Method for producing metal-containing compound particles and metal-containing compound particles

Abstract

The objective is to provide a method for manufacturing metal-containing compound particles such as hydroxyapatite, which have nanoscale and microscale surface irregularities, while controlling the size and variation of surface irregularities, shape, and crystallinity with high precision. [Solution] A method for producing metal-containing compound particles, comprising a primary granulation step of spray-drying and granulating a slurry containing a metal-containing compound raw material to obtain a primary granule, and a secondary granulation step of spray-drying and granulating a slurry containing the primary granule to obtain a secondary granule.

Description

[Technical Field]

[0001] The present invention relates to a method for producing metal-containing compound particles and to metal-containing compound particles. [Background technology]

[0002] Metal-containing compound particles, which have metal atoms as their constituent components, are useful materials used in various fields such as optical materials, electronic materials, medical supplies, and cosmetics. Hydroxyapatite (HAP), one type of metal-containing compound, has the chemical formula Ca 10 Hydroxyapatite is a type of calcium phosphate represented as (PO4)6(OH)2, and because it has a composition very similar to that of human bones and teeth, it has very high biocompatibility and is widely used as a biomaterial in fields such as artificial bones, implants, and tooth polishing agents. Market research by Precedence Research predicts that the global demand for hydroxyapatite will surge due to aging, the expansion of regenerative medicine, and the demand for implants, with a projected market growth of approximately $4.94 billion (CAGR: 6.54%) from 2025 to 2034.

[0003] Hydroxyapatite particles can either bind with newly formed bone in the body (osteoconductive) or be regenerated into new bone after being absorbed (bone remodeling). Therefore, they are used in bone graft materials, implant materials, biomaterial fillers, and medical coatings to regenerate areas of bone loss. The bone remodeling process, in which artificial bone material is added to areas of bone loss and then transformed into bone, can be broadly divided into two parts: absorption of the artificial bone material by osteoclasts and bone formation by osteoblasts that invade the spaces created by the absorption. Among these, osteoblasts are known to recognize the irregularities on the surface of the artificial bone as a scaffold and promote bone regeneration by physically bonding (interlocking). Regarding the size of these irregularities, nanoscale and microscale irregularities are known. This is because filipodia, which are membrane protrusion structures derived from the actin cytoskeleton used by osteoblasts to explore irregularities, are well-suited for recognizing and adhering to protrusions in the nano- to submicron range (0.01-0.9 μm), while lamellipodia are well-suited for recognizing and adhering to protrusions in the micron range (1.0-5.0 μm). Since Filipodia and Lamellipodia proceed to adhesion by recognizing protrusions, if the protrusions are smooth and smaller than their respective regions (0.01-0.9 μm for Filipodia and 1.0-5.0 μm for Lamellipodia), recognition will not proceed, making adhesion difficult. If excessively coarse protrusions exceeding 10 μm are present, the stress on the cells increases, and the likelihood of cell destruction during adhesion increases. Therefore, it is preferable that the size of the protrusions in the micron region is 5.0 μm or less. Regarding surface irregularities of implant materials, it has been reported that by sandblasting, micro- and nano-structured surface samples were created by combining nanoscale irregularities with microscale irregularities on a surface, and that the proliferation ability of osteoblast-like cells was promoted at Ra of 0.6 μm and RSm of 11.1 μm, while cell proliferation was significantly less likely to progress on smooth surfaces that had not undergone sandblasting (see Non-Patent Literature 1). Furthermore, as an artificial bone made of ceramics, an artificial bone has been reported in which the surface of a substrate made of dense ceramics with a purity of 95% or more is formed to have rounded irregularities with a surface roughness Ra of 4 to 40 μm (see Patent Document 1). The shape of the protrusion itself is preferably a spherical protrusion with a high degree of circularity (few edges). When comparing cells cultured on protrusions with similar aspect ratios but different edge sharpness, it has been reported that the probability of cell membrane perforation increases from 10% for smooth protrusions to 70% for sharp protrusions (see Non-Patent Literature 2).

[0004] To date, porous hydroxyapatite materials have been reported that include a porous ceramic member for biocompatible materials made of a calcium phosphate-based sintered body having a large number of pores densely distributed three-dimensionally, with adjacent pores communicating with each other at the skeletal wall portion that partitions them, and in which the pore volume of open pores with a diameter of 5 microns (μm) or more and the pore volume of open pores with a diameter of less than 5 microns (μm) are each within a predetermined range (see Patent Document 2), and a method for manufacturing a porous material that includes the steps of obtaining a slurry in which primary particles of a ceramic material are dispersed, and obtaining secondary particles of the ceramic material by granulating the primary particles, and then adding the secondary particles to the slurry and heating the slurry to fix the secondary particles to each other via the primary particles in order to obtain a porous material (see Patent Document 3). To date, spherical hydroxyapatite particles have been produced by methods such as maintaining an aqueous solution containing an organic acid having two or more carboxyl groups, a calcium compound, a phosphorus compound, and urea at a temperature of 70°C or higher and below the boiling point of the aqueous solution, and precipitating hydroxyapatite particles by a homogeneous precipitation method (see Patent Document 4), or by adding potassium pyrophosphate (K4P2O4) to a mixed solution of a water-soluble organic solvent and water, which causes a unique phase separation, stirring it to form a W / O emulsion, and then adding an aqueous solution of a water-soluble calcium salt. A method has been reported in which hydrogen phosphate ions in the aqueous phase react with calcium to form precursor particles of pyrophosphate, and these precursor particles (spherical particles) are subjected to hydrothermal treatment at a pH of 13 to 16 and a temperature of 110°C to 300°C to rearrange them into spherical hydroxyapatite (see Patent Document 5). Another method has been reported in which a powder mainly composed of hydroxyapatite is obtained by drying a slurry containing primary particles of hydroxyapatite and its aggregates, and then granulating the resulting powder, wherein the bulk density and specific surface area of ​​the powder are within a predetermined range (see Patent Document 6). [Prior art documents] [Patent Documents]

[0005] [Patent Document 1] Japanese Patent Publication No. 2003-164516 [Patent Document 2] Japanese Patent Publication No. 2003-038636 [Patent Document 3] Japanese Patent Publication No. 2011-042516 [Patent Document 4] Japanese Patent Publication No. 2014-084232 [Patent Document 5] Japanese Patent Publication No. 2011-079697 [Patent Document 6] Japanese Patent Publication No. 2011-068539 [Non-patent literature]

[0006] [Non-Patent Document 1] Kosuke Nozaki, Basic research toward the clinical application of bone augmentation implants for osteoporosis with reduced bone quality (Research results report of Grants-in-Aid for Scientific Research, Project Number 26462964), June 8, 2017. [Non-Patent Document 2] Capozza, R.; Caprettini, V.; Gonano, CA; Bosca, A.; Moia, F.; Santoro, F.; De Angelis, F. Cell Membrane Disruption by Vertical Micro- / Nanopillars: Role of Membrane Bending and Traction Forces. ACS Appl. Mater. Interfaces 2018, 10 (34), 29107-29114. DOI: 10.1021 / acsami.8b08218. [Overview of the project] [Problems that the invention aims to solve]

[0007] As described above, when using hydroxyapatite for bone regeneration, it is preferable to use hydroxyapatite having both nanoscale and microscale surface irregularities from the viewpoint of promoting bone regeneration. Non-patent document 1 describes how a micro-nanostructure surface sample was created by sandblasting, combining a nanoscale surface with microscale irregularities, and it was confirmed that cell proliferation was promoted in samples with an Ra of 0.6 μm and an RSm of 11.1 μm. Here, when nanoscale and microscale irregularities are combined, even if the Ra is the same, the average length of the elements in the roughness curve (RSm) increases. This is because a large undulation waveform is formed when a collection of densely packed nanostructure irregularities is contained within the microscale irregularities. Therefore, an improvement in the RSm value is an important indicator of multi-layered particles. Non-patent document 1 reports that cell proliferation was promoted in micro- and nanostructures with the lowest RSm values. However, in processing using sandblasting, there are limitations to the size of the blast beads that can be used, making it very difficult to control fine irregularities in the region where the RSm is 2.0 μm or less. Therefore, for particles with micro- and nanostructures in the region where the Ra is 0.1 to 5.0 μm and the RSm is 1.0 to 2.0 μm, this is an underdeveloped technological area with high potential for application. Furthermore, in the method of forming pores as described in Patent Document 2, the resulting ceramic sintered body has a porous structure, and consequently, irregularities are formed. However, there is room for further investigation into the precise control of the size and variation of these irregularities using such methods. Methods for generating pores within a material include adding a foaming agent to the material before drying or firing, or adding water and a surfactant and stirring to generate bubbles. However, the bubbles generated by these methods have very unstable surface tension, making them unsuitable for the delicate control required to regulate the size of irregularities at the micron or nanometer level, and the bubbles easily collapse even during the drying or firing process. The uneven morphology described in Patent Document 1 is a manufacturing method that forms irregularities on the surface of phosphate ceramics by etching. However, when this method is applied to particles, it is assumed that closed-pore particles will be targeted in order to prevent particle disintegration during processing. This makes it difficult to create a structure that allows cytokines and minerals, which are cell growth factors, to permeate from the particle surface through capillary action, thereby promoting cell growth and differentiation from within the particle. The form described in Patent Document 3 is assumed to have relatively large irregularities and final size. When used for cell adhesion to micro- and nano-sized irregularities, or as a powder for bone graft materials, biomaterials, or medical coatings where fineness and high fluidity are required, there is room for improvement in the irregularities, particle size, and particle shape.

[0008] When considering the use of hydroxyapatite particles as bone graft materials, biomaterials, medical coatings, etc., it is preferable that they be spherical particles, as described in Patent Documents 4-6, in order to improve filling efficiency and fluidity. However, while manufacturing methods like the one described in Patent Document 4 have the advantage of synthesizing spherical particles directly from the material, the particles obtained by such methods have a problem in that they tend to be relatively low in crystallinity because their particle morphology is forcibly induced by external conditions, unlike the plate-like or needle-like morphology that spontaneously forms based on the intrinsic crystal structure of hydroxyapatite. Furthermore, when attempting to control the circularity, particle size, and crystallinity of the particles within a desired range using this method, slight variations in reaction conditions can greatly alter the resulting particle properties, leaving room for improvement in terms of reproducible and continuous production. While synthesis using a hydrothermal method, such as that described in Patent Document 5, can yield highly crystalline spherical hydroxyapatite, it requires maintaining the reaction system at high temperature and pressure, resulting in significant costs for heating energy, adiabatic maintenance energy, and the installation, operation, and maintenance of the pressure-resistant reactor. Therefore, even methods like the one described in Patent Document 5 have room for improvement from the perspective of mass production processes. On the other hand, in the method of producing spherical hydroxyapatite by combining a granulation process such as that of Patent Document 6, since the synthesis step and the granulation step can be carried out separately, it is possible to control the particle size and the roundness with high reproducibility while stably maintaining the crystal state of hydroxyapatite. As a result, since the crystallinity and shape of the particles are likely to be stable without performing synthesis under high pressure and high energy, it is a practical and advantageous method with a balance between quality and mass productivity. However, including Patent Documents 4 and 5, since the particles with a smooth surface are formed, it is difficult to form both microscale and nanoscale irregularities suitable for cell adhesion on the particle surface. In Non-Patent Document 2, it is reported that rounded protrusions suppress cell membrane perforation by relaxing stress concentration. However, regarding the method of forming such protrusions on the surface of powder particles, it is an undeveloped technical field with high application potential. From the above, a mass production process for manufacturing metal-containing compound particles such as hydroxyapatite having both nanoscale and microscale irregularities on the surface while controlling the size, variation, shape, and crystallinity of the surface irregularities with high precision has not been established, and there remains room for consideration.

[0009] In view of the above situation, an object of the present invention is to provide a method for manufacturing metal-containing compound particles such as hydroxyapatite having both nanoscale and microscale irregularities on the surface while controlling the size, variation, shape, and crystallinity of the surface irregularities with high precision.

Means for Solving the Problems

[0010] The inventor has studied a method for producing metal-containing compound particles such as hydroxyapatite having nano-scale irregularities and micro-scale irregularities on the surface, with the size, variation, shape, and crystallinity of the irregularities controlled. After spray-drying and granulating a slurry containing a metal-containing compound raw material to obtain primary granules, the primary granules are slurried again, and the slurry is spray-dried and granulated to obtain secondary granules. When producing metal-containing compound particles by this method, metal-containing compound particles having nano-scale irregularities and micro-scale irregularities on the surface (having spherical micro-protrusions on the surface and nano-protrusions on the surface of the micro-protrusions) can be produced, and it has been found that the size and variation of the irregularities can also be controlled, leading to the completion of the present invention.

[0011] That is, the present invention is as follows. [1] A method for producing metal-containing compound particles, comprising a primary granulation step of spray-drying and granulating a slurry containing a metal-containing compound raw material to obtain primary granules, and a secondary granulation step of spray-drying and granulating a slurry containing the primary granules to obtain secondary granules.

[0012] [2] The method for producing metal-containing compound particles according to [1], further comprising a step of firing the secondary granules at 400 to 1300°C.

[0013] [3] The method for producing metal-containing compound particles according to [1] or [2], wherein the primary granules have an average particle diameter of 1.0 to 10.0 μm, and the secondary granules have an average particle diameter of 10 to 500 μm.

[0014] [4] The method for producing metal-containing compound particles according to any one of [1] to [3], wherein the primary granules have a circularity of 0.80 or more.

[0015] [5] The method for producing metal-containing compound particles according to any one of [1] to [4], wherein the metal-containing compound raw material in the slurry containing the metal-containing compound raw material has an average primary particle diameter of 10 to 900 nm.

[0016] [6] The secondary granules obtained in the secondary granulation step have a crystallinity "(1 - V112 / 300 / I 300 A method for producing metal-containing compound particles as described in any of [1] to [5], wherein the ratio of ) × 100 is 40 to 80.

[0017] [7] The method for producing metal-containing compound particles according to any one of [1] to [6], wherein the primary granulation step is performed using a collision type two-fluid nozzle.

[0018] [8] The metal-containing compound raw material comprises hydroxyapatite. [1] to [7] A method for producing metal-containing compound particles.

[0019] [9] Metal-containing compound particles having a surface roughness measurement of 0.1 to 5.0 μm and an RSm of 1.0 to 2.0 μm as measured by laser microscopy, with microprotrusions of 1.0 to 5.0 μm in diameter on the surface, and nanoprotrusions of 0.01 to 0.9 μm on the surface of the microprotrusions.

[0020]

[10] The metal-containing compound particle according to [9], wherein the micro-protrusions are protrusions made of spherical particles with a circularity of 0.80 or more.

[0021]

[11] BET specific surface area is 1.0 to 100 m 2 Metal-containing compound particles as described in [9] or

[10] , which are / g.

[0022]

[12] Metal-containing compound particles as described in any of [9] to

[11] , having a circularity of 0.80 or higher.

[0023]

[13] A metal-containing compound particle according to any one of [9] to

[12] , characterized in that it has a hollow shell structure, and the gaps between the shells formed by aggregation, sintered necks, or both of the primary granules constitute a communication pore, and the communication pore is in communication with the hollow inside.

[0024]

[14] Metal-containing compound particles according to any of [9] to

[13] , comprising hydroxyapatite and β-tricalcium phosphate.

[0025]

[15] Metal-containing compound particles according to

[14] , wherein the content ratio of β-tricalcium phosphate to hydroxyapatite is 1 to 80% by mass. [Effects of the Invention]

[0026] The present invention provides a method for producing metal-containing compound particles, which have nanoscale and microscale surface irregularities. This method allows for highly precise control of the size and variation of surface irregularities, shape, and crystallinity of the metal-containing compound particles. Therefore, it is suitable for use as a method for producing hydroxyapatite and other materials used in bone regeneration. [Brief explanation of the drawing]

[0027] [Figure 1] This figure shows an SEM image of the primary granules obtained by spray drying under condition No. 1 in the primary granulation process of hydroxyapatite particles in Example 1. [Figure 2] This figure shows an analytical image of the circularity of the primary granules obtained by spray drying under condition No. 1 in the production of hydroxyapatite particles in Example 1, as analyzed from SEM images. [Figure 3] This figure shows an SEM image (spherical protrusion scale analysis image) of the hydroxyapatite particles obtained in Example 1, and the size of the spherical protrusions on the surface of the particle image. [Figure 4] This figure shows the analytical image obtained by analyzing the circularity of the hydroxyapatite of Comparative Example 1 from an SEM image. [Figure 5] This figure shows an SEM image of the hydroxyapatite particles obtained in Comparative Example 2. [Figure 6] This figure shows an SEM image of the hydroxyapatite particles obtained in Comparative Example 3. [Figure 7] This figure shows a three-dimensional scan image of the hydroxyapatite particles obtained in Example 1. [Figure 8] This figure shows a three-dimensional scan image of the hydroxyapatite particles obtained in Comparative Example 3. [Figure 9] This figure shows a three-dimensional scan image of the hydroxyapatite particles obtained in Comparative Example 2. [Figure 10] This figure shows an SEM image (spherical protrusion scale analysis image) of the hydroxyapatite particles obtained in Example 3, and the size of the spherical protrusions on the surface of the particle image. [Figure 11] This figure shows an SEM image of the hydroxyapatite particles obtained in Comparative Example 15. [Figure 12] This figure shows an SEM image of the hydroxyapatite particles obtained in Comparative Example 20. [Figure 13] This figure shows an SEM image (spherical protrusion scale analysis image) of the hydroxyapatite particles obtained in Example 4, and the size of the spherical protrusions on the surface of the particle image. [Figure 14] This figure shows an SEM image (spherical protrusion scale analysis image) of the hydroxyapatite particles obtained in Example 5, and the size of the spherical protrusions on the surface of the particle image. [Figure 15] This figure shows an SEM image (spherical protrusion scale analysis image) of the hydroxyapatite particles obtained in Example 6, and the size of the spherical protrusions on the surface of the particle image. [Figure 16] This figure shows an SEM image of the interior of the hydroxyapatite particles obtained in Example 3 (the area enclosed by the dotted line is the interior of the particle). [Figure 17] This figure shows an SEM image of the interior of the hydroxyapatite particles obtained in Example 4 (the area enclosed by the dotted line is the interior of the particle). [Figure 18] This figure shows an SEM image of the interior of the hydroxyapatite particles obtained in Example 5 (the area enclosed by the dotted line is the interior of the particle). [Figure 19] This figure shows a three-dimensional scan image of the hydroxyapatite particles obtained in Example 3. [Figure 20] This figure shows a three-dimensional scan image of the hydroxyapatite particles obtained in Comparative Example 15. [Figure 21]This figure shows a three-dimensional scan image of the hydroxyapatite particles obtained in Comparative Example 20. [Figure 22] This is the surface roughness distribution of the hydroxyapatite particles obtained in Example 1. [Figure 23] This is the surface roughness distribution of the hydroxyapatite particles obtained in Example 3. [Figure 24] This is the surface roughness distribution of the hydroxyapatite particles obtained in Example 4. [Figure 25] This is the surface roughness distribution of the hydroxyapatite particles obtained in Example 5. [Figure 26] This is the surface roughness distribution of the hydroxyapatite particles obtained in Example 6. [Figure 27] This is the surface roughness distribution of hydroxyapatite particles obtained in Comparative Example 3. [Figure 28] This is a schematic diagram illustrating the definitions of nano-protrusions and micro-protrusions. [Figure 29] This figure shows the results of the analysis of the circularity of the hydroxyapatite particles obtained in Example 1. [Figure 30] This figure shows the analysis results of the circularity of the hydroxyapatite particles obtained in Example 3 and Comparative Example 25. [Figure 31] This figure shows the SEM image of Comparative Example 25. [Figure 32] This figure shows the relationship between the calcination temperature and the BET specific surface area of ​​hydroxyapatite particles in Examples 2-4 and Comparative Examples 14-16, 19-21. [Figure 33] This figure shows the results of X-ray diffraction spectrum measurements of hydroxyapatite particles from Examples 2 to 5. [Figure 34] This figure shows the results of X-ray diffraction spectrum measurements of the hydroxyapatite particles from Example 1 and the samples from Comparative Examples 24 and 25. [Figure 35] This figure shows an image illustrating the structure of the secondary granules of metal-containing compound particles according to the present invention. [Modes for carrying out the invention]

[0028] The following describes preferred embodiments of the present invention in detail, but the present invention is not limited to the following description and can be modified and applied as appropriate without altering the essence of the invention.

[0029] 1. Method for producing metal-containing compound particles The present invention provides a method for producing metal-containing compound particles, comprising a primary granulation step of obtaining a primary granule by spray-drying and granulating a slurry containing a metal-containing compound raw material, and a secondary granulation step of obtaining a secondary granule by spray-drying and granulating a slurry containing the primary granule. Spray-drying and granulation refers to a method of obtaining dried granules by liquefying a slurry and applying hot air to the droplets. By manufacturing metal-containing compound particles using this method, it is possible to produce metal-containing compound particles having surface irregularities of varying sizes, with differences of more than 100 times. Using this manufacturing method, a fine metal-containing compound raw material with a primary particle diameter on the order of nanometers is made into a slurry, and by spray-drying granulation, a primary granule with a microscale particle size and nanoscale irregularities on its surface can be obtained. By making this primary granule into a slurry again and spray-drying granulation, metal-containing compound particles having both nanoscale and microscale irregularities on their surface can be obtained. Although there are numerous parameters that affect the properties of particles obtained by spray drying granulation, such as the solid content concentration of the raw material liquid, the hot air temperature, the atomizer disc rotation speed, and the mixing ratio of atomized air to liquid, these are relatively easy to control artificially or mechanically, allowing for the production of granulated products with high quality stability. In this manufacturing method, it is possible to adjust the size and variation of nanoscale and microscale irregularities on the surface of the final metal compound particles by adjusting the particle size of the metal-containing compound raw material and the particle size distribution of the primary granules. Furthermore, by firing the secondary granules, sintered necks can be formed between nanoscale and macroscale irregularities, making it possible to adjust the size, variation, shape, and crystal structure of the irregularities.

[0030] <Slurry containing metal-containing compound raw materials> In the slurry containing the above-mentioned metal-containing compound raw material, the average primary particle diameter (D50) of the metal-containing compound raw material is preferably 10 to 900 nm. Using such a particle size makes it easy to obtain metal-containing compound particles having nanoscale irregularities on the surface of the secondary granules. Furthermore, even after the calcination process in the manufacturing method of the metal-containing compound particles, a high specific surface area is maintained, resulting in a material that, when used in the body as a biomaterial, has many sites on which cells can adhere. The average primary particle diameter (D50) of the metal-containing compound raw material in the slurry is more preferably 40 to 500 nm, and even more preferably 50 to 80 nm.

[0031] Furthermore, the average secondary particle size of the metal-containing compound raw material in the slurry containing the above-mentioned metal-containing compound raw material is preferably 0.1 to 40 μm. Using such a particle size results in an agglomerating slurry, making it easy to adjust the circularity of the primary granules to 0.80 or higher. Also, a slurry with such an average secondary particle size has strong inter-particle cohesive force, which reduces the uneven distribution of particles within droplets that occurs when droplets are dried with hot air. Therefore, when spray-dried granulation is performed in the subsequent primary granulation step, it becomes easier to create granules with high circularity. The average secondary particle size of the metal-containing compound raw material in the slurry is more preferably 0.5 to 30 μm, and even more preferably 1 to 20 μm. The average primary particle diameter and average secondary particle diameter of the metal-containing compound raw material can be measured by the method described in the examples below. In this invention, the average primary particle size refers to the average particle size (D50) measured when the metal-containing compound in the slurry has undergone secondary aggregation, mainly due to van der Waals forces generated during liquid-phase synthesis or wet grinding, or due to crosslinking caused by the addition of organic binders, and the secondary aggregation has been weakened by mixing and dispersion with a dispersant such as sodium hexametaphosphate or by physical stimulation such as ultrasonic dispersion. In this invention, the average secondary particle diameter refers to the average particle diameter (D50) measured under conditions close to the state in which the metal-containing compound in the slurry has been secondarily aggregated, mainly due to van der Waals forces generated during liquid-phase synthesis or wet grinding, or crosslinking due to the addition of organic binders.

[0032] The method for obtaining a slurry containing a metal-containing compound raw material having the average particle size described above is not particularly limited, but a method of wet grinding the metal-containing compound raw material in the presence of a solvent is preferably used. Furthermore, the slurry containing the metal-containing compound raw material may be prepared by mixing the metal-containing compound raw material with a solvent, or it may be prepared by generating the metal-containing compound raw material through a chemical reaction in the solvent.

[0033] The solvent used in the slurry containing the above-mentioned metal-containing compound raw material is not particularly limited, but considering that the solvent will be evaporated in the subsequent spray drying granulation process, it is preferable to use one or more low-boiling point solvents with a boiling point of 100°C or less at 1 atmosphere, such as water, ethyl alcohol, methanol, isopropanol, and acetone. The amount of solvent used is preferably 50 to 10,000% by mass, relative to 100% by mass of the solid content of the metal-containing compound raw material. More preferably, it is 100 to 8,000% by mass, and even more preferably, 200 to 5,000% by mass.

[0034] When preparing a slurry containing the above-mentioned metal-containing compound raw materials, components other than the solvent may be added. Examples of components other than the solvent include polymeric organic binders and polymeric dispersants. As organic binders, carboxymethylcellulose (CMC) and polyvinyl alcohol (PVA) can be used, and as polymeric dispersants, one or more of the following can be used: polyacrylates, naphthalene sulfonates, nitrohumates, polyethylene glycol, etc. By adding the above-mentioned polymer-based organic binder or polymer-based dispersant, the slurry becomes agglomerated due to crosslinking between primary particles, making it easier to obtain primary granules with high circularity in the spray-drying granulation process of the primary granulation stage.

[0035] The amount of the above-mentioned organic binder or polymer-based dispersant added is preferably 0.01 to 10% by mass, and more preferably 0.1 to 2.0% by mass, relative to the dry powder base of the metal-containing compound particles.

[0036] While there are no particular limitations on the wet grinding method used to obtain the slurry containing the above-mentioned metal-containing compound raw materials, it is preferable to use a bead mill or ball mill using fine media. Here, the media used is preferably made of ceramics such as zirconia with a diameter of 0.05 to 2 mm, and more preferably a media with a diameter of 0.1 to 0.5 mm. By using micromedia within this range, it becomes possible to reduce the primary particle size while suppressing changes in the crystalline structure of the pulverized product, without adding additives such as dispersants.

[0037] The metal-containing compound used as a raw material in the method for producing metal-containing compound particles of the present invention may be any compound having a metal element as a constituent element, and there are no restrictions on the type or number of metal elements contained or the type of compound, but it is preferably a bio-ceramic. More preferably, it is a bio-ceramic consisting of one or more of hydroxyapatite, β-tricalcium phosphate, bioglass, alumina, and zirconia, and particularly preferably, it is a bio-ceramic consisting of one or more of hydroxyapatite and β-tricalcium phosphate. The method for producing metal-containing compound particles of the present invention is suitable as a method for producing hydroxyapatite having nanoscale and microscale irregularities, which is suitable as a material for bone regeneration. Therefore, it is preferable that the metal-containing compound raw material contains hydroxyapatite.

[0038] When hydroxyapatite is used as the raw material for the metal-containing compound mentioned above, commercially available products may be used, or it may be produced by reaction from a calcium source and a phosphate source. When produced by reaction, the method of production is not particularly limited, but for example, a method can be used in which an aqueous solution or slurry containing a phosphate source is added dropwise while stirring an aqueous solution or slurry containing a calcium source, and the mixture is reacted to obtain a dispersion containing hydroxyapatite. Furthermore, by pulverizing hydroxyapatite while dispersed in a solvent, a metal-containing compound raw material having the above-mentioned preferred average primary particle size and average secondary particle size can be obtained.

[0039] The method for producing hydroxyapatite using an aqueous solution of calcium nitrate as a calcium source and an aqueous solution of trisodium phosphate as a phosphate source, and then grinding the obtained hydroxyapatite to obtain a slurry containing hydroxyapatite, is as follows.

[0040] When reacting an aqueous solution of calcium nitrate with an aqueous solution of trisodium phosphate, it is preferable to mix 0.1 to 2.0 moles of trisodium phosphate with 1 mole of calcium nitrate, and more preferably 1.0 to 1.5 moles of trisodium phosphate.

[0041] When reacting an aqueous solution of calcium nitrate with an aqueous solution of trisodium phosphate, there are no particular restrictions on the method of mixing them, but it is preferable to stir the aqueous solution of calcium nitrate while adding the aqueous solution of trisodium phosphate dropwise and allowing the reaction to proceed. By doing so, it becomes easy to obtain hydroxyapatite with a crystallinity of 40 to 80.

[0042] The stirring force used when reacting an aqueous solution of calcium nitrate with an aqueous solution of trisodium phosphate is not particularly limited, but it is preferable to use a high power of 10 to 70 W per 1 kg of slurry. By setting the stirring force within this range, it is possible to improve the reaction efficiency and easily obtain hydroxyapatite with a crystallinity of 40 to 80.

[0043] When reacting an aqueous solution of calcium nitrate with an aqueous solution of trisodium phosphate, it is preferable to add the trisodium phosphate solution dropwise to the aqueous solution of calcium nitrate. In this case, the dropwise addition rate of the trisodium phosphate aqueous solution to the calcium nitrate aqueous solution is preferably 4 to 30 kg / h. By adjusting to this dropwise addition rate and stirring, it becomes possible to react calcium nitrate and trisodium phosphate under milder conditions, making it easier to obtain hydroxyapatite with a crystallinity of 40 to 80.

[0044] The reaction temperature when calcium nitrate aqueous solution and trisodium phosphate aqueous solution is reacted is preferably 30 to 90°C, and more preferably 80 to 90°C. By using this temperature range, it becomes easy to obtain hydroxyapatite with a crystallinity of 40-80.

[0045] The reaction endpoint is controlled by pH measurement, with a pH value of 5.0 to 10.0 at a liquid temperature of 80 to 90°C being preferable, and more preferably 7.0 to 9.0. This pH range makes it easy to obtain hydroxyapatite with a crystallinity of 40 to 80.

[0046] The primary and secondary average particle sizes of the hydroxyapatite obtained after the reaction of the aqueous calcium nitrate solution with the aqueous trisodium phosphate solution are preferably 0.1 to 20 μm, and more preferably 1 to 10 μm. By using this particle size range, sedimentation and screen clogging in the mill are minimized during the subsequent wet grinding process, enabling more efficient grinding. The primary average grain size and secondary average grain size of hydroxyapatite can be measured by the method described in the examples below.

[0047] The hydroxyapatite slurry obtained by synthesis is preferably filtered and dehydrated using a filtration device such as a filter press or centrifugal dehydrator, recovered as a dehydrated cake, and then washed with a polar solvent such as ion-exchanged water. This process removes sodium nitrate, a secondary product of the synthesis, thereby increasing the purity of the synthesized hydroxyapatite.

[0048] Next, the dehydrated hydroxyapatite cake is dispersed in a solvent, and the hydroxyapatite in the slurry is physically pulverized. By pulverizing the hydroxyapatite dispersed in the solvent in this way, the primary particles are made finer, making it easier to form nanoscale irregularities on the surface of the granulated material in the subsequent primary granulation process.

[0049] There are no particular limitations on the method for physically grinding the hydroxyapatite dispersed in the solvent, but a method similar to the wet grinding method used when obtaining the slurry containing the metal-containing compound raw material described above can be used.

[0050] <Primary granulation process> The primary granulation process involves spray-drying and granulating a slurry containing metal-containing compound raw materials to obtain a primary granulated body. The primary granules obtained in the primary granulation process preferably have an average particle size (D50) of 1.0 to 10.0 μm. When the primary granules have such a particle size, it becomes easy to form microscale irregularities (spherical protrusions of 1.0 to 5.0 μm) on the surface of the secondary granules obtained through the secondary granulation process. The average particle size of the primary granules is more preferably 2.0 to 8.0 μm, and even more preferably 3.0 to 4.9 μm, with a D95 (where 95% of particles in the cumulative distribution are below the specified particle size) of 10.0 μm or less. The average particle size (D50) and D95 ​​of the primary granules can be measured by the method described in the examples below.

[0051] The above primary granules preferably have a circularity of 0.80 or higher. More preferably, the average value when measuring the circularity of 100 or more particles is 0.80 or higher, and even more preferably, the average value when measuring the circularity of 100 or more particles is 0.80 or higher and the standard deviation is 0.08 or lower. When the circularity of the primary granules is 0.80 or higher, the surface of the secondary granules obtained from the primary granules becomes more three-dimensional and has a larger surface area compared to, for example, a plate-like structure. Particles with a larger surface area are preferable because they have more surface area for cell adhesion when used in vivo. Furthermore, compared to sharp protrusions with low circularity, it is expected that stress concentration will be reduced, thereby suppressing membrane perforation during cell adhesion. Primary granules with a circularity of 0.80 or higher can be easily obtained by performing the primary granulation process by spray drying granulation. The circularity of the primary granules can be determined by analysis using the method described in the examples below.

[0052] As long as the above primary granulation process is carried out by spray drying granulation, the apparatus used for spray drying granulation is not particularly limited; however, the atomization method for dropletizing the slurry is preferably carried out using a collision-type two-fluid nozzle. Using a collision-type two-fluid nozzle makes it easy to adjust the average particle size of the primary granules to a range of 1.0 to 10.0 μm. In the manufacturing method of the present invention, it is preferable to use a two-fluid nozzle (hereinafter referred to as a "collision-type two-fluid nozzle") which has an edge through which the liquid raw material and the gas (e.g., compressed air or nitrogen) come into contact and mix in the step of spray-drying and granulating the liquid raw material, and which has a configuration in which droplets sprayed from the edge collide with each other in space to form even finer droplets. In this case, the specific structure of the nozzle used is not particularly limited, and even if the shape and material differ depending on the manufacturer, as long as the atomization principle is "atomization by collision of droplets formed by mixing liquid and gas," it falls within the technical scope of the present invention.

[0053] During spray drying granulation, the ratio of the air flow rate (L / min) to the liquid flow rate (L / min) supplied to the impact-type two-fluid nozzle, i.e., the gas / liquid ratio (gas flow rate ÷ liquid flow rate), is preferably 1,000 to 20,000. By setting the gas / liquid ratio within this range, it becomes possible to efficiently granulate D50 within the range of 1.0 to 10.0 μm. The gas / liquid ratio is more preferably 3,000 to 10,000.

[0054] The hot air temperature for spray drying granulation in the above primary granulation process is not particularly limited, but the hot air inlet temperature is preferably 150°C to 400°C and the exhaust air temperature is preferably 50°C to 140°C. By using this temperature range, the moisture in the droplets is efficiently evaporated, the amount of solvent remaining in the particles after drying is reduced to 10 wt% or less, and it becomes easy to obtain a primary granule as a dried powder. More preferably, the hot air inlet temperature is 200-300°C and the exhaust air temperature is 80-130°C.

[0055] <Secondary granulation process> The secondary granulation process involves dispersing the primary granules obtained in the primary granulation process in a solvent to form a slurry, and then spray-drying and granulating it again to obtain secondary granules that are more porous and have a multi-layered structure. By performing the granulation process by spray-drying twice in this way, metal-containing compound particles with surface irregularities of varying sizes can be obtained.

[0056] When preparing the slurry in which the above-mentioned primary granules are dispersed, one or more low-boiling point solvents with a boiling point of 100°C or less at 1 atmosphere, such as water, ethyl alcohol, methanol, isopropanol, and acetone, can be used as the solvent. The amount of solvent used is preferably 50 to 10,000% by mass, relative to 100% by mass of the solid content of the primary granules. More preferably, it is 100 to 8,000% by mass, and even more preferably, 200 to 5,000% by mass. By setting the amount of solvent used to this level, the porosity within the particles after spray drying and granulation increases. This makes it easier to create a hollow shell structure in secondary granulated materials.

[0057] When preparing a slurry in which the above-mentioned primary granules are dispersed, components other than the solvent may be added. Examples of components other than the solvent include organic binders. As organic binders, one or more types of carboxymethylcellulose (CMC) and polyvinyl alcohol (PVA) can be used.

[0058] The amount of organic binder added is preferably 0.01 to 10% by mass on a dry powder basis relative to the dry powder basis of the primary granulated particles. By adding the binder within this range, secondary granules in which the primary granules are aggregated can be obtained more reliably. More preferably, the amount of organic binder added is 0.1 to 5.0% by mass on a dry powder basis relative to the dry powder basis of the primary granulated particles.

[0059] The above-mentioned secondary granules preferably have an average particle size (D50) of 10 to 500 μm. This average particle size makes it easier to obtain granules that are sufficiently dried for use as a powder and have high fluidity. More preferably, the average particle size of the secondary granules is 20 to 150 μm, and even more preferably 30 to 120 μm. The average particle size (D50) of the secondary granules can be measured by the method described in the examples below.

[0060] The secondary granules described above preferably have a circularity of 0.80 or higher. This makes it possible to uniformly distribute the irregularities derived from the primary granules on the surface, and it is expected that when used in a living organism, the multi-value effect (synthetic improvement of adhesive ability due to the simultaneous contact of multiple irregularities) will be more likely to occur. Furthermore, when the circularity of the secondary granules is 0.80 or higher, the entire surface becomes a continuous curved surface, and when metal compound granules are used as a bone regeneration material, the resistance to the extension of osteoblasts and lamellibodia is reduced, and they are more likely to slide and unfold along the adhesive surface, thus promoting bone regeneration. The circularity of the secondary granules is more preferably 0.80 or higher when the average value of the circularity of 100 or more particles is measured, and even more preferably 0.80 or higher when the average value of the circularity of 100 or more particles is measured, and the standard deviation is 0.09 or lower. The circularity of the secondary granules can be determined by analysis using the method described in the examples below.

[0061] The secondary granules obtained in the above secondary granulation process have a crystallinity of '(1-V' as measured by XRD. 112 / 300 / I 300 It is preferable that the value of ') × 100' is between 40 and 80. When the degree of crystallinity is such a value, the secondary granules can be said to be chemically stable, and even when used in vivo, the surface uneven structure will not easily dissolve in the body, and it will be easy to invert to β-tricalcium phosphate during calcination. The degree of crystallinity is more preferably 45 to 70, and even more preferably 50 to 60.

[0062] As long as the above secondary granulation process is carried out by spray drying the slurry of the primary granules, the apparatus used for spray drying granulation is not particularly limited. However, the atomization method for dropletizing the slurry is preferably a disc atomizer, a two-fluid nozzle, or a one-fluid nozzle. By using such an atomizer, it is possible to efficiently granulate the average diameter within the range of 10 to 500 μm.

[0063] In the above-described disk atomizer system, the disk rotation speed is preferably 1,000 to 40,000 rpm. This disk rotation speed allows for granulation with an average diameter within the range of 10 to 500 μm. It becomes easier. More preferably, the speed is 5,000 to 20,000 rpm.

[0064] The temperature during spray drying granulation in the above secondary granulation process is not particularly limited, but the hot air inlet temperature is preferably 150 to 400°C and the exhaust air temperature is preferably 50 to 140°C. By setting the temperature within this range, it is possible to efficiently evaporate the water in the droplets, reduce the amount of solvent remaining in the particles after drying to 10 wt% or less, and easily obtain a secondary granulated material as a dry powder with good fluidity. More preferably, the hot air inlet temperature is 200-300°C and the exhaust air temperature is 80-130°C.

[0065] <Firing Process> The present invention's method for producing metal-containing compound particles preferably further includes a step of calcining the secondary granules at 400 to 1300°C. In particular, when the metal-containing composite particles contain hydroxyapatite, including the calcination step allows for the inversion of a portion of the crystalline phase of hydroxyapatite to β-type tricalcium phosphate, which has high bone resorption potential, thereby obtaining a secondary granule of BCP (biphase calcium phosphate), which is a mixture of hydroxyapatite and β-type tricalcium phosphate. Furthermore, it is possible to reduce the amount of organic binder added during granulation and increase the purity of BCP. Furthermore, the formation of a sintered neck allows for adjustment of variations in surface irregularities and the average surface roughness (Ra). The temperature for firing the secondary granules is more preferably 500 to 1250°C. Even more preferably 700 to 1100°C. Furthermore, the time for firing the secondary granules in the above temperature range is preferably 2 to 20 hours. More preferably, it is 3 to 10 hours, and even more preferably, 4 to 7 hours.

[0066] The atmosphere during the firing process is not particularly limited, but an oxidizing atmosphere that promotes the removal of hydroxyl groups, such as air or an oxygen atmosphere, is preferred.

[0067] The present invention's method for producing metal-containing compound particles may include steps other than the primary granulation step, secondary granulation step, and calcination step. Other steps include grinding with a dry pulverizer or the like, synthesizing by liquid-phase, solid-phase, or hydrothermal method, filtering with a filter press or centrifugal dehydrator, solid-liquid separation with a centrifuge or the like, washing with a polar solvent to remove impurities, drying with a dryer or the like, dissolving with an acid or base, mixing or coating with different materials using a blender or stirrer or the like, neutralizing with an acid or base, and agglomerating with a polymer-based dispersant or organic binder.

[0068] 2. Metal-containing compound particles The metal-containing compound particles of the present invention are characterized by having an Ra of 0.1 to 5.0 μm and an RSm of 1.0 to 2.0 μm as measured by a laser microscope, and having nano-protrusions with a diameter of 0.01 to 0.9 μm and micro-protrusions with a diameter of 1.0 to 5.0 μm on their surface. The metal-containing compound particles of the present invention, having these characteristics, are suitable as materials for use in living organisms, particularly for bone regeneration and artificial bone materials. A surface roughness (Ra) of 0.1 to 5.0 μm results in metal-containing compound particles with an uneven surface that facilitates adhesion between the filipodia and lamellipodia of osteoblasts. Furthermore, a surface roughness (RSm) of 1.0 to 2.0 μm and a multi-layered structure with nano-protrusions of 0.01 to 0.9 μm diameter and micro-protrusions of 1.0 to 5.0 μm diameter on the surface allows for a double, strong interlocking mechanism between the lamellipodia extending in a membrane-like manner from osteoblasts and the micro-protrusions of the present invention, as well as between the filipodia on the lamellipodia surface and the nano-protrusions on the micro-protrusion surface, resulting in a more stable cell scaffold. Furthermore, by controlling the surface roughness (Rz) to 0.1-5.0 μm and making the shape of the micro-protrusions spherical, it is expected that the cells will not be subjected to extreme stress due to roughness or sharpness, thereby reducing the possibility of cell death.

[0069] The Ra of the metal-containing compound particles of the present invention is preferably 0.1 to 5.0 μm, and more preferably 0.2 to 2.0 μm. The RSm of the metal-containing compound particles of the present invention is preferably 1.0 to 2.0 μm. More preferably, it is 1.5 to 1.8 μm. The Rz of the metal-containing compound particles of the present invention is preferably 0.1 to 10.0 μm. More preferably, it is 0.8 to 5.0 μm. The diameter of the nano-protrusions with a diameter of 0.01 to 0.9 μm on the surface of the metal-containing compound particles of the present invention is more preferably 0.02 to 0.8 μm, and even more preferably 0.03 to 0.5 μm. The diameter of the micro-protrusions with a diameter of 1.0 to 5.0 μm of the metal-containing compound particles of the present invention is more preferably 1.5 to 4.0 μm, and even more preferably 2.0 to 3.0 μm. In the present invention, Ra means the arithmetic mean roughness of the roughness curve defined in JIS B0601:2013, RSm means the average length of the elements of the roughness curve defined in JIS B0601:2013, and Rz means the maximum height of the roughness curve defined in JIS B0601:2013. The Ra, RSm, Rz and the diameter of the protrusions of the metal-containing compound particles of the present invention can be measured by the method described in the examples below.

[0070] The metal-containing compound particles of the present invention preferably have a BET specific surface area of 1.0 to 100 m 2 / g. Those having such a BET specific surface area are preferable because they have sites where cells adhere when used in vivo as a biomaterial. The BET specific surface area of the metal-containing compound particles is more preferably 2.0 to 80 m 2 / g, and even more preferably 5.0 to 50 m 2 / g.

[0071] The metal-containing compound particles of the present invention preferably have a circularity of 0.80 or more. When the circularity is 0.80 or more, the entire surface becomes a continuous curved surface. Due to this continuous curved surface, the resistance to the extension of osteoblast bodies and lamellipodia is reduced, and it is likely to be easily developed so as to slide along the adhesion surface, so it can be expected that bone regeneration is easily promoted. Furthermore, it becomes possible to uniformly arrange the irregularities derived from the primary granules across the entire surface, which is expected to facilitate the multi-value effect (synchronistic improvement in adhesive ability due to the simultaneous contact of multiple irregularities) when used in a living organism. The circularity of the metal-containing compound particles can be determined by analysis using the method described in the examples below.

[0072] The metal-containing compound particles of the present invention preferably have a hollow shell structure, and the gaps between the shells formed by the aggregation, sintering necks, or both of the multiple primary granules constitute interconnected pores, and these interconnected pores extend to the internal hollow. Hollow-shell particles refer to particles that have a core-shell structure consisting of an air core and a metal-containing compound shell. When particles with a hollow shell structure are used in vivo, capillary action allows for the entry and diffusion of bodily fluids, nutrients, and cytokines through the gaps in the shell on the particle surface, promoting cell growth and thus making them more desirable as biomaterials. In the present invention, a method for producing metal-containing compound particles is used to produce metal-containing compound particles by spray drying granulation. In spray drying granulation, after droplet formation, drying proceeds from the droplet surface, forming an outer shell. As the internal pressure inside the droplet increases due to the vapor, the constituent particles concentrate at the interface and take on a compacted form. For this reason, the resulting particles tend to have a hollow shell structure.

[0073] The metal-containing compound particles of the present invention preferably contain hydroxyapatite and β-tricalcium phosphate. This makes the metal-containing compound particles suitable as biomaterials for bone regeneration and artificial bone materials. By combining a highly chemically stable hydroxyapatite crystal phase with a highly absorbable β-tricalcium phosphate (β-TCP) crystal phase, it is possible to maintain the nano-textured surface structure of the powder within the body while enhancing absorption by osteoclasts. This composite crystal phase is called biphase calcium phosphate (BCP), and because it is gradually absorbed in the body and replaced by new bone, it is considered ideal for artificial bone applications.

[0074] When the metal-containing compound particles of the present invention contain hydroxyapatite and β-type tricalcium phosphate (β-TCP), the content ratio of β-type tricalcium phosphate to hydroxyapatite is preferably 1 to 80% by mass. Including β-type tricalcium phosphate in such a ratio is expected to provide greater stability derived from hydroxyapatite and greater absorbency derived from β-TCP. More preferably, the content ratio of β-type tricalcium phosphate to hydroxyapatite is 20 to 70% by mass, and even more preferably 25 to 60% by mass. In the present invention, the β-TCP crystal phase refers to a crystal phase in which specific diffraction peaks are observed around 31 degrees and 34.5 degrees 2θ in XRD measurements. The hydroxyapatite content (wt%) and β-TCP content (wt%) were calculated using the following formula based on X-ray diffraction spectroscopy. β-TCP content (wt%) = {integrated intensity of the 0210 plane (around 2θ=31 degrees) ÷ integrated intensity of the 211 plane (around 2θ=31.8 degrees)} × 100 Hydroxyapatite content (wt%) = 100 - (β-TCP content)

[0075] When the metal-containing compound particles of the present invention contain hydroxyapatite and β-type tricalcium phosphate, the total content ratio of hydroxyapatite and β-type tricalcium phosphate to the total metal-containing compound particles is preferably 10% by mass or more. More preferably, it is 50% by mass or more, and even more preferably, 70% by mass or more. Particularly preferably, it is 90% by mass or more, and most preferably, 100% by mass, i.e., the metal-containing compound particles consist only of hydroxyapatite and β-type tricalcium phosphate. [Examples]

[0076] Specific examples are given below to illustrate the present invention in detail, but the present invention is not limited to these examples.

[0077] Example 1 (Metal-containing compound particle raw material synthesis process) First, 191 kg of calcium nitrate solution (0.81 mol / L, pH 4.7) was stirred using a disperser (Asada Iron Works, model: MH-1200) while adding trisodium phosphate solution (1.01 mol / L) at a dropping rate of 20 kg / h until the pH of the mixture reached 8.9. Subsequently, after 19 hours of aging and stirring, the final pH of the mixture was 8.6. During the dropping and aging stirring, the tank was covered, nitrogen gas was flowed into the headspace above the liquid surface, and the liquid temperature was maintained at 80-90°C. The stirring speed of the mixture was maintained at 800-900 rpm (peripheral speed 13.8-15.5 m / s), and the stirring force was 10-70 W per 1 kg of mixture. Furthermore, the molar ratio of calcium nitrate to trisodium phosphate in the above synthesis is 1.3 moles of trisodium phosphate for every 1 mole of calcium nitrate. Next, the obtained slurry was filtered and dewatered using a filter press (manufactured by Nippon Filtration Equipment Co., Ltd., model 600) in which a P89C filter cloth manufactured by Shikishima Campus Co., Ltd. was set in a 15 mm thick filter frame. After that, the filter cake filled inside the machine was washed by passing deionized water through it, and the washing process ended when the electrical conductivity of the discharged washing filtrate reached 0.4 mS / cm. (Wet grinding process) Next, 25.3 kg of the dehydrated cake (11.39 kg dry powder base) and 77.5 kg of deionized water were mixed in a disperser (Asada Iron Works, model: MH-1200). 92.7 kg of the resulting pre-dispersion was then circulated through a bead mill (Asada Iron Works Picomill, model: PCMH-C20M) at a flow rate of 7 kg / min for 400 minutes for wet grinding. The peripheral speed of the bead mill during circulation was set to 12 m / s. The grinding media consisted of 24.4 kg of zirconia beads (manufactured by Nikkatoh, model: YTZ-01) with a diameter of 0.1 mm (78% of the bead mill vessel capacity), which were filled into the bead mill. The particle size distribution of aggregates in the slurry before grinding and the aggregates in the slurry at predetermined circulation times was measured using a laser diffraction particle size distribution analyzer (Horiba, Ltd., model: LA-960). The results are shown in Table 1. The average primary particle size is the volume-average particle size (D50) measured immediately after dispersing the sample in a 0.5 wt% sodium hexametaphosphate solution placed inside the particle size analyzer and dispersing it with ultrasound (power setting: 7) for 1 minute. The average secondary particle diameter is the volume-average particle diameter (D50) measured when the sample is dispersed in ion-exchanged water placed inside the particle size analyzer and measured without ultrasonic dispersion. The moisture content of the slurry containing the pulverized aggregates was measured and found to be 88.92%. The moisture content is the weight loss rate (%) measured using an infrared moisture meter (AND Corporation, model: MX-50) under the following conditions: set temperature of 105°C, drying endpoint setting of 0.05% / min, and sample weight of 6g.

[0078] [Table 1]

[0079] (Primary granulation process) Next, the slurry containing the crushed aggregates was spray-dried and granulated using a spray-drying granulator equipped with a collision-type two-fluid nozzle (GF, micro-mist spray dryer, model: MDP-050) to obtain primary hydroxyapatite granules. Table 2 shows the conditions for spray drying granulation and the measurement results of the volume-average diameter (D50) and moisture content (%) of the primary granules. The average particle size (D50) of the primary granules was measured using a particle size distribution analyzer (Horiba, Ltd., model: LA-960). The sample was dispersed in a 0.05 wt% sodium hexametaphosphate solution placed inside the particle size distribution analyzer, and the volume-average particle size (D50) was measured without ultrasonic dispersion. The D95 of the primary granules is calculated from the particle size distribution during the D50 measurement, and is defined as D95 (where 95% of the particles in the volume cumulative distribution are of the corresponding particle size or smaller). The D10 of the primary granules is calculated from the particle size distribution during the D50 measurement described above, and is defined as D10 (where 10% of the particles in the volume cumulative distribution are of the corresponding particle size or smaller). The moisture content of the primary granules is the weight loss rate (%) measured using an infrared moisture meter (AND Corporation, model: MX-50) under the following conditions: set temperature of 105°C, set drying endpoint of 0.05% / min, and sample weight of 2g.

[0080] [Table 2]

[0081] Figure 1 shows SEM images of dried particles under condition No. 1 in Table 2, taken using a scanning electron microscope (JEOL, model: JCM-7000). The scanning electron microscope (SEM) settings for image acquisition were a magnification of 3700x and an acceleration voltage of 15kV. Furthermore, using DeepCle, an AI image analysis software manufactured by Sakai Chemical Industry Co., Ltd., the circularity of 101 particles was analyzed from the captured SEM images. The average circularity was 0.833, and the standard deviation of circularity was 0.044. The analyzed image is shown in Figure 2.

[0082] (Secondary granulation process) Next, a slurry was prepared by mixing 100g of the primary granule obtained under condition No. 1 with 476.7g of deionized water and 100g of a 1.5 wt% sodium carboxymethylcellulose aqueous solution (1.5-1.6% of the dry weight of the hydroxyapatite dry powder). This slurry was then spray-dried and granulated using a spray dryer equipped with a disc atomizer (IS Japan, research and development spray dryer, model: RDS-1R, disc atomizer type) to obtain secondary granules of hydroxyapatite. A 1.5 wt% aqueous solution of sodium carboxymethylcellulose is prepared by dissolving sodium carboxymethylcellulose (manufactured by Marugo Corporation, product name: CMC) in deionized water to a concentration of 1.5 mass percent. The spray drying conditions were as follows: hot air inlet temperature of 210°C, hot air outlet temperature of 85-109°C, disk rotation speed of 20,000 rpm, and liquid flow rate of 23.7 g / min. The secondary granulated powder was recovered from the bottom of the dryer. The moisture content of the above secondary granulated powder was measured using an infrared moisture meter (AND Corporation, model: MX-50) and was found to be 4.06%. The moisture content was measured under the same conditions as when measuring the moisture content of a single granular material. The average particle size (D50) of the secondary granulated material was measured to be 35.2 μm. The average particle size (D50) of the secondary granules was measured using a particle size distribution analyzer (Horiba, Ltd., model: LA-960). The method for measuring the average particle size (D50) of the secondary granules is the same as the method for measuring the D50 of the primary granules described above. The angle of repose of the above-mentioned secondary granulated powder was measured using an angle of repose measuring instrument (AS ONE, ASK-01), and the result showed that the angle of repose was 30 degrees. The bulk density of 30 ml of the above secondary granulated powder was measured using a 50 ml graduated cylinder, and the results showed a static bulk density of 0.61 g / ml and a density of 0.64 g / ml after 100 taps. Furthermore, SEM images of the secondary granules were observed using a scanning electron microscope (JEOL, model: JCM-7000) to capture images of the particles and measure the size of the spherical protrusions on the surface. The scanning electron microscope (SEM) settings for image acquisition were configured to have a magnification of 1700x and an acceleration voltage of 10kV. The secondary granules of Example 1 are composed of spherical particles with a D50 of 3.8 μm and an average circularity of 0.80 or higher, indicating that spherical irregularities exist on the particle surface. Figure 3 shows the SEM image (spheroidal protrusion scale analysis image) and the measurement results of the spherical protrusion size of the secondary granules obtained in Example 1. In the method described above, the size of the measured spherical protrusions was 2.80 μm (σ=0.764) on average across 10 points, indicating that they are microscale protrusions (1.0~5.0 μm). The size of the spherical protrusions was determined by measuring the length of the spherical protrusions on the particle surface, as observed from SEM images of the captured particles, using a scanning electron microscope scale.

[0083] Comparative Example 1 500 g of hydroxyapatite filtered and dehydrated cake obtained in Example 1 (metal-containing compound particle raw material synthesis process) was dried for 24 hours at a set temperature of 105°C using a dryer (Yamato Scientific Co., Ltd., forced-air low-temperature constant temperature oven, model: DKM300), and the dried hydroxyapatite powder was recovered, which was used as the hydroxyapatite of Comparative Example 1. The moisture content of this dried powder was measured using an infrared moisture meter (AND Corporation, model: MX-50), and the result showed a moisture content of 0.36%. The moisture content is the weight loss rate (%) measured using an infrared moisture meter (AND Corporation, model: MX-50) under the following conditions: set temperature of 105°C, drying endpoint setting of 0.05% / min, and sample weight of 4g. A slurry was prepared by dispersing 100 g of this dried powder in 476.7 g of deionized water, and the particle size distribution was measured using a particle size analyzer (HORIBA, model: LA-960). The measured volume-average particle size (D50) was 4.34 μm. The measurement conditions for D50 were the same as those for the primary and secondary granules in Example 1.

[0084] The circularity of hydroxyapatite in Comparative Example 1 was analyzed using DeepCle, an AI image analysis software manufactured by Sakai Chemical Industry Co., Ltd. Analysis of the circularity of 104 particles from SEM images taken with a scanning electron microscope (JEOL, model: JCM-7000) revealed an average circularity of 0.724 and a standard deviation of 0.099. The analyzed circularity image is shown in Figure 4. The scanning electron microscope (SEM) settings used for acquiring the circularity analysis images were configured to have a magnification of 2000x and an acceleration voltage of 15kV.

[0085] Comparative Example 2 A slurry was prepared by adding 476.7 g of deionized water to 100 g of the dry powder obtained in Comparative Example 1 and dispersing it. 559.05 g of this slurry was mixed with 96.94 g of 1.5 wt% sodium carboxymethylcellulose aqueous solution (1.5-1.6% of the dry powder weight relative to the hydroxyapatite dry powder), and spray-dried using a spray dryer equipped with a disc atomizer {IS Japan, research and development spray dryer (model: RDS-1R, disc atomizer type)} to obtain a primary granulated material of hydroxyapatite. The 1.5 wt% sodium carboxymethylcellulose aqueous solution used was prepared by the same method as in Example 1. The spray drying conditions were as follows: hot air inlet temperature of 210°C, hot air outlet temperature of 88-97°C, disk rotation speed of 20,000 rpm, and liquid flow rate of 27.6 g / min. Primary granules with D50 granulated to 31.2 μm were recovered from the bottom of the dryer and used as the metal compound particles for Comparative Example 2. The measurement conditions for D50 were the same as for the primary and secondary granules in Example 1. Figure 5 shows the SEM image of Comparative Example 2. From the obtained SEM image, it can be seen that Comparative Example 2 is composed of aggregated plate-like particles from Comparative Example 1, which have a D50 of 4.34 μm and an average circularity of less than 0.80, and that the particle surface of the primary granules is in a state where plate-like particles are randomly arranged.

[0086] Comparative Examples 3 and 4 750 g of the slurry obtained in the wet grinding process of Example 1 was mixed with 83.18 g of a 1.5 wt% sodium carboxymethylcellulose aqueous solution (1.5-1.6% of the dry weight of the hydroxyapatite dry powder), and the mixture was spray-dried using a spray dryer equipped with a disc atomizer (IS Japan, research and development spray dryer, model: RDS-1R, disc atomizer type) to obtain a primary granulated material of hydroxyapatite. The 1.5 wt% sodium carboxymethylcellulose aqueous solution used was prepared by the same method as in Example 1. The spray drying conditions were as follows: hot air inlet temperature of 210°C, hot air outlet temperature of 88-101°C, disk rotation speed of 20,000 rpm, and liquid flow rate of 25.9 g / min. Primary granulated material with D50 granulated to 17.2 μm was recovered from the bottom of the dryer. The obtained particles were designated as the particles for Comparative Example 3. Furthermore, primary granules with a D50 of 13.0 μm, recovered from the bottom of the cyclone (fine powder side), were used as the particles for Comparative Example 4. The D50 measurement conditions for the particles of Comparative Examples 3 and 4 were the same as those for the primary and secondary granules in Example 1. Figure 6 shows the SEM image of the particles in Comparative Example 3. The scanning electron microscope model and conditions used for SEM image acquisition were the same as those in Example 1. As can be seen from the SEM image in Figure 6, the particles of Comparative Example 3 have a smooth surface, which is due to the fact that they were granulated after being pulverized to a D50 of 0.078 μm by wet milling.

[0087] <Capturing 3D scan images> Three-dimensional scan images of the secondary granules of Example 1 and Comparative Examples 2 and 3 were captured using a white-light interferometry laser microscope (Keyence, model: VK-X3000). From the 3D scan images, it was found that the secondary granules of Example 1 were composed of microscale spherical particles, and their surface state was clearly different from that of the particles of Comparative Example 3 and Comparative Example 2. Figure 7 shows the 3D scan image of Example 1. Figure 8 shows the 3D scan image of the particles of Comparative Example 3, and Figure 9 shows the 3D scan image of the particles of Comparative Example 2.

[0088] Examples 2-5 2.00 g of the secondary granules from Example 1 were weighed into an alumina magnetic dish and fired in an electric muffle furnace (Yamato Scientific Co., Ltd., Model: FO510). The heating rate was set to 16°C / min. Samples fired at 400°C for 4 hours were designated as Example 2, samples fired at 700°C for 4 hours as Example 3, samples fired at 900°C for 4 hours as Example 4, and samples fired at 1,100°C for 4 hours as Example 5.

[0089] Example 6 The secondary granules from Example 1 were subjected to calcination at 1,250°C for 4 hours using a thermal analyzer (Shimadzu Corporation, model: DTG-60H) with a heating rate of 16°C / min, and the resulting sample was designated as Example 6.

[0090] Comparative Examples 5-8 In the primary granulation process of Example 1, 2.00 g of the primary granules obtained under the spray drying conditions of Condition No. 1 was weighed into an alumina magnetic dish and calcined in an electric muffle furnace (manufactured by Yamato Scientific, model: FO510). The heating rate was set to 16°C / min. The sample fired at 400°C for 4 hours was designated as Comparative Example 5, the sample fired at 700°C for 4 hours as Comparative Example 6, the sample fired at 900°C for 4 hours as Comparative Example 7, and the sample fired at 1,100°C for 4 hours as Comparative Example 8.

[0091] Comparative Example 9 Comparative Example 9 was obtained by calcining a sample of the primary granules obtained in the primary granulation process of Example 1 under the spray drying conditions of Condition No. 1, using a thermal analyzer (Shimadzu Corporation, DTG-60H) with a heating rate set to 16°C / min at 1,250°C for 4 hours.

[0092] Comparative Examples 10-13 2.00 g of the primary granules from Comparative Example 4 were weighed into an alumina magnetic dish and calcined in an electric muffle furnace (Yamato Scientific Co., Ltd., Model: FO510). The heating rate was set to 16°C / min. The sample calcined at 400°C for 4 hours was designated as Comparative Example 10, the sample calcined at 700°C for 4 hours was designated as Comparative Example 11, the sample calcined at 900°C for 4 hours was designated as Comparative Example 12, and the sample calcined at 1,100°C for 4 hours was designated as Comparative Example 13.

[0093] Comparative Examples 14-17 2.00 g of the primary granule of Comparative Example 3 was weighed into a magnetic dish made of alumina and fired in an electric muffler furnace (manufactured by Yamato Scientific Co., Ltd., model: FO510). The heating rate was set at 16 °C / min, and the samples fired at 400 °C for 4 h were designated as Comparative Example 14, those fired at 700 °C for 4 h as Comparative Example 15, those fired at 900 °C for 4 h as Comparative Example 16, and those fired at 1,100 °C for 4 h as Comparative Example 17.

[0094] Comparative Example 18 The primary granule of Comparative Example 3 was fired using a thermal analyzer (manufactured by Shimadzu Corporation, DTG-60H) with the heating rate set at 16 °C / min, and the sample fired at 1,250 °C for 4 h was designated as Comparative Example 18.

[0095] Comparative Examples 19 to 22 2.00 g of the primary granule of Comparative Example 2 was weighed into a magnetic dish made of alumina and fired in an electric muffler furnace (manufactured by Yamato Scientific Co., Ltd., model: FO510). The heating rate was set at 16 °C / min, and the samples fired at 400 °C for 4 h were designated as Comparative Example 19, those fired at 700 °C for 4 h as Comparative Example 20, those fired at 900 °C for 4 h as Comparative Example 21, and those fired at 1,100 °C for 4 h as Comparative Example 22.

[0096] Comparative Example 23 The primary granule of Comparative Example 2 was fired using a thermal analyzer (manufactured by Shimadzu Corporation, DTG-60H) with the heating rate set at 16 °C / min, and the sample fired at 1,250 °C for 4 h was designated as Comparative Example 23.

[0097] <Taking SEM Images> SEM images of the particles produced in Examples 3 to 6 and Comparative Examples 15 and 20 were observed with a scanning electron microscope (manufactured by JEOL Ltd., model: JCM-7000), and images of the particles were taken. The model and conditions of the scanning electron microscope at the time of taking SEM images were in accordance with Example 1. Figure 10 shows the SEM image (protrusion scale analysis image) and spherical protrusion size of Example 3, which was fired at 700°C for 4 hours. Figure 11 shows the SEM image of Comparative Example 15, and Figure 12 shows the SEM image of Comparative Example 20. From a comparison of these SEM images, it can be seen that Example 3 is a secondary granulated material composed of microscale spherical particles, similar to the material before firing. Furthermore, Figure 13 shows the SEM image (spherical protrusion scale analysis image) and spherical protrusion size of Example 4, which was fired at 900°C for 4 hours; Figure 14 shows the SEM image (protrusion scale analysis image) and spherical protrusion size of Example 5, which was fired at 1,100°C for 4 hours; and Figure 15 shows the SEM image (spherical protrusion scale analysis image) and spherical protrusion size of Example 6, which was fired at 1,250°C for 4 hours. From these SEM images, it can be seen that neck formation begins at the grain boundaries between spherical particles on the surface from around a firing temperature of 1,100°C. The tendency for the specific surface area to decrease with increasing firing temperature is due to this phenomenon. The size of the spherical protrusions was measured using the same method as in Example 1. Measurement results of the spherical protrusion size show that the secondary granules of Examples 3 to 6 also have microscale (1.0 to 5.0 μm) spherical protrusions, similar to those before firing.

[0098] The interior of the particles in the secondary granules obtained in Example 3 was observed using a scanning electron microscope (JEOL, model: JCM-7000, acceleration voltage 15kV, 3000x magnification), and images were captured. The obtained SEM images are shown in Figure 16. In the SEM image in Figure 16, the area enclosed by the dotted line is the interior of the particle. The interior of the particles in the secondary granules obtained in Example 4 was observed using a scanning electron microscope (JEOL, model: JCM-7000, acceleration voltage 10kV, 3500x magnification), and images were captured. The obtained SEM image is shown in Figure 17. In the SEM image in Figure 17, the area enclosed by the dotted line is the interior of the particle. The interior of the particles in the secondary granules obtained in Example 5 was observed using a scanning electron microscope (JEOL, model: JCM-7000, acceleration voltage 10kV, 3000x magnification), and images were captured. The obtained SEM images are shown in Figure 18. In the SEM image in Figure 18, the area enclosed by the dotted line is the intraparticle image. Since the inside of the particles in Examples 3, 4, and 5 is hollow, it can be seen that they have a core-shell structure (hollow shell structure) consisting of an air core (hollow) and a shell (shell) composed of primary granules. Similarly, SEM images reveal that there are gaps within the shell, indicating that the intershell gaps, composed of primary granules, form interconnected pores that extend all the way to the internal air core (hollow).

[0099] <Surface roughness distribution measurement> Three-dimensional scan images of the secondary granulated material and measurement of its surface roughness distribution were performed using a white-light interferometry laser microscope (Keyence, model: VK-X3000). Figure 19 shows the 3D scan image of Example 3, which was fired at 700°C for 4 hours, Figure 20 shows the 3D scan image of Comparative Example 15, and Figure 21 shows the 3D scan image of Comparative Example 20. From a comparison of these 3D scan images, it can be seen that the fired body of Example 3 is a secondary granulated body composed of microscale spherical particles. The surface roughness distribution was measured by taking a 3D scanned particle image captured with a white-light interferometry laser microscope (Keyence, model: VK-X3000), and determining the evaluation length between two points from edge to edge of a single particle to measure the linear roughness distribution. The surface roughness distribution of Example 1 is shown in Figure 22, and the surface roughness distribution of Example 3 is shown in Figure 23. The surface roughness distribution of Example 4 is shown in Figure 24, and the surface roughness distribution of Example 5 is shown in Figure 25. Figure 26 shows the surface roughness distribution of Example 6, and Figure 27 shows the surface roughness distribution of Comparative Example 3.

[0100] <Confirmation of micro- and nano-protrusions based on surface roughness distribution> Based on the surface roughness distribution described above, it was confirmed that the secondary granulated material surface has micro-protrusions (1.0 to 5.0 μm) and nano-protrusions (0.01 to 0.9 μm). In the present invention, micro-protrusions refer to peaks (undulation roughness) in the grain surface roughness distribution where the peak width is 1.0 to 5.0 μm, and both the convex and concave heights relative to the peak top are 1.0 to 5.0 μm, and which have multiple nano-protrusions inside. Furthermore, nanoprotrusions refer to peaks that exist in multiple locations within a microprotrusion, where either the convex or concave height relative to the peak top is 0.01 to 0.9 μm. A schematic diagram illustrating the definitions of nano-protrusions and micro-protrusions is shown in Figure 28. By examining the surface roughness distribution and its scale in Figures 22-27, it can be seen that the surface of the secondary granules has micro-protrusions (1.0-5.0 μm) and nano-protrusions (0.01-0.9 μm). Furthermore, it can be seen that Comparative Example 3, which is a primary granule, has nano-protrusions but no micro-protrusions.

[0101] <Surface roughness> Table 3 shows the surface roughness indices Ra, RSm, and Rz, which were calculated from a laser microscope during the aforementioned surface roughness distribution measurement. <Variation of unevenness> Table 3 shows the variation in surface roughness (standard deviation of the Z-value of the surface roughness distribution) calculated from the aforementioned surface roughness distribution.

[0102] [Table 3]

[0103] <Comparison of surface roughness> Comparison of Examples 3-6 and Comparative Examples 6, 11, and 15 Table 3 shows that Examples 3-6 have higher RSm values ​​compared to Comparative Examples 6, 11, and 15, and are within the range of 1.0-2.0 μm. Comparing Example 3 and Comparative Example 6, which were fired at the same temperature, we can see that although the Ra values ​​are almost the same (0.37 μm for Example 3 compared to 0.38 μm for Comparative Example 6), there is a significant difference in the RSm values ​​(RSm of Example 3 is 1.78 μm, compared to 0.63 μm for Comparative Example 6). This means that while Comparative Examples 6, 11, and 15 are aggregates of densely packed nanostructures, Examples 3-6 form large undulating waveforms due to the combination of microscale irregularities. This comparison shows that Examples 3-6 form a multi-layered structure composed of nano- and micro-irregularities. Comparison of Examples 3-6 and Comparative Example 20 Table 3 shows that Comparative Example 20 has an RSm of 2.61 μm. Compared to secondary granules with RSm values ​​of 1.03 to 1.78 μm, this suggests the presence of smooth and broad protrusions, and it is presumed that the surface has poor three-dimensionality, making it difficult for lamellipodia, which are the sensing structures of microprotrusions on osteoblasts, to recognize the surface. A comparison of the SEM images in Figure 12 and Figure 13, and a comparison of the 3D scan images in Figure 19 and Figure 21, show that Comparative Example 20 has smooth protrusions with lower three-dimensionality compared to the secondary granules of the Example. This is presumably due to the fact that the constituent particles are relatively flat, plate-like particles with low circularity.

[0104] <Comparison of firing temperature ranges> Table 3 shows that the standard deviation of the Z-value for Examples 3-6 tended to decrease with increasing firing temperature. This is presumed to be because firing creates sintered necks between particles, resulting in smoother particle surfaces. A comparison of the particle surface state in SEM images of secondary granules at different firing temperatures, shown in Figures 13, 14, and 15, reveals that the formation of a sintered neck is progressing. Similarly, Ra also tends to decrease in the high-temperature range of 1,100-1,250°C due to the formation of a sintered neck. Therefore, the roughness and variation of the surface can be controlled by adjusting the firing temperature.

[0105] <Analysis of circularity> Using DeepCle, an AI image analysis software manufactured by Sakai Chemical Industry Co., Ltd., the circularity of the SEM images from Example 1 was analyzed, and the average circularity was found to be between 0.819 and 0.831. The circularity analysis was performed in three different fields of view. The results of the circularity analysis are shown in Figure 29. The SEM images used for circularity analysis were acquired using a scanning electron microscope (JEOL, model: JCM-7000) with an acceleration voltage of 15kV and the magnification settings shown in Figure 29. Using the same method as in Example 1, the circularity was analyzed from the SEM images of Example 3, and the average circularity was found to be 0.817 to 0.822. The circularity analysis was performed in two different fields of view. The results of the circularity analysis are shown in Figure 30. The SEM images used for the circularity analysis were acquired under the acceleration voltage of 15kV and magnification conditions shown in Figure 30. Using the same method as in Example 1, the circularity of Comparative Example 25, a commercially available spherical hydroxyapatite (Sangi, HAP-C-BEADS), was analyzed from SEM images. The average circularity was found to be 0.808. The results of the circularity analysis are shown in Figure 30. The acceleration voltage used for SEM image acquisition for the circularity analysis was 15kV, and the magnification was as shown in Figure 30. These circularity analysis results show that the secondary granules of the present invention have a circularity similar to that of commercially available hydroxyapatite in spherical form. Figure 31 shows an SEM image of Comparative Example 25 (manufactured by Sangi, HAP-C-BEADS). The SEM image in Figure 31 was captured using a scanning electron microscope (JEOL, model: JCM-7000) at a magnification of 1700x and an acceleration voltage of 10kV.

[0106] <Average particle size measurement> The average particle size (D50) was measured for Examples 2-4, Comparative Examples 10-12, Comparative Examples 14-16, and Comparative Examples 19-21. The measurement conditions for D50 are the same as those for the primary and secondary granules in Example 1. The measurement results for D50 obtained are shown in Table 4.

[0107] <Measurement of BET Specific Surface Area> The BET specific surface area was measured using a specific surface area measurement device (manufactured by Mountec, model Marcsorb-1201). The measurement results of the obtained specific surface area are shown in Table 4. Figure 32 shows the relationship between the firing temperature and the BET specific surface area of the hydroxyapatite particles in Examples 2 to 4 and Comparative Examples 14 to 16, 19 to 21.

[0108]

Table 4

[0109] Comparison between Examples 2 to 4 and Comparative Examples 14 to 16 All particles were wet-milled before granulation, and the original slurry raw materials were the same. However, in the high-temperature range of 700 to 900 °C, the Examples have a higher specific surface area despite having a larger D50. This is presumably because increasing the firing temperature promotes neck formation within the particles, making the influence of the outer surface area greater. At firing temperatures of 700 to 900 °C, secondary granulates with micro-scale irregularities on the surface have a higher specific surface area, indicating that they have many cell adhesion sites. [[ID=​​​​​​​​​​The X-ray diffraction spectra of Examples 1-5 and Comparative Examples 6, 15, and 20 were measured using an X-ray diffractometer (Shimadzu Corporation, Model: XRD-6100). The X-ray diffraction spectrum measurement results for Examples 2-5 are shown in Figure 33. [Measurement conditions for X-ray diffraction spectra] ·X-ray tube: Cu (1.54060Å) • Tube voltage: 40.0kV ·Tube current: 30.0mA Step width: 0.020 degrees

[0112] <Mass ratio of β-TCP in hydroxyapatite> Table 5 shows the results of calculating the mass ratio of β-TCP (β-type tricalcium phosphate) in hydroxyapatite (HAP) using the formula "{integrated intensity of the 0120 plane ÷ (integrated intensity of the 211 plane + 0210 plane)} × 100" from the measured X-ray diffraction spectrum. The β-TCP mass ratio (wt%) is calculated as follows: "Integrated intensity of the 0210 plane (around 2θ=31 degrees) ÷ {Integrated intensity of the 211 plane (around 2θ=31.8 degrees) + Integrated intensity of the 0210 plane} × 100" It was calculated from the above. The HAP mass ratio (wt%) was calculated from "100 - (β-TCP mass ratio)".

[0113] [Table 5]

[0114] Table 5 shows that at the same firing temperature, the X-ray diffraction spectrum data does not change significantly between the example and the comparative example with different pretreatments. However, as the firing temperature is increased, the X-ray diffraction spectrum gradually changes, and the β-TCP ratio increases.

[0115] <Measurement of crystallinity of hydroxyapatite before firing> The X-ray diffraction spectrum of the sample from Example 1 was measured using an X-ray diffractometer (Shimadzu Corporation, model: XRD-6100). As comparative examples, measurements were also performed on eggshell-derived hydroxyapatite (product name: Pure Bioapatite) (Comparative Example 24), commercially available from Bioapatite Co., Ltd., and spherical hydroxyapatite (product name: HAP-C-BEADS) (Comparative Example 25), commercially available from Sangi Co., Ltd. The X-ray diffraction spectrum measurement results for Example 1, Comparative Examples 24 and 25 are shown in Figure 34 and Table 6. The degree of crystallinity is {1-(V 112 / 300 / I 300 It was calculated using the formula: )} × 100. V 112 / 300 This represents the height (intensity) of the valley formed between the peak at the 112 plane (around 2θ = 31.8 degrees) and the peak at the 300 plane (around 2θ = 32.7 degrees) in the XRD chart. I 300 This represents the peak intensity at 300. [Measurement conditions for X-ray diffraction spectra] ·X-ray tube: Cu (1.54060Å) • Tube voltage: 40.0kV ·Tube current: 30.0mA Step width: 0.020 degrees

[0116] [Table 6]

[0117] Table 7 shows the firing temperature, overview, and particle shape classification of the samples, examples, and comparative examples used in the present invention.

[0118] [Table 7]

Claims

1. A method for producing metal-containing compound particles, comprising: a primary granulation step of obtaining a primary granule by spray-drying and granulating a slurry containing a metal-containing compound raw material having an average primary particle diameter of 10 to 900 nm and an average secondary particle diameter of 0.1 to 40 μm; and a secondary granulation step of obtaining a secondary granule by spray-drying and granulating a slurry containing the primary granule.

2. A method for producing metal-containing compound particles according to claim 1, further comprising the step of firing the secondary granules at 400 to 1300°C.

3. The method for producing metal-containing compound particles according to claim 1, wherein the primary granules have an average particle diameter of 1.0 to 10.0 μm, and the secondary granules have an average particle diameter of 10 to 500 μm.

4. The method for producing metal-containing compound particles according to claim 1, wherein the primary granule has a circularity of 0.80 or more.

5. The secondary granules obtained in the above secondary granulation process have a crystallinity of '' (1-V) determined by XRD measurement. １１２／３００ / I ３００ A method for producing metal-containing compound particles according to claim 1, wherein the value of ') × 100' is 40 to 80.

6. The method for producing metal-containing compound particles according to claim 1, wherein the primary granulation step is performed using a collision-type two-fluid nozzle.

7. The method for producing metal-containing compound particles according to claim 1, wherein the metal-containing compound raw material includes hydroxyapatite.

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