KR810000341B1 - Process for preparing dextrin hydroxy caboxylic acid polyiron olated complex - Google Patents

Abstract

This invention is directed to an iron complex used in treatment of iron-deficiency anema. The complex is formed by reacting a reactive polyiron olated compound with dextrine and at least one hydroxycarboxylic acid. A dextrin-hydroxycarboxylate-polyiron olated complex is produced. The reaction product contains substantially no free iron. Iron concentration is between about 35 and 47%. The complex can be administered non-orally.

Description

Dextrin, hydroxycarboxylic acid, ferric multinuclear complex

1 is an infrared absorption spectrum obtained by potassium embrittlement purification of the composite of Example 1. FIG.

2 is a schematic of the polarogram in walpole buffer at pH 5.45 of the composite of Example 1. FIG.

3 is a composite gel filtration elution curve of (1) and (2) of Examples 1 and 21, respectively.

4 is a relationship between the heating time and the amount of free iron in a sample solution prepared from the composite of Example 1. FIG.

5 is an infrared absorption spectrum of the complex of Example 21 relating to ultrafiltration.

6 is his gel filtration elution curve.

The present invention relates to iron complexes useful for the treatment of iron deficiency, and more particularly, to a method for producing parenterally administrable dextrin, hydroxycarboxylic acid and ferric multinuclear complex.

Treatment of iron deficiency anemia mainly depends on oral iron administration. However, when a large amount of iron is required, oral iron is not adequately absorbed. In case of no resistance to administration, iron loss by parenteral administration is administered instead of oral administration in cases where iron loss due to chronic persistent bleeding is higher than iron absorption and loss of storage iron is observed.

In the case of oral administration of iron, the rate of absorption in the intestinal tract depends on the concentration of free iron, so that the more favorable the iron is, the more effective the treatment effect is. .

On the other hand, in the case of iron for parenteral use, it is known that free iron makes the biological body administered according to its quantity extremely dangerous. Therefore, efforts are made to manufacture iron having a low ratio of free iron. In which the amount thereof is moderately high, the excretion to urinalysis is high, the iron concentration is high, it is easy to obtain the injection solution of body fluid and isotonic, stable in solution near the neutral and solution Since the storage stability in the state is required, etc., it is fundamentally different from oral iron, and an incomparable manufacturing technique is required in order to have the stability and safety of a product.

There are several techniques that have shown that complexes consisting of ferric salts with mono or oligosaccharides and hydroxycarboxylic acids are effective in the treatment of iron deficiency anemia.

For example, Japanese Patent Application Publication Nos. 40-7296 and 40-17782 show a method for obtaining an iron combination by reacting ferric salt, hexitol and 1-3 basic hydroxy carboxylic acids in the presence of a dispersion stabilizer. . However, in this method, only a combination of relatively low iron content of 15-16% can be obtained, and acute toxicity has a drawback of high toxicity of LD ₅₀ 35 mg / kg when injected into mice. In addition, Patent Publication No. 46-3196 discloses 1 mol of ferric hydroxide, about 1.5 mol of sorbitol, about 4.0 mol of gluconic acid, and 0.5 mol of dextrin, dextran, hydrogenated dextrin, or hydrogenated dextran with an average molecular weight of 500-1200. A method of obtaining an iron compound by reacting with 2 moles of a complex compound forming agent (with glucose) is shown.

Also in this method, the iron content of the obtained iron combination is only 21-26%, and when administered to the human body, 10% of the administered iron is excreted in the urine, and LD _{50 in} rats is 380 mg / It has a point of improvement, such as showing a relatively high toxicity in kg. These saccharide, hydroxycarboxylic acid, and ferric complexes may have damage to blood cells, blood vessels, muscles, etc. due to their relatively low molecular weight, in addition to the drawbacks described above, and the complex solution may have a higher pH than blood and body fluids. It is unstable as a parenteral iron only when it is stable.

In addition, dextran and ferric complexes, which are conventionally used as parenteral steels, are expensive, decompose very slowly in the body, have a high accumulation, and are parenterally administered dextran ferric complexes. In this case, the infiltration into the reticulum endothelial system in vivo is poor, there is a report that blood accumulation is confirmed, and it acts as an antigen to produce an antibody, and has carcinogenicity. On the other hand, in the dextrin ferric complex, its composition, dextrin, does not accumulate as shown in dextran due to the presence of a degrading enzyme in the raw material, and does not produce harmful immune antibodies. In addition, in the dextrin ferric complex having a large molecular weight, it is advantageous in that it is not filtered in the kidney and there is little excretion in urine. However, dextrins have a reducing group, so it is easy to generate ferrous ions of glass by reducing ferric iron to ferrous iron. In addition, dextrin and ferric complex have disadvantages such as insufficient long-term storage stability and thermal stability in aqueous solution.

The present inventors attempted to improve the stability of these preparations using high molecular weight dextrins, but could not obtain the desired effect and only the poor therapeutic effect with low iron content. Conversely, attempts have been made to produce a dextrin ferric complex which increases the effect of iron by increasing the iron content, reduces the effect of dextrin reducing groups, and is unlikely to generate ferrous ions of glass. The water retention decreased and only an unstable one could be obtained.

The present inventors believe that an alkali salt of dextrin having an appropriate molecular weight and a hydroxycarboxylic acid selected from citric acid, gluconic acid, tartaric acid, malic acid and succinic acid is at least one, preferably sodium citrate or potassium citrate. By coordinating at a suitable ratio in the present invention, the present inventors have succeeded in making an iron complex that satisfies these requirements, and have completed the present invention.

In the present invention, the iron content is 35-47%, and the administered iron provides little or no excretion in urine, substantially free of iron, and extremely high stability and stability.

According to the present invention, when the ferric multinucleus is left in the flame and the 2% solution is left at 4 ° C. for 7 days, no precipitation occurs, and the average determined by the reduced number of terminals measured by the Somongyi Nelson method. Dextrins of molecular weight 2,500-10,000, preferably 3,500-6,000 (hereinafter simply referred to as dextrins) and hydroxycarboxylic acids (hereinafter simply referred to as hydroxycarboxylic acids) selected from citric acid, gluconic acid, tartaric acid, malic acid, succinic acid or their alkali salts At least one, preferably citric acid or its sodium salt or potassium salt is 0.02-0.2 mol, preferably 0.05-0.16 mol with respect to 1 mol of iron, and at least one alkali carbonate selected from sodium carbonate or potassium carbonate. The mixture is mixed with water and prepared by heating and stirring for 1-5 hours in a temperature range of 100 ° -130 ° C, preferably 102 ° -120 ° C in a heat-stirrable container (劑) dextrin, hydroxy carboxylic acid, the polynuclear iron (III) to obtain a conjugate solution.

On the other hand, the ferric polynuclear oligomer and dextrin are heated and stirred for 1-5 hours at a temperature of 102 ° -120 ° C. in the temperature range of 100 ° -130 ° C. in the presence of alkali carbonate, and to the obtained reaction solution. Dilute by adding water, filter this solution and remove unreacted material. Next, at least one of lower alkyl alcohols selected from methyl alcohol, ethyl alcohol and isopropyl alcohol is added to the filtrate, and the dextrin ferric polynuclear complex is precipitated and separated by centrifugation.

Preferably, by repeating the above operation, it is possible to obtain a purified dextrin ferric multinuclear complex containing alcohol water. The lower alkyl alcohol used in this process requires a concentration of at least 30 V / V% or more, but unnecessarily increasing the alcohol concentration is undesirable because it lowers the purification efficiency.

The thus-obtained purified dextrin ferric multinuclear complex contains alcoholic water but is dissolved as it is or after being dried once with water. When using the purified dextrin ferric multinuclear complex containing lower alkyl alcohol water, it is preferable to boil for an appropriate time, and to evaporate the lower alkyl alcohol component. At least one alkali salt of hydroxycarboxylic acid is added to the obtained dextrin ferric multinuclear complex solution in an amount of 0.02-0.2 mol, preferably 0.05-0.16 mol, per mol of iron, at a temperature of 110 ° -130 ° C. The prepared dextrin, hydroxycarboxylic acid and ferric multinuclear complex solution are obtained by heating and stirring in a closed container for 1-5 hours.

The dextrin-hydroxycarboxylic acid-ferric multinuclear complex solution obtained by the above-mentioned method is filtered, and the complex is precipitated by adding at least one lower alkyl alcohol selected from methyl alcohol, ethyl alcohol and isopropyl alcohol, and centrifugation. Isolation is repeated as desired and a purified dextrin, hydroxycarboxylic acid, and ferric multinuclear complex is obtained. Next, this composite containing lower alkyl alcohol water is dried by warm air or reduced pressure, pulverized and stored as desired, so that it can be prepared as parenteral iron at the time of use.

This purification process is effective for the removal of unreacted hydroxycarboxylic acid alkali salts, free iron, low iron content complexes and low molecular complexes, and contributes to the improvement of the stability and safety of the complex of the present invention.

For example, the ferric polynuclear oligomer used in the present invention is slowly added dropwise with an excess amount of an aqueous solution of alkaline carbonate while stirring the ferric chloride aqueous solution at low temperature to room temperature, and distilled water is produced. Or relatively simple by washing, filtration or centrifugation with pure water. In the ferric polynuclear oxidized compound thus obtained, it is preferable that the electrolyte, which interferes with the coordination bond with other components and thus decreases the iron content, is preferably removed. According to the method, ion exchange and dialysis are relatively simple. Such a condition can be achieved economically more advantageously than performing (dialysis) or the like. In addition, the hydroxycarboxylic acid or its alkali salt used in this invention, and its usage amount have an important meaning. In other words, by using hydroxycarboxylic acid or its alkali salt as a constituent of the composite of the present invention, a negative charge is imparted to the target substance, and the stability in solution is dramatically compared to that of the dextrin / ferric iron complex. Improve. In particular, when the alkali citric acid salt is used in an amount of 0.02-0.2 mol, preferably 0.05-0.16 mol with respect to 1 mol of iron, the most significant improvement in stability in solution is confirmed. Moreover, as the reaction amount of the hydroxycarboxylic acid alkali salt increases, the molecular weight of the obtained composite tends to be low, and therefore has the significance of controlling the molecular weight of the complex. In addition, as shown in the experiments described below, the amount of dextrin of the complex of the present invention greatly affects the stability in the solution of the complex, and in general, the amount of free iron increases as the amount of dextrin increases and the content of raw iron decreases. And the result that the safety falls. On the other hand, extremely low amount of dextrin is not preferable because the water retention of the complex is lowered and the safety in solution is also lowered.

In the present invention, the amount of dextrin is reduced to the minimum required, the composite is made of a high iron content, and hydroxycarboxylic acid is used to compensate for the decrease in hydrophilicity of the complex. Therefore, the composite of the present invention preferably contains no amount of dextrin to the extent that a composite having a moderately high molecular weight is obtained without deteriorating stability in the solution of the composite, and in the method of the present invention, 0.75-1.6 with respect to 1 mol of iron. By using molar (glucose) dextrin, a complex satisfying these conditions was obtained. The dextrin-hydroxycarboxylic acid-ferric multinuclear complex thus obtained is a dark brown odorless amorphous powder, which gradually dissolves in cold water, readily dissolves in hot water, and once dissolved, forms a stable solution that does not precipitate upon cooling. This solution is also sufficiently stable near neutral. It is almost insoluble in organic solvents such as ethanol, methanol, acetone and ether. In addition, the composite has a load loading, and the average molecular weight measured by osmotic pressure is about 140,000, which has a characteristic molecular weight distribution.

The iron composite produced by the present invention has the following characteristics.

1. It is very advantageous in preparation and storage because of high iron content.

2. When administered intravenously, it is rapidly injected into endothelial cells such as bone marrow, liver and spleen, and does not show blood accumulation like ferric dextrin.

3. The aqueous solution of the complex is stable near the neutral, so there is no danger of damaging the tissue.

4. The iron components of the complex are all metabolic dextrins and hydroxycarboxylic acids, so they do not accumulate at the time of administration, and no very serious side effects are seen.

5. The storage and thermal stability in solution is extremely high, so it is very advantageous in the sterilization, storage and distribution stage of the preparation.

Toxicity and pharmacological action in the complex of the present invention were investigated. Acute toxicity of the dextrin, citric acid, and ferric multinuclear complexes of the present invention was investigated in 8 male rats of 1 dose group. The LD ₅₀ obtained by intravenous administration was about 460 mgFe / kg, in case of subcutaneous administration. More than 2,500 mgFe / kg was shown. In addition, 10 male Fe / kg of the complex was inoculated three times every other day by subcutaneous abdominal or posterior neck skin into 6 male moles, followed by systemic anaphylaxis after 3 weeks. The Schltz-Dale reaction and the like were examined using sensitized morphote ileum, and antigen bodies were examined, but negative in any test.

Dextrin, citric acid and ferric multinuclear complex of the present invention containing ⁵⁹ Fe having a 250 mg iron content in patients with adolescent iron deficiency anemia, mixed with 20% glucose, We investigated the dynamics of iron. The iron half-life in the blood iron loss curve was about 29 minutes, and the red blood cell iron utilization curve continued to increase until 14 days, and the iron utilization rate was 70% or more. In addition, the body distribution of ⁵⁹ Fe by body surface measurement of radiation was highest in the liver after 24 hours, followed by bone marrow and splenic liquor, and bone marrow became the best after 3-4 days. It began to decrease, an increase in concentration was observed in the heart, which indicates blood levels, and the appearance of red blood cells was observed. In addition, 55 cases of iron-deficiency anemia patients caused by gynecological diseases were treated according to the symptoms. As a result of intravenous or intramuscular injection of 50 mg) sorbitol 80 mg, distilled water for injection) at a rate of 2-7 times per week, 38 cases of hemoglobin increased more than 1.5 g / dl, 1.4-1.0 g 12 cases of / dl and 5 cases of 1.0g / dl or less were found, and most cases showed an improvement in anemia. No adverse effects were found in all cases, and acute iron poisoning symptoms, allergic symptoms, and liver failure were not observed.

The composite of the present invention is dissolved in distilled water, and is preferably injected by adding at least one of non-reducing isotonic agents such as hexitols such as salt, sorbitol and mannitol, or polyhydric alcohols such as glycerin. It is possible to do

Example 1

185 g of the new ferric polynucleating agent (0.25 mol in terms of iron atom), 34 g of dextrin having a molecular weight of 5,000, 7.4 g of sodium citrate dihydrate, and 2.8 g of anhydrous sodium carbonate were added to the autoclave together with a small amount of water. After filling and stirring well, the mixture was reacted at 120 ° C for 2 hours with stirring. A dark brown brown dextrin, citric acid and ferric polynuclear complex solution were obtained. 500 ml of water was added to this solution, and it filtered and the water insoluble thing was removed. Water was added to the filtrate to make the total amount 1,000 ml, and then 640 ml of methyl alcohol was added to precipitate the product. After standing still for a while, the supernatant was discarded, and 350 ml of water was added to the precipitate obtained by centrifugation of the precipitate, and the solution was heated and dissolved in a boiling bath. Filtration was carried out after cooling, and water was added to the filtrate to make 600 ml. 600 ml of ethyl alcohol was added to this solution, and after standing still for a while, the supernatant was removed and centrifuged to obtain a cake-like purified dextrin citric acid ferric nucleus complex containing ethyl alcohol. The precipitate was dried under reduced pressure on calcium chloride at room temperature, and the dried product was pulverized to give 26.3 g of a dark brown powdery dextrin, citric acid, and ferric polynuclear complex. Iron content 43.5%, yield 81.4% (based on iron).

Example 2

New ferric polynucleating agent 78g (5.6g as iron), molecular weight 5,100 dextrin 19.5g, sodium citrate dihydrate 2.9g (0.01mol) and 1.2g anhydrous sodium carbonate with a small amount of water well in a glass simple autoclave It was made to react at 115 degreeC for 3 hours, stirring, and the thick solution of dextrin, citric acid, and ferric polynuclear complex was obtained. 200 ml of water was added, followed by filtration. Water was added to the filtrate to prepare a total amount of 400 ml. This was added to 285 ml of methyl alcohol to precipitate the complex and centrifuged. After separation, the mixture was heated and dissolved in 150 ml of water, cooled, and pulp was filtered precisely. Water was added to the filtrate to prepare a total amount of 230 ml. This was added 250 ml of ethyl alcohol to precipitate the complex and centrifuged. The obtained precipitate was dried under reduced pressure and dried over calcium chloride to obtain 10.4 g of dextrin, citric acid, and ferric polynuclear complex. Iron content 43.0%, yield 80.4% (based on iron).

Example 3

Instead of the sodium citrate dihydrate used in Example 2, 1.0 g (0.01 mol) of sodium glycolate was used, and 11.9 g of dextrin glycolic acid ferric nucleus complex was obtained in the same manner as in Example 2. Iron content 38.7, yield 82.1% (based on iron).

Example 4

Instead of the sodium citrate dihydrate of Example 2, 2.2 g (0.01 mol) of sodium gluconate was used, and 10.9 g of dextrin-gluconic acid-ferric polynuclear complex was obtained in the same manner as in Example 2. Iron content 42.8, yield 83.9%.

Example 5

Instead of sodium citrate dihydrate, 2.3 g (0.01 mol) of sodium tartrate dihydrate was used, and 11.0 g of dextrin-tartaric acid-ferric nucleus complex was obtained in the same manner as in Example 2. Iron content 42.1%, yield 82.1%.

Example 6

Instead of sodium citrate dihydrate, 1.8 g (0.01 mol) of sodium malate was used, and 10.8 g of dextrin, malic acid, and ferric polynuclear complex were obtained in the same manner as in Example 2. Iron content 39.3%, yield 75.0% (based on iron).

[Thermal Stability Test]

An aqueous solution with an iron concentration of 25 mg / ml, respectively, using the dextrin-citric acid-ferric polynuclear complex obtained in Example 2 and the dextrin-ferric polynuclear complex prepared in Example 2 without adding sodium citrate dihydrate. Was prepared, the ampoule was filled, this ampoule was heated at 100 degreeC, and the thermal stability test was done. The thermal stability was judged every 25 hours by the appearance and electrophoretic experiments of each sample.

As a result of the above test, in the dextrin-citric acid-ferric iron-nuclear complex sample, no abnormality was observed in its appearance even after 200 hours, and the electrophoretic state was good, but the dextrin ferric-nuclear complex sample without sodium citrate was added. It gelled after 25 hours, and the origin residue was also confirmed by electrophoresis. Similar experiments were carried out on the hydroxycarboxylic acid alkali salts that can be used in the present invention other than sodium citrate, and as a result, a slight improvement in thermal stability was observed over dextrin-ferric polynuclear complex without any sodium citrate alone. In addition, the thermal stability test performed below was performed on the conditions similar to the said method.

Example 7-11

Sodium citrate dihydrochloride having 0.01, 0.02, 0.10, 0.15, and 0.3 molar ratios relative to the iron component, together with 146 g of new ferric polynudeolate (0.2 moles as iron), 42 g of dextrin having a molecular weight of 5,600, and 2.3 g of anhydrous sodium carbonate, respectively. Reaction was carried out substantially in the same manner as in Example 1, and the yield, iron content and thermal stability of the obtained dextrin citric acid and ferric polynuclear complex were examined. The results are shown in Table 1.

TABLE 1

** The composite of Example 11 had undesirable characteristics such as high PH, osmotic pressure, low molecular weight, and the like compared with other dextrin citric acid and ferric polynuclear complexes.

Example 12

158 g of a new ferric nucleoolating agent (0.2 mol as iron), 32.1 g of dextrin having a molecular weight of 3,800, and 2.0 g of anhydrous sodium carbonate were heated with a small amount of water while heating in an oil bath. Heating to quiet reflux controls the temperature to about 102 ° C. When the reaction was continued for about 2 hours, the dark brown reaction solution was changed into a dark brown uniform solution to obtain a rich solution of the dextrin ferric polynuclear complex. 400 ml of water was added to the solution, diluted, cooled, and filtered to remove a small amount of unreacted unreacted material. Water was added to the obtained filtrate to make the total amount 800 ml, and then 520 ml of methyl alcohol was added to separate the precipitate. 600 ml of water was added to the obtained precipitate, and it was dissolved by heating and stirring in a boiling bath. After cooling, the solution was pulp filtered, the filtrate was added to water to prepare a total amount of 700 ml, and then 880 ml of methyl alcohol was added to precipitate the dextrin ferric nucleus complex.

After allowing to stand for a while, the upper liquid was removed, 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 the mixture was heated, bent to dissolve, and the methyl alcohol contained therein was evaporated off. After cooling, the mixture was filtered and water was added to prepare 400 ml. Part of this was taken and a quantitative test of iron. The yield was 89.6% based on iron.

The solution was charged to a simple autoclave, and 0.95 g of sodium citrate dihydrate was added thereto and reacted at 120 ° C for 2 hours. After cooling, the solution was filtered through a silk cloth, and water was added to the filtrate to make the whole amount 400 ml. By adding 290 ml of ethyl alcohol to this solution, precipitation of dextrin citric acid and ferric nucleus complex was obtained.

The dextrin citric acid and ferric nucleus complex containing the obtained ethyl alcohol water was dried under reduced pressure at room temperature in the presence of calcium chloride, and the dried product was pulverized to obtain 18.8 g of a dark brown brown dextrin, citric acid and ferric nucleus complex. Iron content 46.5%, yield 77.7% (based on iron).

Example 13

1,072 g (1.4 mol as iron) of a new ferric polynuclear oligomer, 280 g of dextrin having a molecular weight of 5,300, and 15.7 g of anhydrous sodium carbonate were added to a reaction vessel with reflux along with 120 ml of water, and reacted at 103 DEG C for 4 hours while being bent. The solution of the dextrin ferric polynuclear complex was obtained. 280 ml of water was added thereto, pulp filtered, and water was added to make 5,600 ml. 3,800 ml of methyl alcohol was added to the solution, and the complex was precipitated and centrifuged. 4,200 ml of water was added to this precipitate, it was heated and dissolved, and it was pulp filtered again after cooling, and water was added to the filtrate to make the total amount 5,000. 6300 ml of methyl alcohol was added to this solution to precipitate the complex. This precipitate was separated, heated and dissolved in 2,100 ml of water, and methyl alcohol was evaporated off. Water was added to this solution to obtain 2,800 ml of a solution of dextrin / ferric polynuclear complex. Yield 92.2% (based on iron).

23.7 g of dextrin, citrate, and ferric nucleus complex were obtained from the obtained dextrin ferric polynuclear complex solution 400 ml (10.3 g as iron) and 5.4 g of sodium citrate dihydrate in substantially the same manner as in Example 12. Iron content 39.6%, yield 83.9%.

Example 14

Dextrin glycolic acid ferric nucleus complex of 400 ml (10.3 g as iron) and 1.81 g of sodium glycolate obtained in Example 13 in substantially the same manner as in Example 12 23.8 g were obtained. Iron content 38.8%, yield 82.1%.

Example 15

Dextrin-gluconic acid-ferric polynuclear nucleus in 400 ml (10.3 g as iron) and 4.0 g of sodium gluconates in 400 ml (10.3 g as iron) and 4.0 g of dextrin ferric-nuclear complex liquid obtained by the said Example 13 24.0 g of the complex was obtained. Iron content 39.8%, yield 85.7%.

Example 16

Dextrin, succinic acid, ferric nucleus in 400 ml (10.3 g as iron) and 5.0 g of sodium succinate hexahydrate obtained in Example 13 in substantially the same manner as in Example 12 above. 24.5 g of the complex was obtained. Iron content 38.2%, yield 83.9% (based on iron).

Example 17

Dextrin-tartaric acid / ferric polynuclear complex 24.3 in 400 ml (10.3 g as iron) and 4.2 g of sodium tartrate dihydrate in 400 ml of dextrin-ferric polynuclear complex solution obtained in Example 13, in substantially the same manner as in Example 12. g was obtained. Iron content 38.2%, yield 83.0% (based on iron).

Example 18

24.2 g of dextrin, malic acid, and ferric multinuclear complex were obtained in 400 ml (10.3 g as iron) and 3.3 g of sodium malate in 400 ml of the dextrin / ferric iron multinuclear complex solution obtained in Example 13. Got it. Iron content 39.0%, yield 83.9%.

[Thermal Stability Test]

The thermal dexterity test was conducted on the intermediate dextrin-ferric polynuclear complex solution and the final product dextrin-citric acid-ferric polynuclear complex obtained in Example 13.

The dextrin ferric nucleus complex ampoule to which no citric acid was added was gelled at 25 hours when the heating was continued at 100 ° C, and the origin residue was also confirmed in the electrophoretic experiment. On the other hand, in the dextrin-citric acid-ferric polynuclear complex ampoule, even if heating was continued at 100 degreeC for 200 hours, no abnormality was recognized in the external appearance, and the electrophoresis test showed favorable electrophoresis.

As a result of the thermal stability test for the compound of Example 14-18, the thermal stability was slightly inferior to the dextrin-citric acid-ferric polynuclear complex, but the improvement of the thermal stability was superior to that of the dextrin-ferric polynuclear complex. .

Example 19-23

2,400 ml of dextrin and ferric polynuclear complex solution were obtained in the same manner as in Example 13 with 240 g of dextrin having a molecular weight of 5,000 and 907 g of a new ferric polynuclear oligomer (1.2 mol as iron) and 13.5 g of anhydrous sodium carbonate. 400 ml (10.25 g as iron) of this solution was reacted with a dextrin-citric acid-ferric polynuclear complex obtained by reacting sodium citrate dihydrate at a molar ratio of 0.01, 0.05, 0.10, 0.15, and 0.50 with respect to 1 mol of iron, respectively. Iron content, yield (based on iron) and thermal stability were investigated. The results are shown in Table 2.

TABLE 2

** The complex of Example 23 had undesirable characteristics such as higher PH and osmotic pressure and lower molecular weight than other dextrin-citric acid-ferric polynuclear complexes.

The structure of the complex of the present invention is a dextrin-hydroxycarboxylic acid-ferric polynuclear complex which can be stably dispersed in water by coordinating a hydrophilic dextrin and hydroxycarboxylic acid to a hydrophobic ferric polynuclear chain. Although it is estimated to form, it is a high molecular substance which contains some free dextrin and has a molecular weight distribution. About the composite of this invention, the result of the measurement experiments, such as the element composition, the residue composition, the infrared absorption spectrum, molecular weight, particle size distribution, electrophoresis, thin layer chromatography, intrinsic viscosity, polar lograph, and gel filtration, is shown below.

[a Elemental Composition]

[How to measure]

○ Iron content analysis: The sample was digested with hydrochloric acid, reduced with zinc powder to ferrous ion, and measured by redox method using ferric cerium ammonium sulfate as an indicator as a 0-phenanthroline reagent.

Sodium content analysis: measured using a flame photometer.

[result]

The measurement result of Table 3 was obtained by the said method.

TABLE 3

[b residue composition]

[How to measure]

○ Second iron polynuclear body residue (FeOOH): It was calculated | required by the said iron content.

○ Dextrin residue and free dextrin (C ₆ H ₁₀ O ₅ ): Each sample was hydrolyzed with hydrochloric acid, and all dextrin was quantified by Bertrand method as glucose, and converted into the amount of dextrin. The free dextrin content is that the complex portion of the complex of the present invention utilizes the property of loading, and co-precipitates the complex portion with an excess amount of the solution of the titration reagent methyl glycol chitosan with a positive charge, The colloid titration reagent polyvinyl sulfate solution having a load before loading was added to precipitate, and the free dextrin remaining in the supernatant was hydrolyzed with hydrochloric acid to make glucose, quantified by Bertran method, and converted to the amount of dextrin. The difference between the total dextrin content and the free dextrin content was taken as the dextrin residue content.

○ Residual citrate (C ₆ H ₅ O ₇ ): After hydrolyzing each sample with 6N hydrochloric acid, iron is lowered in the column filled with strong acidic exchange resin (Amberlite 1R-120) to interfere with the measurement. Was dissolved in ethanol water, transferred to a cell for conductivity titration, conductivity titration was carried out with 0.1N NaOH solution, and the amount of citric acid residues in the amount of 0.1N NaOH required for neutralization was removed. Saved.

[result]

The measurement results are shown in Table 4.

TABLE 4

[c infrared spectrum]

[How to measure]

It measured by the potassium embrittlement purification method using the infrared spectrophotometer (Hitachi Corporation EPI-G3 type | mold).

[result]

Infrared absorption spectra of the measured samples were in good agreement with each other. As a representative example, the infrared absorption spectrum and the respective absorption characteristics of the composite of Example 1 are shown in FIG.

TABLE 5

The results of the characteristics shown in FIG. 1 and Table 5 support the structure of the complex of the present invention, which is thought to coordinate coordination of dextrin and citric acid to the ferric polynuclear residue.

[d number average molecular weight]

[How to measure]

C=O의 관계식에서 수평균분자량

을 구했다. (단 R=84.7ℓ.7ℓ.㎝ 수두/deg.mol, T=측정계의 절대온도).For the composites of Examples 1 and 21, the relationship between the sample concentration (c) and the osmotic pressure (π) was obtained by a high-speed membrane osmometer.

Number average molecular weight in the relationship of C = O

Saved. (Where R = 84.7 l.7 l.cm head / deg.mol, T = absolute temperature of the measuring system).

In the composite of the present invention, the freedextrin moiety was 2.34 × 10 ⁵ by ultrafiltration.

[result]

The measurement results described above were obtained in Table 6.

TABLE 6

[e particle size distribution]

[How to measure]

6W / V% aqueous solution of each composite of Examples 1, 12, and 21 was filtered through an ultrafiltration membrane of each pore size, and the iron concentration of the filtrate was measured by colorimetry with 0-phenanthroline, The particle size distribution of each sample was calculated | required from iron component filtration rate.

[result]

The particle size in the aqueous solution of each sample has a distribution of about 0.03-0.1 μm, of which about 90% has a particle size in the range of 0.05-0.08 μ.

[f electrophoresis]

[How to measure]

A cellulose acetate film (5 × 6 cm) was immersed in each of the phosphate buffers (PH 5.7, 6.0, 7.0, 7.5, and 8.0), and the excess buffer solution was lightly inserted to remove the phosphate buffer solution of the same PH. A 6 W / V% sample solution was attached to the electrophoretic cell on the center line of the cellulose acetate film, energized for 40 minutes at a voltage of 90 V, and the movement of the brown spot of the sample was observed.

[result]

Each sample moved to the anode.

The operating distance is shown in Table 7.

TABLE 7

In addition, in the present experiment, if iron ions in the glass are present, it is thought to produce pale yellow iron phosphate (FePO ₄ ) by sodium phosphate and remain at the origin, but no corresponding spot was identified.

[g Thin Layer Chromatograph]

[How to measure]

About the composite of Example 1, a silica gel oil powder was spotted on a sintered thin plate (5 × 20 cm) and developed solvent (I) n-butanol, acetone, water (4: 5: 1), (II) Ethyl acetate, glacial acetic acid, water (3: 1: 1), (III) ethanol, water, and ammonia water (25: 3: 4) were each developed and then colored with a mixture of potassium ferrocyanide solution, potassium dichromate and sulfuric acid. And Rf was measured.

[result]

Since the composite of the present invention is a high molecular compound, the spot did not move from the origin. In addition, free citric acid or sodium citrate and free glucose were not detected.

[h extreme viscosity]

[How to measure]

를 구했다.As each sample, sample solutions of various concentrations were prepared. The specific gravity of the solution and water was measured at 30 ° C. ± 0.1 ° C. by the method of Sprengel-Ostwald Picnometang, and the dripping time was measured at 30 ° C. , Extreme viscosity by extrapolation

Saved.

(ηsp: specific viscosity, C: concentration of sample).

[result]

The intrinsic viscosity η of the sample is shown in Table 8.

TABLE 8

[i Polarography]

[How to measure]

5 ml of a supporting salt solution (Wolfol buffer PH 3.50, 4.50, 5.45) were taken into an electrolytic bottle by the method described in JIS-KO III, and 20 µl of sample solution (60.0 mg / ml, Ca.25 mgFe / ml) or 5 µl of cerium ammonium sulfate solution (25 mg Fe / ml) was added as ferric ion, and the mixture was placed in a 25 ° C. thermostatic bath and passed through nitrogen for about 15 minutes to remove dissolved oxygen, thereby preparing an electrolyte solution.

및 파고(i)를 측정했다.This electrolytic solution was subjected to half-wave potential in the polarography obtained by manipulating a DC polarography based on a mercury column 60 cm, a current sensitivity of 30 mA / mm, a damping 5, and a saturated calorie electrode standard (vsSCE).

And crest (i) were measured.

[result]

The measurement values of the half wave potential and wave height and the polarogram of the composite and ferric ion in Example 1 are shown in Table 9 and FIG. 2, respectively.

TABLE 9

In this experiment, it is thought that the half wave potential of the composite of the present invention shifts negatively to the half wave potential of ferric ions at any pH, and thus the composite of the present invention forms a stable composite. Digging is less than about one quarter of the ferric ion compared to the unit iron concentration in the electrolytic solution, which is thought to be due to the formation of a complex with a large molecular weight. Under this condition, no wave was observed in the half-wave potential corresponding to the first wave of ferric ion in the polarogram of the sample, and the presence of ferric ion was not confirmed.

[j gel filtration]

Gels were subjected to the following conditions for the complexes of Examples 1 and 21, and iron and dextrin were quantified for each elution fraction.

[Condition]

Sample adhesion amount 6.00 mg, gelseFollowers 6B, column 40 × 2.5 cm

0.05 m buffer, citric acid buffer (PH6.0), fraction 5 ml.

[result]

Each measurement result is shown in FIG. 3A and FIG. 3B.

[k stability test]

In the composite of Example 1, the amount of the sample containing 5 g as iron was measured, 80 ml of water was added thereto, heated in a boiling water bath, and cold water was added thereto to make 100 ml. This solution was used as a thick sample solution (50 mg Fe / ml).

10 ml of the concentrated sample solution was accurately weighed, and water was added to make 20 ml, and this solution was used as the sample solution I.

10 ml of the concentrated sample solution was accurately weighed, and 0.1 g, 0.2 g, 0.4 g and 0.8 g of dry dextrin were added and dissolved, and 20 ml of water was added to make the sample solutions II, III, IV and V. Table 10 shows the sample solution dextrin concentration and iron content in the preparation.

TABLE 10

Each sample solution was sealed in an ampoule, heated in a boiling water bath for 0 hours, 1 hour, 3 hours, 6 hours, 10 hours, 25 hours, and 50 hours, and the amount of free iron was measured. The results are shown in FIG.

[l Dextrin, Citric Acid, Ferric Iron (Ultrafiltration)]

The aqueous phase, the iron content, the dextrin content, the infrared absorption spectrum, and the gel filtration state of the sample obtained by ultrafiltration were examined for the aqueous solution of the composite of Example 12. The results are shown in Table 11.

Infrared absorption spectra and gel filtration curves are shown in FIGS. 5 and 6, respectively.

TABLE 11

Claims (1)

Reacting the ferric core with at least one of dextrin, citric acid, gluconic acid, tartaric acid, malic acid and succinic acid selected from succinic acid or alkali salts thereof in the presence of alkali carbonate at a temperature in the range of 100 ° -130 ° C. A method for producing a dextrin, hydroxycarboxylic acid, and ferric polynuclear complex.

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