JPH0696586B2 - Hexose-ferric acid ferrous salt, method for producing the same, and iron supplier containing the same - Google Patents

Description

Description: TECHNICAL FIELD The present invention relates to a novel ferrous hexose phosphate, more specifically, a ferrous hexose phosphate, a method for producing the same, and an iron supplier containing the same. Regarding

[Conventional technology and its problems]

Iron is an essential metal that is involved in the transport of oxygen and the redox mechanism in the living body and is necessary for sustaining life. This iron deficiency is known to show symptoms such as anorexia, indefinite complaints, anemia, fatigue, headache, shortness of breath on exertion, and pallor of the face.The causes of iron deficiency are insufficient iron intake and iron loss. Increase, demand for iron, and malabsorption.

As a treatment for such iron deficiency, it is known that administration of an iron supplier by oral and intravenous injection is effective,
Since iron is absorbed from the duodenum in the form of divalent ferrous ions, reduced iron and ferrous ions are mainly used as iron supplying agents. Specifically, reduced iron, ferrous sulfate, ferrous succinate, ferrous lactate, etc. are known. Among them, ferrous sulfate is inexpensive and effective. It is used. However, there has been a problem in the conventionally known iron supplying agent that divalent ferrous ions are oxidized by oxygen in the air into trivalent ferric ions that are not absorbed in the duodenum.

Therefore, there has been a demand for an iron supplying agent that is highly safe and is not easily oxidized.

[Means for solving problems]

As a result of intensive studies on the iron salt of a compound existing in the body, the present inventors have found that the novel compound, ferrous hexose phosphate, is an alkaline earth metal hexose phosphate and a neutral or acidic ferrous iron. The present invention has been completed by finding that they are synthesized by the reaction of salts and that this ferrous hexose phosphate is useful as an iron supplier.

That is, the present invention provides a novel compound, ferrous hexose phosphate, a method for producing the same, and an iron supplier containing the same.

Conventionally, as a metal salt of hexose phosphate, sodium, potassium, calcium, barium, magnesium and the like are known. For example, as a method for producing glucose-1-phosphate calcium salt, glucose-1-phosphate and calcium hydroxide are used. Method of reacting (Japanese Patent Publication Sho 43-10620)
Etc. are known. The present inventors tried a method of synthesizing a ferrous hexose phosphate by reacting hexose phosphate with ferrous hydroxide, but it was difficult to synthesize with good purity. It is considered that this is because the divalent ferrous ion is relatively stable to oxidation by oxygen in acidic and neutral, but unstable in alkaline.

Therefore, the present inventors, by reacting a neutral alkaline earth metal salt and a neutral or acidic ferrous salt, that hexose phosphate ferrous salt can be produced while suppressing oxidation, and If the iron ion of ferrous ion is selected so that the salt by-produced in the reaction is hardly soluble in water, the ferrous hexose phosphate can be easily separated from the inorganic salt by-produced. It was found that the synthesized ferrous hexose phosphate was useful as an iron supplier.

The hexose ferrous phosphate according to the present invention is a ferrous salt of a phosphoric acid ester in which one or more hydrogen groups of hexose are substituted with a phosphate group, and examples thereof include glucose-1-phosphate and glucose- 6-phosphate, glucose-1,6-diphosphate, fructose-6-phosphate, fructose-1,
Examples thereof include ferrous salts such as 6-diphosphoric acid, and among them, as the iron supplier, glucose-1-phosphate ferrous salt and glucose-6-phosphate ferrous salt are particularly preferable from the viewpoint of cost. preferable.

Examples of the alkaline earth metal of the starting material, alkaline earth metal salt of hexose phosphate, include barium and calcium, with barium being preferred. This alkaline earth metal hexose phosphate is obtained by neutralizing hexose phosphoric acid with an alkaline earth metal hydroxide. Normal
It can be obtained by adding dropwise 1 to 20% of hexose phosphoric acid to an aqueous alkaline earth metal hydroxide solution of 0.5 to 10% by weight (hereinafter simply referred to as "%") and mixing. The reaction temperature is −10 to 70 ° C.,
It is preferably 10 to 40 ° C.

Examples of the neutral or acidic ferrous salt that is another starting material include ferrous sulfate and ferrous carbonate, with ferrous sulfate being preferred. The molar ratio of the ferrous salt used for the reaction to the alkaline earth metal hexose phosphate is 1 mol or more, preferably 1 to 2 mol, based on the phosphoric acid group.

The solvent for reacting the alkaline earth metal hexose phosphate with the neutral or acidic ferrous salt is preferably water, but may be coexistent as long as it is a water-soluble solvent that does not interfere with the reaction. Usually, the ferrous hexose phosphate is obtained by adding 1-50% aqueous ferrous salt solution dropwise to an aqueous solution of 0.5-10% alkaline earth metal hexose phosphate and mixing. Reaction temperature is -10 ~
The temperature is 70 ° C, preferably 10 to 40 ° C.

The inorganic salt produced as a by-product in the above reaction is preferably barium sulfate, barium carbonate, calcium carbonate or the like, which is poorly soluble in water, and these can be easily removed by mistake. From the aqueous solution of ferrous hexose phosphate after removing the inorganic salt, hexose powder in powder form can be obtained by freeze-drying or by adding a water-soluble solvent and reprecipitating and then over-drying the precipitate. The ferrous acid salt can be isolated.

〔The invention's effect〕

Hexose ferrous phosphate is useful as an iron supplier and can be administered in the form of additives to foods, tablets, capsules, drinks, etc., and is effective in improving and preventing anemia. To be It should be noted that the present invention is not limited to the administration form of the ferrous hexose phosphate.

〔Example〕

 Next, the present invention will be described in more detail with reference to examples.

Example _{1 Ba (OH) 2 · 8H} 2 O12.1g a (0.0385 mol) was dissolved in water of 900 ml, 4 wt% glucose-6-phosphate aqueous solution
Add 250 g (0.0385 mol) and stir at 25 ° C for 30 minutes to neutralize. After substituting this aqueous solution with nitrogen, salt exchange is performed in a nitriding atmosphere. 10.7 g of ferrous sulfate ・ 7H ₂ O in this aqueous solution
Add a solution of (0.0386 mol) in 100 ml of water and add it to 25 ℃.
After stirring for 30 minutes, a white precipitate of BaSO ₄ is produced. A white precipitate is removed by centrifugation, and 2000 ml of ethanol is added to the obtained transparent green-blue aqueous solution to precipitate a pale green solid. Under a nitrogen atmosphere, the precipitate was filtered, washed with ethanol, and then dried under reduced pressure to obtain 9.9 g of glucose-1-phosphate ferrous salt · 2H ₂ O. The analysis results of elemental analysis, NMR and IR are as follows.

Elemental analysis (as molecular formula _{C 6 H 15 O 11 PFe)} : Fe P C H analysis 16.0 8.7 20.2 4.7 theoretical 16.0 8.9 20.6 4.3 H-NMR ( 60MHz, D 2 O solvent): δ 3.3~3.5 b, 2H 3.7 -4.0 b, 4H 4.5-4.6 b, 1H Infrared absorption spectrum (KBr method): Wave number (cm ^-1 ) Intensity attribution 3350 S O-H stretch 2930 M C-H stretch 2840 M C-H stretch 1660 M 1150 S 1090 S 980 S 950 S 860 M The ferrous ion contained in this product was determined by the KMnO ₄ redox method to be 14.6%.

Example _{2 Ba (OH) 2 · 8H} 2 O12.1g a (0.0385 mol) was dissolved in water of 900 ml, 4 wt% glucose-6-phosphate aqueous solution
Add 250 g (0.0385 mol) and stir at 25 ° C for 30 minutes to neutralize. After substituting this aqueous solution with nitrogen, salt exchange is performed in a nitriding atmosphere. 10.7 g of ferrous sulfate ・ 7H ₂ O in this aqueous solution
Add a solution of (0.0385 mol) in 100 ml of water and add it to 25 ℃.
After stirring for 30 minutes, a white precipitate of BaSO ₄ is produced. A white precipitate is removed by centrifugation, and 2000 ml of ethanol is added to the obtained transparent green-blue aqueous solution to precipitate a pale green solid. Under a nitrogen atmosphere, the precipitate was filtered, washed with ethanol, and then dried under reduced pressure to obtain glucose-6-ferrous phosphate (1H) .2H ₂ O (10.1 g). The elemental analysis results are as follows.

Elemental analysis (as molecular formula C ₆ H ₁₅ O ₁₁ PFe): Fe P C H analysis value 16.3 9.0 21.2 4.1 Theoretical value 16.0 8.9 20.6 4.3 Quantitative analysis of ferrous iron contained in this product by KMnO ₄ redox method gave 14.2 It was in%.

Example 3 23.2 g (0.0735 mol) of Ba (OH) ₂ .8H ₂ O was dissolved in 1700 ml of water, and 250 g (0.0368 mol) of a 5 wt% glucose-1,6-diphosphoric acid aqueous solution was added to this solution at 25 ° C. Stir for 30 minutes to neutralize. After substituting this aqueous solution with nitrogen, salt exchange is performed in a nitriding atmosphere. In this aqueous solution, ferrous sulfate ・ 7H ₂ O 20.4
Add a solution of g (0.0735 mol) in 200 ml of water and add it to 25 ℃.
After stirring for 30 minutes, a white precipitate of BaSO ₄ is produced. The white precipitate is removed by centrifugation, and 4000 ml of ethanol is added to the obtained transparent green-blue aqueous solution to precipitate a pale green solid. Under a nitrogen atmosphere, the precipitate is filtered, washed with ethanol, and then dried under reduced pressure to give glucose-1,6-diphosphorous ferrous salt.3H ₂ O (12.4 g). The elemental analysis results are as follows.

Elemental analysis (as molecular formula C ₆ H ₁₆ O ₁₅ P ₂ Fe ₂ ): Fe P CH analysis value 21.8 11.9 13.8 3.0 theoretical value 22.3 12.4 14.3 3.2 Ferrous iron contained in this product by KMnO ₄ redox method It was 17.2% when quantified.

Example _{4 Ba (OH) 2 · 8H} 2 O12.1g a (0.0385 mol) was dissolved in water of 900 ml, 4 wt% glucose-6-phosphate aqueous solution
Add 250 g (0.0385 mol) and stir at 25 ° C for 30 minutes to neutralize. After substituting this aqueous solution with nitrogen, salt exchange is performed in a nitriding atmosphere. 10.7 g of ferrous sulfate ・ 7H ₂ O in this aqueous solution
Add a solution of (0.0385 mol) in 100 ml of water and add it to 25 ℃.
After stirring for 30 minutes, a white precipitate of BaSO ₄ is produced. A white precipitate is removed by centrifugation, and 2000 ml of ethanol is added to the obtained transparent green-blue aqueous solution to precipitate a pale green solid. Under a nitrogen atmosphere, the precipitate was filtered, washed with ethanol, and then dried under reduced pressure to give fructose-6-ferrous phosphate ferrous salt 2H ₂ O (9.8 g). The elemental analysis results are as follows.

Elemental analysis (as molecular formula C ₆ H ₁₅ O ₁₁ PFe): Fe P C H analysis value 15.6 8.5 19.4 4.1 Theoretical value 16.0 8.9 20.6 4.3 Quantitative analysis of ferrous iron contained in this product by KMnO ₄ redox method gives 13.3 It was in%.

Example _{5 Ba (OH) 2 · 8H} 2 O23.2g a (0.0735 mol) was dissolved in water of 1700 ml, this solution 5 wt% fructose-1,6-diphosphate aqueous solution 250 g (0.0368 mol) was added 25 ° C. Stir for 30 minutes to neutralize. After substituting this aqueous solution with nitrogen, salt exchange is performed in a nitriding atmosphere. In this aqueous solution, ferrous sulfate ・ 7H ₂ O 2
Add a solution of 0.4 g (0.0735 mol) in 200 ml of water and add 2
After stirring for 30 minutes at 5 ° C, a white precipitate of BaSO ₄ is produced.
The white precipitate is removed by centrifugation, and 4000 ml of ethanol is added to the obtained transparent green-blue aqueous solution to precipitate a pale green solid. Under a nitrogen atmosphere, the precipitate was filtered, washed with ethanol, and dried under reduced pressure to give fructose-1,6-diphosphorous ferrous salt.3H ₂ O (12.1 g). The elemental analysis results are as follows.

Elemental analysis (as molecular formula C ₆ H ₁₆ O ₁₅ P ₂ Fe ₂ ): Fe P CH analysis value 21.8 11.9 13.8 3.0 theoretical value 22.3 12.4 14.3 3.2 Ferrous iron contained in this product by KMnO ₄ redox method When quantified, it was 18.5%.

Example 6 SD rats (male, 6 weeks old, weight around 350 g, 10 animals per group) were bred for 10 days on a powdered feed with or without the addition of ferrous glucose-1-phosphate, and then the same feed. About 1/200 of body weight (about 1.75 ml) of blood was collected from the jugular vein once a day for 20 days while continuing to be kept in the laboratory
The erythrocyte count, hematocrit level, and hemoglobin level were measured at any time. The results are shown in FIGS.

The feed composition used in this experiment is as follows.

As is clear from FIGS. 1 to 3, glucose-1-
The addition of ferrous phosphate showed a preventive effect on anemia.

Example 7 Tablets: Lactose 80% Corn starch 4 Crystalline cellulose 10 Carboxymethylcellulose 3.5 Glucose-1-phosphate ferrous salt 2.5 10 women aged 26-35 with an anemia of hematocrit value of 30-35% of the above composition. When tablets (0.5 g per tablet) were taken 4 tablets a day for 1 month, all hematocrit values after 1 month became 35-40%, and the anemia state could be greatly improved.

Example 8 Capsule: Medium chain fatty acid triglyceride 89.5% Glucose-1-phosphate ferrous salt 10 Natural tocopherol 0.5 The above components were well mixed and filled to 300 mg with a capsule filling machine to prepare a capsule. 3 capsules per day
Take to a grain.

Example 9 Drinking agent: Apple cider vinegar 1.0% Citric acid 0.3 Sodium citrate 0.3 Granyu sugar 12.0 Honey 3.0 Ethanol 1.0 Glucose-1-phosphate ferrous salt 1.0 Drink flavor 0.3 Mineral water 81.1 The above formulation was mixed and dissolved. , A uniform drink was obtained.

Test Example 1 Glucose-1-phosphate ferrous salt · 2H ₂ O (Example 1),
A 1% aqueous solution of glucose-6-phosphate ferrous salt · 2H ₂ O (Example 2) and ferrous sulfate · 7H ₂ O was prepared. The pH of a 1% aqueous solution of glucose-1-phosphate ferrous salt · 2H ₂ O and glucose-6-phosphate ferrous salt · 2H ₂ O is 6.8,
It was 6.9. 1% aqueous solution of ferrous sulfate ・ 7H ₂ O is NaO
The pH was adjusted to 6.8 with a H aqueous solution. 50 ml of each sample was placed in a closed container having a volume of 100 ml and left at 25 ° C. Table 1 shows the appearance of the aqueous solution and the change with time of the content of ferrous ions. The ferrous ion was quantified by the KMnO ₄ redox method.

As is clear from this result, ferrose hexose phosphate is less susceptible to air oxidation in an aqueous solution having a neutral pH.

[Brief description of drawings]

FIGS. 1 to 3 are drawings showing the daily changes of blood components when the rat is put into an experimental anemia state, in which FIG. 1 is the number of red blood cells, FIG. 2 is the hematocrit value,
FIG. 3 shows the daily change in hemoglobin value.

 ─────────────────────────────────────────────────── --- Continuation of the front page (72) Inventor Kenji Hara 1022-53 Himurocho, Utsunomiya City, Tochigi Prefecture

Claims (3)

[Claims] 1. A ferrous hexose phosphate salt. 2. An alkaline earth metal salt of hexose phosphate,
A process for producing a ferrous hexose phosphate, which comprises reacting a neutral or acidic ferrous salt. 3. An iron supply agent containing a ferrous hexose phosphate as an active ingredient.