CN115531414A - Novel iron sucrose compound and preparation method thereof - Google Patents
Novel iron sucrose compound and preparation method thereof Download PDFInfo
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Abstract
The invention discloses a novel sucrose-iron complex and a preparation method thereof. The ratio of the iron content to the total sugar content in the sucrose iron complex is 1.9-1, the pH value of the complex is 9.0-11.0, the free sugar content accounts for 80% -95% of the total sugar content, and the redox T75 is less than 20 minutes. The in vivo bioequivalence test of the sucrose-iron compound in the range proves that the in vivo bioequivalence of the self-made product and the original medicine is achieved.
Description
Technical Field
The invention belongs to the field of pharmacy, and relates to a novel sucrose-iron complex and a preparation method thereof.
Background
Iron is a necessary trace element for human bodies, the treatment of iron deficiency is very necessary for patients with iron deficiency anemia, and intravenous injection of iron is an effective means for treating various iron deficiency diseases, such as severe iron deficiency anemia, intestinal iron absorption disorder, intestinal iron absorption intolerance and oral ineffectiveness iron deficiency diseases (such as dialysis patients).
The iron-sucrose complex is an iron supplement agent widely used at present for resisting iron-deficiency anemia, has the advantages of good absorption and low side effect compared with the traditional oral iron supplement agent (such as ferrous sulfate, ferric fumarate and the like), and is particularly suitable for iron-deficiency anemia caused by kidney disease hemodialysis.
The original research manufacturer of the sucrose-iron complex is Switzerland Weifu international company, and generally speaking, the detailed preparation process parameters of the original research manufacturer are all core secrets of the enterprise and cannot be obtained through open channels. The laboratory refers to the preparation method reported in the prior literature to prepare the ferric sucrose injection, and the result shows that the T75 result of the product is far more than 20 minutes, while the T75 outside the ferric sucrose injection is required to be not more than 20 minutes according to the patent CN1685227B reported by Weifu company of the original research manufacturer.
The Sucrose-Iron complex is distinguished from conventional small molecular compounds, and is generally divided into Non-Biological complex compounds (NBCDs) internationally, and because the chemical structure of the compounds is difficult to accurately characterize, the U.S. Food and Drug Administration (FDA) issues a technical guide for the development of the product in imitation pharmaceuticals in 2013, namely "Draft Duides On Iron surgery sunlight surgery", and provides specific requirements for the research On the in vivo bioequivalence of the product:
study type: hollow web
Designing: single dose, randomized, parallel in vivo studies
Specification: 100mg/5mL (dose 100 mg)
Study subjects: healthy male and female, the general population
Additional notes: the product is administered by intravenous injection of 100mg slowly over 5 minutes without dilution.
Analytes to be determined (in a suitable body fluid): each of the following was determined:
1. serum [ total iron ]
2. Serum [ transferrin binding iron ] (TBI)
Bioequivalence (90% confidence interval) was based on:
maximum of the difference in concentration of total iron and transferrin-bound iron determined at all time points; and
the difference in AUC for total iron and AUC for transferrin bound iron.
Disclosure of Invention
The invention aims to provide a novel iron sucrose compound and a preparation method thereof, the iron sucrose compound provided by the invention is equivalent to the original medicine in vivo, and the preparation method has the characteristics of mild conditions, low requirements on production equipment, low energy consumption, simple operation and the like compared with the prior art.
Through repeated experiments, the laboratory researchers unexpectedly find that after any one of glucose, maltose, dextrin and syrup is added into sucrose, the prepared iron sucrose bulk drug is biologically equivalent to the original ground drug in vivo under a milder complexing reaction condition, such as a lower complexing reaction temperature, compared with the prior art. It is believed that the degradation products of the added sugar components under strong alkaline conditions may act synergistically with the iron sucrose complex to affect biological processes in vivo, while reducing the activation energy of the reaction. At present, the prior published technologies have the defects of harsh preparation process conditions and high energy consumption, and do not show the in vivo bioequivalence of the product and the original medicine.
The purpose of the invention can be realized by the following technical scheme:
specifically, the invention relates to a sucrose iron complex for preparing injection, which comprises free sugar compounded with ferric hydroxide and a small amount of combined sugar compounded with ferric hydroxide, and the sucrose iron complex and the combined sugar must simultaneously meet the following conditions: the mass ratio of (1) the iron content to the total sugar content in the sucrose iron complex is 1; (2) the pH value of the sucrose-iron complex is 9.0-11.0; (3) the mass percentage of the free sugar is between 80 and 95 percent; (4) the redox T75 of the complex is less than 20 minutes.
Preferred iron sucrose complexes for the preparation of injections comprise free sugars complexed with iron hydroxide and small amounts of bound sugars complexed with iron hydroxide, which simultaneously fulfil the following conditions: the ratio of (1) iron content to total sugar content in the sucroferric complex is 1; (2) the pH value of the sucrose-iron complex is 9.0-10.5; (3) the mass percentage of the free sugar is 83-95%; (4) the redox T75 of the complex is less than 18 minutes.
Further preferred iron sucrose complexes for the preparation of injections comprise free sugar complexed with iron hydroxide and a small amount of bound sugar complexed with iron hydroxide, which simultaneously fulfil the following conditions: (1) The ratio of iron content to total sugar content is 1; (2) the pH value of the sucrose-iron complex is 9.0-10.0; (3) the mass percentage content of the free sugar is between 83 and 92 percent; (4) the redox T75 of the complex is less than 15 minutes.
Further preferably, the iron sucrose complex of the present invention is prepared by the following method:
(1) Dissolving ferric salt by using 1-1.2 times of purified water, and then adding 1.7-2 times of equivalent of sodium carbonate solution;
(2) Reacting at room temperature for 11-14 hours, and adjusting the pH value to 9.0-13.5 by using a sodium carbonate solution;
(3) Filtering the prepared ferric oxide hydroxide colloidal solution, then adding a polysaccharide mixture and purified water according to a certain weight ratio, and then adjusting the pH value by using a sodium hydroxide solution; the polysaccharide mixture consists of two kinds of sugar, wherein one of the two kinds of sugar is sucrose, and the other one is any one of maltose, glucose, dextrin and syrup, and the weight ratio of the two kinds of sugar is 10.0;
(3) Heating for complexing until the reaction temperature rises to 50-80 ℃, continuing to react for 12-24 hours, finishing the reaction, cooling the feed liquid, and discharging;
(4) The raw material medicinal purified water prepared by the method is prepared into liquid medicine by containing 20mg of iron per 1ml, and the liquid medicine is sterilized at the high temperature of 121 ℃ for 15 minutes to obtain the final preparation product.
The preparation method of the sucrose iron compound comprises the following steps:
(1) Dissolving ferric salt by using 1-1.2 times of purified water, and then adding 1.7-2 times of equivalent of sodium carbonate solution;
(2) Reacting at room temperature for 11-14 hours, and adjusting the pH value to 9.0-13.5 by using a sodium carbonate solution;
(3) Filtering the prepared ferric oxide hydroxide colloidal solution, then adding a polysaccharide mixture and purified water according to a certain weight ratio, and then adjusting the pH value by using a sodium hydroxide solution; the polysaccharide mixture consists of two kinds of sugar, wherein one of the two kinds of sugar is sucrose, and the other one of the two kinds of sugar is maltose, glucose, dextrin and syrup, and the weight ratio of the two kinds of sugar is 13.0-17.0;
(3) Heating for complexing until the reaction temperature rises to 50-80 ℃, continuing to react for 12-24 hours, finishing the reaction, cooling the feed liquid, and discharging;
(4) The raw material medicinal purified water prepared by the method is prepared into liquid medicine by containing 20mg of iron per 1ml, and the liquid medicine is sterilized at the high temperature of 121 ℃ for 15 minutes to obtain the final preparation product.
In a preferred embodiment of the present invention, the water-soluble iron salt in step (1) is ferric chloride.
Preferably, the adding weight ratio of the polysaccharide to the iron (calculated by iron) in the step (3) is 10.5:1 to 18.5:1, adjusting the pH value of a sodium hydroxide solution to 8.5-10.5; step (4) the reaction temperature in the step (4) is 50-70 ℃, and the reaction time is 12-16 hours.
As a further optimization of the invention, the adding weight ratio of the sugar to the iron in the step (3) is 11.0:1 to 14.5:1, adjusting the pH value of a sodium hydroxide solution to 9.0-10.5; the reaction temperature in the step (4) is 50-65 ℃, and the reaction time is 12-14 hours.
As a further preferable aspect of the present invention, the adding weight ratio of the sugar to the iron in the step (3) is 11.0:1 to 13.0:1, adjusting the pH value of a sodium hydroxide solution to 9.5-10.5; the reaction temperature in the step (4) is 55-65 ℃, and the reaction time is 12-13 hours.
The invention has the beneficial effects that:
compared with the prior art, the invention provides a novel sucrose-iron compound and a preparation method thereof. The sucrose-iron complex is in vivo bioequivalent to the original drug, and the preparation method has the advantages of mild process conditions, low equipment requirements, low energy consumption, simple operation and the like, and can replace the original drug in clinical medication, thereby effectively reducing the medication cost of patients.
DETAILED DESCRIPTION OF EMBODIMENT (S) OF INVENTION
Example 1
5kg of ferric trichloride and 5kg of purified water are added into a reaction kettle, 9.5kg of 20% sodium carbonate solution is added, the mixture reacts for 12 hours at room temperature, and then the pH value is adjusted to 13.2 by using the 20% sodium carbonate solution. Filtering the prepared ferric oxide hydroxide colloid, transferring the ferric oxide hydroxide colloid into a reaction kettle, adding 24kg of polysaccharide mixture (the weight ratio of sucrose to glucose is 10.3.
The samples were tested for total sugar content, free sugar content, sugar to iron ratio, pH, T75, and the results were as follows:
| item | Total sugar content | Free sugar content | Sugar to iron ratio | pH | T75 |
| Results | 285mg/mL | 265mg/mL | 14.3:1 | 10.7 | 19.3 minutes |
Example 2
5kg of ferric trichloride and 6kg of purified water are added into a reaction kettle, 9.0kg of 20% sodium carbonate solution is added, the reaction is carried out for 11 hours at room temperature, and then the pH value is adjusted to 13.8 by using the 20% sodium carbonate solution. Filtering the prepared ferric oxide hydroxide colloid, transferring the ferric oxide hydroxide colloid into a reaction kettle, adding 18.8kg of polysaccharide mixture (the weight ratio of sucrose to maltose is 13.8.
The samples were tested for total sugar content, free sugar content, sugar to iron ratio, pH, T75, and the results were as follows:
| item | Total sugar content | Free sugar content | Sugar to iron ratio | pH | T75 |
| Results | 278mg/mL | 259mg/mL | 13.6:1 | 10.1 | 17.5 minutes |
Example 3
5kg of ferric trichloride and 5.4kg of purified water are added into a reaction kettle, 9.6kg of 20% sodium carbonate solution is added, reaction is carried out for 12 hours at room temperature, and then the pH value is adjusted to 13.2 by the 20% sodium carbonate solution. Filtering the prepared ferric oxide hydroxide colloid, transferring the ferric oxide hydroxide colloid into a reaction kettle, adding 31.5kg of polysaccharide mixture (the weight ratio of sucrose to corn syrup is 13.8.
The samples were tested for total sugar content, free sugar content, sugar to iron ratio, pH, T75, and the results were as follows:
| item | Total sugar content | Free sugar content | Sugar to iron ratio | pH | T75 |
| Results | 275mg/mL | 250mg/mL | 13.8:1 | 10.0 | 15.9 minutes |
Example 4
5kg of ferric trichloride and 6kg of purified water are added into a reaction kettle, 9.9kg of 20% sodium carbonate solution is added, the mixture reacts for 12 hours at room temperature, and then the pH value is adjusted to 13.2 by using the 20% sodium carbonate solution. Filtering the prepared ferric oxide hydroxide colloid, transferring the ferric oxide hydroxide colloid into a reaction kettle, adding 20.7kg of polysaccharide mixture (the weight ratio of sucrose to maltodextrin is 15.8.
The samples were tested for total sugar content, free sugar content, sugar to iron ratio, pH, T75, and the results were as follows:
| item | Total sugar content | Free sugar content | Sugar to iron ratio | pH | T75 |
| Results | 260mg/mL | 234mg/mL | 13.8:1 | 9.5 | 11.3 minutes |
Example 5
5kg of ferric trichloride and 5.6kg of purified water are added into a reaction kettle, 8.8kg of 20% sodium carbonate solution is added, the mixture reacts for 13 hours at room temperature, and then the pH value is adjusted to 13.2 by using the 20% sodium carbonate solution. Filtering the prepared ferric oxide hydroxide colloid, transferring the ferric oxide hydroxide colloid into a reaction kettle, adding 27kg of polysaccharide mixture (the weight ratio of sucrose to glucose is 16.8.
The samples were tested for total sugar content, free sugar content, sugar to iron ratio, pH, T75, and the results were as follows:
| item | Total sugar content | Free sugar content | Sugar to iron ratio | pH | T75 |
| Results | 285mg/mL | 268mg/mL | 14.3:1 | 10.8 | 19.0 minutes |
Example 6
5kg of ferric trichloride and 6kg of purified water are added into a reaction kettle, 10kg of 20% sodium carbonate solution is added, reaction is carried out for 12 hours at room temperature, and then the pH value is adjusted to 13.2 by using the 20% sodium carbonate solution. Filtering the prepared ferric oxide hydroxide colloid, transferring the ferric oxide hydroxide colloid into a reaction kettle, adding 25kg of polysaccharide mixture (the weight ratio of sucrose to maltodextrin is 14.0.
The samples were tested for total sugar content, free sugar content, sugar to iron ratio, pH, T75, and the results were as follows:
| item | Total sugar content | Free sugar content | Sugar to iron ratio | pH | T75 |
| Results | 289mg/mL | 265mg/mL | 14.5:1 | 9.3 | 16.5 minutes |
Example 7
5kg of ferric trichloride and 6kg of purified water are added into a reaction kettle, 9.7kg of 20% sodium carbonate solution is added, the reaction is carried out for 11 hours at room temperature, and then the pH value is adjusted to 13.2 by using the 20% sodium carbonate solution. Filtering the prepared ferric oxide hydroxide colloid, transferring the ferric oxide hydroxide colloid into a reaction kettle, adding 24kg of polysaccharide mixture (the weight ratio of sucrose to corn syrup is 13.2.
The samples were tested for total sugar content, free sugar content, sugar to iron ratio, pH, T75, and the results were as follows:
| item | Total sugar content | Free sugar content | Sugar to iron ratio | pH | T75 |
| Results | 296mg/mL | 275mg/mL | 14.8:1 | 11.3 | 19.7 minutes |
Example 8
5kg of ferric trichloride and 5.2kg of purified water are added into a reaction kettle, 10kg of 20% sodium carbonate solution is added, the reaction is carried out for 12 hours at room temperature, and then the pH value is adjusted to 13.2 by using the 20% sodium carbonate solution. Filtering the prepared ferric oxide hydroxide colloid, transferring the ferric oxide hydroxide colloid into a reaction kettle, adding 22.5kg of polysaccharide mixture (the weight ratio of sucrose to glucose is 13.1.
The samples were tested for total sugar content, free sugar content, sugar to iron ratio, pH, T75, and the results were as follows:
| item | Total sugar content | Free sugar content | Sugar to iron ratio | pH | T75 |
| Results | 245mg/mL | 200mg/mL | 12.3:1 | 10.3 | 16.9 minutes |
Example 9
5kg of ferric trichloride and 6kg of purified water are added into a reaction kettle, 10kg of 20% sodium carbonate solution is added, the mixture reacts for 13 hours at room temperature, and then the pH value is adjusted to 13.2 by using the 20% sodium carbonate solution. Filtering the prepared ferric oxide hydroxide colloid, transferring the ferric oxide hydroxide colloid into a reaction kettle, adding 22.5kg of cane sugar and 22.5kg of purified water into the reaction kettle, adjusting the pH value to 9.5 by using 20% sodium hydroxide solution, heating for complexing, reacting at 63 ℃ for 15 hours, cooling the reacted feed liquid to room temperature, preparing each 1mL of feed liquid containing 20mg of iron by using the purified water, filtering, and sterilizing at 121 ℃ for 15 minutes to prepare a finished product.
The samples were tested for total sugar content, free sugar content, sugar to iron ratio, pH, T75, and the results were as follows:
| item | Total sugar content | Free sugar content | Sugar to iron ratio | pH | T75 |
| As a result, the | 280mg/mL | 263mg/mL | 14.0:1 | 10.8 | 35.6 minutes |
The samples obtained in example four were selected, the original drug selected iron sucrose injection (trade name: vileyfur, concentration: 20mgFe/mL, expiration date: 2022.01) on the market at home, and healthy people were selected, and each group had 12 cases, and bioequivalence tests were performed in vivo, and the test results were as follows:
as can be seen from the above table, the 90% confidence interval of the difference ratio of pK parameters between the home-made product and the original drug is within the 80.00-125.00% equivalent interval, which indicates that the home-made product and the original drug are bioequivalent in vivo.
The invention relates to terms and methods:
1. free sugar: sugars in the iron sucrose complex that are not bound to the iron hydroxide colloid or iron oxyhydroxide.
2. Binding sugar: sugars in sucrose iron complexes combined with iron hydroxide colloids or iron oxyhydroxides.
3. TI: total iron in blood.
4. TBI: transferrin in blood binds iron.
5. Cmax: maximum blood concentration (in terms of iron).
6、AUC 0-T,TI-TBI : peak area of blood concentration from 0 to t.
7、AUC 0-∞,TI-TBI : peak area of blood concentration from 0 to infinity.
8. The method for measuring the free sugar comprises the following steps: preparing a 20mg iron/ml iron sucrose compound solution, placing the solution in a 500-1,000Da dialysis membrane, placing a dialysis bag in purified water for 24 hours, and measuring the total sugar content in the iron sucrose compound solution before and after dialysis, wherein the difference of the total sugar content is the free sugar content.
9. Total sugar determination method:
the method refers to high performance liquid chromatography (appendix V D of the second part of 2010 edition of Chinese pharmacopoeia).
Chromatographic conditions and system applicability test: taking a styrene-divinylbenzene copolymer as a filler and water as a mobile phase; the column temperature is 50 ℃; the flow rate is 0.5ml/min; a differential refractometer with a detector temperature of 50 ℃.
Preparation of control solutions: the glucose control was weighed accurately, dissolved in water and quantitatively diluted with 1ml of solutions containing 0.5, 0.6, 0.8, 1.0, 1.5 and 2.0mg of glucose.
Preparation of a test solution: taking 0.2g of sample, precisely weighing, placing in a 100ml saline bottle, adding 25ml of 5% sulfuric acid solution (m/v) for dissolving, plugging and sealing, placing in an autoclave at 121 ℃ for 10 minutes, cooling to room temperature, transferring into a 100ml beaker, adding 10ml of 10% sodium hydroxide solution, adjusting the pH to 5.5-6.5 by using 10% sodium hydroxide, transferring into a 100ml measuring flask, adding water for diluting to a scale, shaking uniformly, filtering by using a 0.02 mu m filter membrane, and taking a subsequent filtrate to obtain the product.
The determination method comprises injecting 10 μ l of each of the reference solution and the sample solution into a liquid chromatograph, recording chromatogram, and calculating glucose content by standard curve.
10. T75 test method
Preparing a solution A: 9.00g of sodium chloride was weighed into a 1000ml volumetric flask, dissolved in water and diluted to the scale to prepare a 0.9% diluted solution of sodium chloride (solution A), which was then stored in a water bath at 37 ℃.
Preparing a solution B: approximately 8.8g of ascorbic acid are weighed into a 50ml volumetric flask, and the desired amount of solution A is then added, which is likewise stored in a water bath at 37 ℃.
Preparing a ferric saccharate injection stock solution: a sample solution (5 ml) was precisely measured and placed in a 50ml volumetric flask, diluted to the mark with water and stored in a water bath at 37 ℃.
Preparation of monitoring solution: when the temperature of the solution is stabilized at 37 +/-1 ℃, respectively measuring 20.0ml of solution A, 4.0ml of solution B and 1.0ml of ferric saccharate injection storage solution, and adding the solution into a 25ml volumetric flask. The solution was mixed well and then an appropriate amount was transferred to a 1cm quartz cell in a temperature controlled UV/VIS spectrophotometer set at 37 ℃ ± 1 ℃ and the absorption at 450nm was measured at 5 minute intervals for a total reaction time of 80 minutes using solution a as a blank calibration.
And (3) drawing a linear equation: linear regression is performed with "Log (percentage of ferric concentration) as ordinate and time as abscissa (within 60 min), and the correlation coefficient should not be lower than 0.98. Calculating the formula:
ferric iron concentration percentage (%) =100 [ (absorbancy measurement value-absorbancy end value)/(absorbancy initial value-absorbancy end value) ]
T75＝(1.3979-b)/m
Wherein b represents the intercept on the Y-axis of the above "Log (percentage ferric concentration)" versus "time" linear equation; m is the slope of the linear equation; 1.3979 is the absolute value of the percentage ferric concentration at the 75% reduction time point (i.e., ferric concentration percent = 25%).
Claims (9)
1. A sucrose-iron complex comprising a minor amount of sucrose complexed with ferric oxide hydroxide and a major amount of free sugar not complexed with ferric hydroxide, wherein: in the sucrose iron compound, the mass ratio of (1) the iron content to the total sugar content is 1; (2) the pH value of the sucrose-iron complex is 9.0-11.0; (3) the mass of the free sugar accounts for 80-95% of the mass of the total sugar; (4) the redox T75 of the complex is less than 20 minutes.
2. The sucrose iron complex of claim 1, wherein: in the sucrose iron compound, the ratio of (1) iron content to total sugar content is 1; (2) the pH value of the sucrose-iron complex is 9.0-10.5; (3) the content of free sugar is between 83 and 95 percent; (4) the redox T75 of the sucroferric complex is less than 18 minutes.
3. The sucrose iron complex of claim 2, wherein: in the sucrose iron complex, the ratio of (1) iron content to total sugar content is 1; (2) the pH value of the sucrose-iron complex is 9.0-10.0; (3) the free sugar content is between 83 and 92 percent; (4) the redox T75 of the sucroferric complex is less than 15 minutes.
4. The sucroferric complex according to any one of claims 1-3, characterized in that: the sucrose iron compound is prepared by the following steps:
(1) Dissolving ferric salt by using 1-1.2 times of purified water, and then adding 1.7-2 times of equivalent of sodium carbonate solution;
(2) Reacting at room temperature for 11-14 hours, and adjusting the pH value to 9.0-13.5 by using a sodium carbonate solution;
(3) Filtering the prepared ferric oxide hydroxide colloidal solution, then adding a polysaccharide mixture and purified water according to a certain weight ratio, and then adjusting the pH value by using a sodium hydroxide solution; the polysaccharide mixture consists of two kinds of sugar, wherein one of the two kinds of sugar is sucrose, and the other one is any one of maltose, glucose, dextrin and syrup, and the weight ratio of the two kinds of sugar is 10.0;
(3) Heating for complexing until the reaction temperature rises to 50-80 ℃, continuing to react for 12-24 hours, finishing the reaction, cooling the feed liquid, and discharging;
(4) The raw material medicinal purified water prepared by the method is prepared into liquid medicine according to the condition that each 1ml of the raw material medicinal purified water contains 20mg of iron, and the liquid medicine is sterilized for 15 minutes at the high temperature of 121 ℃ to obtain a final preparation product.
5. A method for preparing the sucroferric complex according to any one of claims 1 to 3, characterized in that: the preparation method comprises the following steps:
(1) Dissolving ferric salt by using 1-1.2 times of purified water, and then adding 1.7-2 times of equivalent of sodium carbonate solution;
(2) Reacting at room temperature for 11-14 hours, and adjusting the pH value to 9.0-13.5 by using a sodium carbonate solution;
(3) Filtering the prepared ferric oxide hydroxide colloidal solution, then adding a polysaccharide mixture and purified water according to a certain weight ratio, and then adjusting the pH value by using a sodium hydroxide solution; the polysaccharide mixture consists of two kinds of sugar, wherein one of the two kinds of sugar is sucrose, and the other one of the two kinds of sugar is maltose, glucose, dextrin and syrup, and the weight ratio of the two kinds of sugar is 13.0-17.0;
(3) Heating for complexing until the reaction temperature rises to 50-80 ℃, continuing to react for 12-24 hours, finishing the reaction, cooling the feed liquid, and discharging;
(4) The raw material medicinal purified water prepared by the method is prepared into liquid medicine according to the condition that each 1ml of the raw material medicinal purified water contains 20mg of iron, and the liquid medicine is sterilized for 15 minutes at the high temperature of 121 ℃ to obtain a final preparation product.
6. The method of claim 5, wherein: the water-soluble ferric salt in the step (1) is ferric trichloride.
7. The method according to claim 5 or 6, characterized in that: the weight ratio of the two sugars in the step (3) is 15.0-17.0, the adding weight ratio of the polysaccharide to the iron (calculated by iron) is 10.5:1 to 18.5:1, adjusting the pH value of a sodium hydroxide solution to 8.5-10.5; the reaction temperature in the step (4) is 50-70 ℃, and the reaction time is 12-16 hours.
8. The method of claim 7, wherein: the adding weight ratio of the sugar to the iron in the step (3) is 11.0:1 to 14.5:1, adjusting the pH value of a sodium hydroxide solution to 9.0-10.5; the reaction temperature in the step (4) is 50-65 ℃, and the reaction time is 12-14 hours.
9. The method of claim 8, wherein: the adding weight ratio of the sugar to the iron in the step (3) is 11.0:1 to 13.0:1, adjusting the pH value of a sodium hydroxide solution to 9.5-10.5; the reaction temperature in the step (4) is 55-65 ℃, and the reaction time is 12-13 hours.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11834471B2 (en) | 2019-02-28 | 2023-12-05 | Renibus Therapeutics, Inc. | Iron compositions and methods of making and using the same |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11834471B2 (en) | 2019-02-28 | 2023-12-05 | Renibus Therapeutics, Inc. | Iron compositions and methods of making and using the same |
| US11840552B2 (en) | 2019-02-28 | 2023-12-12 | Renibus Therapeutics, Inc. | Iron compositions and methods of making and using the same |
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