to 10 ℃, standing for 25h, filtering to obtain inferior refined heparin sodium, dissolving the inferior refined heparin sodium by using sodium chloride solution, adding ethanol, cooling to 10 ℃, standing for 25h, filtering, washing the solid by using ethanol, drying to obtain refined heparin sodium, dissolving the refined heparin sodium by using sodium chloride solution, adding the dissolved refined heparin sodium into calcium chloride solution with the same volume and mass concentration of 2%, stirring and mixing uniformly to obtain solidification liquid, dripping sodium alginate solution into the solidification liquid by using a high-pressure electrostatic droplet generator (the diameter of a needle hole is 200 mu m, the distance between the needle head and the liquid level of the solidification liquid is 1.4cm, the voltage is 5000V, and the flow rate is 6mL/h), centrifuging and mixing uniformly to obtain sodium alginate solutionAnd transferring the obtained solid microspheres to a carboxymethyl chitosan aqueous solution with the mass concentration of 5%, stirring for 50min, centrifuging, and finally performing low-temperature freeze drying to obtain the finished product heparin sodium.
FeCl3/Al2O3The oxidizing agent and carboxymethyl chitosan were prepared in the same manner as in example 1.
Example 3:
a preparation method of heparin sodium comprises the following steps:
dissolving 20g of crude heparin sodium with 200mL of 1.5 mass percent sodium chloride solution, adjusting the pH to 8.0 with 5 mass percent sodium hydroxide solution, heating to 75 ℃, stirring for 60min, and adding 5g of FeCl3/Al2O3Oxidizing agent, stirring for 3h, cooling and filtering, adjusting the pH of the filtrate to 5.8 with hydrochloric acid, adding 10% active carbon for decolorization and filtering again, adding 10 times of ethanol into the filtrate, cooling to 5 ℃, standing for 20h and filtering to obtain inferior refined heparin sodium, dissolving the inferior refined heparin sodium with sodium chloride solution, adding ethanol and cooling to 5 ℃, standing for 20h, filtering, washing the solid with ethanol and drying to obtain refined heparin sodium, dissolving the refined heparin sodium with sodium chloride solution, adding the dissolved refined heparin sodium with calcium chloride solution with the same volume and mass concentration of 1%, stirring and mixing uniformly to obtain a solidification solution, dripping sodium alginate solution into the solidification solution through a high-voltage electrostatic droplet generator (the diameter of a needle hole is 200 μm, the distance between the needle head and the liquid level of the solidification solution is 1cm, the voltage is 5000V, the flow rate is 4mL/h), centrifuging, transferring the obtained solid microspheres to a carboxymethyl chitosan aqueous solution with the mass concentration of 3%, stirring for 30min, centrifuging, and freeze drying at low temperature to obtain heparin sodium product.
FeCl3/Al2O3The oxidizing agent and carboxymethyl chitosan were prepared in the same manner as in example 1.
Example 4:
a preparation method of heparin sodium comprises the following steps:
dissolving 20g of crude heparin sodium by 200mL of sodium chloride solution with the mass concentration of 3%, adjusting the pH to 8.2 by using sodium hydroxide solution with the mass concentration of 5%, heating to 75 ℃, stirring for 90min, and adding 5g of FeCl3/Al2O3Oxidizing agent, stirring for 3h, cooling and filtering, adjusting the pH of the filtrate to 6.5 with hydrochloric acid, adding 10% active carbon for decolorization and filtering again, adding 10 times of ethanol into the filtrate, cooling to 5 ℃, standing for 25h and filtering to obtain inferior refined heparin sodium, dissolving the inferior refined heparin sodium with sodium chloride solution, adding ethanol and cooling to 5 ℃, standing for 25h, filtering, washing the solid with ethanol and drying to obtain refined heparin sodium, dissolving the refined heparin sodium with sodium chloride solution, adding the dissolved refined heparin sodium with calcium chloride solution with the same volume and mass concentration of 1%, stirring and mixing uniformly to obtain a solidification solution, dripping sodium alginate solution into the solidification solution through a high-voltage electrostatic droplet generator (the diameter of a needle hole is 200 μm, the distance between the needle head and the liquid level of the solidification solution is 1cm, the voltage is 5000V, the flow rate is 6mL/h), centrifuging, transferring the obtained solid microspheres to a carboxymethyl chitosan aqueous solution with the mass concentration of 3%, stirring for 50min, centrifuging, and freeze drying at low temperature to obtain heparin sodium product.
FeCl3/Al2O3The oxidizing agent and carboxymethyl chitosan were prepared in the same manner as in example 1.
Example 5:
a preparation method of heparin sodium comprises the following steps:
dissolving 20g of crude heparin sodium with 200mL of 1.5 mass percent sodium chloride solution, adjusting the pH to 8.0 with 10 mass percent sodium hydroxide solution, heating to 80 ℃, stirring for 60min, and adding 5g of FeCl3/Al2O3Adding oxidant, stirring for 5 hr, cooling, filtering, adjusting pH of the filtrate to 5.8 with hydrochloric acid, decolorizing with 10% active carbon, filtering, adding 10 times volume of ethanol into the filtrate, cooling to 10 deg.C, standing for 20 hr, filtering to obtain hypofine heparin sodium, dissolving hypofine heparin sodium with sodium chloride solution, adding ethanol, cooling to 10 deg.C, standing for 20 hr, filtering, washing the solid with ethanol, drying to obtain fine heparin sodium, dissolving the fine heparin sodium with sodium chloride solution, adding into 2% calcium chloride solution, stirring to obtain coagulating liquid, and dripping sodium alginate solution into the coagulating liquid via high-voltage electrostatic droplet generator (with pinhole diameter of 200 μm and needle head diameter of 2 μm)And (3) the distance between the solid microspheres and the liquid level of the solidification solution is 1.4cm, the voltage is 5000V, the flow rate is 4mL/h), the solid microspheres are centrifuged, the obtained solid microspheres are transferred to a carboxymethyl chitosan aqueous solution with the mass concentration of 5%, the mixture is stirred for 30min and then centrifuged, and finally the finished product heparin sodium is obtained through low-temperature freeze drying.
FeCl3/Al2O3The oxidizing agent and carboxymethyl chitosan were prepared in the same manner as in example 1.
Comparative example 1
Comparative example 1 is essentially the same as example 1 except that FeCl is replaced by potassium permanganate3/Al2O3An oxidizing agent.
Comparative example 2
Comparative example 2 is essentially the same as example 1 except that H is used2O2In place of FeCl3/Al2O3An oxidizing agent.
Comparative example 3
Comparative example 3 is substantially the same as example 1 except that carboxymethyl chitosan is replaced with chitosan.
Measuring the titer, the absorbance and the yield:
for the refined heparin sodium prepared in the examples 1-5 and the comparative examples 1-2, the titer of the heparin sodium is measured by adopting an azure A colorimetric method, the absorbance is measured at the wavelength of 260 nm and 280nm by using 0.4% aqueous solution, the absorbance is measured at the wavelength of 400 nm, 420 nm and 470nm by using 5% aqueous solution, and the yield is the percentage of the refined heparin sodium to the crude heparin sodium.
The results are shown in Table 1 below:
table 1:
as shown in the above Table 1, the refined heparin sodium prepared by the method has the yield of over 90 percent and higher titer, and the light absorbances at 260 nm, 280nm, 400 nm, 420 nm and 470nm are in negative correlation with the titer, so that the result accords with the prediction.
The encapsulation efficiency and drug loading data of the finished heparin sodium prepared in the embodiments 1-5 and the comparative examples 1-3 are shown in the table 2:
table 2:
| encapsulation efficiency/% | Loading capacity/% | |
| Example 1 | 93.18 | 23.29 |
| Example 2 | 93.05 | 22.94 |
| Example 3 | 93.11 | 23.15 |
| Example 4 | 92.84 | 23.21 |
| Example 5 | 93.06 | 23.02 |
| Comparative example 1 | 92.90 | 23.17 |
| Comparative example 2 | 91.48 | 22.53 |
| Comparative example 3 | 89.04 | 21.12 |
As can be seen from the above table 2, the finished product heparin sodium prepared by the invention has high encapsulation efficiency, large drug loading rate and good slow release performance, and not only can protect the activity of the heparin sodium, but also can reduce the adverse reaction of a human body.
The above examples are only intended to illustrate the technical solution of the present invention, but not to limit it; although the present invention has been described in detail with reference to the foregoing embodiments, it will be understood by those of ordinary skill in the art that: the technical solutions described in the foregoing embodiments may still be modified, or some technical features may be equivalently replaced; and such modifications or substitutions do not depart from the spirit and scope of the corresponding technical solutions of the embodiments of the present invention.
Claims (10)
1. The preparation method of heparin sodium is characterized by comprising the following steps:
s1: dissolving crude heparin sodium with sodium chloride solution, adjusting pH to 8.0-8.2 with sodium hydroxide solution, heating to 75-80 deg.C, stirring for 60-90min, adding oxidant, stirring for 3-5 hr, cooling, filtering, adjusting pH to 5.8-6.5 with hydrochloric acid, adding activated carbon, decolorizing and filtering again, adding ethanol, cooling to 5-10 deg.C, standing for 20-25 hr, and filtering to obtain sub-refined heparin sodium;
s2: dissolving hypo-refined heparin sodium in sodium chloride solution, adding ethanol, cooling to 5-10 deg.C, standing for 20-25 hr, filtering, washing the solid with ethanol, and drying to obtain refined heparin sodium;
s3: dissolving refined heparin sodium with a sodium chloride solution, adding the calcium chloride solution, stirring and mixing uniformly to obtain a solidification solution, dripping a sodium alginate solution into the solidification solution through a high-voltage electrostatic droplet generation device, centrifuging, transferring the obtained solid microspheres into a modified chitosan solution, stirring for 30-50min, centrifuging, and finally freeze-drying at a low temperature to obtain the finished product heparin sodium.
2. The method for preparing sodium heparin according to claim 1, wherein the mass concentration of the sodium chloride solution is 1.5-3%;
the mass concentration of the sodium hydroxide solution is 5-10%;
the mass concentration of the calcium chloride solution is 1-2%.
3. The method of claim 1, wherein the oxidizing agent is FeCl3/Al2O3An oxidizing agent.
4. The method for producing sodium heparin according to claim 3, wherein the FeCl is3/Al2O3The preparation method of the oxidant comprises the following steps:
mixing Al2O3Grinding and sieving to obtain powder, adding FeCl into the powder3Stirring in water solution for 2-4 hr, standing for 20-25 hr, concentrating under reduced pressure, evaporating, and vacuum drying at 150-160 deg.C.
5. The method for producing sodium heparin according to claim 4, wherein the FeCl is3The mass concentration of the aqueous solution is 10-20 percent, and Al2O3Powder and FeCl3The mass ratio of the aqueous solution is 1: 3-5.
6. The method for preparing heparin sodium as claimed in claim 1, wherein the diameter of the pinhole of the high voltage electrostatic droplet generator is 200-400 μm, the distance between the needle and the liquid level of the coagulation liquid is 1-1.4cm, the voltage is 5000V, and the flow rate is 4-6 mL/h.
7. The method for preparing heparin sodium according to claim 1, wherein the high-voltage electrostatic droplet generator has a pinhole diameter of 250 μm, a distance between a needle and a coagulation liquid surface of 1.2cm, a voltage of 5000V and a flow rate of 5 mL/h.
8. The method for preparing heparin sodium according to claim 1, wherein the modified chitosan solution is an aqueous solution of carboxymethyl chitosan.
9. The method for preparing heparin sodium according to claim 8, wherein the carboxymethyl chitosan is prepared by the following steps:
adding chitosan into water, stirring to fully and uniformly disperse the chitosan, adding glyoxylic acid, reacting for 2-5h, adjusting the pH to 8-9 with NaOH, dropwise adding sodium borohydride solution in times, continuously reacting for 2-5h, adjusting the pH to be neutral with hydrochloric acid, adding ethanol for full precipitation, centrifuging, washing the obtained solid with absolute ethanol, and freeze-drying at low temperature.
10. The method for preparing heparin sodium according to claim 9, wherein the mass ratio of chitosan to glyoxylic acid is 1: 1.2-1.5.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN115448993A (en) * | 2022-09-15 | 2022-12-09 | 中盐金坛盐化有限责任公司 | Coated salt product and preparation method and application thereof |
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| WO2018032502A1 (en) * | 2016-08-19 | 2018-02-22 | 苏州融析生物科技有限公司 | Sheep-derived low molecular weight heparin, preparation method therefor and application thereof |
| CN111909288A (en) * | 2020-08-13 | 2020-11-10 | 山东辰龙药业有限公司 | Refining method of heparin sodium |
| CN113648455A (en) * | 2021-08-10 | 2021-11-16 | 太原理工大学 | Double-slow-release drug-loaded hydrogel dressing with double-layer microspheres encapsulated in semi-interpenetrating network, and preparation method and application thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2018032502A1 (en) * | 2016-08-19 | 2018-02-22 | 苏州融析生物科技有限公司 | Sheep-derived low molecular weight heparin, preparation method therefor and application thereof |
| CN111909288A (en) * | 2020-08-13 | 2020-11-10 | 山东辰龙药业有限公司 | Refining method of heparin sodium |
| CN113648455A (en) * | 2021-08-10 | 2021-11-16 | 太原理工大学 | Double-slow-release drug-loaded hydrogel dressing with double-layer microspheres encapsulated in semi-interpenetrating network, and preparation method and application thereof |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115448993A (en) * | 2022-09-15 | 2022-12-09 | 中盐金坛盐化有限责任公司 | Coated salt product and preparation method and application thereof |
| CN115448993B (en) * | 2022-09-15 | 2024-02-27 | 中盐金坛盐化有限责任公司 | Wrapped salt product and preparation method and application thereof |
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