Oral composition for removing metals and method for recovering metals

Abstract

One of our goals is to provide a new agent that can remove harmful metals that have entered the body, and that is safe and easy to ingest. [Solution] The above problem is solved by providing an oral composition for removing metals, which contains calcium phosphate as an active ingredient.

Description

[Technical Field]

[0001] This disclosure relates to an oral composition for removing metals and a method for recovering metals. [Background technology]

[0002] Many metal-derived toxins enter the body from outside through food. Specifically, these include heavy metals from fish, rice, and old water pipes, as well as aluminum in canned goods and cookware. For example, cadmium (Cd), a heavy metal, has been identified as the cause of Itai-itai disease in Japan, which was a pollution-related disease that occurred in areas of the Jinzu River basin where rice is consumed. Heavy metals, including cadmium, still exist at high concentrations in soil near volcanoes and in river basins into which mine and industrial wastewater flows. In particular, it is assumed that there are many problems that do not become apparent in developing countries where regular water quality testing is not adequately carried out.

[0003] Common materials used to remove metal-derived toxins include chelating agents and activated carbon. Chelating agents possess negatively charged functional groups (e.g., carboxyl groups and phosphate groups), which trap positively charged metal ions by sandwiching them between these groups. Activated carbon, on the other hand, has a positively charged surface and exhibits the property of adsorbing many molecules. Furthermore, it has a large specific surface area, allowing it to adsorb a large quantity of molecules. Due to these properties, both chelating agents and activated carbon are used as emergency toxin removers in medical settings, and supplements containing chelating agents and activated carbon are also commercially available for daily use.

[0004] However, because activated charcoal has excellent adsorption capacity, it tends to adsorb and remove essential nutrients from the body, and there are concerns that its excessive use may lead to a deterioration of health. Furthermore, activated charcoal is known to adsorb to organs, especially the digestive tract, and as a result of using activated charcoal, the digestive tract is often discolored black. Excessive adsorption of activated charcoal to the digestive tract is undesirable as it may impair the secretion of digestive juices from glandular cells. In addition, chelating agents may cause side effects, and their use requires strict prescription by a physician.

[0005] Other methods for removing metal-derived toxins include, for example, Patent Document 1, which describes how lactoferrin forms complexes with heavy metal ions that accumulate in the body with age, thereby preventing and treating heavy metal poisoning by promoting their excretion from the body. Furthermore, Patent Document 2 describes a metal deposition inhibitor characterized by the combined use of a processed product of a plant in the Apiaceae family and trehalose and / or maltitol as active ingredients.

[0006] However, no material is yet known that can efficiently remove harmful metals that have entered the body, while also being safe and easy to ingest. [Prior art documents] [Patent Documents]

[0007] [Patent Document 1] International Publication No. 2007 / 001006 [Patent Document 2] Japanese Patent Publication No. 2002-080385 [Patent Document 3] International Publication No. 2004 / 112856 [Patent Document 4] Japanese Patent Application Publication No. 4-321507 [Patent Document 5] Japanese Patent Publication No. 2008-303115 [Patent Document 6] Japanese Patent Application Publication No. 03-183605 [Patent Document 7] Japanese Patent Application Publication No. 6-122510 [Non-patent literature]

[0008] [Non-Patent Document 1] Kensuke Kuroda and Masazumi Okido. Hydroxyapatite Coating of Titanium Implants Using Hydroprocessing and Evaluation of Their Osteoconductivity. Bioinorganic Chemistry and Applications, Volume 2012, Article ID 730693. [Non-Patent Document 2] Hideki Monma, Yu Goto, Hiroshi Nakajima, and Koichi Hashimoto, Synthesis of Tetracalcium Phosphate, Gypsum & Lime No. 202 (1986) pp. 151-155. [Non-Patent Document 3] Kiyoshi Ban, Jiro Hasegawa, and Shigeo Maruno, Synthesis of octacalcium phosphate and its conversion to apatite, Dental Materials and Instruments Vol. 15, No. 3 210-217 (1996). [Non-Patent Document 4] Osamu Fujii, Atsuo Ito, Ryohei Otsuka, Hideki Aoki, and Masaru Akao, Wet synthesis of microparticle calcium monohydrogen phosphate, Gypsum & Lime No. 219 (1989). [Non-Patent Document 5] LC Chow. Solubility of Calcium Phosphates. Monogr. Oral. Sci., 2001, vol. 18, p. 94-111. [Non-Patent Document 6] Yasue, Jin; Arai, Yasuo. Recent studies on amorphous calcium phosphate. Gypsum & Lime No. 243 (1993) pp. 108-116. [Overview of the project] [Problems that the invention aims to solve]

[0009] The present invention has been made in view of the above problems of the prior art, and in one aspect, an object is to provide a new agent that can remove harmful metals that have invaded a living body and can be easily ingested.

Means for Solving the Problems

[0010] Calcium phosphate is a major component of bones and teeth, and it is known that in the process of bone remodeling in the body, the decomposition and re-precipitation of calcium phosphate are repeated. The decomposition of calcium phosphate mainly proceeds by acid secretion in osteoclasts, and the locally decomposed calcium and phosphate with increased concentration are re-precipitated as new calcified substances in a region where the nearby pH is neutral or higher. Based on the original idea of applying the property of calcium phosphate, which dissolves in acid and re-precipitates in neutrality, to the digestive tract (Fig. 14), the present inventors considered that this material might dissolve once in the stomach and re-precipitate in the intestine, and during this process, metals that have invaded the body could be removed by incorporating them into the structure, and thus made intensive research efforts from this perspective. As a result, surprisingly, it was found that by orally administering calcium phosphate, metals that have invaded the living body can be captured by calcium phosphate particles and removed from the living body.

[0011] That is, in one aspect, the present invention solves the above problems by providing an oral composition for removing metals, which contains calcium phosphate as an active ingredient.

Effects of the Invention

[0012] The oral composition according to one aspect of the present invention is simple and can be safely ingested, and can also remove harmful metals that have invaded the body.

Brief Description of the Drawings

[0013] [Figure 1] It is a diagram showing the SEM image of the powder containing calcium phosphate particles obtained in Experiment 1 and the analysis results by SEM-EDX. [Figure 2]This figure shows the powder X-ray diffraction patterns of calcium phosphate particle-containing powder. (A) "HAp untreated" represents the calcium phosphate particle-containing powder obtained in Experiment 1. "HAp 1.60-g pH 3.0, 4.0, or 5.0" represents the powder recovered after immersing 1.60 g of the calcium phosphate particle-containing powder obtained in Experiment 1 in a gastric juice imitation solution with pH 3.0, 4.0, or 5.0 for a predetermined time. "HAp 0.16-g pH 3.0, 4.0, or 5.0" represents the powder recovered after immersing 0.16 g of the calcium phosphate particle-containing powder obtained in Experiment 1 in a gastric juice imitation solution with pH 3.0, 4.0, or 5.0 for a predetermined time. (B) "HAp 1.60-g pH 3.0, 4.0, or 5.0 to 7.0" represents the powder recovered after immersing 1.60 g of the calcium phosphate particle-containing powder obtained in Experiment 1 in a gastric juice mimic with pH 3.0, 4.0, or 5.0 for a predetermined time, and then further immersing it in an intestinal juice mimic with pH 7.0 for a predetermined time. "HAp 0.16-g pH 3.0, 4.0, or 5.0 to 7.0" represents the powder recovered after immersing 0.16 g of the calcium phosphate particle-containing powder obtained in Experiment 1 in a gastric juice mimic with pH 3.0, 4.0, or 5.0 for a predetermined time, and then further immersing it in an intestinal juice mimic with pH 7.0 for a predetermined time. The names of the samples are the same in the following drawings. [Figure 3] This figure shows SEM images of calcium phosphate particle-containing powder obtained in Experiment 1; calcium phosphate particle-containing powder treated with a gastric juice mimicry solution at a predetermined pH; and calcium phosphate particle-containing powder treated with a gastric juice mimicry solution at a predetermined pH, followed by treatment with an intestinal juice mimicry solution. The arrows in the figure indicate the precipitation of dicalcium phosphate dihydrate. [Figure 4]This figure shows the amount of calcium phosphate (HAp) or activated carbon (AC) dissolved when immersed in a gastric juice mimicry solution with pH 3.0, 4.0, or 5.0 ("pH 3.0", "pH 4.0", or "pH 5.0"); and the amount of calcium phosphate (HAp) or activated carbon (AC) dissolved when immersed in a gastric juice mimicry solution with pH 3.0, 4.0, or 5.0 and then adjusted to pH 7.0 ("pH 3.0 to 7.0", "pH 4.0 to 7.0", or "pH 5.0 to 7.0"). [Figure 5] This figure shows the cadmium recovery efficiency from an aqueous solution containing a predetermined amount of cadmium using calcium phosphate (HAp) or activated carbon (AC). [Figure 6] This figure shows the powder X-ray diffraction patterns of stomach contents, intestinal contents, and feces collected from mice that ingested a diet containing the calcium phosphate particle powder obtained in Experiment 1. [Figure 7] This figure shows a photograph of feces collected from mice that were fed drinking water containing cadmium and diet containing calcium phosphate (HAp) or activated carbon (AC), as well as the results of the quantitative analysis of cadmium contained in the feces. [Figure 8] This figure shows the quantitative results of cadmium and calcium concentrations in the blood of mice that were fed drinking water containing cadmium and diet containing calcium phosphate (HAp) or activated carbon (AC). [Figure 9] This figure shows the quantitative results of cadmium concentrations in tissues recovered from mice that were fed drinking water containing cadmium and diet containing calcium phosphate (HAp) or activated carbon (AC). [Figure 10] This is a micrograph showing the histological condition of liver tissue recovered from mice that were fed drinking water containing cadmium and diet containing calcium phosphate (HAp) or activated carbon (AC). In the figure, arrows indicate coagulation necrosis. [Figure 11]These are micrographs showing the histological condition of kidney tissue recovered from mice that were fed drinking water containing cadmium and diet containing calcium phosphate (HAp) or activated charcoal (AC). In the figures, arrows indicate coagulation necrosis, and circles indicate glomerular necrosis. [Figure 12] This figure shows the quantitative results of cadmium and calcium concentrations in the femurs of mice that were fed drinking water containing cadmium and diet containing calcium phosphate (HAp) or activated carbon (AC). [Figure 13] This figure shows the results of a three-point bending test using bones recovered from mice that were fed drinking water containing cadmium and diet containing calcium phosphate (HAp) or activated carbon (AC). [Figure 14] This figure illustrates an overview of an oral composition relating to one aspect of the present invention, in comparison to the bone remodeling process in the body. [Modes for carrying out the invention]

[0014] The oral compositions relating to one aspect of the present invention will be described in more detail below.

[0015] An oral composition according to one aspect of the present invention is an oral composition containing calcium phosphate.

[0016] In this disclosure, "calcium phosphate" means a compound containing phosphoric acid and calcium as its composition. Calcium phosphate has pH-dependent solubility; its solubility increases in an acidic environment, while it precipitates when the pH of an aqueous solution containing phosphate and calcium ions is neutral or higher. One aspect of the present invention utilizes the property of calcium phosphate that it dissolves at the acidic pH of gastric juice and reprecipitations at the neutral pH of intestinal juice to capture the metals to be removed in the reprecipitationd calcium phosphate, thereby removing metals that have entered the body (Figure 14).

[0017] The calcium phosphate that can be used in the oral composition according to one aspect of the present invention may be, but is not limited to, crystalline calcium phosphate such as hydroxyapatite, tricalcium phosphate, tetracalcium phosphate, octacalcium phosphate, and calcium hydrogen phosphate, as well as amorphous calcium phosphate.

[0018] Hydroxyapatite has the chemical formula Ca 10 Hydroxyapatite is a type of calcium phosphate with a representative composition represented by (PO4)6(OH)2, and its Ca / P ratio (the molar ratio of calcium to phosphorus constituting calcium phosphate; the same applies hereinafter) is 1.67. Hydroxyapatite has excellent biocompatibility and is used, for example, as a bone graft material for artificial bones and artificial teeth.

[0019] Hydroxyapatite can be synthesized by appropriate methods. Known synthesis methods include dry synthesis, wet synthesis, hydrothermal synthesis, and sol-gel synthesis, but wet synthesis is the most common. In the wet synthesis method, for example, an aqueous solution containing calcium ions and an aqueous solution containing phosphate ions are mixed in a predetermined ratio to prepare a mixture containing calcium ions and phosphate ions. By adjusting the pH of this mixture to neutral or higher, hydroxyapatite can be obtained as a precipitate. Alternatively, a solution containing phosphate ions may be added dropwise to a solution containing calcium ions so that the ratio of calcium ions to phosphate ions is predetermined, thereby producing a hydroxyapatite precipitate. The resulting precipitate can be collected and dried to obtain hydroxyapatite powder. Furthermore, sintering the hydroxyapatite powder is also advantageous.

[0020] Hydroxyapatite, known as a major component of bone, is found in natural bones such as pig bones and cow bones. However, the hydroxyapatite that can be used in the oral composition according to one aspect of the present invention is preferably artificially synthesized hydroxyapatite. Natural bones are rich not only in hydroxyapatite but also in other components that make up bone tissue, such as proteins and lipids. These impurities can hinder the crystallization of calcium phosphate, and reprecipitation of calcium phosphate on its surface is less likely to occur compared to artificially synthesized hydroxyapatite. Therefore, the hydroxyapatite that can be used in the oral composition according to one aspect of the present invention is preferably artificially synthesized hydroxyapatite that is substantially free of proteins and lipids.

[0021] Furthermore, in one preferred embodiment, the hydroxyapatite may be a non-stoichiometric hydroxyapatite in which its constituent calcium ions, phosphate ions, and hydroxide ions are omitted or substituted with other components. In this disclosure, the term hydroxyapatite includes non-stoichiometric hydroxyapatite unless otherwise specified or it is clear from the context that non-stoichiometric hydroxyapatite is excluded. Examples of non-stoichiometric hydroxyapatites include fluorine apatite (FAp), in which some or all of the hydroxyl groups of hydroxyapatite are substituted with fluorine atoms; chloride apatite (ClAp), in which some or all of the hydroxyl groups of hydroxyapatite are substituted with chlorine atoms; and carbonate apatite (CO3Ap), in which some or all of the phosphate or hydroxyl groups of hydroxyapatite are substituted with carbonate groups. In particular, carbonate apatite is known to have a large difference in solubility between low pH and neutral pH environments (for example, Patent Document 3), and can be suitably used as an active ingredient in the oral composition of the present invention. Methods for producing carbonate apatite are well known and are also described in Patent Document 3, for example.

[0022] Tricalcium phosphate is a type of calcium phosphate with a representative composition represented by the chemical formula Ca3(PO4)2, and its Ca / P ratio is 1.5. Tricalcium phosphate is sometimes called tricalcium phosphate. Two crystalline forms of tricalcium phosphate are known: α-type tricalcium phosphate ("α-TCP"), which is stable at high temperatures, and β-type tricalcium phosphate ("β-TCP"), which is stable at low temperatures. α-TCP is unstable at low temperatures and is easily hydrolyzed under conditions of pH 7 or higher, forming hydroxyapatite. On the other hand, β-TCP is stable even at low temperatures, making it easy to handle, and it is difficult to hydrolyze at neutral pH but has high solubility at acidic pH (for example, Non-Patent Document 5). Therefore, β-TCP may be more preferable than α-TCP as calcium phosphate used in the oral composition according to one aspect of the present invention.

[0023] Tricalcium phosphate can be synthesized by appropriate methods by those skilled in the art, and for example, methods for synthesizing tricalcium phosphate are described in Patent Documents 4 and 5. Common methods for synthesizing tricalcium phosphate include dry synthesis and wet synthesis. Non-limiting examples include dry synthesis, which involves reacting calcium pyrophosphate with calcium carbonate, and wet synthesis, which involves producing amorphous calcium phosphate from a calcium nitrate solution and a diammonium hydrogen phosphate solution.

[0024] Tetracalcium phosphate is a type of calcium phosphate with a representative composition represented by the chemical formula Ca4(PO4)2O, and its Ca / P ratio is 2.0. The synthesis method of tetracalcium phosphate is well known and is described, for example, in Patent Document 6 and Non-Patent Document 2.

[0025] Octacalcium phosphate is a type of calcium phosphate with the chemical formula Ca8H2(PO4)6 as its representative composition, and its Ca / P ratio is 1.33. Octacalcium phosphate is known to have excellent bone regeneration capabilities, and its application in the medical field as a bone graft agent is progressing. The synthesis method of octacalcium phosphate is well known and is described, for example, in Patent Document 7 and Non-Patent Document 3.

[0026] Calcium hydrogen phosphate is a type of calcium phosphate with the chemical formula CaHPO4 as its representative composition, and its Ca / P ratio is 1.0. Calcium hydrogen phosphate is sometimes also called monocalcium hydrogen phosphate or dicalcium phosphate. Calcium hydrogen phosphate is known in both anhydrous and dihydrate forms; anhydrous calcium hydrogen phosphate is called DCPA, and dihydrate calcium hydrogen phosphate is called DCPD. The synthesis method of calcium hydrogen phosphate is well known and is described, for example, in Non-Patent Document 4.

[0027] Calcium phosphate may be amorphous calcium phosphate. Amorphous calcium phosphate is sometimes called amorphous calcium phosphate (ACP). Methods for synthesizing amorphous calcium phosphate are well known and can be prepared by methods such as rapid precipitation at low temperatures of about 0-25°C, sol-gel method, and hydrolysis method. One such synthesis method is also described in Non-Patent Document 6.

[0028] As described above, the oral composition according to one aspect of the present invention utilizes the properties of calcium phosphate, which dissolves at the acidic pH of gastric juice and reprecipitates at the neutral pH of intestinal juice. By capturing the metals to be removed in the reprecipitated calcium phosphate, metals that have entered the body can be removed. In other words, the calcium phosphate used in the oral composition according to one aspect of the present invention is preferably one that dissolves easily at an acidic pH and precipitates easily at a neutral pH; in other words, calcium phosphate with a large difference in solubility between acidic and neutral pH.

[0029] Acidic pH is preferably the pH in the stomach, for example, pH 1.0 to 3.0, typically pH 1.0 to 2.0. Neutral pH is preferably the pH in the intestines, for example, pH 6.5 to 8.0, typically pH 6.5 to 7.5. There are no particular restrictions on the difference in solubility between acidic pH and neutral pH, but for example, it is preferable that the solubility at the above acidic pH is 100 times or more greater than the solubility at the above neutral pH, more preferably 200 times or more greater, even more preferably 500 times or more greater, and even more preferably 1000 times or more greater.

[0030] Examples of calcium phosphates whose solubility at acidic pH is greater than that at neutral pH include hydroxyapatite, tricalcium phosphate, octacalcium phosphate, and calcium hydrogen phosphate. Among these, hydroxyapatite, tricalcium phosphate, and octacalcium phosphate are preferred, with hydroxyapatite being more preferred. The pH-dependent solubility of these calcium phosphates is described, for example, in Non-Patent Document 1.

[0031] The calcium phosphate used in the oral composition according to one aspect of the present invention does not necessarily have to consist solely of one of the above-mentioned types of calcium phosphate, but may substantially consist of or be a mixture of one or more types selected from the above-mentioned types of calcium phosphate. In particular in such cases, calcium phosphate can be preferably defined by the molar ratio of calcium to phosphorus contained in the calcium phosphate, i.e., the Ca / P ratio. In one preferred embodiment, the Ca / P ratio of calcium phosphate may be, for example, 1.00 to 2.00, preferably 1.25 to 1.90, more preferably 1.50 to 1.80, even more preferably 1.55 to 1.75, and even more preferably 1.60 to 1.70. In this disclosure, when "~" is used to indicate a numerical range, it means a numerical range including the upper and lower limits unless otherwise specified.

[0032] In one preferred embodiment, the calcium phosphate contained in the oral composition according to one aspect of the present invention is preferably particulate, that is, calcium phosphate particles. There is no particular upper limit to the particle size of the calcium phosphate particles, but from the viewpoint of reactivity with the metals to be removed, it is preferable that the particle size of the calcium phosphate particles be small, for example, 500 μm or less, preferably 200 μm or less, more preferably 100 μm or less, and even more preferably 50 μm or less. On the other hand, there is no particular lower limit to the particle size of the calcium phosphate particles, but from the viewpoint of providing a reaction site for the reprecipitation of calcium phosphate without completely dissolving in the stomach, it is preferable that the particle size of the calcium phosphate particles be large, for example, 0.5 μm or more, preferably 1 μm or more, more preferably 5 μm or more, and even more preferably 10 μm or more. Considering these viewpoints together, the particle size of the calcium phosphate particles may be, for example, 0.5 to 500 μm, preferably 1 to 200 μm, more preferably 5 to 100 μm, and even more preferably 10 to 50 μm. The particle size of calcium phosphate particles can be observed using an electron microscope, for example, as shown in the experimental examples described later.

[0033] The particle size of the calcium phosphate particles can be adjusted, for example, by grinding the calcium phosphate particles. Grinding of the calcium phosphate particles can be carried out, for example, using an appropriate grinder. Examples of grinders include, but are not limited to, centrifugal grinders, pneumatic grinders, and grinders. The calcium phosphate particles ground by the grinder may be further sieved using a sieve of a predetermined mesh size.

[0034] There are no particular restrictions on the calcium phosphate content in the oral composition according to one aspect of the present invention, but for example, it may be 1% or more by weight, 2% or more by weight, 3% or more by weight, 4% or more by weight, 5% or more by weight, 6% or more by weight, 7% or more by weight, 8% or more by weight, 9% or more by weight, 10% or more by weight, 11% or more by weight, 12% or more by weight, 13% or more by weight, 14% or more by weight, 15% or more by weight, 16% or more by weight, 17% or more by weight, 18% or more by weight, 19% or more by weight, or 20% or more by weight. As shown in the experimental examples described later, a remarkable metal removal effect has been obtained by ingesting an oral composition containing 20% ​​by weight of calcium phosphate.

[0035] The above-mentioned composition relating to one aspect of the present invention may be used for the removal of metals and / or the suppression of metal absorption.

[0036] In this disclosure, "removal of metals" means removing metals that have entered the body from the body. Removal of metals from the body can occur, for example, by the excretion of metals that have entered the body. That is, removal of metals may result in an increase in the amount of metals excreted from the body compared to when the oral composition according to one aspect of the present invention is not used. Furthermore, in one preferred embodiment, the oral composition according to one aspect of the present invention can be suitably used as an oral composition for excreting metals that have entered the body from the body, in other words, as an oral composition for metal detoxification.

[0037] On the other hand, in this disclosure, "inhibition of metal absorption" means reducing the amount of metal absorbed into the body. Reducing the amount of metal absorbed into the body may mean that the amount of metal absorbed into the body is reduced compared to when the oral composition according to one aspect of the present invention is not used. Inhibition of absorption may, for example, be inhibition of absorption from the gastrointestinal tract, and more specifically, inhibition of absorption from the stomach or intestinal tract.

[0038] The removal and / or suppression of absorption of metals can be evaluated, for example, based on the blood concentration of the metals to be removed, the amount of metal deposition in tissues, and the like. When the metals are removed and / or their absorption is suppressed, the blood concentration of the metals to be removed and / or the amount of deposition in tissues decreases, and / or the increase in the blood concentration of the metals to be removed and / or the amount of deposition in tissues is suppressed. The methods for evaluating the blood concentration of metals and the amount of metal deposition in tissues are described, for example, in the experimental examples described later. However, the methods for evaluating the removal of metals or the suppression of metal absorption are not limited to these, and those skilled in the art can evaluate them by appropriate methods. For example, as shown in the experimental examples described later, it may be evaluated based on the amount of metal contained in feces.

[0039] The "metals" to be removed may be, for example, cadmium, strontium, barium, lead, zinc, magnesium, manganese, iron, radium, aluminum, yttrium, cesium, neodymium, lanthanum, chromium, arsenic, vanadium, uranium, germanium, etc., but are not limited thereto. Metal ions derived from the above metals can be incorporated into the crystal structure of calcium phosphate and co-precipitated. For example, when hydroxyapatite precipitates as calcium phosphate, cadmium ions (Cd 2+ ), strontium ions (Sr 2+ ), barium ions (Ba 2+ ), lead ions (Pb 2+ ), zinc ions (Zn 2+ ), magnesium ions (Mg 2+ ), manganese ions (Mn 2+ ), iron ions (Fe 2+ ), radium ions (Ra 2+ ), aluminum ions (Al 3+ ), yttrium ions (Y 3+ ), cesium ions (Ce 3+ ), neodymium ions (Nd 3+ ), lanthanum ions (La 3+ ) etc. are incorporated into the positions of calcium ions constituting hydroxyapatite, while arsenate ions (AsO43- ), vanadate ion (VO4 3- ), germanate ion (GeO4 4- These ions can be incorporated into the phosphate ions or hydroxide ions that make up the hydroxyapatite. However, this only shows a typical way in which metal ions are incorporated when hydroxyapatite precipitates as calcium phosphate, and the metal ions captured by the precipitated calcium phosphate do not necessarily have to be incorporated into the above positions.

[0040] Metals can accumulate in water, agricultural products, fish and shellfish, meat, etc., from wastewater, soil, cooking utensils, pipes, etc., and may enter the body when these are ingested. An oral composition according to one aspect of the present invention, which can remove metals and / or inhibit the absorption of metals, is particularly suitable for use in removing and / or inhibiting the absorption of orally ingested metals.

[0041] Furthermore, some metals can cause toxicity or poisoning symptoms if taken into the body in excess. Examples of diseases or symptoms caused by metals include, but are not limited to, bone diseases such as fractures, osteomalacia, and osteoporosis caused by cadmium, renal dysfunction, and anemia; digestive disorders, renal dysfunction, peripheral neuropathy, and central nervous system disorders caused by lead; digestive disorders caused by zinc; neurological disorders caused by mercury; digestive disorders, lung diseases, and peripheral circulatory disorders caused by arsenic; and central nervous system disorders and cerebral edema caused by tin. An oral composition relating to one aspect of the present invention, which can efficiently remove metals from the body, can be suitably used for detoxification of the above-mentioned metal toxicity, or for the prevention, mitigation, or treatment of one or more of the above-mentioned diseases or symptoms caused by metals.

[0042] Furthermore, if the metals are radioactive, for example, strontium, cesium, uranium, or radium, various diseases may occur due to the radiation emitted by the radioactive elements. The oral compositions according to one aspect of the present invention can also be suitably used to remove and / or suppress the absorption of radioactive metals. Unless otherwise specified, various diseases caused by radiation emitted by radioactive elements are also included in the metal toxicity and / or diseases or symptoms caused by metals as referred to in this disclosure.

[0043] An oral composition relating to one aspect of the present invention can be ingested simultaneously with or before or after consuming food and beverages such as water, agricultural products, or seafood that may contain the metals to be removed. Alternatively, it may be ingested daily by humans and animals other than humans who may ingest food and beverages such as water, agricultural products, or seafood that may contain the metals to be removed.

[0044] An oral composition relating to one aspect of the present invention may be provided, for example, as a pharmaceutical product, a quasi-drug, or a food or beverage. Here, food and beverages may include functional foods, health foods, nutritional supplements, or medical foods.

[0045] More specific forms of oral compositions relating to one aspect of the present invention include, but are not limited to, ice cream, wafers, nutritional drinks, nutritional bars, oatmeal, candy, cookies, gummies, granola, cakes, coffee, cocoa, konpeito (sugar candy), cornflakes, rice crackers, jelly, snack foods, sports drinks, tablets, chocolate, near water, dairy beverages, bread, biscuits, bran, protein bars, potato chips, bolo (a type of biscuit), yogurt, and ramune (a type of soda). For example, they may be provided as solid formulations such as tablets, granules, capsules, and powders, or as liquid formulations such as liquids and syrups.

[0046] An oral composition according to one aspect of the present invention may contain other components besides calcium phosphate. For example, if an oral composition according to one aspect of the present invention is provided as a pharmaceutical or quasi-drug, it may further contain other pharmaceutically acceptable components (e.g., excipients, binders, bulking agents, disintegrants, surfactants, lubricants, dispersants, buffers, osmotic pressure regulators, pH adjusters, emulsifiers, preservatives, stabilizers, thickeners, flow improvers, flavoring agents, foaming agents, fragrances, coating agents, diluents, etc.). Furthermore, if an oral composition according to one aspect of the present invention is provided as a food, it may further contain other food-acceptable components (e.g., sweeteners, colorants, preservatives, thickeners, stabilizers, gelling agents, antioxidants, color fixatives, bleaching agents, antifungal agents, emulsifiers, leavening agents, seasonings, acidulants, bittering agents, glazing agents, nutritional fortifiers, fragrances, etc.).

[0047] In one preferred embodiment, the oral composition according to one aspect of the present invention may further optionally contain biocompatible metals, such as magnesium, iron, zinc, copper, selenium, chromium, manganese, and molybdenum. When the oral composition according to one aspect of the present invention contains these metals, it can remove harmful metals while supplying beneficial metals, making it extremely useful as an oral composition that can remove harmful metals while maintaining mineral balance.

[0048] <Methods for collecting metals> Next, a method for recovering metals according to another aspect of the present invention will be described. As shown in the experimental examples described later, by using an approach in which calcium phosphate containing the metal ions to be removed is precipitated on calcium phosphate particles, metals can be efficiently recovered even in a diluted environment such as the intestines. The method for recovering metals according to one aspect of the present invention is based on this finding discovered by the inventors.

[0049] A method for recovering metals according to one aspect of the present invention is: A step of precipitating calcium phosphate containing the metal ions on calcium phosphate particles in a liquid containing the metal ions derived from the aforementioned metals, and A step of separating the calcium phosphate particles from which the calcium phosphate containing the metal ions has precipitated, It is characterized by having the following features.

[0050] As described above, the method for recovering metals according to one aspect of the present invention includes a step of precipitating calcium phosphate containing metal ions derived from the metals to be recovered onto calcium phosphate particles in a liquid containing the metal ions, and in this respect, it differs from a method of simply adsorbing metal ions onto calcium phosphate particles. According to the above method according to one aspect of the present invention, in which calcium phosphate containing metal ions to be recovered is precipitated onto calcium phosphate particles, a larger amount of metal ions can be retained on the calcium phosphate particles and more stably compared to the case of simply adsorbing metal ions onto calcium phosphate particles, and metal ions can be recovered efficiently.

[0051] Furthermore, the above method relating to one aspect of the present invention differs from a method of precipitating calcium phosphate from scratch in a liquid containing metal ions derived from the metals to be recovered, that is, a method that does not use calcium phosphate particles. When precipitating calcium phosphate from scratch in a liquid that does not contain calcium phosphate particles, it is necessary to supply phosphate ions and calcium ions to the liquid at concentrations exceeding the supersaturation concentration in order to form calcium phosphate crystal nuclei. In contrast, when calcium phosphate particles, which serve as a scaffold for the precipitation of calcium phosphate, are provided, and calcium phosphate containing metal ions is precipitated on these calcium phosphate particles, the surface of the calcium phosphate particles provides a starting point for the generation of new crystals, so the crystal formation of calcium phosphate can occur more efficiently. For example, as shown in the experimental examples described later, the capture of metals by precipitation of calcium phosphate has been confirmed even in dilution environments such as mouse intestinal fluid.

[0052] Furthermore, when depositing calcium phosphate containing metal ions onto calcium phosphate particles, the deposits containing the metals to be recovered are deposited on the calcium phosphate particles. This offers the advantage of easily separating the metals by dissolving the area near the surface of the calcium phosphate particles. In contrast, when depositing calcium phosphate from scratch in a liquid without calcium phosphate particles, the metals to be recovered are not necessarily present on the surface of the deposited calcium phosphate but are incorporated into its interior. Therefore, to recover the metals trapped in the calcium phosphate, the entire calcium phosphate must be dissolved. Moreover, in such cases, an excess amount of phosphate and calcium ions is generally used, resulting in a low metal content in the deposited calcium phosphate, making it difficult to recover the metals trapped in it.

[0053] There are no particular limitations on the specific method for precipitating calcium phosphate containing metal ions on calcium phosphate particles in a liquid containing metal ions derived from the metals to be recovered. For example, precipitation may be carried out by maintaining the pH of the liquid containing the metal ions derived from the metals to be recovered and the calcium phosphate particles within a predetermined range in the presence of phosphate ions, calcium ions, and calcium phosphate particles. That is, in one preferred embodiment, the above method according to one aspect of the present invention may include the step of precipitating calcium phosphate containing the metal ions on the calcium phosphate particles by maintaining the pH of the liquid containing metal ions derived from the metals to be recovered within a predetermined range in the presence of phosphate ions, calcium ions, and calcium phosphate particles.

[0054] There are no particular restrictions on the predetermined range, and an appropriate range can be set depending on the type of calcium phosphate precipitated. For example, the lower limit may be pH 6.0, pH 6.2, pH 6.4, pH 6.6, pH 6.8, or pH 7.0 or higher, and the upper limit may be pH 9.0, pH 8.5, or pH 8.0 or lower. Many calcium phosphates are known to have low solubility and precipitate easily at pH levels above neutral. If the pH of the liquid containing metal ions derived from the metals to be recovered is not within the above range, typically if the pH is lower than the above pH, the pH may be adjusted using an appropriate base such as an aqueous sodium hydroxide solution.

[0055] Furthermore, a method for recovering metals according to one aspect of the present invention may include a step of adding calcium phosphate particles to a liquid containing metal ions derived from the metals to be recovered.

[0056] Furthermore, in one preferred embodiment, the calcium phosphate particles used in the above method according to one aspect of the present invention are preferably calcium phosphate particles treated with acid. That is, in one preferred embodiment, the above method according to one aspect of the present invention may include a step of treating calcium phosphate particles with acid. Calcium phosphate has the property of dissolving under acidic conditions (for example, Non-Patent Document 1). By treating calcium phosphate particles with acid, their surface partially dissolves, which increases the surface roughness and / or surface area, and can facilitate the formation of new calcium phosphate crystals on the calcium phosphate particles.

[0057] There are no particular restrictions on the specific method of treating calcium phosphate particles with acid, as long as the calcium phosphate particles do not completely dissolve. For example, the calcium phosphate particles may be immersed in an acidic liquid. That is, in one preferred embodiment, the above step of treating calcium phosphate particles with acid may be the step of immersing the calcium phosphate particles in an acidic liquid. The acidic liquid may be an acidic aqueous solution, and its pH may be, for example, pH 5.0, pH 4.0, pH 3.5, pH 3.0, pH 2.5, pH 2.0, pH 1.5, or pH 1.0 or less.

[0058] If the liquid containing metal ions derived from the metals to be recovered does not contain phosphate ions and / or calcium ions, phosphate ions and / or calcium ions may be added to the liquid. That is, in one preferred embodiment, the above method according to one aspect of the present invention may include a step of supplying phosphate ions and / or calcium ions to a liquid containing metal ions derived from the metals to be recovered.

[0059] There are no particular restrictions on the method of supplying phosphate ions, but for example, phosphoric acid and / or its salts may be added to a liquid containing metal ions derived from the metals to be recovered. The phosphate can be basically any type, but it is preferably a water-soluble phosphate. Examples of water-soluble phosphoric acid and / or its salts include, but are not limited to, ammonium phosphate, sodium phosphate, sodium hydrogen phosphate, potassium phosphate, pyrophosphate, sodium hexametaphosphate, etc. Similarly, there are no particular restrictions on the method of supplying calcium ions, but for example, a calcium salt may be added to a liquid containing metal ions derived from the metals to be recovered. The calcium salt can be basically any type, but it is preferably a water-soluble calcium salt. Examples of water-soluble calcium salts include, but are not limited to, calcium hydroxide, calcium acetate, calcium carbonate, calcium chloride, calcium citrate, calcium lactate, etc.

[0060] Furthermore, if the liquid containing metal ions derived from the metals to be recovered also contains phosphate ions and / or calcium ions, it is sufficient to use the phosphate ions and / or calcium ions contained in the liquid to precipitate calcium phosphate, so it is not always necessary to supply phosphate ions and / or calcium ions. Of course, even if the liquid containing metal ions derived from the metals to be recovered also contains phosphate ions and / or calcium ions, it goes without saying that phosphate ions and calcium ions may be supplied to facilitate the precipitation of calcium phosphate.

[0061] On the other hand, in one preferred embodiment, a method for recovering metals according to one aspect of the present invention may include the steps of immersing calcium phosphate particles in an acidic liquid and adding and / or mixing the acidic liquid in which the calcium phosphate particles were immersed with a liquid containing metal ions derived from the metals to be recovered. Since phosphate ions and calcium ions derived from calcium phosphate dissolve into the acidic liquid in which the calcium phosphate particles were immersed, by adding and / or mixing the acidic liquid in which the calcium phosphate particles were immersed with a liquid containing metal ions derived from the metals to be recovered, calcium phosphate particles can be added to the liquid, and phosphate ions and calcium ions can be supplied. For example, when calcium phosphate particles are ingested orally, phosphate ions and calcium ions derived from the calcium phosphate particles dissolve into the gastric juice, and it is thought that these are supplied to the intestines together with the calcium phosphate particles, thereby assisting in the precipitation of calcium phosphate in the intestines.

[0062] In one preferred embodiment, phosphate ions and calcium ions may be supplied by adding and / or mixing calcium phosphate particles to a liquid containing metal ions derived from the metals to be recovered and maintaining the pH of the liquid within a predetermined range. That is, in one preferred embodiment, the above method according to one aspect of the present invention may include the steps of adding and / or mixing calcium phosphate particles to a liquid containing metal ions derived from the metals to be recovered and maintaining the pH of the liquid within a predetermined range. There are no particular limitations on the predetermined range, but for example, it may be an acidic pH, and more specifically, it may be pH 5.0, pH 4.0, pH 3.5, pH 3.0, pH 2.5, pH 2.0, pH 1.5, or pH 1.0 or less. There are no particular limitations on the lower limit, but it is typically pH 1.0 or higher. If the pH of the liquid containing metal ions derived from the metals to be recovered is not within the above range, typically the pH is higher than the above pH, the pH may be adjusted using an appropriate acid such as hydrochloric acid or phosphoric acid.

[0063] Furthermore, if the method for recovering metals according to one aspect of the present invention includes the steps of adding and / or mixing calcium phosphate particles to a liquid containing metal ions derived from the metals to be recovered, and maintaining the pH of the liquid within a predetermined range, then after the first step, an appropriate base such as an aqueous sodium hydroxide solution can be added to the reaction solution to bring the pH of the reaction solution within the predetermined range, thereby precipitating calcium phosphate containing metal ions on the calcium phosphate particles.

[0064] In one preferred embodiment, the method according to one aspect of the present invention may include a step of separating calcium phosphate particles containing precipitated calcium phosphate. Here, separating calcium phosphate particles may mean separating the solid content contained in the liquid. Since the calcium phosphate particles containing precipitated calcium phosphate are solid, they can be subjected to solid-liquid separation treatment by appropriate methods. There are no particular limitations on the separation method, but for example, separation may be performed by centrifugation, filtration, decantation, filter press, screw press, roller press, belt press, etc. The separated calcium phosphate particles, or the solid content containing calcium phosphate particles, may be subjected to drying treatment as appropriate.

[0065] The separated calcium phosphate particles may be disposed of as is, such as by landfill, but in one preferred embodiment, metals may be separated from the separated calcium phosphate particles. That is, in one preferred embodiment, the method for recovering metals according to one aspect of the present invention may include a step of recovering metal ions from the separated calcium phosphate particles. In the method for recovering metals according to one aspect of the present invention, calcium phosphate containing metal ions derived from the metal to be recovered precipitates on the calcium phosphate particles, so the metal ions can be recovered by partially dissolving the separated calcium phosphate particles. In order to recover the metal ions, it is only necessary to dissolve the vicinity of the surface of the calcium phosphate particles, and it is not necessary to completely dissolve the calcium phosphate particles, so there is an advantage in that metal ions can be recovered at a relatively high concentration. After the recovery of metal ions, the remaining calcium phosphate particles may be used again for recovering metals, etc.

[0066] There are no particular restrictions on the specific method for partially dissolving calcium phosphate particles, but for example, the calcium phosphate particles may be treated with an acid and / or a chelating agent. Examples of chelating agents that can be used include, but are not limited to, ethylenediaminetetraacetic acid (EDTA), etidronic acid, pentetic acid, metaphosphoric acid, citric acid, phytic acid, and their salts. By treating calcium phosphate particles, which have precipitated calcium phosphate containing metal ions derived from the metals to be recovered, with an aqueous solution containing an acid and / or a chelating agent, a mixed solution containing phosphate ions, calcium ions, and metal ions derived from the metals to be recovered is obtained.

[0067] Furthermore, in one preferred embodiment, the method relating to one aspect of the present invention may further include a step of separating and / or recovering metal ions from a mixture containing metal ions derived from the metals to be recovered. The separation and / or recovery of metal ions can be, for example, performed by column chromatography or solvent extraction, but is not limited to these. The method may also include a step of concentrating the metal ions before and / or after separation and recovery.

[0068] The metals to be recovered may, but are not limited to, cadmium, strontium, barium, lead, zinc, magnesium, manganese, iron, radium, aluminum, yttrium, cesium, neodymium, lanthanum, chromium, arsenic, vanadium, uranium, and germanium. For example, it can also be suitably used to recover rare earth elements such as scandium, yttrium, lanthanum, cerium, praseodymium, neodymium, promethium, samarium, gadolinium, terbium, dysprosium, holmium, erbium, thulium, ytterbium, and lutetium.

[0069] Liquids containing metal ions derived from metals can be basically any liquid as long as they contain metal ions derived from metals, but typically they are aqueous solutions containing metal ions derived from metals, such as bodily fluids like gastric juice, intestinal juice, and saliva, wastewater and treated water discharged from factories, power plants, or mines, river water, seawater, lake water, and well water. These liquids may be concentrated and purified as appropriate.

[0070] The present invention will be described in more detail below using experimental examples, but the scope of the present invention is not limited to these experimental examples.

[0071] Experiment 1: Synthesis of calcium phosphate particle-containing powder Calcium phosphate particles were synthesized by a wet process according to a conventional method. First, while stirring with a magnetic stirrer, 28% aqueous ammonia was added to an aqueous solution of calcium nitrate tetrahydrate (Ca(NO3)2·4H2O) (42 mM, 800 mL) in a 1 L Erlenmeyer flask to adjust the pH of the aqueous solution to 10. To the pH 10 aqueous solution of calcium nitrate tetrahydrate, an aqueous solution of diammonium hydrogen phosphate ((NH4)2HPO4) (100 mM, 200 mL) was added, and the mixture was stirred with a magnetic stirrer at room temperature for 24 hours to obtain a dispersion containing calcium phosphate particles. Hydroxyapatite has a chemically hypothesis Ca / P ratio of 1.67, and can be synthesized by supplying Ca and P at the above concentrations. The calcium phosphate particles contained in the obtained dispersion were washed several times by centrifugation until the pH became neutral. The washed samples were dried overnight at 135°C, ground in a mortar, and passed through a sieve (mesh size: 160 μm, manufactured by Tokyo Screen Co., Ltd.). The resulting powder was baked at 800°C for 1 hour to obtain a powder containing calcium phosphate particles.

[0072] The calcium phosphate particle-containing powder obtained in Experiment 1 was analyzed using scanning electron microscopy (SEM) and energy-dispersive X-ray spectroscopy (SEM-EDX). The powder was found to be a mixture of rod-shaped and spherical particles, with a Ca / P ratio of 1.66. This Ca / P ratio was in close agreement with the theoretical Ca / P ratio of 1.67 for hydroxyapatite (Figure 1). Furthermore, when the calcium phosphate particle-containing powder obtained in Experiment 1 was analyzed by powder X-ray diffraction (XRD), a diffraction peak corresponding to hydroxyapatite was observed, as shown in Figure 2A (labeled "HAp untreated" in Figure 2). These results indicate that the calcium phosphate particle-containing powder obtained in Experiment 1 mainly contains hydroxyapatite as calcium phosphate.

[0073] Experiment 2: Behavior of calcium phosphate particles in a gastrointestinal tract model The behavior of calcium phosphate particles in the digestive tract was investigated using model solutions that mimicked gastric and intestinal fluids. First, a 0.03 mol / L NaCl aqueous solution was prepared, and its pH was adjusted to 3.0, 4.0, or 5.0 using 6 mol / L HCl to create gastric fluid model solutions (GFM). 1.60 g or 0.16 g of the calcium phosphate particle-containing powder obtained in Experiment 1 was immersed in 40 mL of the gastric fluid model solution, and the mixture was shaken at 50 rpm at 37°C for 2 hours. During this time, the pH of the sample was maintained at 3.0, 4.0, or 5.0 by adding 6.00 mol / L HCl or 1.00 mol / L NaOH as needed. The precipitate in the gastric fluid model solution was collected by centrifugation, dried overnight at 37°C, and then weighed. It was also subjected to analysis by XRD and SEM.

[0074] Furthermore, in the same procedure as described above, 1.60 g or 0.16 g of the calcium phosphate particle-containing powder obtained in Experiment 1 was immersed in 40 mL of gastric juice mimicry solution, and after shaking at 50 rpm for 2 hours at 37°C, the pH of the gastric juice mimicry solution was adjusted to 7.0 using 1.00 mol / L NaOH (intestine fluid model (IFM)). Immediately after adjusting the pH to 7.0, the precipitate in the intestine fluid mimicry solution was collected by centrifugation, dried overnight at 37°C, and then weighed. It was also subjected to analysis by XRD and SEM.

[0075] The amount of calcium phosphate particles dissolved in the gastric juice mimicry solution or intestinal juice mimicry solution was determined according to the following formula. Amount of dissolved inorganic particles (%) = (W0 - W) i ) / W0× 100% In the formula, W0 is the initial weight (g) of the inorganic particles, W i This represents the weight (g) of the recovered inorganic particles.

[0076] Figure 2A shows the X-ray diffraction patterns of the powder recovered after immersion in a gastric juice mimicry solution at pH 3.0, 4.0, or 5.0 for a predetermined time. As shown in Figure 2A, diffraction peaks corresponding to hydroxyapatite (diffraction peaks indicated as "H" in Figure 2A) were detected in all powders recovered after immersion in the gastric juice mimicry solutions at pH 3.0, 4.0, and 5.0. Furthermore, the presence of residual hydroxyapatite particles was confirmed by SEM (Figure 3). These results indicate that even after immersion in a gastric juice mimicry solution at pH 3.0, 4.0, or 5.0 for a predetermined time, the hydroxyapatite in the powder does not completely dissolve and retains its structure as hydroxyapatite.

[0077] On the other hand, Figure 2B shows the X-ray diffraction patterns of the powder recovered after being immersed in a gastric juice mimicry solution at pH 3.0, 4.0, or 5.0, and then in an intestinal juice mimicry solution at pH 7.0. As shown in Figure 2B, diffraction peaks corresponding not only to hydroxyapatite (HAp) but also to dicalcium phosphate dihydrate (DCPD) were detected in the powder recovered after being immersed in a gastric juice mimicry solution at pH 3.0 and then in an intestinal juice mimicry solution at pH 7.0 (indicated as "HAp 1.60-g pH 3.0 to 7.0" and "HAp 0.16-g pH 3.0 to 7.0" in Figure 2B) (diffraction peaks indicated as "D" in Figure 2B). SEM also confirmed that hydroxyapatite and dicalcium phosphate dihydrate were present on the surface of the particles constituting the powder recovered after being immersed in a gastric juice mimicry solution at pH 3.0 and then in an intestinal juice mimicry solution at pH 7.0 (Figure 3). On the other hand, no diffraction peaks corresponding to dicalcium phosphate were detected in the powder recovered after immersion in a gastric juice mimicry solution with pH 4.0 or 5.0, and then in an intestinal juice mimicry solution with pH 7.0 (Figure 2B), and no precipitation of dicalcium phosphate dihydrate was confirmed by SEM (Figure 3).

[0078] Furthermore, Figure 4 shows the results of evaluating the amount of calcium phosphate particles dissolved in a gastric juice mimic solution with a pH of 3.0, 4.0, or 5.0 after immersion for a predetermined time, and the amount dissolved in an intestinal juice mimic solution with a pH of 7.0 after further immersion for a predetermined time. As shown in Figure 4, calcium phosphate particles dissolved in the gastric juice mimic solution, which is an acidic aqueous solution, and the amount dissolved increased as the pH of the gastric juice mimic solution decreased from 5.0, 4.0, to 3.0. On the other hand, when the pH was adjusted to 7.0 after immersion in the gastric juice mimic solution for a predetermined time to create an intestinal juice mimic solution, the amount of calcium phosphate particles dissolved decreased significantly. This result indicates the reprecipitation of calcium phosphate in the intestinal juice mimic solution.

[0079] On the other hand, when the same experiment was conducted using activated carbon powder instead of the calcium phosphate particle-containing powder prepared in Experiment 1, the dissolution and reprecipitation behavior due to pH changes observed with calcium phosphate was not observed (Figure 4).

[0080] Experiment 3: Cadmium removal in a gastrointestinal tract model The effect of calcium phosphate particle-containing powder on removing cadmium (Cd) from the digestive tract was investigated using the gastric juice mimicry solution and intestinal juice mimicry solution prepared in Experiment 2. Specifically, a cadmium chloride (CdCl2) aqueous solution was added to the gastric juice mimicry solution used in Experiment 2 to prepare a cadmium-containing aqueous solution with a final cadmium concentration of 5-1,000 mg / L. 0.16 g of calcium phosphate powder or activated carbon powder prepared in Experiment 1 was added to 40 mL of this cadmium-containing aqueous solution. The pH of the aqueous solution at this time was 3.0. This aqueous solution was shaken for 2 hours at 37°C and 50 rpm, and then the pH was adjusted to 7.0 using a 1.00 mol / L sodium hydroxide (NaOH) aqueous solution. After adjusting the pH to 7.0, the supernatant was immediately collected by centrifugation (4,000 g; 10 min), and the cadmium concentration in the collected supernatant was determined using an atomic absorption spectrophotometer (AAS) (model: Z-9000, manufactured by Hitachi, Ltd.).

[0081] The results obtained are shown in Figure 5. As shown in Figure 5, when activated carbon powder was used, the cadmium recovery efficiency by simply immersing the activated carbon powder in a cadmium-containing aqueous solution was approximately 67% at a cadmium concentration of 1,000 mg / L (in Figure 5, "AC pH 7.0"). Furthermore, no change in cadmium recovery efficiency was observed even when the pH was changed from 3.0 to 7.0 (in Figure 5, "AC pH 3.0 to 7.0").

[0082] In contrast, when the calcium phosphate particle-containing powder prepared in Experiment 1 was used, the cadmium recovery efficiency at a constant pH of 7.0 was approximately 81% at a cadmium concentration of 1,000 mg / L (indicated as "HAp pH 7.0" in Figure 5), and the cadmium recovery efficiency reached approximately 97% when the pH was changed from 3.0 to 7.0 (indicated as "HAp pH 3.0 to 7.0" in Figure 5). These results indicate that calcium phosphate can exhibit particularly excellent metal recovery capabilities in the gastrointestinal environment with pH changes, suggesting that the dissolution and reprecipitation of calcium phosphate due to pH changes in the gastrointestinal environment is involved.

[0083] Experiment 4: Investigation of the behavior of calcium phosphate particles in the gastrointestinal tract The behavior of calcium phosphate particles in the digestive tract was investigated in a mouse model. First, 6-week-old male ICR mice (Nippon SLC Co., Ltd.) were housed for one week to acclimate to the environment. After fasting for 18 hours, the mice were divided into five groups. Group 1 was given a normal diet ("control" group), Group 2 a diet containing 2 wt% activated carbon ("2% AC-diet" group), Group 3 a diet containing 20 wt% activated carbon ("20% AC-diet" group), Group 4 a diet containing 2 wt% calcium phosphate particle powder prepared in Experiment 1 ("2% HAp-diet" group), and Group 5 a diet containing 20 wt% calcium phosphate particle powder prepared in Experiment 1 ("20% HAp-diet" group). Each group was given for one hour, and the contents of the stomach and small intestine, as well as feces, were collected after 3 hours. The recovered stomach and small intestine contents were washed with 0.9% NaCl and dried overnight at 37°C. The dried contents were subjected to analysis by powder X-ray diffraction.

[0084] The results obtained are shown in Figure 6. As shown in Figure 6, diffraction peaks corresponding to hydroxyapatite were observed in the stomach contents as well. This result indicates that calcium phosphate particles do not completely dissolve in gastric juice and retain their structure as hydroxyapatite. On the other hand, diffraction peaks corresponding to hydroxyapatite were observed more clearly in the contents of the small intestine and feces than in the stomach contents. This result suggests partial dissolution of calcium phosphate particles in the stomach and reprecipitation of calcium phosphate in the small intestine and feces.

[0085] Experiment 5: Examination of the effect of metal removal in a mouse model. The metal removal effect of calcium phosphate particles was investigated in a mouse model. First, six-week-old male ICR mice (manufactured by Nippon SLC Co., Ltd.) were reared for one week to allow them to adapt to the environment. Subsequently, the mice were divided into six groups: Group 1 received normal diet and drinking water ("control" group), Group 2 received normal diet and drinking water containing 100 mg / mL of cadmium ("Cd100 + Normal diet" group), Group 3 received diet containing 2 wt% activated carbon and drinking water containing 100 mg / mL of cadmium ("Cd100 + 2% AC-diet" group), Group 4 received diet containing 20 wt% activated carbon and drinking water containing 100 mg / mL of cadmium ("Cd100 + 20% AC-diet" group), Group 5 received diet containing 2 wt% of the calcium phosphate particle powder prepared in Experiment 1 and drinking water containing 100 mg / mL of cadmium ("Cd100 + 2% HAp-diet" group), and Group 6 received diet containing 20 wt% of the calcium phosphate particle powder prepared in Experiment 1 and 100 mg / mL of cadmium. The group was given drinking water containing mg / mL of cadmium ("Cd100 + 20% HAp-diet") and reared for 4 weeks. Various evaluations were performed during and after rearing.

[0086] <5-1. Excretion of cadmium from feces> Each group was fed once a day, and feces were collected from the cages daily. Cadmium in the collected feces was quantified using an atomic absorption spectrophotometer (AAS) (model: Z-9000, manufactured by Hitachi, Ltd.).

[0087] Figure 7 shows photographs of the collected feces and the results of the quantification of cadmium contained in the collected feces. As shown in Figure 7, the feces of the groups fed with the diet containing calcium phosphate particle powder prepared in Experiment 1 (the "Cd100 + 2%HAp-diet" group and the "Cd100 + 20%HAp-diet" group in the figure) and the groups fed with the diet containing activated carbon (the "Cd100 + 2%AC-diet" group and the "Cd100 + 20%AC-diet" group in the figure) excreted a larger amount of Cd compared to the group fed with a normal diet that did not contain either calcium phosphate or activated carbon (the "Cd100 + Normal diet" group in the figure). Here, in the groups fed with the diet containing calcium phosphate particle powder, the amount of Cd contained in the feces and excreted from the body was greater in both the 2wt% and 20wt% concentrations compared to the group fed with a diet containing the same concentration of activated carbon. These results indicate that, when ingested orally, calcium phosphate powder can remove metals that have entered the body, including cadmium, more efficiently than activated carbon.

[0088] <5-2. Cadmium concentrations in blood and tissues> After four weeks of rearing, the mice were fasted for 12 hours, and then blood was collected from the stomach, heart, brain, kidneys, liver, lungs, spleen, femur, vertebrae, intestines, and submandibular veins according to standard procedures. All tissues other than blood were washed with phosphate-buffered saline (PBS), weighed, and stored at -80°C until testing. Meanwhile, plasma was separated from the collected blood by centrifugation at 3000 rpm at room temperature for 15 minutes, and the resulting plasma was stored at -80°C until testing. Each tissue sample was treated with 69% nitric acid (HNO3) overnight at room temperature, and then digested by heating at 70°C for 4 hours. The resulting solutions were diluted with ultrapure water as appropriate, cooled to room temperature, and stored at 4°C until testing. Cadmium and calcium in the lysates of each tissue and in the plasma were quantified according to standard procedures using an atomic absorption spectrophotometer (AAS) (model: Z-9000, manufactured by Hitachi, Ltd.).

[0089] Figure 8 shows the quantitative results of calcium and cadmium levels in the blood. As shown in Figure 8, the blood cadmium concentrations in the group fed with feed containing calcium phosphate particle powder and the group fed with feed containing activated charcoal were lower than those in the group fed with regular feed containing neither calcium phosphate nor activated charcoal. It is thought that feeding with feed containing calcium phosphate particle powder or activated charcoal promotes the excretion of cadmium contained in ingested drinking water from the body, thereby lowering blood cadmium concentrations. The decrease in blood cadmium concentrations was particularly pronounced in the group fed with feed containing calcium phosphate particle powder; even when fed with feed containing 2 wt% calcium phosphate particle powder, the blood cadmium concentration was lower than in the group fed with feed containing 20 wt% activated charcoal. This result indicates that calcium phosphate particle powder can excrete cadmium from the body more efficiently than activated charcoal, thereby lowering blood cadmium concentrations.

[0090] On the other hand, Figure 9 shows the quantitative results of cadmium in each recovered tissue. As shown in Figure 9, the cadmium concentration in each tissue of the group fed with feed containing calcium phosphate particle powder and the group fed with feed containing activated carbon was lower compared to the group fed with feed containing neither calcium phosphate nor activated carbon. This result indicates that feeding with feed containing calcium phosphate particle powder or activated carbon reduces the amount of cadmium accumulated in the tissue. Furthermore, the reduction in the amount of cadmium accumulated in each tissue was particularly pronounced in the group fed with feed containing calcium phosphate particle powder. This result suggests that calcium phosphate particle powder is superior to activated carbon in its ability to suppress the deposition of cadmium and other metals that have entered the body.

[0091] <5-3. Histological evaluation> Tissue sections were prepared from the tissues (liver and kidney) recovered using the procedure described above, according to standard methods. Specifically, the recovered tissues were fixed with 4% PFA (paraformaldehyde), embedded in paraffin wax, and cut into 5 μm thick sections. After staining the sections with hematoxylin and eosin, tissue / cellular changes were observed using a microscope (ECLIPSE Ti2, Nikon Corporation).

[0092] Stained tissue sections of liver tissue are shown in Figure 10, and stained tissue sections of kidney tissue are shown in Figure 11. As shown in Figures 10 and 11, in the group that was given water containing a predetermined amount of cadmium and fed a normal diet, cadmium deposition was clearly observed in both the kidneys and livers, and deformation of the cellular structure of the tissues, as well as coagulation necrosis (indicated by arrows in the figures) and glomerular necrosis (indicated by circles in the figures) were observed. In contrast, in the group that was fed a diet containing calcium phosphate particle powder, in particular the group that was fed a diet containing 20 wt% calcium phosphate particle powder, these histological changes were significantly suppressed. This result indicates that cadmium deposition in tissues is suppressed by a diet containing calcium phosphate particle powder.

[0093] <5-4. Evaluation of cadmium concentration in the femur> The inorganic ion content of the recovered femurs was evaluated using an atomic absorption spectrophotometer (AAS) (model: Z-9000, manufactured by Hitachi, Ltd.) according to a standard procedure.

[0094] As shown in Figure 12, in the control group given drinking water containing cadmium, a significant increase in cadmium content was observed in the femur, confirming cadmium deposition in the femur. In contrast, in the groups given feed containing calcium phosphate particle powder or activated carbon, the cadmium content in the femur was significantly reduced. The reduction in cadmium content was particularly pronounced in the group given feed containing calcium phosphate particle powder than in the group given feed containing activated carbon. This result indicates that calcium phosphate particle powder can excrete cadmium from the body more efficiently than activated carbon and can suppress cadmium deposition in bone tissue, including the femur.

[0095] <5-5.3-point bending test> The bone tissue was collected and subjected to a three-point bending test according to standard procedures to evaluate bone strength. The results are shown in Figure 13.

[0096] As shown in Figure 13, the group given drinking water containing cadmium and a normal diet (labeled "cd group" in Figure 13) showed a significant decrease in bone strength compared to the control group. In contrast, the group given a diet containing calcium phosphate particle powder did not show a significant decrease in bone strength, and normal bone strength was maintained. On the other hand, the group given a diet containing activated charcoal showed almost no effect in maintaining bone strength. These results indicate that calcium phosphate particle powder is extremely useful in suppressing the decrease in bone strength caused by cadmium intake. [Industrial applicability]

[0097] Many metals exist in the environment that can cause toxicity or poisoning symptoms if absorbed in excess into the body. These metals can be ingested and accumulated in the human body through water, agricultural products, seafood, etc. The present invention, which can remove and recover such metals simply and efficiently, has great industrial potential.

Claims

1. An oral composition for removing metals, containing calcium phosphate as an active ingredient.

2. An oral composition containing calcium phosphate as an active ingredient for inhibiting the absorption of metals.

3. The composition according to claim 1 or 2, wherein the calcium phosphate comprises one or more selected from hydroxyapatite, tricalcium phosphate, tetracalcium phosphate, octacalcium phosphate, calcium hydrogen phosphate, and amorphous calcium phosphate.

4. The composition according to claim 3, comprising 1% by weight or more of the calcium phosphate.

5. The composition according to claim 3, wherein the particle size of the calcium phosphate is 0.5 μm to 500 μm.

6. The composition according to claim 3, wherein the aforementioned metals are one or more selected from cadmium, strontium, barium, lead, zinc, magnesium, manganese, iron, radium, aluminum, yttrium, cesium, neodymium, lanthanum, chromium, arsenic, vanadium, uranium, and germanium.

7. A method for recovering metals, A step of precipitating calcium phosphate containing metal ions derived from the aforementioned metals onto calcium phosphate particles in a liquid containing the aforementioned metals, A step of separating the calcium phosphate particles from which the calcium phosphate containing the metal ions has precipitated, A method characterized by comprising:

8. The method according to claim 7, wherein the calcium phosphate comprises one or more selected from hydroxyapatite, tricalcium phosphate, tetracalcium phosphate, octacalcium phosphate, calcium hydrogen phosphate, and amorphous calcium phosphate.

9. The method according to claim 8, characterized in that the calcium phosphate particles are calcium phosphate particles treated with acid.

10. The method according to claim 9, characterized in that the calcium phosphate particles treated with acid are calcium phosphate particles treated with an aqueous solution with a pH of 1 to 4 for a predetermined time.

11. The method according to any one of claims 7 to 10, comprising the step of partially dissolving the separated calcium phosphate particles to recover the metals and / or metal ions derived from the metals.

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