Ferric carboxyl maltose and preparation process thereof

Abstract

The invention belongs to the field of medicines, and discloses a preparation process of ferric carboxymaltose, which comprises the following steps: oxidizing maltodextrin, performing ultrafiltration concentration, dissolving in a ferric trichloride aqueous solution, and performing coordination, ultrafiltration and spray drying to obtain powdery ferric carboxymaltose. The process has the advantages of simple amplification, no need of solvent application, low raw material cost and manufacturing cost, uniform product molecular weight distribution and the like, the dissolution rate of the obtained product is obviously higher than that of a product obtained by a precipitation process, and technical support is provided for more efficient preparation production.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceuticals, and in particular relates to a novel method for preparing and purifying carboxylated maltose iron. Background Technology

[0002] Currently, there are six types of intravenous iron preparations available for clinical use worldwide: low-molecular-weight iron dextran, high-molecular-weight iron dextran, sodium ferricgluconate, iron sucrose, ferumoxytol, and iron carboxymaltose. Iron carboxymaltose injection was approved by the US FDA on July 25, 2013. Iron carboxymaltose can be used to treat iron deficiency when oral iron supplements are ineffective or unavailable. The goal of treatment is to replenish the body's iron and eliminate anemia, which is caused by insufficient red blood cells due to iron deficiency. Currently, the most widely used iron injections are iron sucrose and iron dextran; however, the ultra-high molecular weight iron polymers in these products can easily cause allergic reactions in patients, and in severe cases, may even lead to respiratory distress or shock. Compared to other iron injections, carboxymaltose iron injection has a better safety profile, requires no small-dose testing before use, has a shorter injection time (once a week), and can deliver a large dose of 1000mg of iron in a single injection. This greater convenience leads to higher patient compliance.

[0003] Carboxymaltose iron is a polysaccharide-iron complex with iron-hydroxide as the core and carboxymaltose as the ligand. The polysaccharide and iron core interact through coordination and electrostatic interactions to form stable nanoparticles. The size of these nanoparticles is directly related to their molecular weight, influencing the release and absorption of iron in vivo. Due to its structural characteristics, the production process of carboxymaltose iron, including maltodextrin oxidation and iron core coordination, significantly impacts its molecular weight and molecular weight distribution. Currently, the industry primarily uses ethanol precipitation to prepare carboxymaltose iron. However, this precipitation process has almost no effect on optimizing the molecular weight of the iron complex. These small-molecule iron complexes can interfere with the release and absorption of iron in vivo, affecting product quality and stability. The molecular weight control of the product obtained by this method mainly depends on strict limitations of process parameters during preparation. In actual production, even slight disturbances can cause significant changes in the product's molecular weight and molecular weight distribution. Furthermore, the precipitated product is mostly viscous, and after drying, the particles are coarse, requiring pulverization using a granulator. However, the formulation process still requires prolonged heating for reconstitution, which can easily lead to sample contamination and increase production costs.

[0004] Chinese patent application CN 115844922 A discloses a carboxylated maltose iron complex and its preparation method. The preparation method has the following steps: (1) Dissolve maltose dextrin in purified water, add tetrabutylammonium bromide catalyst, and stir to dissolve; (2) Prepare oxidized dextrin solution by adding sodium hypochlorite solution at room temperature; (3) Mix the oxidized dextrin solution prepared in step (2) with ferric chloride solution, and adjust the pH value to 8-11 with sodium carbonate solution; (4) Heat to 50-60℃ and react for 4-8 hours, continue to heat to 130-140℃ and react for 2-5 hours. After the reaction is completed, the liquid is cooled and discharged; (5) Adjust the pH value of the liquid to 4-7 with dilute hydrochloric acid solution, then remove inorganic salts and small molecule compounds by ultrafiltration, and then spray dry to prepare the raw material. The carboxymaltose iron complex obtained by this preparation method has a stable structure and the content of divalent iron ions is stable during the stabilization process. However, the molecular weight of the carboxymaltose iron complex obtained by this method is still not well controlled and the loss is large, resulting in insufficient yield. At the same time, it is difficult to achieve kilogram-scale preparation. Summary of the Invention

[0005] This invention discloses a process for preparing carboxymaltose iron by dialysis purification and spray drying. The process uses series ultrafiltration to simplify the molecular weight control method, making it easier to achieve kilogram-level preparation, reducing raw material and production costs, and producing a product with a uniform molecular weight distribution and faster dissolution in water.

[0006] To achieve the above objectives, the following technical solution is adopted:

[0007] A method for preparing carboxylated maltose iron includes the following steps:

[0008] (1) Under the catalysis of sodium bromide, maltodextrin and sodium hypochlorite undergo an oxidation reaction. After the reaction is completed, sodium chloride, low molecular weight dextrin oxide and maltodextrin are removed by membrane filtration to obtain maltodextrin oxide concentrate.

[0009] (2) The maltodextrin oxide concentrate obtained in step (1) undergoes a coordination reaction with ferric salt to obtain carboxy maltodextrin iron aqueous solution. Then, the small molecular weight iron polymer and the maltodextrin that did not participate in the coordination are removed by ultrafiltration to obtain carboxy maltodextrin iron concentrate.

[0010] (3) Add sodium chloride to the carboxymaltose iron concentrate obtained in step (2), and then obtain carboxymaltose iron dry product by spray drying.

[0011] Preferably, the oxidation reaction in step (1) is carried out under alkaline conditions;

[0012] The ratio of sodium hypochlorite to maltodextrin is 1 to 10:1.

[0013] Preferably, in step (1), the membrane filtration method is 100Da-1kDa ultrafiltration membrane, and the ultrafiltration pressure is 3.5-25.0MPa.

[0014] Preferably, in step (2), the ultrafiltration is a continuous series ultrafiltration, used to remove small molecule iron complexes, inorganic salts and ultra-large molecular weight iron polymers, and then the product is obtained by spray drying.

[0015] Preferably, in step (2), the dialysis membrane used for ultrafiltration has one or more molecular weights in the range of 5kDa to 200kDa.

[0016] Preferably, in step (2), the ultrafiltration pressure is 2.5-3.5 MPa.

[0017] Preferably, in step (4), the spray drying inlet air temperature is 105-130℃, the spray drying fan frequency is 30-50Hz, and the spray drying feed pump speed is 10-30rpm.

[0018] Preferably, in step (4), the spray drying inlet air temperature is 115-120℃, the spray drying fan frequency is 40-45Hz, and the spray drying feed pump speed is 20rpm.

[0019] The present invention also provides a carboxylated maltose iron obtained by the above preparation method, wherein the carboxylated maltose iron has a weight-average molecular weight of 120kDa-200kDa, a number-average molecular weight of 90kDa-110kDa, and a molecular weight distribution of less than 1.9.

[0020] Furthermore, the production process of carboxylated maltose iron of the present invention specifically includes the following steps:

[0021] (1) Dissolve maltodextrin and sodium bromide in purified water, add 30% sodium hydroxide, and add sodium hypochlorite (available chlorine ≥10%) dropwise over 0.5-3 hours at room temperature. After the addition is complete, keep at room temperature for 1-3 hours, and then ultrafilter through a 100Da-1kDa filter membrane at an ultrafiltration pressure of 3.5-25.0MPa to obtain a concentrated maltodextrin oxide solution, which can be used directly.

[0022] (2) Dissolve ferric chloride hexahydrate in purified water, add maltodextrin oxide concentrate, rinse the pipeline with purified water, and stir for 2 hours. Raise the temperature of the reactor to 30-50℃, adjust the pH of the system to 2-4 with 1M sodium carbonate solution, and then adjust the pH of the system to 9-11 with 30% sodium hydroxide solution at the same temperature. Keep the system at 30-50℃ and stir for 1 hour. After stirring, adjust the pH to 5-7 with 1M hydrochloric acid and raise the temperature to 100℃. React for 0.5 hours and then cool to room temperature. Use 1M hydrochloric acid again to adjust the pH to 5-7.

[0023] (3) The reaction solution was ultrafiltered through a 5kDa-40kDa filter membrane in series at an ultrafiltration pressure of 2.5-3.5 MPa to obtain a carboxymaltose iron concentrate. 6.90 g of sodium chloride was added to the concentrate and stirred for 1 hour.

[0024] (4) Spray drying of carboxymaltose iron concentrate, with the inlet air temperature at 105-130℃, the fan frequency at 30-50Hz, and the feed pump speed at 10-30rpm, to obtain carboxymaltose iron brown powder.

[0025] Compared with the prior art, the beneficial effects of the present invention are reflected in:

[0026] (1) After the oxidation reaction is completed, the present invention first removes sodium chloride, low molecular weight dextrin oxide and maltodextrin by ultrafiltration. Then, after the coordination reaction is completed, it performs a continuous series ultrafiltration to remove low molecular weight iron polymer and maltodextrin that has not participated in coordination. Then, sodium chloride is added and spray dried. The resulting carboxymaltose iron product has a better molecular weight and molecular weight distribution, which can effectively reduce the occurrence of allergic reactions.

[0027] (2) The preparation method of the present invention has good stability, can easily achieve kilogram-level preparation, and has low loss during the preparation process, resulting in high product yield. Attached Figure Description

[0028] Figure 1 GPC spectrum of carboxy-maltose iron obtained in Example 1;

[0029] Figure 2 GPC spectrum of carboxy-maltose iron obtained in Example 2;

[0030] Figure 3 The GPC spectrum of carboxy-maltose iron obtained in Example 3;

[0031] Figure 4 GPC spectrum of carboxy-maltose iron obtained in Example 4;

[0032] Figure 5 GPC spectrum of carboxy-maltose iron obtained in Example 5. Detailed Implementation

[0033] Example 1 (1) Dissolve 63.00 g of maltodextrin and 4.20 g of sodium bromide in 200 mL of purified water, add 31.00 g of 30% sodium hydroxide, and add 16.00 g of sodium hypochlorite (12% available chlorine) dropwise over 1 hour at room temperature. After the addition is complete, keep at room temperature for 2 hours, and then ultrafilter through a 100 Da filter membrane at an ultrafiltration pressure of 20.0 MPa to obtain a concentrated maltodextrin oxide solution, which can be used directly.

[0034] (2) Dissolve 125.00 g of ferric chloride hexahydrate in 100 mL of purified water, add maltodextrin oxide concentrate, rinse the pipeline with 50.00 mL of purified water, and stir for 2 hours. Raise the temperature of the reactor to 35°C, adjust the pH of the system to 2 with 1M sodium carbonate solution, and then adjust the pH of the system to 9 with 30% sodium hydroxide solution at the same temperature. Keep the system at 35°C and stir for 1 hour. After stirring, adjust the pH to 5.5 with 1M hydrochloric acid, raise the temperature to 100°C, react for 0.5 hours, and then cool to room temperature. Use 1M hydrochloric acid again to adjust the pH to 5.5.

[0035] (3) The reaction solution was ultrafiltered through a 5kDa filter membrane at an ultrafiltration pressure of 3.5 MPa to obtain a carboxymaltose iron concentrate. 6.90 g of sodium chloride was added to the concentrate and stirred for 1 hour.

[0036] (4) Carboxymaltose iron concentrate was spray-dried at an air inlet temperature of 105℃, a fan frequency of 30Hz, and a feed pump speed of 10rpm to obtain 101.00 g of carboxymaltose iron brown powder. Mw = 139kDa, Mn = 82kDa, PDI = 1.7.

[0037] Example 2

[0038] (1) Dissolve 63.00 g of maltodextrin and 4.20 g of sodium bromide in 100 mL of purified water, add 40.00 g of 30% sodium hydroxide, and add 16.00 g of sodium hypochlorite (11% available chlorine) dropwise over 1 hour at room temperature. After the addition is complete, keep the solution at room temperature for 2 hours, and then ultrafilter it through a 500 Da filter membrane at an ultrafiltration pressure of 10.0 MPa to obtain a concentrated maltodextrin oxide solution, which can be used directly.

[0039] (2) Dissolve 128.00 g of ferric chloride hexahydrate in 100 mL of purified water, add maltodextrin oxide concentrate, rinse the pipeline with 50.00 mL of purified water, and stir for 2 hours. Raise the temperature of the reactor to 30°C, adjust the pH of the system to 3 with 1M sodium carbonate solution, and then adjust the pH of the system to 11 with 30% sodium hydroxide solution at the same temperature. Keep the system at 35°C and stir for 1 hour. After stirring, adjust the pH to 5.5 with 1M hydrochloric acid, raise the temperature to 100°C, react for 0.5 hours, and then cool to room temperature. Use 1M hydrochloric acid again to adjust the pH to 5.5.

[0040] (3) The reaction solution was ultrafiltered through a 3kDa filter membrane at an ultrafiltration pressure of 3.5 MPa, and then ultrafiltered through a 10kDa filter membrane at an ultrafiltration pressure of 2.5 MPa to obtain a carboxymaltose iron concentrate. 6.90 g of sodium chloride was added to the concentrate and stirred for 1 hour.

[0041] (4) Carboxymaltose iron concentrate was spray-dried at an inlet air temperature of 120°C, a fan frequency of 50 Hz, and a feed pump speed of 30 rpm to obtain 93.00 g of carboxymaltose iron brown powder. Mw = 142 kDa, Mn = 81 kDa, PDI = 1.8.

[0042] Example 3

[0043] (1) Dissolve 1.2 kg of maltodextrin and 100 g of sodium bromide in 4 L of purified water, add 700 g of 30% sodium hydroxide, and add 400 g of sodium hypochlorite (10% available chlorine) dropwise over 1 hour at room temperature. After the addition is complete, keep the solution at room temperature for 2 hours, and then ultrafilter it through a 500 Da filter membrane at an ultrafiltration pressure of 10.0 MPa to obtain a concentrated maltodextrin oxide solution, which can be used directly.

[0044] (2) Dissolve 2.5 kg of ferric chloride hexahydrate in 2 L of purified water, add maltodextrin oxide concentrate, rinse the pipeline with 200 mL of purified water, and stir for 2 hours. Raise the temperature of the reactor to 35°C, adjust the pH of the system to 3.8 with 1M sodium carbonate solution, and then adjust the pH of the system to 11 with 30% sodium hydroxide solution at the same temperature. Keep the system at 50°C and stir for 1 hour. After stirring, adjust the pH to 5.8 with 1M hydrochloric acid, raise the temperature to 100°C, react for 0.5 hours, and then cool to room temperature. Use 1M hydrochloric acid again to adjust the pH to 5.8.

[0045] (3) The reaction solution was ultrafiltered through a 10kDa filter membrane at an ultrafiltration pressure of 2.5 MPa, and then ultrafiltered through a 20kDa filter membrane at an ultrafiltration pressure of 2.5 MPa to obtain a carboxymaltose iron concentrate. 150 g of sodium chloride was added to the concentrate and stirred for 1 hour.

[0046] (4) Carboxymaltose iron concentrate was spray-dried at an inlet air temperature of 120°C, a fan frequency of 40 Hz, and a feed pump speed of 20 rpm to obtain 1.8 kg of carboxymaltose iron brown powder. Mw = 153 kDa, Mn = 94 kDa, PDI = 1.6.

[0047] The method of the present invention can achieve kilogram-level preparation, and under kilogram-level preparation conditions, the molecular weight distribution is also good, and the yield is also high.

[0048] Example 4

[0049] (1) Dissolve 63.00 g of maltodextrin and 4.20 g of sodium bromide in 200 mL of purified water, add 31.00 g of 30% sodium hydroxide, and add 16.00 g of sodium hypochlorite (12% available chlorine) dropwise over 1 hour at room temperature. After the addition is complete, keep at room temperature for 2 hours to obtain a concentrated maltodextrin oxide solution, which can be used directly.

[0050] (2) Dissolve 125.00 g of ferric chloride hexahydrate in 100 mL of purified water, add maltodextrin oxide concentrate, rinse the pipeline with 50.00 mL of purified water, and stir for 2 hours. Raise the temperature of the reactor to 35°C, adjust the pH of the system to 2 with 1M sodium carbonate solution, and then adjust the pH of the system to 9 with 30% sodium hydroxide solution at the same temperature. Keep the system at 35°C and stir for 1 hour. After stirring, adjust the pH to 5.5 with 1M hydrochloric acid, raise the temperature to 100°C, react for 0.5 hours, and then cool to room temperature. Use 1M hydrochloric acid again to adjust the pH to 5.5.

[0051] (3) Anhydrous ethanol was added to the reaction system, and the mixture was stirred to obtain a brown suspension. After crystallization and filtration, the crude product was slurried in ethanol overnight. After filtration, the filter cake was washed with ethanol and dried at 50°C for 4 hours to obtain a black solid of carboxymaltose iron. After pulverization, 99.0 g of brown powder was obtained. Mw = 442 kDa, Mn = 119 kDa, PDI = 3.7.

[0052] Example 5

[0053] (1) Dissolve 63.00 g of maltodextrin and 0.007 g of tetrabutylammonium bromide in 200 mL of purified water. Add 16.00 g of sodium hypochlorite (12% available chlorine) dropwise over 1 hour at room temperature. After the addition is complete, keep the solution at room temperature for 2 hours to obtain a concentrated maltodextrin oxide solution, which can be used directly.

[0054] (2) Dissolve 125.00 g of ferric chloride hexahydrate in 100 mL of purified water, add maltodextrin oxide concentrate, adjust the pH value to 8-11 with sodium carbonate solution; heat to 50-60℃ and react for 6 h, continue to heat to 135℃ and react for 4 h, the reaction is completed, and the liquid is cooled and discharged.

[0055] (3) The pH of the feed solution was adjusted to 6 with dilute hydrochloric acid solution, and then inorganic salts and small molecule compounds were removed by ultrafiltration. Finally, the solution was spray-dried to obtain 85g of carboxymaltose iron brown powder. Mw=124kDa, Mn=77kDa, PDI = 1.6.

[0056] Test Example 1

[0057] Weigh 3.00 g of carboxymaltose iron solid obtained in Examples 1, 2, and 3, as well as the ethanol precipitation process, and place it in a beaker. Add 10.00 mL of purified water and a stir bar, and stir in a water bath at 25°C until dissolved. Record the dissolution time and measure the pH as follows:

[0058]

[0059] .

Claims

1. A method for preparing carboxylated maltose iron, characterized in that, Includes the following steps: (1) Under the catalysis of sodium bromide, maltodextrin and sodium hypochlorite undergo an oxidation reaction. After the reaction is completed, sodium chloride, low molecular weight dextrin oxide and maltodextrin are removed by membrane filtration to obtain maltodextrin oxide concentrate. (2) The maltodextrin oxide concentrate obtained in step (1) undergoes a coordination reaction with ferric salt to obtain carboxy maltodextrin iron aqueous solution. Then, the small molecular weight iron polymer and the maltodextrin that did not participate in the coordination are removed by ultrafiltration to obtain carboxy maltodextrin iron concentrate. (3) Add sodium chloride to the carboxymaltose iron concentrate obtained in step (2), and then obtain carboxymaltose iron dry product by spray drying.

2. The method for preparing carboxylated maltose iron according to claim 1, characterized in that, The oxidation reaction in step (1) is carried out under alkaline conditions; The ratio of sodium hypochlorite to maltodextrin is 1 to 10:

1.

3. The method for preparing carboxylated maltose iron according to claim 1, characterized in that, In step (1), the membrane filtration method is 100Da-1kDa ultrafiltration membrane, and the ultrafiltration pressure is 3.5-25.0MPa.

4. The method for preparing carboxylated maltose iron according to claim 1, characterized in that, In step (2), the ultrafiltration is a continuous series ultrafiltration, used to remove small molecule iron complexes, inorganic salts and ultra-large molecular weight iron polymers, and then the product is obtained by spray drying.

5. The method for preparing carboxylated maltose iron according to claim 4, characterized in that, In step (2), the dialysis membrane used for ultrafiltration has one or more molecular weights in the range of 5kDa-200kDa.

6. The method for preparing carboxylated maltose iron according to claim 4, characterized in that, In step (2), the ultrafiltration pressure is 2.5-3.5 MPa.

7. The method for preparing carboxylated maltose iron according to claim 1, characterized in that, In step (4), the inlet air temperature for spray drying is 105-130℃, the frequency of the spray drying fan is 30-50Hz, and the speed of the spray drying feed pump is 10-30rpm.

8. The method for preparing carboxylated maltose iron according to claim 7, characterized in that, In step (4), the inlet air temperature for spray drying is 115-120℃, the frequency of the spray drying fan is 40-45Hz, and the speed of the spray drying feed pump is 20rpm.

9. A carboxylated maltose iron obtained by the preparation method according to any one of claims 1 to 8, characterized in that, The carboxylated maltose iron has a weight-average molecular weight of 120kDa-200kDa, a number-average molecular weight of 90kDa-110kDa, and a molecular weight distribution of less than 1.9.

Images