CN114668746B - Preparation method of heparin sodium - Google Patents
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- 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 bulk drug production, in particular to a preparation method of sodium heparin, which comprises the steps of preparing secondary refined sodium heparin from crude sodium heparin, dissolving the secondary refined sodium heparin in sodium chloride solution, adding ethanol, cooling, standing, filtering, drying solids, dissolving the secondary refined sodium heparin, adding the dissolved secondary refined sodium heparin into calcium chloride solution, stirring and mixing the dissolved secondary refined sodium heparin with the calcium chloride solution uniformly to obtain a coagulating liquid, dripping sodium alginate solution into the coagulating liquid through a high-voltage electrostatic droplet generator, centrifuging the sodium alginate solution, transferring the obtained solid microspheres into a modified chitosan solution, stirring and centrifuging the sodium alginate solution, and drying.
Description
Technical Field
The invention relates to the technical field of production of bulk drugs, in particular to a preparation method of heparin sodium.
Background
Heparin sodium is a sodium salt of heparin, and its physicochemical properties are substantially the same as heparin. Heparin, which was originally obtained from the liver (Heparin), was an acidic glycosaminoglycan found in 1861 when Mclean studied the suspicious blood mechanism. In 1939, brinkhous et al demonstrated that heparin has anticoagulant activity, and from this point on, heparin has been regarded as a natural anticoagulant substance and has been paid attention to in various countries, and a great deal of clinical application thereof has been reported so far, 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 sodium 4 Or H 2 O 2 The oxidation process, but the N-sulfuric acid group of heparin sodium is sensitive, the oxidant can degrade heparin into acidic products, the refining yield is low by about 80%, and the preparation method needs to be further optimized for improving the heparin sodium yield.
Disclosure of Invention
The invention aims to: aiming at the technical problems, the invention provides a preparation method of heparin sodium.
The technical scheme adopted is as follows:
the preparation method of heparin sodium comprises the following steps:
s1: dissolving crude heparin sodium with sodium chloride solution, regulating pH to 8.0-8.2 with sodium hydroxide solution, heating to 75-80deg.C, stirring for 60-90min, adding oxidant, stirring for 3-5 hr, cooling, filtering, regulating pH of filtrate to 5.8-6.5 with hydrochloric acid, decolorizing with active carbon, filtering again, adding ethanol into filtrate, cooling to 5-10deg.C, standing for 20-25 hr, and filtering to obtain secondary refined heparin sodium;
s2: dissolving secondary refined heparin sodium with sodium chloride solution, adding ethanol, cooling to 5-10deg.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 sodium chloride solution, adding into calcium chloride solution, stirring and mixing to obtain coagulating liquid, dripping sodium alginate solution into coagulating liquid by high-voltage electrostatic droplet generator, centrifuging, transferring the obtained solid microsphere into modified chitosan solution, stirring for 30-50min, centrifuging, and lyophilizing at low temperature to obtain 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 formed by FeCl 3 /Al 2 O 3 An oxidizing agent.
Further, the FeCl 3 /Al 2 O 3 The preparation method of the oxidant comprises the following steps:
al is added with 2 O 3 Grinding and sieving to obtain powder, adding FeCl into the powder 3 Stirring in water solution for 2-4 hr, standing for 20-25 hr, concentrating under reduced pressure, evaporating to dryness, and vacuum drying at 150-160deg.C.
Further, the FeCl 3 The mass concentration of the aqueous solution is 10-20%, al 2 O 3 Powder and FeCl 3 The mass ratio of the aqueous solution is 1:3-5.
Further, the diameter of a pinhole of the high-voltage electrostatic liquid drop generating device is 200-400 mu m, the distance between a needle head and the liquid level of the coagulating liquid is 1-1.4cm, the voltage is 5000V, and the flow rate is 4-6mL/h.
Further, the pinhole diameter of the high-voltage electrostatic liquid drop generator is 250 μm, the distance between the needle and the solidification liquid level is 1.2cm, the voltage is 5000V, and the flow rate is 5mL/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, adding glyoxylic acid, reacting for 2-5h, regulating pH to 8-9 with NaOH, slowly dripping sodium borohydride solution for several times, continuously reacting for 2-5h, regulating to neutrality 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 problem of KMnO 4 Or H 2 O 2 The oxidant can degrade heparin into acidic products, resulting in lower heparin sodium refining yield, and the oxidant and corresponding parameters have influence on heparin sodium titer 3 /Al 2 O 3 The oxidant has good oxidation effect, has positive effects on improving refining yield and heparin sodium titer, and in addition, the inventor prepares the heparin sodium into finished microspheres, and because of using composite encapsulation, the sodium alginate prefabricated microspheres are formed first and then encapsulated by using modified chitosan, so that the encapsulation rate and drug loading rate of the microspheres are improved, and the sustained release performance is good, thereby not only protecting heparin sodium activity, but also reducing adverse reactions to human bodies.
Detailed Description
The specific conditions are not noted in the examples and are carried out according to conventional conditions or conditions recommended by the manufacturer. The reagents or apparatus used were conventional products commercially available without the manufacturer's attention.
Example 1:
a preparation method of heparin sodium comprises the following steps:
dissolving 20g of crude heparin sodium with 200mL of sodium chloride solution with mass concentration of 2%, regulating pH to 8.2 with sodium hydroxide solution with mass concentration of 5%, heating to 80deg.C, stirring for 60min, and adding 5g of FeCl 3 /Al 2 O 3 And (3) continuously stirring the oxidant for 5 hours, cooling and filtering, regulating the pH value of the filtrate to 6.0 by using hydrochloric acid, adding 10% active carbon for decolorization and filtering again, adding 10 times of ethanol into the filtrate, cooling to 10 ℃, standing for 25 hours, filtering to obtain secondary refined heparin sodium, dissolving the secondary refined heparin sodium by using sodium chloride solution, adding ethanol and cooling to 10 ℃, standing for 25 hours, filtering, washing the solid by using ethanol, drying to obtain the refined heparin sodium, dissolving the refined heparin sodium by using sodium chloride solution, adding the same volume of 1% calcium chloride solution, stirring and mixing uniformly to obtain a coagulating liquid, dripping the sodium alginate solution into the coagulating liquid (with the needle diameter of 200 mu m, the distance between a needle and the liquid level of the coagulating liquid of 1.4cm, the voltage of 5000V and the flow rate of 4 mL/h), centrifuging, transferring the obtained solid microspheres to an aqueous solution of carboxymethyl chitosan with the mass concentration of 5%, stirring for 40 minutes, centrifuging, and finally freezing and drying at low temperature to obtain the finished heparin sodium.
Wherein FeCl 3 /Al 2 O 3 The preparation method of the oxidant comprises the following steps:
al is added with 2 O 3 Grinding and sieving to obtain powder, adding FeCl with mass concentration of 15% 3 In aqueous solution, al 2 O 3 Powder and FeCl 3 The 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 adding glyoxylic acid, wherein the mass ratio of the chitosan to the glyoxylic acid is 1:1.4, after 3 hours of reaction, regulating the pH to 9 by NaOH, slowly dropwise adding sodium borohydride solution for a plurality of times, continuing to react for 5 hours, regulating to be neutral by hydrochloric acid, adding ethanol for full precipitation, centrifuging, washing the obtained solid by absolute ethanol, and freeze-drying at low temperature.
Example 2:
a preparation method of heparin sodium comprises the following steps:
dissolving 20g of crude heparin sodium with 200mL of 3% sodium chloride solution by mass concentration, regulating pH to 8.2 with 10% sodium hydroxide solution by mass concentration, heating to 80 ℃, stirring for 90min, and adding 5g of FeCl 3 /Al 2 O 3 And (3) continuously stirring for 5 hours, cooling and filtering, regulating the pH value of the filtrate to 6.5 by using hydrochloric acid, adding 10% active carbon for decolorization and filtering again, adding 10 times of ethanol into the filtrate, cooling to 10 ℃, standing for 25 hours, filtering to obtain secondary refined heparin sodium, dissolving the secondary refined heparin sodium by using sodium chloride solution, adding ethanol and cooling to 10 ℃, standing for 25 hours, filtering, washing the solid by using ethanol, drying to obtain the refined heparin sodium, dissolving the refined heparin sodium by using sodium chloride solution, adding the same volume of calcium chloride solution with the mass concentration of 2%, stirring and mixing uniformly to obtain a coagulating liquid, dripping the sodium alginate solution into the coagulating liquid (with the pinhole diameter of 200 mu m, the distance between a needle head and the liquid level of the coagulating liquid of 1.4cm, the voltage of 5000V and the flow rate of 6 mL/h), centrifuging, transferring the obtained solid microspheres to an aqueous solution of carboxymethyl chitosan with the mass concentration of 5%, stirring for 50 minutes, centrifuging, and finally freezing and drying at low temperature to obtain the finished heparin sodium.
FeCl 3 /Al 2 O 3 The preparation method of the oxidant and carboxymethyl chitosan is the same as that of 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% sodium chloride solution by mass concentration, regulating pH to 8.0 with 5% sodium hydroxide solution by mass concentration, heating to 75deg.C, stirring for 60min, and adding 5g of FeCl 3 /Al 2 O 3 The oxidant is stirred for 3 hours continuously, cooled and filtered, the pH value of the filtrate is regulated to 5.8 by hydrochloric acid, 10 percent of active carbon is added for decolorization and filtering again, 10 times of volume of ethanol is added into the filtrate, the temperature is reduced to 5 ℃, the mixture is kept stand for 20 hours and filtered, the secondary refined heparin sodium is obtained, the secondary refined heparin sodium is dissolved by sodium chloride solution, the ethanol is added and the temperature is reduced to 5 ℃,standing for 20h, filtering, washing the solid with ethanol, drying to obtain refined heparin sodium, dissolving the refined heparin sodium with sodium chloride solution, adding the solution into calcium chloride solution with the same volume and mass concentration of 1%, stirring and mixing uniformly to obtain a coagulating liquid, dripping sodium alginate solution into the coagulating liquid (the diameter of a needle hole is 200 mu m, the distance between a needle head and the liquid level of the coagulating liquid is 1cm, the voltage is 5000V, the flow speed is 4 mL/h), centrifuging, transferring the obtained solid microspheres into an aqueous solution of carboxymethyl chitosan with the mass concentration of 3%, stirring for 30min, centrifuging, and finally freezing and drying at low temperature to obtain the finished heparin sodium.
FeCl 3 /Al 2 O 3 The preparation method of the oxidant and carboxymethyl chitosan is the same as that of example 1.
Example 4:
a preparation method of heparin sodium comprises the following steps:
dissolving 20g of crude heparin sodium with 200mL of 3% sodium chloride solution by mass concentration, regulating pH to 8.2 with 5% sodium hydroxide solution by mass concentration, heating to 75deg.C, stirring for 90min, and adding 5g of FeCl 3 /Al 2 O 3 And (3) continuously stirring for 3 hours, cooling and filtering, regulating the pH value of the filtrate to 6.5 by using hydrochloric acid, adding 10% active carbon for decolorization and filtering again, adding 10 times of ethanol into the filtrate, cooling to 5 ℃, standing for 25 hours, filtering to obtain secondary refined heparin sodium, dissolving the secondary refined heparin sodium by using sodium chloride solution, adding ethanol and cooling to 5 ℃, standing for 25 hours, filtering, washing the solid by using ethanol, drying to obtain the refined heparin sodium, dissolving the refined heparin sodium by using sodium chloride solution, adding the same volume of 1% calcium chloride solution, stirring and mixing uniformly to obtain a coagulating liquid, dripping the sodium alginate solution into the coagulating liquid (with the needle diameter of 200 mu m, the distance between a needle head and the liquid level of the coagulating liquid of 1cm, the voltage of 5000V and the flow rate of 6 mL/h), centrifuging, transferring the obtained solid microspheres to an aqueous solution of carboxymethyl chitosan with the mass concentration of 3%, stirring for 50 minutes, centrifuging, and finally freezing and drying at low temperature to obtain the finished heparin sodium.
FeCl 3 /Al 2 O 3 Oxidizing agent and carboxymethyl chitosanThe sugar was 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% sodium chloride solution by mass concentration, regulating pH to 8.0 with 10% sodium hydroxide solution by mass concentration, heating to 80 ℃, stirring for 60min, and adding 5g of FeCl 3 /Al 2 O 3 And (3) continuously stirring the oxidant for 5 hours, cooling and filtering, regulating the pH value of the filtrate to 5.8 by using hydrochloric acid, adding 10% active carbon for decolorization and filtering again, adding 10 times of ethanol into the filtrate, cooling to 10 ℃, standing for 20 hours, filtering to obtain secondary refined heparin sodium, dissolving the secondary refined heparin sodium by using sodium chloride solution, adding ethanol and cooling to 10 ℃, standing for 20 hours, filtering, washing the solid by using ethanol, drying to obtain the refined heparin sodium, dissolving the refined heparin sodium by using sodium chloride solution, adding the refined heparin sodium into 2% calcium chloride solution with the same volume mass concentration, stirring and mixing uniformly to obtain a coagulating liquid, dripping the sodium alginate solution into the coagulating liquid (with the pinhole diameter of 200 mu m, the distance between a needle head and the liquid level of the coagulating liquid is 1.4cm, the voltage of 5000V and the flow speed of 4 mL/h), centrifuging, transferring the obtained solid microspheres to an aqueous solution of carboxymethyl chitosan with the mass concentration of 5%, stirring for 30 minutes, centrifuging, and finally freezing and drying at low temperature to obtain the finished heparin sodium.
FeCl 3 /Al 2 O 3 The preparation method of the oxidant and carboxymethyl chitosan is the same as that of example 1.
Comparative example 1
Comparative example 1 is essentially the same as example 1, except that potassium permanganate is used in place of FeCl 3 /Al 2 O 3 An oxidizing agent.
Comparative example 2
Comparative example 2 is essentially the same as example 1, except that H is used 2 O 2 Instead of FeCl 3 /Al 2 O 3 An oxidizing agent.
Comparative example 3
Comparative example 3 is substantially the same as example 1 except that chitosan is used instead of carboxymethyl chitosan.
Potency, absorbance, yield determination:
for the refined heparin sodium prepared in the examples 1-5 and the comparative examples 1-2, the titer of heparin sodium is determined by adopting an azure A colorimetric method, the absorbance is determined at the wavelength of 260 and 280nm by using a 0.4% aqueous solution, the absorbance is determined at the wavelength of 400, 420 and 470nm by using a 5% aqueous solution, and the yield is the percentage of the refined heparin sodium and the crude heparin sodium.
The results are shown in Table 1 below:
table 1:
as shown in the table 1, the yield of the refined heparin sodium prepared by the method is up to more than 90%, the refined heparin sodium has higher titer, the light absorption degree at 260, 280, 400, 420 and 470nm is inversely related to the titer, and the result accords with the prediction.
(2) Encapsulation efficiency and drug loading data of the finished heparin sodium prepared in the invention examples 1-5 and comparative examples 1-3 are shown in Table 2:
table 2:
| encapsulation efficiency/% | Drug loading/% | |
| 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 shown in the table 2, the finished heparin sodium prepared by the invention has high encapsulation efficiency, large drug loading and good slow release performance, and can protect the activity of heparin sodium and reduce adverse reactions of human bodies.
The above embodiments are only for illustrating the technical solution of the present invention, and are not limiting; although the 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 scheme described in the foregoing embodiments can be modified or some technical features thereof can be replaced by equivalents; such modifications and substitutions do not depart from the spirit and scope of the technical solutions of the embodiments of the present invention.
Claims (6)
1. The preparation method of heparin sodium is characterized by comprising the following steps:
s1: dissolving crude heparin sodium with sodium chloride solution, regulating pH to 8.0-8.2 with sodium hydroxide solution, heating to 75-80deg.C, stirring for 60-90min, adding oxidant, stirring for 3-5 hr, cooling, filtering, regulating pH of filtrate to 5.8-6.5 with hydrochloric acid, decolorizing with active carbon, filtering again, adding ethanol into filtrate, cooling to 5-10deg.C, standing for 20-25 hr, and filtering to obtain secondary refined heparin sodium;
s2: dissolving secondary refined heparin sodium with sodium chloride solution, adding ethanol, cooling to 5-10deg.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 sodium chloride solution, adding into calcium chloride solution, stirring and mixing to obtain coagulating liquid, dripping sodium alginate solution into coagulating liquid by high-voltage electrostatic droplet generator, centrifuging, transferring the obtained solid microsphere into modified chitosan solution, stirring for 30-50min, centrifuging, and lyophilizing at low temperature to obtain heparin sodium;
the oxidant is FeCl 3 /Al 2 O 3 Oxidizing agent, the FeCl 3 /Al 2 O 3 The preparation method of the oxidant comprises the following steps:
al is added with 2 O 3 Grinding and sieving to obtain powder, adding FeCl into the powder 3 Stirring in water solution for 2-4 hr, standing for 20-25 hr, concentrating under reduced pressure, evaporating to dryness, and vacuum drying at 150-160deg.C;
the modified chitosan solution is an aqueous solution of carboxymethyl chitosan, and the preparation method of the carboxymethyl chitosan comprises the following steps:
adding chitosan into water, stirring to fully and uniformly disperse, adding glyoxylic acid, reacting for 2-5h, regulating pH to 8-9 with NaOH, slowly dripping sodium borohydride solution for several times, continuously reacting for 2-5h, regulating to neutrality with hydrochloric acid, adding ethanol to fully precipitate, centrifuging, washing the obtained solid with absolute ethanol, and freeze-drying at low temperature.
2. The method for preparing heparin sodium 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 for preparing heparin sodium according to claim 1, wherein the feci 3 The mass concentration of the aqueous solution is 10-20%, al 2 O 3 Powder and FeCl 3 The mass ratio of the aqueous solution is 1:3-5.
4. The method for preparing heparin sodium according to claim 1, wherein the diameter of a pinhole of the high-voltage electrostatic liquid drop generating device is 200-400 μm, the distance between a needle and the liquid level of the coagulating liquid is 1-1.4cm, the voltage is 5000V, and the flow rate is 4-6mL/h.
5. 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 the needle and the solidification liquid surface of 1.2cm, a voltage of 5000V and a flow rate of 5mL/h.
6. The method for preparing heparin sodium according to claim 1, wherein the mass ratio of chitosan to glyoxylic acid is 1:1.2-1.5.
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