Hydroxyapatite

Abstract

This hydroxyapatite has high biocompatibility and is suitable for applications such as food additives, cosmetic raw materials, pharmaceutical raw materials, artificial bones, etc. The hydroxyapatite of the present invention contains Mg.

Description

Technical Field

[0001] The present invention relates to hydroxyapatite with high biocompatibility.

Background Art

[0002] Hydroxyapatite (Ca 10 (PO4)6(OH)2) is the main component of bone and teeth, and is a biomaterial with high biocompatibility, neutral pH, and high safety. Therefore, it is used in biomaterials such as industrial raw materials, food additives, cosmetic raw materials, pharmaceutical raw materials, and artificial bones.

[0003] Regarding the method for producing hydroxyapatite, there is a method in which a substrate into which a site for precipitating hydroxyapatite crystals is introduced is immersed in an aqueous solution containing a hydroxyapatite component to precipitate hydroxyapatite crystals on the surface of the substrate (Patent Document 1). Further, there is a method in which after applying or printing a predetermined hydroxyapatite dispersion liquid on a substrate, the solvent contained in the hydroxyapatite dispersion liquid is evaporated from the substrate to generate low-crystalline hydroxyapatite particles on the surface of the substrate (Patent Document 2).

Prior Art Documents

Patent Documents

[0004]

Patent Document 1

Patent Document 2

Summary of the Invention

Problems to be Solved by the Invention

[0005] Although hydroxyapatite has high biocompatibility as described above, in applications such as food additives, cosmetic raw materials, pharmaceutical raw materials, and artificial bones, the demand for those with high biocompatibility has been unceasing. Therefore, an object of the present invention is to provide hydroxyapatite having higher biocompatibility than conventional ones.

Means for Solving the Problems

[0006] The inventors of the present invention have conducted intensive studies to solve the above problems and have found that hydroxyapatite containing Mg has high biocompatibility, leading to the present invention.

[0007] That is, the present invention provides: [1] Hydroxyapatite containing Mg, [2] The hydroxyapatite of [1], including microcrystalline hydroxyapatite, [3] Represented by the chemical formula (Ca:Mg) 10 (PO4)6(OH)2 (In the above formula, (Ca:Mg) 10 means that the total number of elements of Ca and Mg is 10, Ca is 9 to 7, and Mg is 1 to 3.) The hydroxyapatite of [1] or [2] represented by [4] Hydroxyapatite of any one of [1] to [3], composed of a biologically-derived material, [5] Further, hydroxyapatite of any one of [1] to [4], containing at least one mineral selected from Na, K, and Si, is provided.

Effects of the Invention

[0008] The hydroxyapatite of the present invention has high biocompatibility by containing Mg.

Brief Description of the Drawings

[0009]

Figure 1

Modes for Carrying Out the Invention

[0010] Hereinafter, the hydroxyapatite of the present invention will be described more specifically. The hydroxyapatite of the present invention contains Mg (magnesium). Mg is a kind of mineral contained in living bone. In living bone, Mg has the effect of activating osteoblasts and osteoclasts and promoting bone cells. The hydroxyapatite of the present invention containing Mg having such an effect has higher biocompatibility in applications of biomaterials such as food additives, cosmetic raw materials, pharmaceutical raw materials, and artificial bone than conventional hydroxyapatite.

[0011] The Mg content is preferably in the range of about 100 to 20000 mass ppm within the range that can be included in the chemical formula described later. When the Mg content is 100 mass ppm or more, the effect of containing Mg appears well. The upper limit of the Mg content is not particularly limited, but about 20000 mass ppm is sufficient from the viewpoint of biocompatibility. The Mg content is more preferably 500 to 6000 mass ppm.

[0012] The hydroxyapatite of the present invention preferably contains microcrystalline hydroxyapatite. Microcrystalline hydroxyapatite means that it is only microcrystalline hydroxyapatite, or a mixture of microcrystalline hydroxyapatite and low-crystalline hydroxyapatite with a distorted crystal shape or crystal defects and a low degree of crystallization. That is, "microcrystalline hydroxyapatite" is not limited to the form of only microcrystalline hydroxyapatite, but also includes the form in which low-crystalline hydroxyapatite is mixed in microcrystalline hydroxyapatite. And the low-crystalline hydroxyapatite can be contained in the hydroxyapatite of the present invention at a ratio of 50% by mass or less.

[0013] Hydroxyapatite containing Mg and microcrystals does not have each molecule tightly bound together but only aggregated, so it shows a flexible reaction to other substances and has a greater adsorption capacity compared to the crystalline form. Furthermore, the particles are fine, the texture is smooth, and it does not cause irritation.

[0014] Microcrystalline hydroxyapatite, that is, hydroxyapatite that is only microcrystallized or a mixture of microcrystallized hydroxyapatite and low-crystalline hydroxyapatite with a low degree of crystallization can be identified by X-ray structure analysis. Specifically, in X-ray structure analysis, hydroxyapatite with a crystallite size of 10 - 200 Å at the peak where 2θ appears at 31.500 - 32.500° can be said to be hydroxyapatite that is only microcrystallized or a mixture of microcrystallized hydroxyapatite and low-crystalline hydroxyapatite with a low degree of crystallization. Note that the crystallite size represents the size of crystallites and is a numerical value serving as a measure of crystallinity. The larger the numerical value of the crystallite size, the higher the crystallinity of the substance being measured. Conversely, the smaller the numerical value of the crystallite size, the lower the crystallization or the more microcrystalline the hydroxyapatite is. The crystallite size can be measured, for example, by an X-ray analyzer, model number: RINT2200V / PC, manufactured by Rigaku Corporation. Preferably, the crystallite size of the peak where 2θ appears at 31.500 - 32.500° is 30 - 150 Å, more preferably 50 - 120 Å.

[0015] In X-ray structural analysis, since the crystallite size of the peak appearing at 2θ of 31.500 to 32.500° is within the above range for hydroxyapatite, the surface of the hydroxyapatite is complex and charged with surface potential. As a result, the adsorption force is large, and it has excellent adsorption rates for proteins, lipids, bacteria, pollen, etc., so it is suitable for use in filters, etc. Also, since it adsorbs dyes, it is effective for tooth whitening. Further, hydroxyapatite with a crystallite size within the above range can be made into hydroxyapatite with fine particles, a smooth texture, and little irritation.

[0016] Hydroxyapatite containing Mg has, in terms of chemical formula, (Ca:Mg) 10 (PO4)6(OH)2 (In the above formula, (Ca:Mg) 10 means that the total number of elements of Ca and Mg is 10, Ca is 9 to 7, and Mg is 1 to 3.) It is preferably represented by. That is, it is preferably a structure in which a part of Ca constituting the hydroxyapatite is replaced by Mg.

[0017] The hydroxyapatite of the present invention is preferably made of a bio-derived material. Conventionally known hydroxyapatite is synthesized and manufactured by various production methods using slaked lime derived from minerals as the main raw material. And hydroxyapatite using slaked lime derived from minerals as the main raw material contains almost no mineral components typified by Mg, and thus has lower biocompatibility than the hydroxyapatite of the present invention. In contrast, the hydroxyapatite of the present invention made of a bio-derived material can contain an appropriate amount of Mg, and the above-described effects of the hydroxyapatite of the present invention can be obtained. For example, by firing a bio-derived material, calcium oxide can be obtained, and by treating it by the following method, the hydroxyapatite of the present invention can be obtained. The firing conditions are not particularly limited, and known conditions can be adopted. Examples of the firing conditions include firing at a temperature of 900 to 1300°C for 1 to 72 hours using an electric furnace or the like. Moreover, by being made of a biologically-derived material, it can be made into hydroxyapatite that is safe for the human body even for oral administration or for consumption, such as for use as a calcium supplement.

[0018] Examples of the biologically-derived material include eggshells and corals. Among them, eggshells are more preferable because they have a higher Mg content than other biological materials.

[0019] The hydroxyapatite of the present invention preferably further contains at least one mineral selected from Na, K, and Si. Na (sodium) is a mineral involved in bone metabolism, resorption processes, and cell adhesion. K (potassium) is a mineral involved in many functions in biochemical reactions. Si (silicon) acts on the metabolic mechanism involved in bone formation and is involved in the expression of bone cells and engagement cells. Therefore, hydroxyapatite containing at least one of these minerals has better biocompatibility. Hydroxyapatite made of a biologically-derived material contains Mg and at least one mineral selected from Na, K, and Si. Therefore, hydroxyapatite containing 100 mass ppm or more of Mg and at least one mineral selected from Na, K, and Si is presumed to be made of the above-mentioned biologically-derived material.

[0020] The content of each of Na, K, and Si is not particularly limited. For example, it is preferable that Na contains about 100 to 5000 mass ppm, K contains about 10 to 100 mass ppm, and Si contains about 10 to 100 mass ppm, respectively, because the above effects can be sufficiently obtained. In addition, hydroxyapatite made of a biologically-derived material can contain at least one of Na, K, and Si within the above range with respect to the Mg content due to the mineral balance, so the above effects can be sufficiently obtained, and it is also a preferable material in this regard.

[0021] At least one mineral selected from Na, K, and Si can be incorporated into hydroxyapatite, for example, by producing hydroxyapatite using the aforementioned bio-derived material containing Na, K, and Si.

[0022] The method for producing the hydroxyapatite of the present invention is not particularly limited. For example, an aqueous or alcoholic solution of phosphoric acid is added to an aqueous or alcoholic suspension of calcium oxide obtained by calcining the above-mentioned bio-derived material, or an aqueous or alcoholic suspension of calcium oxide is added to an aqueous or alcoholic solution of phosphoric acid to obtain a hydroxyapatite slurry. This hydroxyapatite slurry can be applied or printed on a substrate and evaporated, or the slurry can be evaporated as it is to obtain hydroxyapatite particles. At this time, by using a bio-derived material as the raw material of calcium oxide in the calcium oxide suspension, hydroxyapatite containing Mg can be easily produced.

[0023] When preparing the hydroxyapatite slurry, it is not necessary to adjust the pH. Also, the ratio of the total amount of calcium oxide in the calcium oxide suspension to the total amount of phosphoric acid in the phosphoric acid solution is preferably, for example, such that the molar ratio of calcium ions:phosphate ions is 10:6. Of course, it is also possible to change the ratio depending on reaction conditions and the like. Adjustment of such a molar ratio can be achieved by adjusting the concentration and amount of the added solution and the solution to be added.

[0024] The temperature conditions when adding the added solution to the solution to be added are preferably, for example, such that the temperatures of the added solution and the solution to be added are in the range of 5 to 90°C, more preferably in the range of 15 to 60°C, and even more preferably in the range of 20 to 40°C. By setting the temperatures of the added solution and the solution to be added within such a range, the crystallization of hydroxyapatite can be suppressed, and the effect of smoothly progressing the reaction for obtaining hydroxyapatite can be obtained. It is also possible to add the added solution while stirring the solution to be added.

[0025] When evaporating the hydroxyapatite slurry, it is not particularly necessary to heat it, and it may be evaporated by natural drying at ambient temperature. However, in order to achieve good production efficiency and promote the low crystallization of fine crystallized apatite, the substrate or the slurry may be heated during and / or after evaporation of the solvent. The heating temperature when heating the substrate is preferably 40 to 300 °C, more preferably 40 to 180 °C, and even more preferably 80 to 150 °C. By setting the heating temperature within the above range, low-crystalline hydroxyapatite particles with an appropriate particle size can be formed on the substrate surface, and the detachment of the low-crystalline hydroxyapatite particles from the substrate surface can be suppressed. There is no particular limitation on the heating time, and it may be carried out until low-crystalline hydroxyapatite particles are formed on the substrate surface. However, if the substrate after coating or printing is heated excessively, there is a risk that the low-crystalline hydroxyapatite will change into crystalline hydroxyapatite. Since low-crystalline hydroxyapatite is superior in the performance of adsorbing minute biological substances such as bacteria and pollen and heavy metal substances, etc. compared to crystalline hydroxyapatite, as a guideline for heating conditions, for example, when heating at a temperature of 100 °C or higher, it is preferable to set the heating time to 720 minutes or less to suppress the change of low-crystalline hydroxyapatite into crystalline hydroxyapatite.

Example

[0026] Hereinafter, the content of the present invention will be described in more detail with reference to examples. Needless to say, the scope of the present invention is not limited by the examples.

[0027] (Test 1) Hydroxyapatite was prepared using eggshells baked at 1000°C for 20 hours as the CaO raw material, and hydroxyapatite was prepared using coral baked at 1000°C for 20 hours as the CaO raw material. In addition, commercially available hydroxyapatite (reagent) was prepared for comparison. These hydroxyapatites were analyzed for trace elements using an ICP emission spectrometer (Shimadzu Corporation ICPS-8100). For the analysis, standard solutions of Mg, Na, and K, each of which was 1000 ppm, manufactured by Wako Pure Chemical Industries, were used as reagents. In addition, 1.00 g of each sample was placed in a 50 mL measuring flask, dissolved in a small amount of hydrochloric acid, and then the solution was measured after being made up to 50 mL by measuring. The analysis results are shown in Table 1. The values in Table 1 indicate mass ppm (mg / kg).

[0028] [Table 1]

[0029] As can be seen from Table 1, hydroxyapatite made from biological raw materials contains Mg. In particular, hydroxyapatite derived from eggshells has a high Mg content, close to the 5,500 ppm Mg content found in human bones, suggesting that it has high biocompatibility.

[0030] (Experiment 2) The bioactivity of eggshell-derived hydroxyapatite was evaluated using simulated body fluid (SBF). In this evaluation, samples were immersed in the simulated body fluid (SBF) and the amount of hydroxyapatite formed on the sample surface after a certain period of time was measured. The simulated body fluid has an inorganic ion concentration almost equal to that of human body fluid, and was prepared from the following components.

[0031] NaCl: 7.996 g, NaHCO3: 0.350 g, KCl: 0.224 g, K2HPO4·3H2O: 0.228 g, MgCl2·6H2O: 0.350 g, 1 M HCl: 40 mL, CaCl2·2H2O: 0.278 g, NaSO4: 0.071 g, Tris (buffer, tris(hydroxymethyl)aminomethane): 6.057 g. These reagents were added to 700 mL of distilled water, adjusted to pH 7.4, and then distilled water was added to make 1000 mL.

[0032] As the hydroxyapatite for performing the bioactivity evaluation, hydroxyapatite (hydroxyapatite A. Containing 1974 ppm of Mg) produced using eggshells calcined at 1000 °C for 20 hours as the raw material of CaO and hydroxyapatite (hydroxyapatite B. Containing no Mg) produced using reagent Ca(OH)2 (manufactured by Wako Pure Chemical Industries, Ltd., purity 99%) calcined at 1000 °C for 20 hours as the raw material of CaO were prepared as slurries.

[0033] The slurries of hydroxyapatite A and hydroxyapatite B were each applied to 6 pieces of felt cloth with a size of 1 cm × 5 cm, dried at 120 °C for 2 hours, and hydroxyapatite particles were generated on the felt cloth to obtain samples. The mass of the generated hydroxyapatite particles was calculated by measuring the mass of the felt cloth before and after generation.

[0034] Each sample was immersed one by one in 50 mL of simulated body fluid and left at 37 °C for 7 days. Then, the sample was taken out from the simulated body fluid, dried at 130 °C for 2 hours, and then stored in a desiccator. After that, the mass of each sample was measured to calculate the mass increase of hydroxyapatite. The measurement results of hydroxyapatite A are shown in Table 2.

[0035]

Table 2

[0036] The measurement results of hydroxyapatite B are shown in Table 3.

Table 3

[0037] The percentage of the mass increase after immersion relative to the mass of hydroxyapatite before immersion is defined as the increase rate. The average increase rate of hydroxyapatite A derived from eggshell shown in Table 2 is 1.84%, and the amount of hydroxyapatite generated in simulated body fluid was larger compared to the average increase rate of 1.06% of hydroxyapatite B shown in Table 3. This means that hydroxyapatite A containing Mg has higher biocompatibility than hydroxyapatite B not containing Mg. The results of Table 2 and Table 3 are shown graphically in Fig. 1.

Claims

【Claim 1】 A step of firing calcium carbonate derived from eggshells to obtain calcium oxide, A step of adding a water or alcohol suspension of phosphoric acid to a water or alcohol suspension of calcium oxide under temperature conditions of 15 to 60°C, A step of heating at 80 to 150°C when evaporating the solvent of the water or alcohol suspension, A method for producing hydroxyapatite, comprising: The hydroxyapatite contains hydroxyapatite having a crystallite size of 50 to 120 Å calculated from a peak at 2θ = 31.500 to 32.500° in X-ray diffraction using CuKα radiation as a radiation source, and further contains 500 to 6000 ppm by mass of Mg, 100 to 5000 ppm by mass of Na, 10 to 100 ppm by mass of K, and 10 to 100 ppm by mass of Si. A method for producing hydroxyapatite.

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