CN113018256B

CN113018256B - Preparation process of ferric carboxymaltose injection

Info

Publication number: CN113018256B
Application number: CN201911356756.9A
Authority: CN
Inventors: 万辉; 黄春玉; 袁铎; 李剑; 徐向阳; 谢俊
Original assignee: Jinling Pharmaceutical Co ltd
Current assignee: Jinling Pharmaceutical Co ltd
Priority date: 2019-12-25
Filing date: 2019-12-25
Publication date: 2023-02-17
Anticipated expiration: 2039-12-25
Also published as: CN113018256A

Abstract

The invention discloses a preparation process of carboxyl ferric maltose injection, which comprises the following steps: taking maltodextrin as an initial reaction raw material, oxidizing by sodium hypochlorite to generate carboxyl maltodextrin, and complexing with ferric trichloride solution to obtain carboxyl ferric maltose solution; adding anhydrous ethanol into the ferric carboxymaltose solution to separate out ferric carboxymaltose, and filtering; the filter cake is not required to be dried, and is directly dissolved by adding water, and the pH value is adjusted to 5.0-7.0; supplementing water until the iron content is 48-52 mg/mL; filtering, bottling, and sterilizing. The key indexes of the product of the method of the invention are consistent with those of the original research, but the synthesis of the ferric carboxymaltose to the completion of the injection is a continuous process, the processes of refining, drying, packaging and the like of materials are avoided in the middle, and other organic solvents are not involved except that the ferric carboxymaltose is separated out from the aqueous solution of the ferric carboxymaltose and ethanol is used, so that a large amount of solvents and energy sources are saved, the economy is good, the process is easy to realize in production, and the practicability is higher.

Description

Preparation process of ferric carboxymaltose injection

Technical Field

The invention belongs to the field of drug synthesis and preparation processes, and relates to a preparation process of a carboxyl ferric maltose injection.

Background

At present, about 20 hundred million people all over the world suffer from anemia, and more than 90 percent of the anemia is iron-deficiency anemia according to clinical statistics; that is, 9 of 10 anemia patients are iron deficiency anemia patients. 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.

For iron deficiency anemia, oral administration or injection of iron preparations is the most commonly used. Because of being effective, cheap and safe, the oral iron supplement is often used as the first choice medicine for iron-deficiency anemia at present and is still mainly taken orally for iron supplement in China. However, oral iron administration often has significant gastrointestinal discomfort, and patients have to discontinue treatment due to intolerance, and in addition, it is affected by food component interference and iron stores in vivo, especially in many chronic diseases and cancer patients, there is an increase in inflammatory cell mediators in vivo, which can induce liver to synthesize iron regulatory protein, which down-regulates the expression of iron transporters on the surface membrane of gastrointestinal tract and iron storage cells in vivo, thereby affecting iron absorption and utilization, and the oral iron administration 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, the common intravenous iron agents for clinical use in the world include iron dextran, complex ferric sodium gluconate, ferric saccharate, ferric isomaltose anhydride 1000, ferumoxyytol, and ferric carboxymaltose. Iron carboxymaltose is a novel therapeutic or prophylactic agent for the treatment of iron deficiency anemia, is a colloidal iron (III) hydroxide complexed with carboxymaltose, an iron-releasing glycomer with the chemical name polynuclear iron (III) hydroxide 4 (R) - [ poly- (1 → 4) -O- α -D-glucopyranosyl ] -oxy-2 (R), 3 (S), 5 (R), 6-tetrahydroxyhexanoic acid complex of formula: [ FeOx (OH) y (H2O) z ] n { (C6H 10O 5) m (C6H 12O 7) } l ] k, where n ≈ 103, m ≈ 8, l ≈ 11, k ≈ 4 (l represents the average branching degree of the ligand) relative molecular weight: about 150000Da.

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 are not currently 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. The ferric carboxymaltose injection can be rapidly input with 500-1500 mg Fe within 15min, and the maximum approved single dose is 1000mg Fe. The ferric carboxymaltose injection meets the clinical requirement on the rapid administration of a large dose of the iron preparation, and becomes a representative medicine of a novel intravenous iron preparation.

The iron carboxymaltose injection which is currently on the market mainly has two specifications (100 mg/2mL and 500mg/10mL in terms of iron content), and the iron content of the iron carboxymaltose injection is 50mg/mL.

The production of the iron carboxymaltose starting material and the formulation is generally independent. In the production process of the raw materials, the materials are generally subjected to the working procedures of refining, drying, packaging and the like. These steps, such as purification and drying, affect the molecular weight of the carboxymaltose iron, and consume a large amount of solvent and energy, resulting in poor economy.

No report related to the continuous production process of ferric carboxymaltose from synthesis to injection is found.

Disclosure of Invention

The invention aims to provide a continuous production process from the synthesis of ferric carboxymaltose to injection.

The purpose of the invention can be realized by the following technical scheme:

a process for preparing the Fe-maltol injection features that the maltodextrin is used as the initial raw material and the continuous process from the synthesis of Fe-maltol to the completion of injection is used.

The preparation process of the ferric carboxymaltose injection comprises the following steps: taking maltodextrin as an initial reaction raw material, oxidizing by sodium hypochlorite to generate carboxyl maltodextrin, and complexing with ferric trichloride solution to obtain carboxyl ferric maltose solution; adding anhydrous ethanol into the ferric carboxymaltose solution to separate out ferric carboxymaltose, and filtering; the filter cake is not required to be dried, and is directly added with water for injection to be dissolved, and the pH value is adjusted to 5.0-7.0; supplementing water until the iron content is 48-52 mg/mL; filtering with 0.22 μm filter membrane, bottling, and sterilizing.

The inventor researches and discovers that: in a complex reaction system of a ferric trichloride solution and a 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 maltodextrin is only independent of the time for adding the sodium carbonate solution at a constant speed in the whole process and the quantity of materials in the reaction system, and the carboxyl maltodextrin 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, independent of the amount of reactants. The preparation method of the carboxyl maltose iron solution comprises the following steps: dissolving the maltodextrin in 1-2 times of water, regulating pH value to 9.0-11.0 with 30% concentration sodium hydroxide solution, controlling temperature to 25-40 deg.c, and adding 10% concentration sodium hypochlorite solution in 0.8-1 times of the maltodextrin weight while stirring to obtain carboxyl maltodextrin solution; weighing ferric trichloride hexahydrate and sodium carbonate according to the mass ratio of 1 to 2.2 of ferric trichloride hexahydrate to maltodextrin and the mass ratio of 2 to 1 to 3 of ferric trichloride hexahydrate to sodium carbonate, and 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 respectively; mixing the carboxyl maltodextrin solution and the ferric trichloride solution, stirring, controlling the temperature to be between 50 and 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.

The alkali curing is as follows: adjusting the pH value of the solution to 10.0-12.0 by 30% sodium hydroxide solution, controlling the temperature to 50-70 ℃, and stirring for 0.5 hour.

The acid is cured as follows: adjusting the pH value of the solution to 5.0-6.0 by 20% hydrochloric acid, controlling the temperature to 50-70 ℃, and stirring for 0.5 hour.

The high-temperature curing is as follows: stirring for 0.5 hour at 90-100 ℃.

The synthesis reaction of the carboxyl ferric maltose takes water as a solvent, absolute ethyl alcohol is added into a carboxyl ferric maltose solution, the mass ratio of the absolute ethyl alcohol to a maltodextrin raw material is 1.5-1.7, preferably 1.6.

The invention adopts acceptable pH regulator such as hydrochloric acid or sodium hydroxide to regulate the pH of the carboxyl maltose iron solution to 5.0-7.0.

The invention has the beneficial effects that:

the method combines the actual production, fixes the raw material proportion, the material concentration, the pH value, the temperature and the like of the reaction system, controls the sodium carbonate solution to be added into the reaction system at a constant speed (namely the length of the constant speed dripping time), and finally has no obvious difference in the molecular weight of the carboxyl maltose iron and is consistent with the original preparation.

The key indexes of the product of the method of the invention are consistent with those of the original research, but the synthesis of the ferric carboxymaltose to the completion of the injection is a continuous process, the processes of refining, drying, packaging and the like of materials are avoided in the middle, and other organic solvents are not involved except that the ferric carboxymaltose is separated out from the aqueous solution of the ferric carboxymaltose and ethanol is used, so that a large amount of solvents and energy sources are saved, the economy is good, the process is easy to realize in production, and the practicability is higher.

Detailed Description

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

Example 1

Adding 200mL of water into 100g of maltodextrin, and stirring for dissolving; and adding 30% sodium hydroxide solution to adjust the pH value of the maltodextrin aqueous solution to 9.0-11.0, controlling the temperature to be 25-40 ℃, and adding 80g of 10% sodium hypochlorite solution under the stirring condition to obtain the carboxyl maltodextrin solution.

Preparing a ferric trichloride solution: 220g of ferric trichloride hexahydrate and water are added to prepare a 75% (w/w) solution.

Preparing a sodium carbonate solution: 110g of sodium carbonate and water are 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. And after the completion, sequentially carrying out alkali curing, acid curing and high-temperature curing: 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; adding 20% hydrochloric acid 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; heating to 90-100 ℃, and continuing stirring for 0.5 hour to obtain the stable carboxyl ferric maltose solution.

Adding 160g of absolute ethyl alcohol into the ferric carboxymaltose solution to separate out ferric carboxymaltose, filtering, adding 600mL of water for injection into a filter cake, stirring to dissolve, adjusting the pH value to 6.5 by using a 30% sodium hydroxide solution, measuring the iron content by using a complex titration method, calculating the water supplement amount, adding water to 911mL, and repeatedly measuring the iron content to 49.86mg/mL; filtering with 0.22 μm filter membrane, packaging the filtrate in 2mL ampoule, and sterilizing.

Molecular weight and molecular weight distribution assay: the weight average molecular weight (Mw) of the product is 110000-230000 Da, the number average molecular weight (Mn) is not less than 60000Da, and the distribution coefficient (Mw/Mn) is not more than 1.9, which is determined by molecular exclusion chromatography (the general rule 0514 in 2015 of Chinese pharmacopoeia).

Hydrophilic spherical polymer as filler (Shodex) for chromatographic condition and system applicability test ^TM A SB-804HQ chromatographic column,

300mm 8mm and Shodex ^TM An SB-802HQ chromatographic column,

300mm multiplied by 8mm are used in series; or other suitable chromatographic column). Taking 0.02mol/L phosphate buffer solution (taking 7.17g of disodium hydrogen phosphate dodecahydrate, 3.12g of sodium dihydrogen phosphate dihydrate and 0.4g of sodium azide, dissolving in 2000mL of water, and adjusting the pH value to 6.8 by using phosphoric acid) as a mobile phase; the column temperature was 35 ℃ and the flow rate was 0.5ml per minute; a differential refractive detector, a detector temperature of 35 ℃.

Accurately weighing 10mg of each of glucose and a pullulan P-400 reference substance, placing the reference substance into the same 2mL measuring flask, adding a proper amount of water, slightly shaking to dissolve and dilute the reference substance to a scale, slightly shaking uniformly, placing the reference substance at 4 ℃ for 12-24 hours, filtering the reference substance by using a 0.45-micrometer microporous filter membrane, taking 20 mu L of subsequent filtrate, injecting the subsequent filtrate into a liquid chromatograph, recording a chromatogram, and determining that the retention time of a pullulan P-400 main peak is t0 and the retention time of a glucose main peak is tT, wherein in the chromatogram recorded by a test solution, the retention time tR of a carboxymalted iron main peak is between tT and t0, and the number of theoretical plates is not less than 8000 according to the glucose peak.

Shodex is adopted for standard curve drawing ^TM Standard P-82 pullulan is used as a reference substance, 6 known nominal molecular weights (Mp) are selected as the reference substance (the range of Mp is 9000-350000 Da) according to the molecular weight of the product, 10mg of the Standard P-82 pullulan is precisely weighed and respectively placed in a 2mL measuring flask, a proper amount of water is added to slightly shake the Standard P-82 pullulan to dissolve and dilute the Standard P-82 pullulan to scale, the Standard P-82 pullulan is gently shaken to be evenly stirred, the Standard P-82 pullulan is placed at 4 ℃ for 12-24 hours, a 0.45 mu m microporous filter membrane is used for filtration, 20 mu L of subsequent filtrate is taken and injected into a liquid chromatograph, a chromatogram is recorded, GPC software is used for processing data, a three-order Standard curve is made by using the retention time tR of a chromatographic peak to the logarithm value (log Mp) of the nominal molecular weight, and the correlation coefficient r is not less than 0.98.

The determination method comprises precisely measuring 1mL of the product, placing in a 50mL measuring flask, diluting with water to scale, shaking, filtering with 0.45 μm microporous membrane, collecting 20 μ L of filtrate, injecting into a liquid chromatograph, recording chromatogram, and calculating weight average molecular weight (Mw), number average molecular weight (Mn) and distribution coefficient (Mw/Mn) with GPC software.

The weight average molecular weight (Mw), number average molecular weight (Mn) and distribution coefficient (Mw/Mn) of ferric carboxymaltose in the ferric carboxymaltose injection of this example are shown in Table 1.

The method for measuring the iron content comprises the following steps: 2mL of the product is precisely measured by using an internal pipette, the product is placed in a 250mL conical flask, 10mL of hydrochloric acid is added, the solution is shaken until the solution is transparent and is light yellow, 1mL of 30% hydrogen peroxide solution, 100mL of water and 10mL of glacial acetic acid are added, the solution is shaken and uniformly mixed, the pH value is adjusted to 2.2-2.5 by using 32% sodium hydroxide solution, the test solution is placed on an electric furnace and heated to be nearly boiled, after the test solution is taken down and cooled, a ferrotitanium indicating solution (2.0 g of 4, 5-dihydroxybenzene-1, 3-sodium disulfonate monohydrate is added, the solution is diluted to 100mL by using water) to be 2.5mL, and disodium ethylene diamine tetraacetate titration solution (0.05 mol/L) is immediately titrated until the solution is pure yellow. Each 1mL of disodium EDTA titrate (0.05 mol/L) corresponds to 2.7925mg of Fe.

The iron content of the iron carboxymaltose injection of this example was 49.86mg/mL.

The key indexes of the ferric carboxymaltose injection (molecular weight and iron content) in the embodiment are consistent with those of the original preparation.

Example 2

The procedure of example 1 was followed to amplify each material by 2-fold to obtain a stable iron carboxymaltose solution.

Adding 320g of absolute ethyl alcohol into the ferric carboxymaltose solution to separate out ferric carboxymaltose, filtering, adding 1200mL of water for injection into a filter cake, stirring to dissolve, adjusting the pH value to 6.5 by using a 30% sodium hydroxide solution, measuring the iron content by using a complex titration method, calculating the water supplement amount, adding water to 1866mL, and repeatedly measuring the iron content to 49.12mg/mL; then filtered through a 0.22 μm filter membrane, and the filtrate is filled in a 2mL ampoule and sterilized.

The molecular weight and iron content of carboxymaltose iron in the carboxymaltose iron injection of this example were measured by the method of example 1. See table 1, the key indicators of this example are consistent with those of the original formulation.

Example 3

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

Adding 640g of absolute ethyl alcohol into the ferric carboxymaltose solution to separate out ferric carboxymaltose, filtering, adding 2400mL of filter cake for injection, stirring to dissolve, adjusting the pH value to 6.3 by using 30% sodium hydroxide solution, measuring the iron content by using a complexometric titration method, calculating the water supplement amount, adding water to 3629mL, and repeatedly measuring the iron content to be 50.32mg/mL; filtering with 0.22 μm filter membrane, packaging the filtrate in 2mL ampoule, and sterilizing.

Table 1: key indicators for examples 1-3

As seen from the table 1, the key indexes of the final sample of the process are consistent with those of the original research, but the processes from the synthesis of the ferric carboxymaltose to the completion of the injection are continuous processes, the processes of refining, drying, packaging and the like of materials are avoided in the middle, a large amount of solvents and energy sources are saved, the economy is good, the process is easy to realize in production, and the process has higher practicability.

Claims

1. A preparation process of carboxyl ferric maltose injection is characterized in that maltodextrin is used as an initial reaction raw material, and a continuous process is adopted from the synthesis of the carboxyl ferric maltose to the completion of the injection; the method comprises the following steps: dissolving maltodextrin in 1-2 times of water, regulating pH value to 9.0-11.0 with 30% sodium hydroxide solution, controlling temperature to 25-40 deg.c, and adding 10% sodium hypochlorite solution in 0.8-1 times of maltodextrin weight while stirring to obtain carboxyl maltodextrin solution; weighing ferric trichloride hexahydrate and sodium carbonate according to the mass ratio of 1; mixing the carboxyl maltodextrin solution and the 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; then sequentially carrying out alkali curing, acid curing and high-temperature curing to obtain a carboxyl maltose iron solution; adding anhydrous ethanol into the ferric carboxymaltose solution to separate out ferric carboxymaltose, and filtering; the filter cake is not required to be dried, and is directly dissolved by adding water, and the pH value is adjusted to 5.0-7.0; supplementing water until the iron content is 48-52 mg/mL; filtering, filling and sterilizing; wherein the mass ratio of the absolute ethyl alcohol to the maltodextrin raw material is 1.5-1.7.

2. The process for preparing an iron carboxymaltose injection as claimed in claim 1, wherein the concentration of the iron trichloride solution is 70 to 80% w/w.

3. The process according to claim 1, wherein the concentration of the sodium carbonate solution is 20 to 35% w/w.

4. The process for preparing ferric carboxymaltose injection according to claim 1, characterized in that the mass ratio of the anhydrous ethanol to the maltodextrin raw material is 1.6.