Iron supplement

Abstract

[Problem] To provide an iron supplement free from bad taste (metallic taste), which is a drawback of iron agents, and free from side effects such as nausea, vomiting, and constipation, and that has excellent storage stability (oxidation resistance). [Solution] The present invention provides an iron supplement containing a magnesium hydroxide-based solid solution represented by formula (1): (Mg)1-x-y(Fe2+)x(M2+)y(OH)2-nz(An-)z. (In the formula, M2+ represents at least one selected from Zn, Mn, Cu, and Co, An- represents at least one of organic acid ion moieties, x, y and z are in the respective ranges: 0 < x < 0.3, preferably 0.01 ≤ x ≤ 0.2, 0 ≤ y < 0.2, preferably 0 ≤ y ≤ 0.1, and 0 ≤ z < 0.1, preferably 0.001 ≤ z ≤ 0.005, and n represents zero or an integer in the range of 0-4.)

Description

iron supplements

[0001] The present invention relates to a novel iron supplement. More specifically, the present invention relates to an iron supplement containing a magnesium hydroxide solid solution in which part of the Mg is replaced with divalent iron, and more particularly to an iron supplement that is tasteless, has no side effects, and is resistant to oxidation by trivalent iron, exhibiting excellent storage stability.

[0002] Iron deficiency anemia is anemia caused by decreased hemoglobin production due to iron deficiency caused by factors such as menstrual bleeding, postpartum bleeding, gastrointestinal bleeding, and malabsorption from the gastrointestinal tract. Iron deficiency anemia is caused by a lack of iron, one of the substances involved in red blood cell production, and causes symptoms such as headache, dizziness, palpitations, shortness of breath, and / or fatigue. It is estimated that approximately 4.9 million patients in Japan were diagnosed with iron deficiency anemia in 2018. Red blood cells contain hemoglobin, which binds with oxygen to transport oxygen throughout the body. Hemoglobin is produced when divalent iron ions bind with proteins through the action of vitamins and other factors.

[0003] Japanese Patent Laid-Open No. 57-156419 Japanese Patent Laid-Open No. 60-6619 Japanese Patent Laid-Open No. 2005-89237

[0004] Iron supplements improve the symptoms of anemia by replenishing iron in the body, promoting hemoglobin synthesis and increasing blood cells. Iron is absorbed in the duodenum in the form of divalent ferrous ions. There are two types of iron supplements: oral iron supplements are the first choice, and intravenous iron supplements are used only when there is a large amount of iron loss due to heavy bleeding, etc., and oral iron supplements are insufficient to replenish, or when oral iron supplements cannot be taken due to side effects or malabsorption.

[0005] Existing oral iron preparations are divided into two types: those containing divalent iron and those containing trivalent iron. Divalent iron components include ferrous fumarate, ferrous citrate tetrasodium, and ferrous sulfate, while trivalent iron components include ferric citrate hydrate and ferric pyrophosphate. Divalent iron components are easily absorbed because they dissolve to some extent in water, but trivalent iron components are poorly absorbed because they are poorly soluble in water.

[0006] Conventional iron supplements have a distinctive metallic taste, which makes them unpalatable. The metallic taste is caused by iron ions dissolved in water. Furthermore, the irritation caused by the iron ions can cause side effects, primarily in the digestive tract, such as nausea, vomiting, upper abdominal discomfort, stomach and abdominal pain, diarrhea, loss of appetite, constipation, heartburn, and abdominal bloating.

[0007] Trivalent iron is less soluble in water and causes less gastric mucosal irritation than divalent iron, but the level of side effects is still high. The number of days of oral administration required to treat anemia is more than one month to achieve normal hemoglobin levels and more than two months to resolve iron storage deficiency. However, due to the above-mentioned side effects, many people are unable to take conventional oral iron supplements for more than one month.

[0008] The present inventors have found that the following formula (2) (Fe ２＋ ,Mg ２＋ ) ｘ (Al ３＋ ,Fe ３＋ ) ２ (OH) ２ｘ＋６－ｎｚ (A ｎ－ ) ｚ ・mH ２ O (2) (wherein, A ｎ－ represents an n-valent anion, and Mg ２＋ and Fe ３＋ are respectively 0≦Mg ２＋ <x, 0≦Fe ３＋ <2, and x, z, and m are positive numbers satisfying the following conditions: 1≦x<20, 0<z<3, 0≦m<20), and x, z, and m are positive numbers satisfying the following conditions: 1≦x<20, 0<z<3, 0≦m<20). A hydrothermal treatment product of hydrotalcites expressed as a compound represented by the formula (1) in an aqueous medium at about 100 to about 200°C has been proposed (Patent Documents 1 and 2). The compound contained in this iron deficiency treatment is insoluble in water, so it is tasteless and does not have an unpleasant iron taste. It also eliminates the side effects of conventional iron supplements, except for constipation. However, this compound is extremely susceptible to oxidation. When this compound is oxidized to trivalent iron hydroxide, it becomes poorly soluble in acid, resulting in poor iron absorption.

[0009] Furthermore, the present inventors have found that the following formula (3) (M １ ２＋ )１－ｘ (M ２ ２＋ ) ｘ (OH) ２ (3) (wherein, M １ ２＋ represents Ca and / or Mg, and M ２ ２＋ A mineral supplement for plants has been proposed, which contains as an active ingredient a divalent metal hydroxide solid solution represented by the formula (where x represents at least one of the essential minerals Mn, Fe, Cu, and Zn, and x represents a positive number satisfying the range of 0<x<0.4) (Patent Document 3). However, Patent Document 3 does not describe or suggest an iron supplement for use in animals such as humans.

[0010] To resolve iron deficiency anemia, for example, oral iron supplements must be taken daily for approximately two months or more. However, existing oral iron supplements have side effects and a distinctive, unpleasant metallic taste, leading many people to abandon the use of these supplements midway. Discontinuing the use of these supplements midway does not cure anemia. The prevalence of anemia is high, at approximately 10% for men and 13% for women (according to the 2019 National Health Survey Report compiled by the Ministry of Health, Labor and Welfare). Therefore, in one aspect, the present invention aims to provide a novel iron supplement that is easy to take, has no metallic taste, and is easy to administer, making it easier to achieve continuous administration over long periods of time. In another aspect, the present invention aims to provide a novel iron supplement that has reduced or no side effects, has no metallic taste, and is easy to administer, making it easier to achieve continuous administration for, for example, two months or more.

[0011] As a result of intensive research to solve the above problems, the present inventors have found that a compound represented by the following formula (1) (Mg) １－ｘ－ｙ (Fe ２＋ ) ｘ (M ２＋ ) ｙ (OH) ２－ｎｚ (A ｎ－ ) ｚ (1) (wherein, M ２＋represents at least one essential mineral selected from Zn, Mn, Cu, and Co, A represents at least one organic acid ion moiety and / or organic ligand, x, y, and z are within the following ranges: 0<x<0.3, 0≦y<0.2, 0≦z<0.1, and n represents zero or an integer ranging from 0 to 4.

[0012] The basic concept of the present invention is as follows. To improve the absorbability of iron, it is desirable that the iron be a divalent iron compound. Furthermore, to suppress irritation of the gastrointestinal mucosa by divalent iron ions and reduce or eliminate side effects, the iron must be insoluble in water. If the iron is insoluble in water, it will be tasteless and will not have a metallic taste. Furthermore, even if the iron is insoluble in water, if it is easily soluble in acids such as gastric acid, the iron will be well absorbed.

[0013] The present inventors have focused on hydrotalcites as a material that satisfies the above conditions. Specifically, the present inventors have focused on hydrotalcites, which are water-insoluble hydroxides of divalent iron: Fe(OH) ２ The present inventors have investigated the typical composition of Fe, ４ Al ２ (OH) １２ CO ３ ・3H ２ It was discovered that Fe(2+)-Al hydrotalcites can be gradually dissolved by gastric acid and release divalent iron ions (Patent Document 1). These Fe(2+)-Al hydrotalcites are tasteless and have no metallic taste, making them easy to take, and can eliminate the side effects of existing iron preparations other than constipation. However, a drawback of these hydrotalcites other than constipation is that they are extremely susceptible to oxidation, and can be oxidized to Fe(OH) ３ It was found that this part becomes insoluble in acid, which means that iron absorption is reduced, which also poses storage stability problems.

[0014] After extensive research, the inventors have discovered a solution to the problems associated with the Fe(2+)-Al hydrotalcites. First, aluminum hydroxide, which is used as an antacid, has the side effect of causing constipation, so removing the Al portion of the Fe(2+)-Al hydrotalcites can prevent constipation. On the other hand, magnesium hydroxide is also used as a laxative. Therefore, the side effect of constipation can be addressed by using Mg(OH), which is also a laxative. ２ The inclusion of Fe(OH) can counteract constipation. ２ The larger the primary particles (crystallites) are, and the more the particles are surrounded by a non-oxidizable metal such as Mg, the better the oxidation resistance of the alloy.

[0015] Based on the above considerations, we have arrived at the iron preparation of the present invention, whose main component is a magnesium hydroxide-based substituted solid solution in which part of the Mg in magnesium hydroxide, which has a simpler crystal structure than hydrotalcites, is substituted with divalent Fe(2+). This solid solution also includes solid solutions in which part of the hydroxyl groups (OH) are substituted with organic acid ions and / or organic ligands. The organic ligands contribute to the growth of primary particles. Because magnesium hydroxide has a simpler structure than hydrotalcites, it is stable and crystals grow easily.

[0016] The drawback of Fe(2+)-Al-based hydrotalcites, which are extremely susceptible to oxidation, can be improved by significantly increasing the size of the primary particles. Hydrothermal treatment is effective for growing primary particles, and the higher the applicable temperature, the more effective it is. The maximum temperature at which the above-mentioned hydrotalcites begin to decompose is approximately 170°C, while that for magnesium hydroxide-based solid solutions is approximately 300°C. Therefore, with the magnesium hydroxide-based solid solution of the present invention, the hydrothermal treatment temperature can be higher than that of the above-mentioned hydrotalcites, and the primary particles (crystallites) can be made larger accordingly. The maximum primary particle size obtained by hydrothermal treatment is 0.5 μm for Fe(2+)-Al-based hydrotalcites, while it is 5 μm for magnesium hydroxide-based solid solutions. The present invention provides the following. [Item 1] A magnesium hydroxide-based solid solution represented by the following formula (1): (Mg) １－ｘ－ｙ (Fe ２＋ ) ｘ (M ２＋ ) ｙ (OH)２－ｎｚ (A ｎ－ ) ｚ (1) (wherein, M ２＋ An iron supplement containing a magnesium hydroxide-based solid solution represented by the formula (1): (where x represents at least one element selected from Zn, Mn, Cu, and Co; A represents at least one organic acid ion moiety and / or organic ligand; x, y, and z each fall within the following ranges: 0<x<0.3, preferably 0.01≦x≦0.2, particularly preferably 0.05≦x≦0.15, 0≦y<0.2, preferably 0≦y≦0.1, particularly preferably 0≦y≦0.05, 0≦z<0.1, preferably 0.001≦z≦0.05, particularly preferably 0.002≦z≦0.02; and n represents an integer of 0 to 4. [Item 2] The iron supplement according to Item 1, wherein y is 0 in formula (1). [Item 3] The iron supplement according to any one of Items 1 and 2, wherein x is 0.01≦x≦0.2 in formula (1). [Item 4] The iron supplement according to any one of Items 1 to 3, further comprising, in addition to the solid solution, an organic acid in an amount equal to or less than the amount required to neutralize the solid solution. [Item 5] The iron supplement according to any one of Items 1 to 4, wherein the organic acid is at least one selected from the group consisting of malic acid, tartaric acid, citric acid, and ascorbic acid. [Item 6] In the formula (1), A ｎ－ [Item 7] The iron supplement according to any one of Items 1 to 5, wherein is an organic ligand, and the organic ligand is glycolic acid and / or lactic acid. [Item 7] The iron supplement according to any one of Items 1 to 6, wherein z is z=0. [Item 8] The iron supplement according to any one of Items 1 to 7, which is an agent for treating iron deficiency. [Item 9] An iron supplement represented by the following formula (1): (Mg) １－ｘ－ｙ (Fe ２＋ ) ｘ (M ２＋ ) ｙ (OH) ２－ｎｚ (A ｎ－ ) ｚ (1) (wherein, M ２＋represents at least one selected from Zn, Mn, Cu, and Co; A represents at least one organic acid moiety and / or organic ligand; x, y, and z are each within the following ranges: 0<x<0.3, preferably 0.01≦x≦0.2, particularly preferably 0.05≦x≦0.15, 0≦y<0.2, preferably 0≦y≦0.1, particularly preferably 0≦y≦0.05, 0≦z<0.1, preferably 0.001≦z≦0.05, particularly preferably 0.002≦z≦0.02; and n represents zero or an integer ranging from 0 to 4. [Item 10] A method for producing the iron supplement according to any one of Items 1 to 9, comprising: preparing a mixed aqueous solution of a water-soluble Mg salt and a divalent Fe salt, or (B) a water-soluble Mg salt, a divalent iron salt, and at least one divalent metal salt selected from a divalent Zn salt, a Mn salt, a Cu salt, and a Co salt; adding an alkali in an amount equal to or less than the total equivalent of the water-soluble divalent metal, preferably 0.7 to 0.9 equivalents, to the mixed aqueous solution while stirring, and conducting a coprecipitation reaction in a non-oxidizing atmosphere to obtain a coprecipitation reaction product; and hydrothermally treating the coprecipitation reaction product at 100°C or higher, preferably 150 to 250°C, for 1 hour or more, preferably 2 to 10 hours, to obtain a magnesium hydroxide-based solid solution; and preparing an iron supplement using the magnesium hydroxide-based solid solution. [Item 11] A method for producing an iron supplement according to Item 10, comprising adding an organic acid and / or an organic ligand in an amount of at least 10 mol% relative to the total moles of the water-soluble divalent metal to the mixed aqueous solution before adding the alkali to the mixed aqueous solution. [Item 12] The method according to Item 10 or 11, further comprising subjecting the magnesium hydroxide-based solid solution obtained by the hydrothermal treatment to one or more of a filtration treatment, a water washing treatment, and a drying treatment. [Item 13] The method according to Item 12, wherein the one or more treatments are performed in a non-oxidizing atmosphere.

[0017] The iron supplement of the present invention, particularly the solid solution contained therein, has at least one of the following effects: (1) While conventional iron supplements are colored green, yellow-green, or brown, the iron supplement of the present invention is white or nearly white, giving it a pleasant appearance. (2) The iron supplement of the present invention is tasteless and therefore easy to take. On the other hand, conventional iron supplements have a metallic taste and are difficult to take. (3) The iron supplement of the present invention has no or reduced side effects. Conventional iron supplements have side effects, mainly affecting the digestive tract, such as nausea, vomiting, abdominal pain, diarrhea, and constipation. (4) The iron supplement of the present invention enables long-term administration, such as the 1-2 months required for complete cure of anemia. This is particularly because the iron supplement has no or reduced side effects. (5) The iron supplement of the present invention can be used, for example, as an agent for treating iron deficiency (iron supplement) or as a highly absorbable multimineral supplement. By further dissolving at least one essential mineral selected from Zn, Mn, Cu and Co other than Mg and Fe in the solid solution contained in the iron supplement in magnesium hydroxide, a highly absorbable multi-mineral supplement can be provided.

[0018] Figure 1 is a graph showing the results of an acid reactivity test using the pH-STAT method. Figure 2 is a graph showing the results of an administration test of an iron supplement. The graph shows changes in serum iron concentration.

[0019] The present invention relates to a compound represented by the following formula (1): (Mg) １－ｘ－ｙ (Fe ２＋ ) ｘ (M ２＋ ) ｙ (OH) ２－ｎｚ (A ｎ－ ) ｚ (1) (wherein, M ２＋represents at least one essential mineral selected from Zn, Mn, Cu, and Co, A represents at least one organic acid and / or organic ligand, x, y, and z are each within the following ranges: 0<x<0.3, preferably 0.01≦x≦0.2, particularly preferably 0.05≦x≦0.15, 0≦y<0.2, preferably 0≦y≦0.1, particularly preferably 0≦y≦0.05, 0≦z<0.1, preferably 0.001≦z≦0.05, particularly preferably 0.002≦z≦0.02, and n is an integer of 0 to 4. The iron supplement may be used, for example, as an agent for treating iron deficiency (i.e., an iron preparation). In the magnesium hydroxide-based solid solution contained in the iron supplement according to the present invention, a portion of Mg may be substituted with divalent iron or with divalent iron and a divalent essential mineral, and a portion of OH may be substituted with an organic acid ion and / or an organic ligand. The magnesium hydroxide-based solid solution may be a solid solution having the same crystal structure as magnesium hydroxide. The magnesium hydroxide-based solid solution may be an active ingredient of an iron preparation. That is, the iron preparation may be a preparation containing the magnesium hydroxide-based solid solution as an active ingredient. In formula (1), Mg represents magnesium. Fe ２＋ indicates ferrous iron. ２＋As described above, represents at least one mineral selected from Zn, Mn, Cu, and Co. A represents an organic acid ion moiety and / or an organic acid ligand. Specific examples thereof are described later. Furthermore, any of the following embodiments regarding x, y, and z may be employed. (A) When 0<x<0.3: In one embodiment, in Formula (1), x, y, and z may each satisfy 0<x<0.3, 0≦y<0.2, and 0≦z<0.1. In one embodiment, in Formula (1), x, y, and z may each satisfy 0<x<0.3, 0≦y<0.2, and 0.001≦z≦0.05. In one embodiment, in Formula (1), x, y, and z may each satisfy 0<x<0.3, 0≦y<0.2, and 0.002≦z≦0.02. In one embodiment, in formula (1), x, y, and z may each satisfy 0<x<0.3, 0≦y≦0.1, and 0≦z<0.1. In one embodiment, in formula (1), x, y, and z may each satisfy 0<x<0.3, 0≦y≦0.1, and 0.001≦z≦0.05. In one embodiment, in formula (1), x, y, and z may each satisfy 0<x<0.3, 0≦y≦0.1, and 0.002≦z≦0.02. In one embodiment, in formula (1), x, y, and z may each satisfy 0<x<0.3, 0≦y≦0.05, and 0≦z<0.1. In one embodiment, in formula (1), x, y, and z may each satisfy 0<x<0.3, 0≦y≦0.05, and 0.001≦z≦0.05. In one embodiment, in formula (1), x, y, and z may each satisfy 0<x<0.3, 0≦y≦0.05, and 0.002≦z≦0.02. (B) When 0.01≦x≦0.2 In one embodiment, in formula (1), x, y, and z may each satisfy 0.01≦x≦0.2, 0≦y<0.2, and 0≦z<0.1. In one embodiment, in formula (1), x, y, and z may each satisfy 0.01≦x≦0.2, 0≦y<0.2, and 0.001≦z≦0.05. In one embodiment, in formula (1), x, y, and z may each satisfy 0.01≦x≦0.2, 0≦y<0.2, and 0.002≦z≦0.02.In one embodiment, in formula (1), x, y, and z may each satisfy 0.01≦x≦0.2, 0≦y≦0.1, and 0≦z<0.1. In one embodiment, in formula (1), x, y, and z may each satisfy 0.01≦x≦0.2, 0≦y≦0.1, and 0.001≦z≦0.05. In one embodiment, in formula (1), x, y, and z may each satisfy 0.01≦x≦0.2, 0≦y≦0.1, and 0.002≦z≦0.02. In one embodiment, in formula (1), x, y, and z may each satisfy 0.01≦x≦0.2, 0≦y≦0.05, and 0≦z<0.1. In one embodiment, in formula (1), x, y, and z may each satisfy 0.01≦x≦0.2, 0≦y≦0.05, and 0.001≦z≦0.05. In one embodiment, in formula (1), x, y, and z may each satisfy 0.01≦x≦0.2, 0≦y≦0.05, and 0.002≦z≦0.02. (C) When 0.05≦x≦0.15 In one embodiment, in formula (1), x, y, and z may each satisfy 0.05≦x≦0.15, 0≦y<0.2, and 0≦z<0.1. In one embodiment, in formula (1), x, y, and z may each satisfy 0.05≦x≦0.15, 0≦y<0.2, and 0.001≦z≦0.05. In one embodiment, in formula (1), x, y, and z may each satisfy 0.05≦x≦0.15, 0≦y<0.2, and 0.002≦z≦0.02. In one embodiment, in formula (1), x, y, and z may each satisfy 0.05≦x≦0.15, 0≦y≦0.1, and 0≦z<0.1. In one embodiment, in formula (1), x, y, and z may each satisfy 0.05≦x≦0.15, 0≦y≦0.1, and 0.001≦z≦0.05. In one embodiment, in formula (1), x, y, and z may each satisfy 0.05≦x≦0.15, 0≦y≦0.1, and 0.002≦z≦0.02. In one embodiment, in formula (1), x, y, and z may be 0.05≦x≦0.15, 0≦y≦0.05, and 0≦z<0.1, respectively.In one embodiment, in formula (1), x, y, and z may be 0.05≦x≦0.15, 0≦y≦0.05, and 0.001≦z≦0.05, respectively. In one embodiment, in formula (1), x, y, and z may be 0.05≦x≦0.15, 0≦y≦0.05, and 0.002≦z≦0.02, respectively. In each of the embodiments described in (A) to (C) above, n represents an integer of 0 to 4 (0, 1, 2, 3, or 4), and particularly preferably n is 0 or 1.

[0020] The magnesium hydroxide solid solution is represented by M in formula (1). ２＋ and in particular M ２＋ may be dissolved in the solid solution. ２＋ may be at least one essential mineral selected from the group consisting of Zn, Mn, Cu and Co. ２＋ Since the magnesium hydroxide solid solution contains Mg(OH), especially since it is solid-solved, the magnesium hydroxide solid solution can be used as a comprehensive mineral supplement, that is, the iron supplement can be used as a comprehensive mineral supplement (e.g., a multi-mineral supplement), which is particularly excellent. Mn, Cu, and Co are elements that are poorly absorbed, just like Fe, but these minerals are easily absorbed by the magnesium hydroxide solid solution. ２ By being solid-solubilized in Mg(OH) ２ It dissolves well in stomach acid, just like M. ２＋ The iron supplement containing the magnesium hydroxide-based solid solution containing the above-mentioned compound can also be used as a comprehensive mineral supplement with excellent absorbability.

[0021] A portion of the hydroxyl groups (OH) in the magnesium hydroxide solid solution can be substituted with organic acid ions and / or organic ligands to form a solid solution. The organic ligand contributes to crystal growth and improves the oxidation resistance of the iron agent. The organic ligand is preferably bidentate and slightly larger than OH. Preferred organic ligands include monovalent hydroxycarboxylic acids such as glycolic acid and lactic acid, amines such as ethylenediamine and triethanolamine, and polyhydric alcohols such as ethylene glycol and glycerin. The organic acid portion serves to thin the crystal thickness. Preferred organic acid ions are those of monovalent carboxylic acids such as formic acid, acetic acid, and propionic acid. Divalent or higher organic acids may be undesirable because they may inhibit crystal growth.

[0022] The iron supplement of the present invention (especially the magnesium hydroxide-based solid solution contained therein) can eliminate the metallic taste and side effects of conventional iron supplements by the following mechanism. In the iron supplement of the present invention, a part of the Mg in the magnesium hydroxide, which has a laxative effect, is replaced with divalent Fe(2+) and solid-solved, so that the surrounding Mg(OH) ２ Molecular Fe(OH) surrounded by ２ This is insoluble in water but can be dissolved in stomach acid by Mg(OH) ２ The iron supplement of the present invention dissolves almost as quickly and completely as magnesium hydroxide, providing easily absorbed divalent iron ions. Because the iron supplement of the present invention is insoluble in water, it is tasteless and has no metallic taste. Since the iron supplement gradually generates divalent iron ions only after encountering gastric acid after reaching the stomach and intestines, the irritation caused by the iron ions to the stomach and intestines is gentle, resulting in reduced side effects. Magnesium hydroxide, which has a long history as an antacid, dissolves quickly in gastric acid (MOL, Ohmsha, September 1977, Figures 1 and 2). Therefore, the iron supplement of the present invention also dissolves completely and at a rate similar to that of magnesium hydroxide, improving iron absorption. Constipation, a side effect of conventional iron supplements, is counteracted by the laxative effect of magnesium hydroxide, the main ingredient of the iron supplement of the present invention, and can be prevented with the iron supplement of the present invention.

[0023] (Method for Producing Magnesium Hydroxide-Based Solid Solution) The magnesium hydroxide-based solid solution contained in the iron supplement of the present invention can be produced by coprecipitation of (A) a mixed aqueous solution of a water-soluble Mg salt and a divalent Fe salt (Fe(2+) salt), or (B) a mixed aqueous solution of a water-soluble Mg salt, an Fe(2+) salt, and a divalent metal salt (M(2+)), with an alkali, followed by hydrothermal treatment. Furthermore, after the hydrothermal treatment, one or more conventional steps such as filtration, washing with water, drying, pulverization, and classification may be optionally performed. The divalent metal salt (M(2+)) contained in the mixed aqueous solution may be appropriately selected depending on the desired metal component, and may include, for example, at least one, two, three, or four selected from divalent Zn salts, Mn salts, Cu salts, and Co salts. Examples of the various water-soluble divalent metal salts mentioned above include chlorides, nitrates, sulfates, acetates, etc. That is, the anion component constituting the metal salt may be, for example, a chloride ion, a nitrate ion, a sulfate ion, or an acetate ion. The Mg salt may be, for example, magnesium chloride, magnesium nitrate, magnesium sulfate, magnesium acetate, or a combination of one or more of these. In one embodiment, the Mg salt preferably contains at least magnesium chloride, and more preferably magnesium chloride. The divalent Fe salt may be, for example, iron chloride, iron nitrate, iron sulfate, iron acetate, or a combination of one or more of these. In one embodiment, the divalent Fe salt preferably contains at least iron chloride, and more preferably iron chloride. With respect to the divalent metal salt (M(2+)), the Zn salt may be zinc chloride, zinc nitrate, zinc sulfate, zinc acetate, or a combination of one or more of these. Furthermore, the Mn salt may be manganese chloride, manganese nitrate, manganese sulfate, manganese acetate, or a combination of one or more of these. The Cu salt may be, for example, copper chloride, copper nitrate, copper sulfate, copper acetate, or a combination of one or more of these. The Co salt may be, for example, cobalt chloride, cobalt nitrate, cobalt sulfate, or cobalt acetate, or a combination of one or more thereof. The alkali may be, for example, NaOH, KOH, NH ３ , Ca(OH) ２The coprecipitation reaction is carried out in an aqueous solution or slurry of the above-mentioned metals. The amount of alkali used in the coprecipitation reaction is, for example, 0.6 to 0.9 equivalents relative to the aqueous solution of the water-soluble divalent metal mixture. The coprecipitation reaction temperature is, for example, 100°C or lower, preferably 5 to 70°C, and more preferably 10 to 40°C. To prevent oxidation of Fe(2+), production is preferably carried out using conventional oxidation-preventing equipment and conditions, such as drying in a nitrogen atmosphere. For example, the coprecipitation reaction may be carried out preferably in a non-oxidizing atmosphere, particularly a nitrogen atmosphere. Furthermore, the hydrothermal treatment may also be carried out preferably in a non-oxidizing atmosphere, particularly a nitrogen atmosphere. Furthermore, the various steps described above after the hydrothermal treatment (e.g., one or more of filtration, water washing, drying, pulverization, and classification) may also be carried out preferably in a non-oxidizing atmosphere, particularly a nitrogen atmosphere. As described above, the present invention also provides a method for producing an iron supplement (or a magnesium hydroxide-based solid solution) according to the present invention. The manufacturing method includes at least the co-precipitation reaction as described above.

[0024] Hydrothermal treatment after the coprecipitation reaction promotes the growth of primary particles and improves the resistance of Fe(2+) to oxidation. The hydrothermal treatment is preferably carried out at 100°C or higher, preferably 140°C or higher, and particularly preferably 170°C to 250°C, for at least 1 hour, preferably 4 to 10 hours. Hydrothermal treatment allows the primary particles to grow to a maximum width of 5 μm. Without hydrothermal treatment, the primary particles would be at most 0.2 μm. That is, the method for producing an iron supplement (or magnesium hydroxide-based solid solution) according to the present invention preferably further includes hydrothermal treatment of the magnesium hydroxide-based solid solution obtained by the coprecipitation reaction described above. Furthermore, the production method may further include performing one or more of the various steps described above (e.g., filtration, washing, drying, pulverization, and classification) after the hydrothermal treatment. This allows particles with the desired quality to be obtained, facilitating formulation.

[0025] (Preparation Method) The magnesium hydroxide-based solid solution contained in the iron supplement of the present invention includes particles having a plate-like outer shape and a shape close to a hexagon. The average diameter of the primary particles (crystallites) of the magnesium hydroxide-based solid solution is preferably in the range of 0.2 to 5 μm. This reduces aggregation and improves dispersibility. In other words, it is preferable that the size of the secondary particles is close to that of the primary particles. Therefore, the magnesium hydroxide-based solid solution may be used as is. For example, the magnesium hydroxide-based solid solution obtained by the above-mentioned production method may be administered to animals such as humans as is. Alternatively, the magnesium hydroxide-based solid solution may be combined with any pharmaceutically acceptable diluent, carrier, and other additives and adjuvants to form a composition having any dosage form and administered to animals such as humans. The iron supplement is useful for iron supplementation or iron and other minerals in humans or non-human animals. The iron supplement is also useful for preventing or treating (e.g., curing) iron deficiency syndrome or mineral deficiency syndrome in humans or non-human animals. That is, in one embodiment, the iron supplement of the present invention may be administered (orally) to an animal (particularly a human). The iron supplement of the present invention may also be administered to an animal (particularly a human) in need of iron supplementation. The iron supplement of the present invention may be used to supplement iron in the animal, or to prevent or treat iron deficiency in the animal.

[0026] The iron supplement of the present invention can be administered orally or intravenously, with oral administration being preferred from the standpoint of ease, simplicity, and cost-effectiveness. The dosage can be varied as appropriate depending on the desired amount of iron supplementation, the type and symptoms of iron deficiency to be treated, and the dosage form. For example, the daily dosage for an adult can be 10 to 1,000 mg, expressed as the amount of iron component (Fe) of the magnesium hydroxide solid solution of formula (1). The daily dosage for an adult is preferably 20 to 400 mg, and particularly preferably 40 to 100 mg. The entire daily dosage may be administered in one dose, or in multiple doses (e.g., two to three doses per day).

[0027] The iron supplement of the present invention may be prepared appropriately using the magnesium hydroxide-based solid solution. The preparation may be appropriately selected by those skilled in the art depending on various factors, such as the dosage form, the type of ingredients, and / or the composition of the preparation. The iron supplement of the present invention may be in various dosage forms. Examples of such dosage forms include powders, granules, pills, tablets, capsules, suspensions, and emulsions. Furthermore, the iron supplement of the present invention may also be in the form of a paste, chewing gum, or drinkable preparation. When preparing such various dosage forms, any pharmaceutically acceptable diluents or carriers, and other additives or adjuvants may be used. For example, water, alcohol, various animal and vegetable-derived or synthetic oils and fats, lactose, starches, dextrin, glucose, sucrose, white sugar, honey, yeast, yeast extract, egg yolk, egg white, agar, gelatin, lanolin, starch syrup, glycerin, anhydrous silicic acid, talc, kaolin, magnesium sulfate, sodium chloride, potassium bromide, potassium iodide, boric acid, magnesium oxide, calcium phosphate, magnesium carbonate, calcium carbonate, sodium or potassium hydrogen carbonate, malic acid or its salts, citric acid or its salts, tartaric acid or its salts, potassium hydrogen tartrate, calcium lactate, stearic acid or its magnesium salt or calcium salt, alginic acid or its alkali metal salt, acetylsalicylic acid, ascorbic acid or or salts thereof, reduced glutathione, tragacanth gum, gum arabic, methylcellulose, ethylcellulose, carboxymethylcellulose or salts thereof, carmellose, carmellose calcium, chlorocarmellose sodium, crystalline cellulose, low-substituted hydroxypropyl, corn starch, sodium starch glycolate, pregelatinized starch, carboxymethyl starch sodium, crospovidone, polyvinylpyrrolidone or other disintegrants, polyethylene glycol, sorbitan monostearate, fatty acid monoglycerin esters, other surfactants or emulsifiers, and various other known liquid or solid diluents or carriers, and other additives or adjuvants can be appropriately selected and used.

[0028] Among these, organic acids are preferred because they further improve iron absorption. The iron supplement of the present invention is alkaline and rapidly dissolves in gastric acid to provide iron ions. Therefore, when gastric acid levels are insufficient, the addition of an acid contributes to improved iron absorption. The added acid is preferably one that is solid at room temperature, has low toxicity, and is highly water-soluble. Examples of such organic acids include malic acid, citric acid, tartaric acid, and ascorbic acid. The amount of organic acid added is preferably equal to or less than the amount required to neutralize the iron supplement of the present invention (especially the magnesium hydroxide-based solid solution contained in the iron supplement), more preferably 0.2 to 0.8 equivalents. Reducing agents such as ascorbic acid are preferred because they prevent the oxidation of Fe(2+). Other medicinal substances, such as sedatives, vitamins, preservatives, stabilizers, sweeteners, and flavorings, can also be incorporated into the iron supplement. Preparations of the above-mentioned dosage forms into various dosage forms are well known, and can be similarly employed in the present invention.

[0029] The present invention will be described in more detail below with reference to examples, but the present invention is not limited to these examples.

[0030] (Acid Reactivity Test: pH-STAT Test) 50 mL of 30°C deionized water was placed in a 100 mL beaker, 50 mg of the test sample was added, and the beaker was placed in a pH-STAT device (manufactured by Toa DKK). The electrodes of a pH meter were immersed in the beaker, and after stirring with a magnetic stirrer for 1 minute, 0.1 mol / L hydrochloric acid (a concentration similar to that of gastric acid) was automatically supplied to maintain a pH of 3.0, and the amount of hydrochloric acid consumed over 10 minutes was measured over time. From these results, the release rate (speed and amount) of Fe(2+) ions produced by reaction with gastric acid could be evaluated.

[0031] Deionized water was boiled for approximately 30 minutes, then nitrogen gas was blown in to remove as much dissolved oxygen as possible. The water (approximately 20°C) was then cooled using reagent salts (manufactured by Fujifilm Wako Pure Chemical Industries). 250 ml of a mixed aqueous solution of magnesium chloride and ferrous chloride (Mg = 4.0 mol / L, Fe(2+) = 0.2 mol / L) was added to 10 cc of a 1 mol / L sodium lactate solution, and a sodium hydroxide aqueous solution (4 mol / L) was prepared. The mixed aqueous solution was placed in an approximately 1 L four-neck flask, and while blowing in nitrogen gas, 420 mL of sodium hydroxide was added under stirring to cause coprecipitation. The coprecipitation product was immediately transferred to a 1 L Hastelloy C autoclave, purged with nitrogen gas, and hydrothermally treated at 200°C for 4 hours. After air-cooling to room temperature, the hydrothermally treated product was filtered under reduced pressure, washed with water, and the filtered cake was dried in vacuo at 120°C. In this way, a magnesium hydroxide-based solid solution was obtained. The dried magnesium hydroxide solid solution was white, indicating that Fe(2+) was hardly oxidized. After passing this through a 60 mesh sieve, XRD measurement revealed a slight shift to a lower angle, but the same diffraction pattern as magnesium hydroxide was observed, indicating that Fe(2+), which has a larger ionic radius than Mg, had substituted a portion of the Mg in the magnesium hydroxide into a solid solution. A portion of the sieved sample was taken and dissolved in hydrochloric acid, after which Mg was measured by chelate titration, and divalent and trivalent iron were separately quantified by absorptiometry (Handbook of Analytical Chemistry, edited by the Chemical Society of Japan, Maruzen Publishing, p. 185). Lactic acid was measured by absorptiometry, revealing the following chemical composition: Mg ０．９４ Fe(2+) ０．０６ (OH) １．９９ (C ３ H ５ O ３ － ) ０．０１(Fe content = 56 mg / 1 g, Fe(3+) = 0%). The results of an acid reactivity test using the sieved sample are shown in Figure 1. The acid reactivity test results for magnesium hydroxide obtained in the same manner as in Example 1, except that the mixed aqueous solution of divalent metals in Example 1 contained only Mg. The results showed that 4 cc of hydrochloric acid was consumed after 2 minutes, 10 cc after 5 minutes, and the theoretical value of 17 cc of hydrochloric acid was consumed after 10 minutes. Figure 1 shows that the iron preparation of Example 1 exhibits reactivity equivalent to that of magnesium hydroxide. Therefore, it can be seen that the iron supplement of the present invention also has superior iron ion release properties compared to conventional iron preparations (ferrous fumarate).

[0032] The same procedure as in Example 1 was carried out except that sodium lactate was not used, the concentration of the mixed aqueous solution of Mg and Fe(2+) was changed to Mg = 4.0 M / L, Fe(2+) = 0.4 M / L, and the amount of sodium hydroxide was changed to 440 mL. As a result, a magnesium hydroxide-based solid solution was obtained. The obtained magnesium hydroxide-based solid solution was almost white, and although the XRD was slightly shifted to the low angle side, it showed a diffraction pattern similar to that of magnesium hydroxide, indicating that it was a magnesium hydroxide-based substitutional solid solution. Chemical analysis using the same method as in Example 1 revealed the following chemical composition: Mg ０．８８ Fe ０．１２ (OH) ２ (Fe content = 108 mg / 1 g, Fe(3+) = 0.05%, equivalent to 0.5% of the total iron content) The results of the acid reactivity test are shown in Figure 1. Since the acid reactivity is similar to that of the iron supplement (magnesium hydroxide-based solid solution) obtained in Example 1, it is clear that the iron ion release property is also excellent.

[0033] The same procedure as in Example 1 was carried out except that the Mg and Fe(2+) mixed solutions were changed to 3.0 M / L and 0.6 M / L, respectively, sodium lactate was not used, the amount of sodium hydroxide was changed to 375 mL, and the hydrothermal treatment temperature was changed to 150°C. A magnesium hydroxide-based solid solution was thus obtained. The obtained magnesium hydroxide-based solid solution was slightly grayish-white, and its XRD showed the same tendency as in Example 1, indicating that it was a magnesium hydroxide-based solid solution. Chemical analysis using the same method as in Example 1 revealed the following chemical composition: Mg ０．８ Fe０．２ (OH) ２ (Fe content = 172 mg / 1 g, Fe(3+) = 0.2%, equivalent to 1% of the total iron content) Acid reactivity is shown in Figure 1. Since 80% of the theoretical neutralization amount of 15 cc was reached after 10 minutes, iron ion release was generally good.

[0034] Comparative Example 1 Example 1 was repeated except that the concentration of Fe(2+) in Example 3 was changed to 0.24 M / L and the amount of sodium hydroxide was changed to 424 mL. The dried product obtained was brownish, and although the XRD was slightly shifted to the low angle side, a diffraction pattern similar to that of magnesium hydroxide and a diffraction pattern corresponding to hydrotalcites were observed. The sieved product was analyzed in the same manner as in Example 1, and the chemical composition was as follows: Mg ０．６９ Fe ０．３１ (OH) ２ (Fe content = 253 mg / 1 g, Fe(3+) = 3.4%, equivalent to 13.5% of the total iron content.) The acid reactivity of the sieved material is shown in Figure 1. The acid reactivity after 10 minutes was low at 37% of the theoretical amount, and therefore the iron ion release was also low.

[0035] Comparative Example 2: The acid reactivity of the reagent ferrous fumarate (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) was measured, and the results are shown in Figure 1. Although it dissolves quickly in hydrochloric acid, the amount of hydrochloric acid consumed remains low at 1.5 cc both after 1 minute and after 10 minutes, and therefore the iron ion release is also low.

[0036] The procedure of Example 1 was repeated except that the divalent metal mixed solution used in Example 1 was changed to 500 mL of a mixed aqueous solution (Mg = 1.9 M / L, Fe(2+) = 0.04 M / L, Zn = 0.05 M / L, Mn = 0.014 M / L, Cu = 0.008 M / L, Co = 0.0006 M / L) containing zinc chloride, manganese chloride, cupric nitrate, and cobalt chloride, sodium lactate was not used, and sodium hydroxide was changed from 8 M / L to 240 mL. The resulting dried product was white, and XRD showed the same results as in Example 1, indicating that it was a magnesium hydroxide-based solid solution. Composition analysis by XRF revealed the following chemical composition: Mg ０．９４３７ Fe ０．０２ Zn ０．０２５ Mn ０．００７ Cu０．００４ Co ０．０００３ (OH) ２ The acid reactivity test showed that the theoretical amount of about 16 cc was reached after 10 minutes, indicating 100% acid reactivity. This indicates that all minerals were released satisfactorily.

[0037] (Storage Stability Test) 2 g of powder of the magnesium hydroxide solid solution (hereinafter also referred to as iron supplement) obtained in Examples 1 to 3, which had been sieved through a 60 mesh screen, was placed in a weighing bottle and exposed to the air at room temperature. The number of days required for the surface to turn brown was measured. For comparison, Fe(2+)-type hydrotalcites: Fe, which had been hydrothermally treated at 150°C for 15 hours, were also measured. ４ (2+) Al ２ (OH) １２ CO ３ ・3H ２ 0 (a sample was prepared according to the method of Example 2 of JP-A-60-6619). The results are shown in Table 1. Fe(2+) hydrotalcites are oxidized in 3 days, but the iron preparation of the present invention is not oxidized even after 30 days. Therefore, it is clear that the iron supplement of the present invention is highly resistant to oxidation and has good storage stability.

[0038]

[0039] (Reference Example (Administration Test)) Test Method: The subjects were three healthy males aged 30-45 years, weighing 60-70 kg. The iron supplement of the present invention obtained in Example 2 was tested against the ferrous fumarate reagent used in Comparative Example 2 as a control. On the day of the experiment, subjects were prohibited from taking any other medications other than the test drug and from consuming foods such as tea and eggs. They fasted for breakfast and ate lunch at 12:30. For drug administration experiments, blood was drawn at 9:30 AM, and the drug was immediately orally administered. Blood samples were then drawn 2, 4, and 6 hours after administration. 0.5 ml of blood was then drawn from each sample, colored with the Fe-Direct reagent, and spectroscopically analyzed at a wavelength of 535 nm to measure serum iron concentration. As a control, 50 mg of ferrous fumarate (a reagent manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) was administered in an amount equivalent to Fe. Two types of iron supplements of the present invention were administered: 50 mg of the 60-mesh sieved powder obtained in Example 2, calculated as Fe, was administered alone, and 500 mg of ascorbic acid (a reagent manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) powder sieved through a 60-mesh sieve was added to the powder. The results of the administration test are shown in Figure 2. These results demonstrate that the iron supplement of the present invention has a higher iron absorption rate and rate than conventional iron preparations, and that the iron absorption rate is further improved when the iron preparation of the present invention is administered in combination with ascorbic acid, an organic acid.

[0040] The present invention may be configured as follows: [Item A1] The following formula (1) (Mg) １－ｘ－ｙ (Fe ２＋ ) ｘ (M ２＋ ) ｙ (OH) ２－ｎｚ (A ｎ－ ) ｚ(1) An agent for treating iron deficiency (iron preparation) containing as an active ingredient a magnesium hydroxide solid solution represented by the formula: (wherein, M2+ represents at least one essential mineral selected from Zn, Mn, Cu, and Co; A represents at least one organic acid ion and / or organic ligand; x, y, and z are each within the following ranges: 0<x<0.3, preferably 0.01≦x≦0.2, particularly preferably 0.05≦x≦0.15; 0≦y<0.2, preferably 0≦y≦0.1, particularly preferably 0≦y≦0.05; 0≦z<0.1, preferably 0.001≦z≦0.05, particularly preferably 0.002≦0.02; and n represents zero or an integer ranging from 0 to 4). [Item A2] An iron preparation according to Item A1, wherein, in formula (1), y is 0. [Item A3] The iron preparation according to any one of Items A1 to A2, wherein in formula (1), x is in the range of 0.01≦x≦0.2. [Item A4] The iron preparation according to any one of Items A1 to A3, further comprising an organic acid in an amount equivalent to or less than the amount required to neutralize the solid solution. [Item A5] The iron preparation according to any one of Items A1 to A4, wherein the organic acid according to Item A4 is at least one selected from malic acid, tartaric acid, citric acid, and ascorbic acid. [Item A6] The iron preparation according to any one of Items A1 to A4, wherein A in formula (1) ｎ－ [Item A7] The iron preparation according to any one of Items A1 to A6, wherein z is zero (z=0). [Item A8] A method for producing the iron preparation according to any one of Items A1 to A7, characterized in that (1) a mixed aqueous solution of (A) a water-soluble Mg salt and a divalent Fe salt, or (B) a water-soluble Mg salt, a divalent iron salt, and at least one divalent metal salt selected from divalent Zn, Mn, Cu, and Co salts, (2) an organic acid and / or an organic ligand is added to (1) in an amount of at least 10 mol% based on the total moles of the water-soluble divalent metal, or no organic acid and / or organic ligand is added, (3) an alkali of an equivalent or less, preferably 0.7 to 0.9 equivalents based on the total equivalent of the water-soluble divalent metal, is added to (1) or to a mixed aqueous solution of (1) and (2) with stirring, and a coprecipitation reaction is carried out in a non-oxidizing atmosphere, (4) a hydrothermal treatment is carried out at 100°C or higher, preferably 150 to 250°C, for 1 hour or more, preferably 2 to 10 hours, and (5) a filtration, washing with water, and drying are carried out in a non-oxidizing atmosphere.

Claims

1. The following formula (1) (Mg) １－ｘ－ｙ (Fe ２＋ ) ｘ (M ２＋ ) ｙ (OH) ２－ｎｚ (A ｎ－ ) ｚ (1) (wherein, M ２＋ represents at least one selected from Zn, Mn, Cu, and Co; A represents at least one organic acid ion moiety and / or organic ligand; x, y, and z are each within the following ranges: 0<x<0.3, preferably 0.01≦x≦0.2, particularly preferably 0.05≦x≦0.15, 0≦y<0.2, preferably 0≦y≦0.1, particularly preferably 0≦y≦0.05, 0≦z<0.1, preferably 0.001≦z≦0.05, particularly preferably 0.002≦z≦0.02; and n represents an integer of 0 to 4.

2. The iron supplement of claim 1, wherein in formula (1), y is 0.

3. An iron supplement according to any one of claims 1 to 2, wherein in formula (1), x satisfies 0.01≦x≦0.

2.

4. An iron supplement according to any one of claims 1 to 3, further comprising, in addition to the solid solution, an organic acid in an amount equal to or less than the amount required to neutralize the solid solution.

5. The iron supplement according to claim 4, wherein the organic acid is at least one selected from the group consisting of malic acid, tartaric acid, citric acid and ascorbic acid.

6. In the formula (1), A ｎ－ The iron supplement according to any one of claims 1 to 5, wherein is an organic ligand, and the organic ligand is glycolic acid and / or lactic acid.

7. An iron supplement according to any one of claims 1 to 6, wherein z is z=0.

8. The iron supplement according to any one of claims 1 to 7, which is a treatment for iron deficiency.

9. A method for producing an iron supplement according to any one of claims 1 to 8, comprising: preparing a mixed aqueous solution of a water-soluble Mg salt and a divalent Fe salt, or (B) a water-soluble Mg salt, a divalent iron salt and at least one divalent metal salt selected from a divalent Zn salt, a Mn salt, a Cu salt, and a Co salt; adding an alkali in an amount equal to or less than the total equivalent of the water-soluble divalent metal, preferably 0.7 to 0.9 equivalents, to the mixed aqueous solution while stirring, and carrying out a coprecipitation reaction in a non-oxidizing atmosphere to obtain a coprecipitation reaction product; and hydrothermally treating the coprecipitation reaction product at 100°C or higher, preferably 150 to 250°C, for 1 hour or more, preferably 2 to 10 hours, to obtain a magnesium hydroxide-based solid solution; and preparing an iron supplement using the magnesium hydroxide-based solid solution.

10. A method for producing the iron supplement described in claim 9, which includes adding to the mixed aqueous solution at least 10 mol% or less of an organic acid and / or an organic ligand relative to the total number of moles of the water-soluble divalent metal before adding the alkali to the mixed aqueous solution.

11. The method according to claim 9 or 10, further comprising subjecting the magnesium hydroxide-based solid solution obtained by the hydrothermal treatment to one or more of a filtration treatment, a water washing treatment, and a drying treatment.

12. The method of claim 11, wherein the one or more treatments are performed in a non-oxidizing atmosphere.

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