JPH0129482B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to an iron complex compound useful for the treatment of iron deficiency anemia, and more particularly to a method for producing a parenterally administrable dextrin/hydroxycarboxylic acid/ferric polynuclear complex. Treatment for iron deficiency anemia mainly relies on oral administration of iron, but in cases where large doses of iron are required, or when orally administered iron is not absorbed properly, or because of side effects, etc. Parenteral administration of iron is used instead of oral administration in cases where the patient cannot tolerate oral administration of iron, or in cases where iron loss due to chronic persistent bleeding is higher than iron absorption and loss of stored iron is observed. When iron is administered orally, the rate of absorption from the intestinal tract depends on the free iron concentration, so the therapeutic effect is higher when iron is released.As a result, ferrous iron, which can exist as free iron at high concentrations, is often used. There is. On the other hand, in the case of parenteral iron preparations, free iron is known to put the administered body in an extremely dangerous state depending on the amount, so efforts are being made to manufacture iron preparations with a low proportion of free iron. In addition, parenteral iron preparations have a moderately high molecular weight, are excreted little in the urine, have a high iron concentration, are easy to obtain an injection solution that is isotonic with body fluids, and are near neutral. In order to maintain the safety and stability of the product, iron preparations have fundamentally different issues than oral iron preparations, such as being stable in solution and having high storage stability in the solution state. Extremely sophisticated manufacturing technology is required. Several techniques have disclosed that complexes consisting of ferric salts, mono- or oligosaccharides, and hydroxycarboxylic acids are effective in treating iron deficiency anemia. For example, Special Publication No. 40-7296,
-17782 contains ferric salts, hexitol and
A method is presented for reacting tribasic hydroxycarboxylic acids in the presence of dispersion stabilizers to obtain iron formulations. However, in this method, 15~
A formulation with a relatively low iron content of 16% by weight was obtained and was also acutely toxic when administered intravenously to mice.
It has the disadvantage of exhibiting high toxicity with an LD ₅₀ of 35 mg/Kg. In addition, Japanese Patent Publication No. 46-3196 discloses 1 mole of ferric hydroxide, about 1.5 mole of sorbitol, about 0.4 mole of gluconic acid, and 0.5 mole of dextrin, dextran, hydrogenated dextrin, or hydrogenated dextran with an average molecular weight of 500 to 1200 ( (as glucose) to obtain an iron preparation. Even with this method, the iron content of the iron preparation obtained is only 21-26% by weight, and when administered to humans, 10% of the administered iron amount is excreted in the urine, and the LD ₅₀ in mice is also low. It has drawbacks that need to be improved, such as relatively high toxicity of 380 mg/Kg when injected internally. In addition to the drawbacks mentioned above, these saccharide/hydroxycarboxylic acid/ferric iron complexes have relatively small molecular weights, so they may damage blood cells, blood vessels, muscles, etc., and the complex solution is far removed from blood and body fluids. It has disadvantages as a parenteral iron agent, such as being stable only at high pH. In addition, in the dextran/ferric iron complex conventionally used as a parenteral iron preparation, dextran itself is expensive, decomposes extremely slowly in the body, and has a tendency to accumulate. When iron complexes are administered parenterally, their uptake into the reticuloendothelial system in vivo is poor, and accumulation in the blood is observed.
It has various drawbacks as a parenteral iron preparation, as it acts as an antigen and produces antibodies, and is also reported to be carcinogenic. On the other hand, in the dextrin/ferric iron complex, the composition dextrin has degrading enzymes in the living body, so it does not accumulate like dextran does, and does not produce harmful immune antibodies.
Furthermore, the dextrin/ferric iron complex, which has a large molecular weight, has many advantages such as not being filtered by the kidneys and being excreted in the urine. However, dextrins have reducing groups and tend to reduce ferric iron to ferrous iron, producing free ferrous ions. Further, the dextrin/ferric iron complex has drawbacks such as insufficient long-term storage stability and insufficient thermal stability in an aqueous solution state. Therefore, the present inventors attempted to improve the stability of these preparations by using high-molecular-weight dextrins, but the desired effects could not be obtained and only products with low iron content and poor therapeutic effects were obtained. On the other hand, attempts were made to produce a dextrin/ferric iron complex that would enhance the therapeutic effect by increasing the iron content, reduce the influence of the reducing group of dextrin, and be less likely to generate free ferrous ions, but such a complex However, the water holding capacity decreased and only unstable products could be obtained. The present inventors used dextrins with appropriate molecular weights, citric acid, gluconic acid, tartaric acid, malic acid,
Coordinating at least one hydroxycarboxylic acid selected from succinic acid or an alkali salt thereof, preferably sodium citrate or potassium citrate, to a reactive polynuclear ferric iron compound in a preferred ratio. As a result, we succeeded in creating an iron composite that satisfies these requirements, and completed the present invention. The present invention has an iron content of 35-47
In terms of weight percent, the administered iron is hardly excreted in the urine and contains virtually no free iron, providing a parenteral iron preparation with extremely high stability and safety. According to the present invention, a ferric iron polynuclear olated product;
When the 2W/V% solution is left at 4°C for 7 days, no precipitation occurs, and the average molecular weight determined by the number of reducing ends measured by the Somogyi-Nelson method is 2500 or more.
10,000, preferably 3,500 to 6,000 dextrin (hereinafter simply referred to as dextrin) is added to 0.75 to 1.60 mol (glucose residue unit, hereinafter the same) per 1 mol of iron in the presence of an alkali carbonate at a temperature range of 100 to 130°C. Preferably 1 to 5 at a temperature of 102℃ to 120℃
The mixture is heated and stirred for a period of time, water is added to dilute the resulting reaction solution, and the solution is filtered to remove unreacted substances. Next, at least one lower alkyl alcohol selected from methyl alcohol, ethyl alcohol, and isopropyl alcohol is added to the filtrate to precipitate the dextrin/ferric polynuclear complex, which is separated by centrifugation. Preferably, by repeating the above operations, a purified dextrin/ferric polynuclear complex containing alcoholic water can be obtained.
The lower alkyl alcohol used in this step needs to have a concentration of at least 30% v/v, but it is not preferable to unnecessarily increase the alcohol concentration because this will lower the purification efficiency. The purified dextrin/ferric polynuclear complex thus obtained, which contains alcoholic water, may be used as is or after being dried, it is heated and dissolved together with water. When using a purified dextrin/ferric polynuclear complex containing lower alkyl alcohol water, it is preferable to boil it for an appropriate period of time to distill off the lower alkyl alcohol content. The obtained dextrin
At least one hydroxycarboxylic acid selected from citric acid, gluconic acid, tartaric acid, malic acid, and succinic acid (hereinafter simply referred to as hydroxycarboxylic acid) or an alkali salt thereof, preferably citric acid, is added to the ferric polynuclear complex solution. 0.02 acid or its sodium or potassium salt per mole of iron
~0.2 mol, preferably 0.05 to 0.16 mol, is added and heated and stirred in a closed container at a temperature of 110°C to 130°C for 1 to 5 hours to obtain crude dextrin.
Obtain a hydroxycarboxylic acid/ferric polynuclear complex solution. The crude dextrin/hydroxycarboxylic acid/ferric polynuclear complex solution obtained by the above method is filtered and at least one lower alkyl alcohol selected from methyl alcohol, ethyl alcohol, and isopropyl alcohol is added. The complex is then precipitated and centrifuged,
Repeat this process if desired to obtain purified dextrin.
A hydroxycarboxylic acid/ferric polynuclear complex is obtained. The complex containing the lower alkyl alcohol water is then dried with warm air or reduced pressure, crushed if desired, and stored to prepare a parenteral iron preparation at the time of use. This purification process is effective in removing unreacted hydroxycarboxylic acid alkali salts, free iron, low iron content complexes, and low-molecular complex parts, and improves the stability of the complexes of the present invention.
Helps improve safety. The polynuclear olated product of ferric iron used in the present invention is, for example, a suspension formed by slowly adding an excessive amount of an aqueous alkali carbonate solution dropwise to an aqueous ferric chloride solution while stirring well at cold or room temperature. It is relatively easily prepared by washing with distilled or pure water, filtering, or centrifuging. In the ferric polynuclear product thus obtained, electrolytes that interfere with coordination bonds with other components and cause the iron content to be lowered are removed as much as possible. Preferably, by following the above method, such conditions can be achieved relatively easily and economically more advantageously than by performing ion exchange, dialysis, etc. Furthermore, the hydroxycarboxylic acid or alkali salt thereof used in the present invention and the amount used have important meanings. That is, by using hydroxycarboxylic acid or its alkali salt as a component of the complex of the present invention, it imparts a negative charge to the target substance, and its stability in solution is dramatically improved compared to the dextrin/ferric iron complex. . In particular, when the alkali citrate salt is used in an amount ranging from 0.02 to 0.20 mol, preferably from 0.05 to 0.16 mol, per mol of iron, the most remarkable improvement in stability in solution is observed. Furthermore, as the amount of the alkali hydroxycarboxylic acid salt reacted increases, the molecular weight of the resulting composite tends to decrease, and therefore, it also has the significance of controlling the molecular weight of the composite. Furthermore, as is clear from the experiments described later, the amount of dextrin in the composite of the present invention greatly affects the stability of the composite in solution, and generally, as the amount of dextrin increases and the powder iron content decreases, the amount of free iron decreases. The result is that stability and safety generally decrease. On the other hand, it is not preferable to reduce the amount of dextrin to an extremely low level since this will reduce the water retention of the complex and its stability in solution. Therefore, the present invention is characterized in that the amount of dextrin is kept to the necessary and minimum amount, the complex has a high iron content, and hydroxycarboxylic acid is used to compensate for the decrease in hydrophilicity of the complex. Therefore, it is preferable that the complex of the present invention contains dextrin in an amount that does not reduce the stability of the complex in solution and that allows a complex with a suitably high molecular weight to be obtained. 0.75 to 1 mole of iron
By using 1.6 moles (glucose units) of dextrin, a complex satisfying these conditions is obtained. The dextrin/hydroxycarboxylic acid/ferric polynuclear complex thus obtained is a dark brown, odorless, amorphous powder that gradually dissolves in cold water and easily dissolves in hot water, and once dissolved, it precipitates even when cooled. The result is a stable solution. Moreover, this solution is sufficiently stable near neutrality. Ethanol/methanol/
Almost insoluble in organic solvents such as acetone and ether. Furthermore, this complex is a polymer complex that has a negative charge and a molecular weight distribution with a number average molecular weight of about 140,000 as measured from osmotic pressure. The iron composite produced according to the present invention has the following characteristics. 1. Due to its high iron content, it is extremely advantageous in terms of formulation and storage. 2. When administered intravenously, the bone marrow,
It is taken up by endothelial cells such as the liver and spleen, and does not exhibit cumulative effects in the blood like ferric dextran. 3. The aqueous solution of this complex is stable around neutrality, and therefore there is no risk of damaging biological tissues. 4. Since the components other than the iron component that make up this complex are all metabolizable substances, such as dextrin and hydroxycarboxylic acid, there is no accumulation during administration.
No other serious side effects were observed. 5. Since it has extremely high storage and thermal stability in the form of a solution, it is extremely advantageous during preparation sterilization and during storage and distribution stages. The toxicity and pharmacological effects of the complex obtained by the production method of the present invention were investigated. When the acute toxicity of the dextrin-citrate-ferric polynuclear complex of the present invention was investigated using 8 male mice per administration group, the LD ₅₀ after intravenous administration was approximately
It showed 460mgFe/Kg, and more than 2500mgFe/Kg when administered subcutaneously. In addition, six male guinea pigs were sensitized by injecting 10 mg Fe/Kg of the complex into the abdomen or rear neck subcutaneously three times every other day, and 3 weeks later they developed systemic anaphylaxis and were similarly sensitized. Investigating Schltz-Dale reactions using guinea pig ileum,
Antigenicity was investigated, but all tests were negative. The dextrin-citric acid-ferric polynuclear complex of the present invention using ⁵⁹ Fe containing 250 mg of iron was mixed with 20 W/V% glucose and injected intravenously to patients with agastric iron deficiency anemia. We investigated the dynamics of According to the blood iron loss curve, the iron half-life is approximately 29 minutes, and the red blood cell iron utilization curve is
It continued to rise until the 14th, and the iron utilization rate was over 70%. In addition, the distribution of ⁵⁹ Fe in the body based on radioactivity measurements on the body surface is highest in the liver after 24 hours, followed by bone marrow and spleen, reaching the highest level in bone marrow after 3 to 4 days, and decreasing in the liver to almost no level. Therefore, an increase in the number of counts in the heart, which indicates the concentration in the blood, was observed, and it was observed that the drug was being utilized by red blood cells. In addition, 55 patients with iron deficiency anemia due to gynecological diseases received 1 to 2 tubes per day (1 tube, 2 ml) of the dextrin/citric acid/ferric polynuclear complex of the present invention, depending on the symptoms.
110-145 mg (50 mg as iron) sorbitol 80 mg,
After intravenously or intramuscularly injecting an appropriate amount of distilled water for injection 2 to 7 times a week, 38 cases showed an increase in hemoglobin level of 1.5 g/dl or more, 1.4 to 1.0 g/dl.
12 cases of dl, 5 cases of less than 1.0g/dl,
Significant improvement in anemia was observed in most cases. No side effects were observed in all cases, including symptoms of acute iron toxicity,
No allergic symptoms or liver dysfunction were observed. The complex obtained by the production method of the present invention can be dissolved in distilled water and used as it is, preferably with a non-reducing isotonizing agent such as salt, hexites such as sorbitol and mannite, or polyhydric alcohols such as glycerin and ethylene glycol. An injection can be prepared by adding an appropriate amount of at least one of the following. Example 1 158 g (0.2 mole as iron) of a newly manufactured polynuclear olated ferric iron and 32.1 g of dextrin with a molecular weight of 3800.
g and 2.0 g of anhydrous sodium carbonate were heated in an oil bath while stirring with a small amount of water. The contents are heated to a controlled temperature of approximately 102°C to gently reflux. After continuing the reaction for about 2 hours, the brown reaction solution changed to a blackish brown homogeneous solution, yielding a concentrated solution of the dextrin/ferric polynuclear complex. Add water to the solution
400 ml was added to dilute, cool, and then filtered to remove a small amount of insoluble unreacted substances. Water was added to the obtained filtrate to bring the total volume to 800 ml, and 520 ml of methyl alcohol was added to separate the precipitate. 600 ml of water was added to the resulting precipitate and dissolved by heating and stirring in a boiling bath. After cooling, the solution was pulp-filtered, water was added to the filtrate to make a total volume of 700 ml, and 880 ml of methyl alcohol was added to precipitate the dextrin/ferric polynuclear complex. The mixture was allowed to stand for a while, the supernatant was removed, and the precipitate was centrifuged to obtain a purified cake-like dextrin/ferric polynuclear complex containing methyl alcohol water. 260 ml of water was added to the complex and dissolved by heating and stirring, and the methyl alcohol contained therein was distilled off. After cooling, filter and add water.
The volume was adjusted to 400ml. A portion of this was taken for a quantitative test of iron. The yield was 89.6% by weight based on iron. The solution was filled into a simple autoclave, 0.95 g of sodium citrate dihydrate was added, and the mixture was reacted at 120°C for 2 hours. After cooling, the solution was filtered through silk cloth, and water was added to the filtrate to make a total volume of 400 ml. By adding 290 ml of ethyl alcohol to the solution, a dextrin/citric acid/ferric polynuclear complex was precipitated. The obtained dextrin/citric acid/ferric polynuclear complex containing ethyl alcohol water was dried under reduced pressure at room temperature in the presence of calcium chloride, and the dried product was ground to obtain a dark brown powdered dextrin/citric acid/ferric polynuclear complex. 18.8 g of body was obtained. Iron content 46.5% by weight, yield (based on iron) 77.7% by weight. Example 2 1072g of newly manufactured ferric iron polynuclear compound (as iron)
1.4 mol), 280 g of dextrin with a molecular weight of 5300, and 15.7 g of anhydrous sodium carbonate were added to a reaction vessel equipped with a reflux device along with 120 ml of water, and the mixture was stirred to 103
The reaction was carried out at ℃ for 4 hours to obtain a solution of dextrin/ferric polynuclear complex. 280 ml of water was added to this, followed by bulb filtration, and water was added to the filtrate to make 5,600 ml. 3800 ml of methyl alcohol was added to the solution to precipitate the complex, which was then centrifuged. 4,200 ml of water was added to the precipitate and dissolved by heating, and after cooling, pulp filtration was performed again, and water was added to the filtrate to make a total volume of 5,000 ml. 6300 ml of methyl alcohol was added to the solution to precipitate the complex.
The precipitate was separated, 2100 ml of water was added, and the mixture was dissolved by heating to distill off the methyl alcohol. Water was added to the solution to obtain 2800 ml of dextrin/ferric polynuclear complex. Yield (based on iron) 92.2% by weight. Obtained dextrin/ferric polynuclear complex solution
From 400 ml (10.3 g as iron) and 5.4 g of sodium citrate dihydrate, 23.7 g of a dextrin/citric acid/ferric polynuclear complex was obtained in substantially the same manner as in Example 1 above. Iron content 39.6% by weight, yield (based on iron) 83.9% by weight. Example 3 Dextrin, glycolic acid, 23.8 g of ferric polynuclear complex was obtained. Iron content 38.8% by weight. Yield (based on iron) 82.1% by weight. Example 4 From 400 ml of the dextrin/ferric polynuclear complex solution obtained in Example 2 (10.3 g as iron) and 4.0 g of sodium gluconate, dextrin/glycolic acid/ferric acid was prepared in substantially the same manner as in Example 1. 24.0 g of diiron polynuclear complex was obtained. Iron content: 39.8% by weight.
Yield (based on iron) 85.7% by weight. Example 5 Dextrin/ferric polynuclear complex solution obtained in Example 2 was prepared from 400 ml of dextrin/ferric polynuclear complex solution (10.3 g as iron) and 5.0 g of sodium succinate hexahydrate in substantially the same manner as in Example 1. 24.5 g of succinic acid/ferric polynuclear complex was obtained. Iron content 38.2% by weight. Yield (based on iron) 83.9% by weight. Example 6 Dextrin/tartaric acid was prepared in substantially the same manner as in Example 1 from 400 ml of the dextrin/ferric polynuclear complex solution obtained in Example 2 (10.3 g as iron) and 4.2 g of sodium tartrate dihydrate.・24.3g of ferric polynuclear complex was obtained. Iron content 38.2% by weight. Yield (based on iron) 83.0% by weight. Example 7 Dextrin, malic acid, 24.2 g of ferric polynuclear complex was obtained. Iron content: 39.0% by weight. Yield (based on iron) 83.9% by weight. Thermal Stability Test A thermal stability test was conducted on the intermediate dextrin/ferric polynuclear complex solution obtained in Example 2 and the final product dextrin/citric acid/ferric polynuclear complex. When the dextrin/ferric polynuclear complex ampoule without citric acid was heated continuously at 100°C, it gelled in 25 hours, and origin residues were also observed in electrophoresis experiments. On the other hand, the dextrin/citric acid/ferric polynuclear complex ampoule showed no abnormality in appearance even after being heated at 100°C for 200 hours and showed good migration in electrophoresis experiments. As a result of conducting the same thermal stability test for the compounds of Examples 3 to 7, it was found that dextrin, citric acid,
Although slightly inferior to the ferric polynuclear complex, a significant improvement in thermal stability was observed compared to the dextrin/ferric polynuclear complex. Examples 8 to 12 907 g of newly produced ferric iron polynuclear olated product (1.2
mol), a molecular weight of 5000, and 13.5 g of anhydrous sodium carbonate to obtain 2400 ml of a dextrin/ferric polynuclear complex solution in the same manner as in Example 1. Add sodium citrate dihydrate to 400 ml of the solution (10.25 g as iron) per mole of iron.
The iron content, yield (based on iron), and thermal stability of dextrin-citric acid-ferric polynuclear complexes obtained by reacting at molar ratios of 0.01, 0.05, 0.10, 0.15, and 0.50 were determined, respectively. Examined. The results are shown in Table 1.

[Table] The complex of the present invention can be produced by coordinating hydrophilic dextrin and hydroxycarboxylic acid with hydrophobic ferric polynuclear chains, so that dextrin, hydroxycarboxylic acid, and hydroxycarboxylic acid, which can stably branch in water, Although it is presumed to form a ferric iron polynuclear complex, it is a polymer that contains some free dextrin and has a molecular weight distribution. Regarding the complex of the present invention, its elemental composition, residue composition, infrared absorption spectrum, molecular weight, particle size distribution,
The results of measurement experiments such as electrophoresis, thin layer chromatography, intrinsic viscosity, polarography, and gel filtration are shown below. a Elemental composition (measurement method) Γ Iron content analysis: After the sample is decomposed with hydrochloric acid, it is reduced with zinc dust to produce ferrous ions, and then redox titrated with ceric ammonium sulfate using o-phenanthroline test solution as an indicator. It was measured by the method. Γ Sodium content analysis: Measured using a flame photometer. (Results) The measurement results shown in Table 2 were obtained by the above method.

[Table] b Residue composition (measurement method) Γ Ferric polynuclear complex residue [FeOOH] _o : Calculated from the above iron content. Γ Dextrin residue [C ₆ H ₁₀ O ₅ ] _n and free dextrin [C ₆ H ₁₀ O ₅ ] _l : Hydrolyze each sample with hydrochloric acid, quantify the total dextrin as glucose by Bertrand method, and convert it to the amount of dextrin. did. The free dextrin content can be determined by coprecipitating the complex part with an excess amount of a positively charged colloid titration reagent methyl glycol chitozan solution, taking advantage of the fact that the complex part of the complex of the present invention has a negative charge. After precipitating the excess methyl glycol chitozan by adding a negatively charged colloidal titration reagent polyvinyl potassium sulfate solution, the free dextrin remaining in the supernatant was hydrolyzed with hydrochloric acid to produce glucose, and Bertrand The amount of dextrin was determined by the method and converted into the amount of dextrin. The difference between the total dextrin content and the free dextrin content was defined as the dextrin residue content. Γ Citric acid residue [C ₆ H ₅ O ₇ ]: After each sample is hydrolyzed with 6N hydrochloric acid, iron is allowed to flow down through a column packed with a strongly acidic ion exchange resin (Amberlite IR-120) and interferes with the measurement. The solution was concentrated to dryness, then dissolved in ethanol water, transferred to a conductivity titration cell, and conductivity titrated with a 0.1N NaOH solution.
The amount of citric acid residue was determined from the amount of . (Results) The measurement results are shown in Table 3.

【table】

[Table] c Infrared spectrum (measurement method) Measured using an infrared spectrophotometer (Model EPI-G3 manufactured by Hitachi, Ltd.) using the potassium bromide tablet method. (Results) The infrared absorption spectra of each sample measured matched well with each other. d Number average molecular weight (measurement method) For the complex of Example 10, determine the relationship between sample concentration (C) and osmotic pressure (π) using a high-speed membrane osmometer.
The number average molecular weight () was determined from the relational expression Mn=RT(π/C) _c=0 . (However, R = 84.7cm water column/deg
mol, T = absolute temperature of the measurement system. ) The molecular weight of the complex of the present invention after removing as much free dextrin as possible by ultrafiltration was determined to be 2.34×10 ⁵ for reference. (Results) The above measurement results are summarized in Table 5.

[Table] e Particle size distribution (measurement method) A 6w/v% aqueous solution of each of the composites of Examples 1 and 10 was filtered through ultrafiltration membranes with various pore sizes, and the iron concentration of the filtrate was determined by o-phenanthroline. It was measured by a colorimetric method, and the particle size distribution of each sample was determined from the iron component filtration rate. (Results) The particle size of each sample in the aqueous solution had a distribution of about 0.03 to 0.1μ, and about 90% of them had a particle size in the range of 0.05 to 0.08μ. f Electrophoresis (Measurement method) Soak a cellulose acetate membrane (5 x 6 cm) in each phosphate buffer (PH5.7, 6.0, 6.5, 7.0, 7.5 and 8.0) and gently remove excess buffer with filter paper. After removing the cellulose acetate membrane, it was placed in an electrophoresis cell containing a phosphate buffer with the same pH, and a 6w/v% sample solution was deposited on the center line of the cellulose acetate membrane.
A voltage of 90 V was applied for 40 minutes, and the movement of the colored spots on the sample was observed. (Results) All the samples moved to the anode. The migration distances are shown in Table 6.

[Table] In this experiment, if free iron ions were present, pale yellow iron phosphate (FePO ₄ ) would be generated by sodium phosphate and remain at the origin, but no corresponding spots were observed. Nakatsuta. g Intrinsic viscosity (measurement method) Sample solutions of various concentrations were prepared from each sample. The specific gravity of the solution and water was measured at 30 ± 0.1°C using a Schuprengel-Ostwald pycnometer, and the flow time was measured at 30 ± 0.1°C using an Ubbelohde capillary viscometer, and the intrinsic viscosity was determined by extrapolation. [η]=limηsp/c was determined. (ηsp: specific viscosity, c: sample concentration). (Results) Table 7 shows the intrinsic viscosity [η] of each sample.

[Table] h Gel filtration The complex of Example 10 was subjected to gel filtration under the following conditions, and iron and dextrin were quantified in each elution fraction. (Conditions) Sample loading amount 6.00mg, gel Sepharose 6B
Column: 40 x 2.5 cm Buffer: 0.05M citrate buffer (PH6.0) Fraction volume: 5 ml (Results) The measurement results are shown in Figure 1. i Dextrin/citric acid/ferric iron (ultrafiltration) Properties, iron content, dextrin content, infrared absorption spectrum, gel of the sample obtained by ultrafiltration of the aqueous solution of the complex of Example 1 The filtration condition was checked. The results are shown in Table 8. An infrared absorption spectrum diagram and a gel filtration curve diagram are shown in Figures 2 and 3, respectively.

【table】

[Table] Revenue
derived from residues

Claims (1)

[Claims] 1. A dextrin/ferric polynuclear complex is obtained by reacting dextrin with a ferric polynuclear olated product at 100 to 130°C in the presence of an alkali carbonate, and then reacting this with citric acid and gluconic acid. A method for producing a dextrin/hydroxycarboxylic acid/ferric polynuclear complex comprising reacting at least one hydroxycarboxylic acid selected from , tartaric acid, malic acid, and succinic acid or an alkali salt thereof at 100 to 130°C. 2. The manufacturing method according to claim 1, wherein the hydroxycarboxylic acid or its alkali salt is used in an amount ranging from 0.02 to 0.20 mol, preferably from 0.05 to 0.16 mol, per 1 mol of iron. 3. Dextrin is a 2W/V% solution at 4℃.
No precipitation occurs when left for 7 days, and the average molecular weight determined by the number of reducing ends measured by the Somogyi-Nelson method is 2,500 to 10,000, preferably
3,500 to 6,000 dextrin, the manufacturing method according to claim 1. 4 Dextrin is 0.75 to 1.60 per mole of iron
The method according to claim 1, wherein the amount is in the range of moles (glucose residue units). 5. Dextrin is reacted with the ferric polynuclear olated product at 100 to 130°C in the presence of alkali carbonate to obtain a dextrin/ferric polynuclear complex, which is then reacted with citric acid, gluconic acid, tartaric acid, malic acid, Dextrin, hydroxycarboxylic acid, and ferric iron, which is obtained by reacting at least one hydroxycarboxylic acid selected from succinic acid or an alkali salt thereof at 100 to 130°C, and further removing free dextrin from the resulting complex. Method for producing multinuclear complexes. 6. The production method according to claim 5, wherein the hydroxycarboxylic acid or its alkali salt is used in an amount ranging from 0.02 to 0.20 mol, preferably from 0.05 to 0.16 mol, per mol of iron. 7. Dextrin, its 2W/V% solution at 4℃
No precipitation occurs when left for 7 days, and the average molecular weight determined by the number of reducing ends measured by the Somogyi-Nelson method is 2,500 to 10,000, preferably
The manufacturing method according to claim 5, wherein the dextrin has a molecular weight of 3,500 to 6,000. 8 Dextrin is 0.75 to 1.60 per mole of iron
6. The manufacturing method according to claim 5, wherein the amount is in the range of moles (glucose residue units).