CN113004429A

CN113004429A - Refining method of carboxyl ferric maltose

Info

Publication number: CN113004429A
Application number: CN201911330100.XA
Authority: CN
Inventors: 万辉; 黄春玉; 袁铎; 周红燕; 李剑; 徐向阳; 谢俊
Original assignee: Jinling Pharmaceutical Co ltd
Current assignee: Jinling Pharmaceutical Co ltd
Priority date: 2019-12-20
Filing date: 2019-12-20
Publication date: 2021-06-22
Anticipated expiration: 2039-12-20
Also published as: CN113004429B

Abstract

The invention discloses a refining method of carboxyl ferric maltose, wherein a carboxyl ferric maltose aqueous solution is mixed with absolute ethyl alcohol for alcohol precipitation, the number of the alcohol precipitation is at least 2, the obtained carboxyl ferric maltose moist product is washed by the absolute ethyl alcohol to remove water, and a boiling bed is dried to obtain a refined product of the carboxyl ferric maltose. The material obtained by the invention has good uniformity, the molecular weight of the material does not change obviously before and after drying, and each index meets the requirement of medicinal raw materials required by producing the carboxyl maltose iron injection. The method is simple, has low requirements on equipment and technology, is particularly suitable for industrial operation, and has great practical significance in actual production.

Description

Refining method of carboxyl ferric maltose

Technical Field

The invention belongs to the field of pharmaceutical chemical industry, and relates to a refining method of carboxyl ferric maltose.

Background

Iron deficiency anemia is a common nutritional disorder, and occurs as a result of the storage of iron in vivo failing to meet the needs of normal erythropoiesis. At present, about 20 hundred million people worldwide suffer from anemia, of which more than 90% are iron deficiency anemia from clinical statistics.

For iron deficiency anemia, oral administration or injection of iron preparations is the most commonly used. Because of its effectiveness, low price and safety, oral iron supplement is often used as the first choice drug for iron-deficiency anemia, and is still mainly used for oral iron supplement in China. However, oral iron preparations often have significant gastrointestinal discomfort symptoms, patients are interrupted by intolerance, and in addition, the oral iron preparations are influenced by food composition interference and in vivo iron reserves, particularly in many patients with chronic diseases and tumors, in vivo inflammatory cell mediators are increased, the inflammatory mediators can induce liver to synthesize iron regulatory protein, and the liver synthesizes iron regulatory protein which can down regulate the expression of membrane iron transporters on the surfaces of gastrointestinal tracts and in vivo iron storage cells, so that the absorption and utilization of iron are influenced, and the effect of the oral iron preparations is often poor or not effective at all. In addition, in gastrointestinal diseases, when the iron storage needs to be recovered quickly and oral administration is not enough to supplement the needs of human bodies, intravenous iron supplement is required under the conditions that oral iron preparations cannot be tolerated and cannot be complied with.

Currently, common intravenous iron agents for clinical use include iron dextran, complex ferric sodium gluconate, ferric sucrose, ferric isomaltose anhydride 1000, ferumoxyytol, and ferric carboxymaltose. The ferric iron in the carboxyl ferric maltose injection is complexed with carbohydrate polymers in a stable ferric iron state so as to release available iron to in vivo iron transport and storage proteins (ferritin and transferrin), and the carboxyl ferric maltose injection is a novel polysaccharide intravenous injection.

Carboxyferric maltose, developed by vefu medicine, was first marketed in germany in 2007, and in the uk the next 5 months, under the trade name Ferinject, for use in the treatment of iron deficiency anemia where oral iron is ineffective or unavailable. By the end of 2014, ferric carboxymaltose injection has been registered in 63 countries worldwide including numerous european countries and the united states, australia, argentina, korea, singapore, where 54 countries are on the market, but not yet on the market in our country. In the aspect of treating iron-deficiency anemia, the carboxyl ferric maltose has better curative effect than ferric saccharate, more advantage in cost and good tolerance. 500-1500 mg Fe can be rapidly input within 15min, and the maximum single dose approved at present is 1000mg Fe. The carboxyl ferric maltose meets the clinical requirement of large-dose rapid administration of the iron preparation, and becomes a representative medicine of a novel intravenous iron preparation.

The synthesis of the ferric carboxymaltose takes maltodextrin as an initial raw material, the ferric carboxymaltodextrin is obtained after oxidation, and the ferric carboxymaltodextrin is subjected to complex reaction with a raw material containing ferric ions to generate the ferric carboxymaltose.

Related patents CN106977621A, CN108129582A, and CN1705682A all relate to the synthesis of ferric carboxymaltose, but the differences in the expression of the refining method of ferric carboxymaltose are large, and the final drying of the material generally adopts a vacuum drying method, which has poor effect and is liable to cause large changes in the molecular weight of the material. The refining of CN106977621A is complex: the pH value of the carboxyl maltose iron aqueous solution obtained by the reaction is continuously adjusted in the alcohol precipitation process, the carboxyl maltose iron aqueous solution is washed by the glacial ethanol for multiple times and then dried, water is added again for dissolution, the anhydrous ethanol is used for alcohol precipitation, the processes of washing by the glacial ethanol and adjusting the pH value are repeated on the filter cake, and finally the filter cake is dried in vacuum, so that the whole process has complicated water content and does not meet the industrial requirements. CN108129582A and CN1705682A do not relate to the refining process.

Disclosure of Invention

The synthesis of the ferric carboxymaltose takes maltodextrin as an initial raw material, the ferric carboxymaltodextrin is obtained after oxidation, and the ferric carboxymaltodextrin is subjected to complex reaction with a raw material containing ferric ions to generate the ferric carboxymaltose. The inventor researches and discovers that: in a complex reaction system of ferric trichloride solution and carboxyl maltodextrin solution, the proportion of sodium carbonate to ferric trichloride, the concentration of the sodium carbonate solution and the concentration of the ferric trichloride solution are fixed, the molecular weight of the carboxyl maltose ferric is only related to the time (or adding speed) for adding the sodium carbonate solution at a constant speed in the whole process, but is not related to the quantity of materials in the reaction system, and the carboxyl maltose ferric with specific molecular weight and molecular weight distribution coefficient can be obtained by controlling the adding speed of the sodium carbonate solution. The molecular weight of the final product, ferric carboxymaltose, is correlated with the time of addition of the sodium carbonate solution, regardless of the amount of reactants. The inventor adopts the following technical scheme to prepare the carboxyl maltose iron with specific molecular weight, and specifically comprises the following steps: dissolving maltodextrin in 1-2 times of water, taking sodium bromide accounting for 1-2% of the weight of the maltodextrin as a catalyst, adjusting the pH value to 9.0-11.0 by using 30% sodium hydroxide solution, controlling the temperature to be 25-40 ℃, and adding 10% sodium hypochlorite solution accounting for 0.8-1 times of the weight of the maltodextrin under the condition of stirring to obtain carboxyl maltodextrin solution; weighing ferric trichloride hexahydrate and sodium carbonate according to the mass ratio of 1:2.2 of ferric trichloride hexahydrate to maltodextrin and the mass ratio of 2: 1-3: 1 of ferric trichloride hexahydrate to sodium carbonate, and respectively preparing a ferric trichloride solution with the concentration of 70-80% w/w and a sodium carbonate solution with the concentration of 20-35% w/w; mixing a carboxyl maltodextrin solution and a ferric trichloride solution, stirring, controlling the temperature to be 50-70 ℃, setting the flow rate, and dropwise adding a sodium carbonate solution at a constant speed within 1.0 hour; and then sequentially carrying out alkali curing, acid curing and high-temperature curing to obtain the stable carboxyl maltose iron aqueous solution.

Molten iron carboxymaltose solutions generally contain a large amount of inorganic impurities. The inventor finds that the crude product separated by mixing the ferric carboxymaltose aqueous solution and the absolute ethyl alcohol for the first time is a thick colloid like asphalt, is difficult to dry directly, contains more inorganic impurities and has high water content, and the ferric carboxymaltose in the state can not be placed for a long time. If the crude product is directly dried, the caking phenomenon appears in the drying process, and the drying effect is seriously influenced. Therefore, the crude product of the ferric carboxymaltose needs to be refined, inorganic impurities contained in the crude product are sufficiently removed, and then the refined product of the ferric carboxymaltose is obtained after drying.

The invention aims to provide a simple and effective method for refining carboxyl ferric maltose.

The purpose of the invention is realized by the following technical scheme:

mixing a molten iron carboxyl maltose solution with absolute ethyl alcohol for alcohol precipitation, wherein the number of alcohol precipitation is at least 2, washing a wet iron carboxyl maltose product obtained by alcohol precipitation with the absolute ethyl alcohol to remove water, and drying the product in a fluidized bed to obtain a refined iron carboxyl maltose product.

Alcohol precipitation is carried out each time, and the dosage of the absolute ethyl alcohol is 45-60% (w/w) of the weight of the molten iron carboxyl maltose; the alcohol precipitation temperature is 5-30 ℃.

Preferably, the number of times of alcohol precipitation is 2.

Preferably, the carboxyl maltose iron tide product is washed with absolute ethyl alcohol for 2 times. The washing temperature is 5-30 ℃.

The dosage of the absolute ethyl alcohol is 10 to 20 percent (w/w) of the weight of the initial molten carboxyl maltose solution in each washing.

Specifically, the washing method of the carboxyl maltose iron tide product comprises the following steps: adding anhydrous ethanol into the carboxyl maltose iron tide product, stirring, standing for precipitation, filtering, adding anhydrous ethanol, stirring, standing for precipitation, and filtering.

The drying temperature is 30-50 ℃, and the drying time is 30-50 minutes.

Specifically, the method for refining the carboxyl ferric maltose comprises the following steps:

mixing the molten carboxyl maltose iron solution with absolute ethyl alcohol, controlling the amount of the absolute ethyl alcohol precipitated by alcohol to be 45-60% (w/w) of the weight of the molten carboxyl maltose iron solution, precipitating the mixture by alcohol for 1.5-2.0 hours at the temperature of 5-30 ℃, and filtering;

adding water with the amount of 50-60% of the original carboxyl maltose iron water solution into the filter cake for dissolving, mixing the water with absolute ethyl alcohol with the same amount as that of the first alcohol precipitation, precipitating the mixture with alcohol at the temperature of 5-30 ℃ for 1.5-2.0 hours, and filtering to obtain a carboxyl maltose iron moist product;

washing the carboxyl maltose iron moisture product with absolute ethyl alcohol for 2 times at the temperature of 5-30 ℃, wherein the use amount of the ethyl alcohol for each washing is 10-20% (w/w) of the weight of the initial carboxyl maltose iron water solution;

and (4) drying the washed materials by using a fluidized bed, controlling the drying temperature to be 30-50 ℃, and drying for 30-50 minutes to obtain a carboxyl ferric maltose refined product.

The DE value of the maltodextrin is 10-15.

The invention has the beneficial effects that:

the solid precipitated after the initial mixing of the iron carboxymaltose aqueous solution with absolute ethanol was a viscous gum like asphalt and was difficult to dry directly. The invention changes the viscous colloidal physical property of the primary alcohol precipitation product by 2 times of alcohol precipitation, and removes the inorganic impurities. And then the materials are fully washed by absolute ethyl alcohol, washed to remove water, filtered, and quickly dried at a lower temperature in a fluidized bed to fully remove water and organic solvent, so that the molecular weight of the materials is prevented from being greatly changed, and finally the powdery solid materials with good uniformity are obtained.

The method is simple, has low requirements on equipment and technology, is particularly suitable for industrial operation, and has great practical significance in actual production.

Detailed Description

The technical solution of the present invention is further explained by the following embodiments.

Example 1

Adding 1000g of maltodextrin into 2000g of water, and stirring for dissolving; adding 10g of sodium bromide, adding 30% sodium hydroxide solution to adjust the pH value of the maltodextrin solution to 9.0-11.0, controlling the temperature to be 25-40 ℃, and adding 800g of 10% sodium hypochlorite solution under the stirring condition to obtain the carboxyl maltodextrin solution.

Ferric chloride solution: 2200g of ferric trichloride hexahydrate is prepared into a 75% (w/w) solution by adding water.

Sodium carbonate solution: 1100g of sodium carbonate and water were added to prepare a 25% (w/w) solution.

Mixing the carboxyl maltodextrin solution and the ferric trichloride solution, stirring, controlling the temperature to be 50-70 ℃, setting the flow rate, dropwise adding the sodium carbonate solution at a constant speed by using a peristaltic pump, and controlling the addition of the sodium carbonate solution to be finished within 1.0 hour. After the completion, adding 30% sodium hydroxide solution to adjust the pH value of the solution to 10.0-12.0, controlling the temperature to 50-70 ℃, and stirring for 0.5 hour (alkali curing); adding 20% hydrochloric acid solution to adjust the pH value of the solution to 5.0-6.0, controlling the temperature to 50-70 ℃, and stirring for 0.5 hour (acid curing); the temperature is raised to 90-100 ℃, and stirring is continued for 0.5 hour (high-temperature solidification), so that 12382g of stable carboxyl maltose iron aqueous solution is obtained.

Adding 6000g of absolute ethyl alcohol into the molten iron carboxyl maltose, stirring for 15 minutes, standing at normal temperature, and precipitating with ethanol for 90 minutes; filtering, adding 6200g of water into the filter cake, stirring to dissolve, adding 6000g of absolute ethyl alcohol, stirring for 15 minutes, and standing at normal temperature for alcohol precipitation for 90 minutes; filtering, washing the filter cake with anhydrous ethanol for 2 times at normal temperature, and using 1500g of anhydrous ethanol each time.

The washed materials are put into a boiling bed to be dried, the temperature is controlled to be 40 +/-10 ℃, and the drying time is 30 minutes, so that 1430g of the carboxyl ferric maltose refined product is obtained.

Example 2

The procedure of example 1 was followed to magnify each material by a factor of 2 to obtain 24801g of a stable iron carboxymaltose aqueous solution.

Adding 12000g of absolute ethyl alcohol into the molten iron carboxyl maltose solution, stirring for 15 minutes, standing at normal temperature and precipitating with ethanol for 90 minutes; filtering, adding 12400g of water into a filter cake, stirring to dissolve, adding 12000g of absolute ethyl alcohol, stirring for 15 minutes, standing at normal temperature, precipitating with ethanol for 90 minutes; filtering, washing filter cake with anhydrous alcohol 2 times at normal temperature, each time using 3000g of anhydrous alcohol.

The washed material is put into a boiling bed to be dried, the temperature is controlled at 40 +/-10 ℃, and the drying time is 30 minutes, thus obtaining 2916g of the carboxyl ferric maltose refined product.

Example 3

The procedure of example 1 was followed to magnify each material by 3 times to obtain 37364g of a stable iron carboxymaltose aqueous solution.

Adding 20000g of absolute ethyl alcohol into the molten iron carboxyl maltose, stirring for 15 minutes, standing at normal temperature and precipitating with ethanol for 90 minutes; filtering, adding 20000g of water into the filter cake, stirring for dissolving, adding 20000g of absolute ethanol, stirring for 15 minutes, and standing at normal temperature for ethanol precipitation for 90 minutes; filtering, washing filter cake with anhydrous ethanol 2 times at normal temperature, and using 5000g of anhydrous ethanol each time.

The washed materials are put into a boiling bed to be dried, the temperature is controlled at 40 +/-10 ℃, and the drying time is 30 minutes, so that 4227g of the carboxyl ferric maltose refined product is obtained.

Example 4

The procedure of example 1 was followed to magnify each material by a factor of 4 to obtain 49820g of a stable iron carboxymaltose aqueous solution.

Adding 25000g of absolute ethyl alcohol into the molten iron carboxyl maltose solution, stirring for 15 minutes, standing at normal temperature, and precipitating with ethanol for 90 minutes; filtering, adding 25000g of water into a filter cake, stirring to dissolve, adding 25000g of absolute ethyl alcohol, stirring for 15 minutes, standing at normal temperature, precipitating with ethanol for 90 minutes; filtering, washing the filter cake with 6000g of absolute ethanol at room temperature for 2 times.

The washed materials are put into a boiling bed to be dried, the temperature is controlled at 40 plus or minus 10 ℃, and the drying is carried out for 30 minutes, thus obtaining 5768g of carboxyl ferric maltose refined product.

Table 1: examples 1-4 purified carboxymaltase iron

The invention adopts 2 times of alcohol precipitation, can change the shape of asphalt-like viscous jelly precipitated after the carboxyl maltose ferric water solution is mixed with absolute ethyl alcohol for the first time, and removes the contained inorganic impurities. And then washing with absolute ethyl alcohol, and drying the material in a fluidized bed at 40 +/-10 ℃ for 30 minutes to fully remove moisture and organic solvent, thereby avoiding large change of the molecular weight of the material under high-temperature drying.

As shown in Table 1, the key indexes of the ferric carboxymaltose obtained by the refining process of the invention all meet the relevant standards of the original research, completely meet the requirements of medicinal raw materials required by producing ferric carboxymaltose injection, and are suitable for the raw materials of the ferric carboxymaltose injection.

Claims

1. The refining method of carboxyl ferric maltose is characterized in that the carboxyl ferric maltose aqueous solution is mixed with absolute ethyl alcohol for alcohol precipitation, the number of the alcohol precipitation is at least 2, the obtained carboxyl ferric maltose moist product is washed by the absolute ethyl alcohol to remove water, and the product is dried by a boiling bed to obtain the refined product of the carboxyl ferric maltose.

2. The method for refining carboxyferric maltose as claimed in claim 1, wherein the alcohol precipitation temperature is 5 to 30 ℃.

3. The method for refining ferric carboxymaltose as claimed in claim 1, wherein the amount of the absolute ethyl alcohol used in each alcohol precipitation is 45% to 60% by weight of the molten iron carboxymaltose solution.

4. The method of claim 1, wherein the moist carboxymaltose is washed 2 times with ethanol.

5. The method according to claim 1, wherein the amount of the absolute ethyl alcohol used per washing is 10 to 20% by weight of the molten iron carboxymaltose solution.

6. The method for refining carboxyferric maltose according to claim 1, wherein the washing temperature is 5 to 30 ℃.

7. The method for refining carboxyferric maltose according to claim 1, wherein the drying temperature is 30 to 50 ℃ and the drying time is 30 to 50 minutes.

8. The method of refining carboxyferric maltose according to claim 1, comprising the steps of:

mixing the molten carboxyl maltose iron solution with absolute ethyl alcohol, controlling the amount of the absolute ethyl alcohol precipitated by alcohol to be 45-60% of the weight of the molten carboxyl maltose iron solution, precipitating the mixture by alcohol for 1.5-2.0 hours at the temperature of 5-30 ℃, and filtering;

washing the carboxyl maltose iron moisture product with absolute ethyl alcohol for 2 times at the temperature of 5-30 ℃, wherein the use amount of the ethyl alcohol for each washing is 10-20% of the weight of the carboxyl maltose iron aqueous solution;