CN111019014A - Preparation process of nadroparin calcium - Google Patents
Preparation process of nadroparin calcium Download PDFInfo
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- CN111019014A CN111019014A CN201911158487.5A CN201911158487A CN111019014A CN 111019014 A CN111019014 A CN 111019014A CN 201911158487 A CN201911158487 A CN 201911158487A CN 111019014 A CN111019014 A CN 111019014A
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
- C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
- C08B37/006—Heteroglycans, i.e. polysaccharides having more than one sugar residue in the main chain in either alternating or less regular sequence; Gellans; Succinoglycans; Arabinogalactans; Tragacanth or gum tragacanth or traganth from Astragalus; Gum Karaya from Sterculia urens; Gum Ghatti from Anogeissus latifolia; Derivatives thereof
- C08B37/0063—Glycosaminoglycans or mucopolysaccharides, e.g. keratan sulfate; Derivatives thereof, e.g. fucoidan
- C08B37/0075—Heparin; Heparan sulfate; Derivatives thereof, e.g. heparosan; Purification or extraction methods thereof
- C08B37/0078—Degradation products
Abstract
The invention discloses a preparation process of nadroparin calcium, which takes refined nadroparin as a starting raw material and prepares refined nadroparin calcium through the procedures of oxidation, sodium removal, degradation, reduction, ultraviolet irradiation, calcium replacement and the like. By optimizing parameters, the calcium replacement times are reduced, and the molecular weight is effectively controlled. Improving the technical content, reducing the material loss, improving the product yield, reducing the production cost and the like.
Description
Technical Field
The invention relates to a method for preparing refined nadroparin calcium by using refined heparin sodium as a raw material through the processes of oxidation, degradation, reduction, ultraviolet irradiation, calcium replacement and the like.
Background
Heparin is one of glycosaminoglycans, is a linear sulfate-containing natural acidic mucopolysaccharide consisting of two uronic acids and one glucosamine and their derivatives, and is mainly present in porcine small intestinal mucosa and tissue cells of liver, lung, etc. Heparin not only has the effects of anticoagulation and antithrombotic, but also can regulate other functions in human bodies, such as blood fat reduction, inflammation resistance, allergy resistance, blood pressure reduction, cancer resistance and the like. Heparin has the effect of prolonging the blood coagulation time, has a linear chain structure consisting of hexasaccharide or octasaccharide repeating units with molecules thereof, and is combined with protein in an animal body to form a complex, so that the heparin does not show the anticoagulation effect.
Heparin molecules have a lower bioavailability due to: after subcutaneous injection, many heparin molecules are inactivated by binding to the extracellular matrix, and the remaining heparin molecules enter the blood; heparin is inactivated after it enters the blood by binding to receptors on a variety of plasma proteins, endothelial cells and phagocytes. Meanwhile, certain limitation and danger exist in clinical medication, and the use of heparin is limited to a great extent.
Low molecular weight heparins (LWMH) are a class of low molecular weight fractions of oligosaccharide mixtures with lower molecular weights obtained by fractionation or degradation of unfractionated heparin as starting material. The LWMH product gradually replaces the common heparin due to the characteristics of shortened activated thromboplastin time (APTT), higher bioavailability, long half-life of blood plasma, small bleeding tendency, easy absorption by oral administration and the like. The heparin calcium slowly diffuses in blood circulation, does not reduce the calcium colloid of local intercellular capillary, does not change the vascular permeability, so the local hematoma phenomenon is reduced and the pain condition is obviously improved when the heparin calcium is injected subcutaneously, and the heparin products are more prone to be prepared into calcium salt type at present.
In the preparation process of the low molecular heparin calcium, the calcium chloride is added to convert the calcium through long-time stirring in the general process, more than 2 times of calcium conversion processes are needed, the calcium conversion process is complicated to operate and long in time, and incomplete calcium conversion is easily caused. And the molecular weight of the small molecular heparin calcium is often controlled by methods of fractional alcohol precipitation, ultrafiltration membrane separation, molecular sieve and gel adsorption separation, and the methods have the defects of backward technology, large product loss, low yield, high cost and the like, so that the application of the methods in industrial mass production and capacity improvement is limited.
Disclosure of Invention
The invention provides a preparation process of nadroparin calcium, which controls the average distribution of molecular weight, can improve the product yield, is simple and convenient to operate and can improve the production efficiency to a greater extent.
To achieve the object of the invention, the invention is carried out according to the following steps:
1 oxidation of
Dissolving refined heparin sodium in purified water with a proper volume to prepare 8-10% aqueous solution, and adjusting the pH value of the solution to 10-10.5 by using 20% NaOH; oxidizing the mixture for 8 to 10 hours by using 1 to 3 percent hydrogen peroxide under the condition of normal temperature, and adding the mixture in three times; after the oxidation is finished, filtering the mixture by using a filter membrane with the diameter of 0.45 mu m, and washing the filter membrane by using a small amount of purified water; slowly adding 0.8-1 time volume of ethanol into the filtrate at 37 ℃, stirring for 30min, and standing for 4-8 h; and after the precipitation is finished, discarding a supernatant, preparing a 10% solution of insoluble oily substances at the bottom by using 3-5% saline water, adjusting the pH value of the solution to be 6.5-7, filtering by using a 0.22 mu m filter membrane, slowly adding 0.8-1 time volume of ethanol into the filtrate at 37 ℃, stirring for 30min, standing for 4-8 h, discarding the supernatant, and directly using insoluble substances for next sodium removal.
2 sodium removal, degradation and reduction
Dissolving the precipitate obtained in the step 1 in purified water with a proper volume to prepare an 8-10% aqueous solution, adding strong acid type cation exchange resin, adjusting the pH value of the heparin sodium aqueous solution to 2.5-3, then filtering, adding a sodium nitrite solution with the mass percentage concentration of 5-10% into the filtrate, stirring at room temperature for 1-2 h, and detecting with a starch potassium iodide test paper until the solution is colorless; after the degradation reaction is finished, adjusting the value of the solution to be 7-8.5 by using saturated calcium hydroxide, stirring for 20-30 min, and stopping the degradation reaction; adding 5-10% sodium borohydride aqueous solution in batches, stirring and reacting for 10-15 h, adjusting the pH value to 3.5-4.0 by using 4mo1/L hydrochloric acid, and continuously stirring and reacting for 25-30 min; adding ethanol with the volume of 1-2 times of that of the reducing solution into the reducing solution for precipitation for 4-8 hours, and collecting the precipitate.
3 ultraviolet irradiation, calcium replacement and freeze-drying
Preparing the precipitate obtained in the step 2 into a 5-8% aqueous solution, filtering the aqueous solution by using a filter membrane of 0.45 mu m, and washing the filter membrane by using a small amount of purified water; irradiating for 1-3 h by using an ultraviolet lamp with the wavelength of 254nm to eliminate nitroso compounds and nitrite remained in the solution; after the ultraviolet irradiation is finished, adding ethanol with the volume of 1-2 times of that of the mixture for precipitation for 4-8 hours, and collecting precipitates; after the precipitation is finished, removing supernatant, preparing the insoluble oily matter at the bottom into 5-10% solution by using 3-5% calcium chloride solution, filtering by using a 0.22 mu m filter membrane, slowly adding ethanol with the volume of 1-2 times of that of the filtrate at 37 ℃, stirring for 30min, and standing for 4-8 h; after the precipitation is finished, adding 1 time of ethanol for dehydration, and freeze-drying at-45 ℃.
The invention has the advantages that:
(1) according to the invention, after hydrogen peroxide oxidation is started, the non-sulfated uronic acid C2 and C3 are broken, so that the sulfation degree of the heparin sodium is improved, the molecular weight of the prepared heparin sodium is 4500-4600 (the part of 2000-8000 is about 82%), and the molecular weight distribution is relatively uniform.
(2) The method uses the cation resin for sodium removal and then calcium conversion, has simple operation in the calcium conversion process, short time, complete calcium conversion, rich raw material sources, low cost compared with other methods, and stable and controllable product quality.
(3) The invention prepares nadroparin calcium by a nitrous acid degradation method, and the yield of nadroparin calcium obtained by the method is high and reaches 80 percent.
Detailed Description
Example 1
1 oxidation of
Weighing 100g of fine heparin sodium, dissolving the fine heparin sodium in 1.25L of purified water to prepare 8% aqueous solution, and adjusting the pH value of the solution to 10-10.5 by using 20% NaOH; under the condition of normal temperature, 100mL of 1% hydrogen peroxide is added for oxidation for 8 hours in three times, and the addition is finished after 1.5 hours; after the oxidation is finished, filtering the mixture by using a filter membrane with the diameter of 0.45 mu m, and washing the filter membrane by using a small amount of purified water; slowly adding 1L ethanol into the filtrate at 37 deg.C, stirring for 30min, and standing for 4 hr; after the precipitation was completed, the supernatant was discarded, 2L of 3% saline was added to the insoluble oily substance, the pH of the solution was adjusted to 6.5 to 7 with 4mol/L HCl, the solution was filtered with a 0.22 μm filter, 1.8L of ethanol was slowly added to the filtrate at 37 ℃, the mixture was stirred for 30min, and then the mixture was allowed to stand for 4h, the supernatant was discarded, and the insoluble substance was used directly for next sodium removal.
2 sodium removal, degradation and reduction
Dissolving the precipitate obtained in the step 1 in 1.25L of purified water to prepare an 8% aqueous solution, adding strong acid type cation exchange resin, adjusting the pH value of the heparin sodium aqueous solution to 2.5, then filtering, eluting and soaking the strong acid type cation exchange resin by using hydrochloric acid, slowly adding 10g of sodium nitrite solution with the mass percentage concentration of 5% into the filtrate, stirring for 1-2 h at room temperature, and detecting by using a starch potassium iodide test paper until the solution is colorless; after the degradation reaction is finished, adjusting the value of the solution to be 7-8.5 by using saturated calcium hydroxide, stirring for 20-30 min, and stopping the degradation reaction; adding 10g of a 5% sodium borohydride aqueous solution (ready to use) in batches, stirring and reacting for 10-15 h, adjusting the pH value to 3.5-4.0 by using 4mo1/L hydrochloric acid, and continuously stirring and reacting for 25-30 min; adding 1.3L ethanol into the reducing solution for precipitation for 4h, and collecting precipitate.
3 ultraviolet irradiation, calcium replacement and freeze-drying
Adding 2L of purified water into the precipitate obtained in the step 2 to prepare a 5% solution, filtering the solution by using a filter membrane of 0.45 mu m, and washing the filter membrane by using a small amount of purified water; irradiating with 254nm ultraviolet lamp for 1 hr to eliminate nitroso compound and nitrite remained in the solution; after the ultraviolet irradiation is finished, adding 2L of ethanol for precipitation for 4h, removing the supernatant, and collecting the precipitate; preparing the insoluble oily matter at the bottom into 5% solution with 2L calcium chloride solution with mass fraction of 3%, filtering with 0.22 μm filter membrane, slowly adding 2L ethanol into the filtrate at 37 deg.C, stirring for 30min, and standing for 4 hr; after precipitation, 100mL of ethanol was added for dehydration and lyophilized at-45 ℃.
Example 2
1 oxidation of
Weighing 100g of fine heparin sodium, dissolving the fine heparin sodium in 1.1L of purified water to prepare 9% aqueous solution, and adjusting the pH value of the solution to 10-10.5 by using 20% NaOH; under the condition of normal temperature, adding 150mL of 1% hydrogen peroxide for oxidation for 9 hours in three times, and finishing the addition for 1.5 hours; after the oxidation is finished, filtering the mixture by using a filter membrane with the diameter of 0.45 mu m, and washing the filter membrane by using a small amount of purified water; slowly adding 0.9L 95% ethanol into the filtrate at 37 deg.C, stirring for 30min, and standing for 6 hr; after the precipitation was completed, the supernatant was discarded, 1.25L of 3% saline was added to the insoluble oil, the pH of the solution was adjusted to 6.5 to 7 with 4mol/L HCl, the solution was filtered using a 0.22 μm filter, 1.35L of ethanol was slowly added to the filtrate at 37 ℃, the mixture was stirred for 30min, and then the mixture was allowed to stand for 6h, the supernatant was discarded, and the insoluble matter was used directly for next sodium removal.
2 sodium removal, degradation and reduction
Dissolving the precipitate obtained in the step 1 in 1.11L of purified water to prepare a 9% aqueous solution, adding strong acid type cation exchange resin, adjusting the pH value of the heparin sodium aqueous solution to 2.8, then filtering, eluting and soaking the strong acid resin by hydrochloric acid, slowly adding 20g of a sodium nitrite solution with the mass percentage concentration of 5% into the filtrate, stirring for 1-2 h at room temperature, and detecting by using a potassium iodide starch test paper until the solution is colorless; after the degradation reaction is finished, adjusting the value of the solution to be 7-8.5 by using saturated calcium hydroxide, stirring for 20-30 min, and stopping the degradation reaction; adding 20g of a 5% sodium borohydride aqueous solution (which is ready to be prepared) in batches, stirring and reacting for 10-15 h, adjusting the pH value to 3.5-4.0 by using 4mo1/L hydrochloric acid, and continuously stirring and reacting for 25-30 min; adding 1.65L ethanol into the reducing solution for precipitation for 6h, and collecting precipitate.
3 ultraviolet irradiation, calcium replacement and freeze-drying
Adding 1.43L of purified water into the precipitate obtained in the step 2 to prepare a 7% solution, filtering the solution by using a filter membrane with the diameter of 0.45 mu m, and washing the filter membrane by using a small amount of purified water; irradiating with 254nm ultraviolet lamp for 1.5 hr to eliminate residual nitroso compound and nitrite in the solution; after the ultraviolet irradiation is finished, adding 2.15L of 95% ethanol for precipitation for 6h, removing supernatant, and collecting precipitate; preparing the insoluble oily matter at the bottom into 7% solution with 1.43L calcium chloride solution with mass fraction of 3%, filtering with 0.22 μm filter membrane, slowly adding 2L ethanol into the filtrate at 37 deg.C, stirring for 30min, and standing for 6 hr; after precipitation, 100mL of ethanol was added for dehydration and lyophilized at-45 ℃.
Example 3
1 oxidation of
Weighing 100g of fine heparin sodium, dissolving the fine heparin sodium in 1L of purified water to prepare 10% aqueous solution, and adjusting the pH value of the solution to 10-10.5 by using 20% NaOH; under the condition of normal temperature, adding 200mL of 1% hydrogen peroxide for oxidation for 10 hours in three times, and finishing the addition for 1.5 hours; after the oxidation is finished, filtering the mixture by using a filter membrane with the diameter of 0.45 mu m, and washing the filter membrane by using a small amount of purified water; slowly adding 1L ethanol into the filtrate at 37 deg.C, stirring for 30min, and standing for 8 hr; after the precipitation was completed, the supernatant was discarded, 1L of 3% saline was added to the insoluble oily substance, the pH of the solution was adjusted to 6.5 to 7 with 4mol/L HCl, the solution was filtered with a 0.22 μm filter, 1L of ethanol was slowly added to the filtrate at 37 ℃, the mixture was stirred for 30min, and then the mixture was allowed to stand for 8h, the supernatant was discarded, and the insoluble substance was used as it was for next sodium removal.
2 sodium removal, degradation and reduction
Dissolving the precipitate obtained in the step 1 in 1L of purified water to prepare a 10% aqueous solution, adding strong acid type cation exchange resin, adjusting the pH value of the heparin sodium aqueous solution to 3.0, then filtering, eluting and soaking the strong acid resin by hydrochloric acid, slowly adding 40g of a sodium nitrite solution with the mass percentage concentration of 5% into the filtrate, stirring for 1-2 h at room temperature, and detecting by using a starch potassium iodide test paper until the solution is colorless; after the degradation reaction is finished, adjusting the value of the solution to be 7-8.5 by using saturated calcium hydroxide, stirring for 20-30 min, and stopping the degradation reaction; adding 40g of a 5% sodium borohydride aqueous solution (ready to use) in batches, stirring and reacting for 10-15 h, adjusting the pH value to 3.5-4.0 by using 4mo1/L hydrochloric acid, and continuously stirring and reacting for 25-30 min; adding 2L ethanol into the reducing solution for precipitation for 8h, and collecting the precipitate.
3 ultraviolet irradiation, calcium replacement and freeze-drying
Adding 1.25L of purified water into the precipitate obtained in the step 2 to prepare 8% solution, filtering with a 0.45 mu m filter membrane, and washing the filter membrane with a small amount of purified water; irradiating with 254nm ultraviolet lamp for 2 hr to eliminate nitroso compound and nitrite remained in the solution; after the ultraviolet irradiation is finished, adding 2.5L of ethanol for precipitation for 8h, removing supernatant, and collecting precipitate; preparing the insoluble oily matter at the bottom into 8% solution with 1.25L calcium chloride solution with mass fraction of 3%, filtering with 0.22 μm filter membrane, slowly adding 2.5L ethanol into the filtrate at 37 deg.C, stirring for 30min, and standing for 8 hr; after precipitation, 100mL of ethanol was added for dehydration and lyophilized at-45 ℃.
Routine experimentation (comparison with the examples)
This experiment is compared with example 1, 2 and 3, and 100g fine quality heparin sodium is weighed equally, through operating rules such as degradation, reduction, ultraviolet irradiation, calcium replacement, oxidation and twice calcium replacement and stoving, makes nadroparin calcium, and the difference with this embodiment lies in: the sodium removal process is not carried out, and the hydrogen peroxide oxidation and decoloration process is arranged behind the calcium conversion process. The weight average molecular weight is 4320(EP standard 3600-5000), wherein the molecular weight is 67.5% (EP standard 2000-8000 is 75.0% -95%) which does not meet the standard.
Claims (2)
1. The invention relates to a method for preparing refined nadroparin calcium by using refined heparin sodium as a raw material through the procedures of oxidation, degradation, reduction, ultraviolet irradiation, calcium replacement and the like, which can better control the average distribution of molecular weight, improve the product yield, is simple and convenient to operate and can improve the production efficiency to a greater extent.
2. The invention prepares nadroparin calcium according to the following process:
a, oxidation: dissolving refined heparin sodium in purified water with a proper volume to prepare 8-10% aqueous solution, and adjusting the pH value of the solution to 10-10.5 by using 20% NaOH; oxidizing the mixture for 8 to 10 hours by using 1 to 3 percent hydrogen peroxide under the condition of normal temperature, and adding the mixture in three times; after the oxidation is finished, filtering the mixture by using a filter membrane with the diameter of 0.45 mu m, and washing the filter membrane by using a small amount of purified water; slowly adding 0.8-1 time volume of ethanol into the filtrate at 37 ℃, stirring for 30min, and standing for 4-8 h; and after the precipitation is finished, discarding a supernatant, preparing a 10% solution of insoluble oily substances at the bottom by using 3-5% saline water, adjusting the pH value of the solution to be 6.5-7, filtering by using a 0.22 mu m filter membrane, slowly adding 0.8-1 time volume of ethanol into the filtrate at 37 ℃, stirring for 30min, standing for 4-8 h, discarding the supernatant, and directly using insoluble substances for next sodium removal.
b, sodium removal, degradation and reduction: dissolving the precipitate obtained in the step 1 in purified water with a proper volume to prepare an 8-10% aqueous solution, adding strong acid type cation exchange resin, adjusting the pH value of the heparin sodium aqueous solution to 2.5-3, then filtering, adding a sodium nitrite solution with the mass percentage concentration of 5-10% into the filtrate, stirring at room temperature for 1-2 h, and detecting with a starch potassium iodide test paper until the solution is colorless; after the degradation reaction is finished, adjusting the value of the solution to be 7-8.5 by using saturated calcium hydroxide, stirring for 20-30 min, and stopping the degradation reaction; adding 5-10% sodium borohydride aqueous solution in batches, stirring and reacting for 10-15 h, adjusting the pH value to 3.5-4.0 by using 4mo1/L hydrochloric acid, and continuously stirring and reacting for 25-30 min; adding ethanol with the volume of 1-2 times of that of the reducing solution into the reducing solution for precipitation for 4-8 hours, and collecting the precipitate.
c, ultraviolet irradiation, calcium replacement and freeze-drying: preparing the precipitate obtained in the step 2 into a 5-8% aqueous solution, filtering the aqueous solution by using a filter membrane of 0.45 mu m, and washing the filter membrane by using a small amount of purified water; irradiating for 1-3 h by using an ultraviolet lamp with the wavelength of 254nm to eliminate nitroso compounds and nitrite remained in the solution; after the ultraviolet irradiation is finished, adding ethanol with the volume of 1-2 times of that of the mixture for precipitation for 4-8 hours, and collecting precipitates; after the precipitation is finished, removing supernatant, preparing the insoluble oily matter at the bottom into 5-10% solution by using 3-5% calcium chloride solution, filtering by using a 0.22 mu m filter membrane, slowly adding ethanol with the volume of 1-2 times of that of the filtrate at 37 ℃, stirring for 30min, and standing for 4-8 h;
after the precipitation is finished, adding 1 time of ethanol for dehydration, and freeze-drying at-45 ℃.
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