METAL-CONTAINING COMPOUND PARTICLES AND METAL-CONTAINING COMPOUND PARTICLES

Abstract

The object of the present invention is to provide a method for producing particles of metal-containing compounds such as hydroxyapatite, which have nanoscale and microscale irregularities on their surfaces, while controlling with high precision the size and variation of the irregularities on their surfaces, as well as the shape and degree of crystallinity. [Solution] A method for producing metal-containing compound particles includes a primary granulation step in which a slurry containing a metal-containing compound raw material is spray-dried and granulated to obtain primary granules, and a secondary granulation step in which a slurry containing the primary granules is spray-dried and granulated to obtain secondary granules.

Description

[Technical Field]

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

[0002] Metal-containing compound particles, which are composed of metal atoms, are useful materials used in various fields such as optical materials, electronic materials, medicine, and cosmetics. Hydroxyapatite (HAP), a type of metal-containing compound, has the chemical formula Ca 10 It is a type of calcium phosphate represented by (PO4)6(OH)2, and has a composition very similar to that of human bones and teeth, giving it an extremely high affinity with living organisms and making it widely used as a biomaterial in fields such as artificial bones, implants, and tooth abrasives. Market research by Precedence Research predicts that global demand for hydroxyapatite will surge due to factors such as an aging population, the expansion of regenerative medicine, and demand for implants, with market growth predicted to reach approximately $4.94 billion (CAGR: 6.54%) between 2025 and 2034.

[0003] Hydroxyapatite particles can bond with newly formed bone in the body (osteoconductivity) or be regenerated into new bone after being absorbed (bone remodeling), and are therefore used as bone substitutes, implant materials, biomaterial fillers, medical coating agents, and more to regenerate bone defects. The bone remodeling process, in which artificial bone material replenished in bone defects is regenerated as bone, can be broadly divided into two stages: absorption of artificial bone material by osteoclasts and bone formation by osteoblasts that invade the space created by absorption. Osteoblasts, in particular, are known to recognize the irregularities on the surface of artificial bone as a scaffold and promote bone regeneration by physical adhesion (interlocking). Regarding the size of these irregularities, nanoscale irregularities and microscale irregularities are known. This is because filipodia, membrane protrusion structures derived from the actin cytoskeleton that osteoblasts use to explore irregularities, can easily recognize and adhere to protrusions in the nano to submicron range (0.01 to 0.9 μm), while lamellipodia can easily recognize and adhere to protrusions in the micron range (1.0 to 5.0 μm). Since filipodia and lamellipodia proceed to adhesion by recognizing protrusions, recognition does not proceed in the case of smooth protrusions below their respective limits (0.01 to 0.9 μm for filipodia, 1.0 to 5.0 μm for lamellipodia), making adhesion difficult. If excessively coarse protrusions exceeding 10 μm are present, stress on the cells increases, making it more likely that cell destruction will occur during adhesion, so it is preferable that the size of the protrusions in the micron range be 5.0 μm or less. Regarding the surface irregularities of implant materials, micro-nanostructured surface samples were created by sandblasting, combining nanoscale irregularities with microscale irregularities, and it has been reported that the proliferation ability of osteoblast-like cells was promoted when the Ra was 0.6 μm and the RSm was 11.1 μm, while cell proliferation was significantly less likely to progress on smooth surfaces that had not been sandblasted (see non-patent document 1). Furthermore, an artificial bone made of ceramics has been reported in which the surface of a substrate made of dense ceramics with a purity of 95% or more is formed with rounded irregularities with a surface roughness of Ra 4 to 40 μm (see Patent Document 1). The shape of the protrusions themselves is preferably spherical with a high degree of circularity (few edges). When comparing cells cultured on protrusions with the same aspect ratio 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 document 2).

[0004] As porous hydroxyapatite bodies, there have been reported a biocompatible ceramic porous member made of a calcium phosphate sintered body having open, spherical pores in which a large number of pores are densely distributed three-dimensionally and adjacent pores are interconnected at the skeletal walls that separate them, in which the pore volume of open pores with a pore size of 5 microns (μm) or more and the pore volume of open pores with a pore size of less than 5 microns (μm) are each within a predetermined range (see Patent Document 2). There has also been reported a method for producing a porous body, which comprises the steps of obtaining a slurry in which primary particles of a ceramic material are dispersed, granulating the primary particles to obtain secondary particles of the ceramic material, and adding the secondary particles to the slurry and then heating the slurry to bond the secondary particles together via the primary particles to obtain a porous body (see Patent Document 3). To date, spherical particles of hydroxyapatite have been produced by a method for producing spherical hydroxyapatite (see Patent Document 4), which involves 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 above 70°C but below the boiling point of the aqueous solution, and precipitating hydroxyapatite particles by a homogeneous precipitation method; another method involves adding potassium pyrophosphate (K4P2O4) to a mixed solution of a water-soluble organic solvent and water, which causes a unique phase separation, which is then stirred to form a W / O emulsion, to which an aqueous solution of a water-soluble calcium salt is added. Hydrogen phosphate ions contained in an aqueous phase react with calcium to form precursor particles of pyrophosphate. These precursor particles (spherical particles) are then hydrothermally treated at a pH of 13 to 16 and at a temperature of 110 to 300°C to transform them into spherical hydroxyapatite (see Patent Document 5). Another method that has been reported is to dry a slurry containing primary particles of hydroxyapatite and their aggregates, and then granulate the resulting powder, which is mainly composed of hydroxyapatite and has a bulk density and specific surface area within a specified range (see Patent Document 6). [Prior art documents] [Patent documents]

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

[0006] [Non-Patent Document 1] Kosuke Nozaki, Basic research toward clinical application of bone augmentation implants for osteoporosis (Grant-in-Aid for Scientific Research, Research Report No. 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. Summary of the Invention [Problem to be solved by the invention]

[0007] As mentioned above, when using hydroxyapatite for bone regeneration, it is preferable to use hydroxyapatite with both nanoscale and microscale surface irregularities in order to promote bone regeneration. In Non-Patent Document 1, a micro-nanostructured surface sample was created by sandblasting, combining nanoscale and microscale irregularities. 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 mean length of the roughness curve element (RSm) increases. This is because the clusters of densely packed nanostructured irregularities are contained within the microscale irregularities, forming a large undulation waveform. Therefore, an increase in RSm value is an important indicator of multi-layered particles. Non-Patent Document 1 reports that promotion of cell proliferation was observed in micro- and nano-structures with the lowest RSm values. However, in processing using sandblasting, there is a limit to the size of the blast beads that can be used, making it extremely difficult to control minute irregularities in the range where RSm is 2.0 μm or less. Therefore, particles with micro- and nano-structures in the range where Ra is 0.1 to 5.0 μm and RSm is 1.0 to 2.0 μm remain an underdeveloped technological area with high potential for application. Furthermore, in the method of forming pores as described in Patent Document 2, the ceramic sintered body formed has a porous structure, which results in the formation of irregularities. However, there is room for further study regarding the precise control of the size and variation of the irregularities that can be achieved by such a method. Known methods for generating pores internally 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 delicate control of the size of irregularities at the micron or nano level, and the bubbles easily collapse even during the drying or firing process. The uneven shape described in Patent Document 1 is the result of a manufacturing method in which unevenness is formed on the surface of phosphate ceramics by etching. However, when this method is applied to particles, it is expected that particles with a closed pore structure will be used in order to prevent particle collapse during processing. Therefore, it is difficult to create a structure that allows cytokines and minerals, which act as cell growth factors, to permeate from the particle surface by capillary action and promotes cell growth and differentiation from the inside of the particle as well. The shape of the material in Patent Document 3 is expected to have relatively large irregularities and a relatively large size in the final shape. Therefore, when the material is used for powder applications such as bone replacement materials, fillers for biomaterials, and medical coating agents, which require cell adhesion to irregularities in the micro- and nano-scale, or minute particles with high fluidity, there is room for improvement in the irregularities, particle size, and particle shape.

[0008] When considering applications as bone supplements, fillers for biomaterials, medical coating agents, etc., the hydroxyapatite particles are preferably spherical particles as described in Patent Documents 4 to 6 in order to improve filling efficiency and fluidity. However, although the manufacturing method such as that described in Patent Document 4 has the advantage of being able to synthesize spherical particles directly from the material, the particles obtained by this method have a problem in that they tend to be relatively poorly crystalline because the particle shape is forcibly induced by external conditions, rather than the plate-like or needle-like shape that is spontaneously formed based on the original crystalline structure of hydroxyapatite. Furthermore, when attempting to control the circularity, particle size, and crystallinity of the particles within a desired range using this method, the properties of the resulting particles vary greatly even with slight variations in the reaction conditions, so there is room for improvement in terms of reproducibility and continuous production. Synthesis using a hydrothermal method such as that described in Patent Document 5 makes it possible to obtain spherical hydroxyapatite with high crystallinity, but it is necessary to maintain the reaction system at high temperature and high pressure, which requires large costs for heating energy, energy for maintaining insulation, and the installation, operation, and maintenance of the pressure-resistant reaction equipment. Therefore, the method of Patent Document 5 also has room for improvement in terms of mass production processes. On the other hand, a method for producing spherical hydroxyapatite by combining a granulation process, such as that described in Patent Document 6, allows the synthesis and granulation processes to be carried out separately, making it possible to control the particle size and circularity with high reproducibility while maintaining the crystalline state of hydroxyapatite. As a result, the crystallinity and shape of the particles are easily stabilized without the need for synthesis under high pressure and high energy, making this a practical and advantageous method that balances both quality and mass productivity. However, since the resulting particles have a smooth surface, including those described in Patent Documents 4 and 5, it is difficult to form both microscale and nanoscale irregularities on the particle surface that are suitable for cell adhesion. Non-Patent Document 2 reports that rounded protrusions suppress cell membrane perforation by mitigating stress concentration, but methods for forming such protrusions on the surface of powder particles are an underdeveloped technological field with high applicability. For these reasons, no mass production process has been established for producing metal-containing compound particles such as hydroxyapatite, which have both nanoscale and microscale surface irregularities, while controlling the size and variation of the surface irregularities, as well as the shape and crystallinity, with high precision, and there is still room for further study.

[0009] In view of the above-mentioned current situation, an object of the present invention is to provide a method for producing particles of a metal-containing compound such as hydroxyapatite, which has nanoscale and microscale irregularities on its surface, while controlling with high precision the size and variation of the irregularities on the surface, as well as the shape and degree of crystallinity. [Means for solving the problem]

[0010] The present inventors have investigated methods for producing metal-containing compound particles such as hydroxyapatite having nanoscale and microscale surface irregularities with controlled size and variation of the irregularities, shape, and degree of crystallinity. They have found that if metal-containing compound particles are produced by spray-drying and granulating a slurry containing a metal-containing compound raw material to obtain primary granules, then re-slurrying the primary granules and spray-drying and granulating the slurry to obtain secondary granules, it is possible to produce metal-containing compound particles having nanoscale and microscale surface irregularities (having spherical microprotrusions on the surface, and nanoprotrusions on the microprotrusion surfaces), and that it is also possible to control the size and variation of the irregularities, which has led 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 in which a slurry containing a metal-containing compound raw material is spray-dried and granulated to obtain primary granules; and a secondary granulation step in which a slurry containing the primary granules is spray-dried and granulated 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 size of 1.0 to 10.0 μm, and the secondary granules have an average particle size 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 of (1-V) by XRD measurement.112 / 300 / I 300 )×100』は40〜80。

[0021] The method for producing metal-containing compound particles according to any one of [1] to [5], wherein the value of [(1)×100] is 40~80.

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

[0018] [8] The method for producing metal-containing compound particles according to any one of [1] to [7], wherein the metal-containing compound raw material contains hydroxyapatite.

[0019] [9] Metal-containing compound particles having a surface roughness 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 microprotrusions with a diameter of 1.0 to 5.0 μm on the surface thereof, and nanoprotrusions with a diameter of 0.01 to 0.9 μm on the surface of the microprotrusions.

[0020]

[10] The metal-containing compound particles according to [9], wherein the microprotrusions are spherical particles having a circularity of 0.80 or more.

[0021]

[11] BET specific surface area is 1.0 to 100 m 2 / g of the metal-containing compound particles according to [9] or

[10] .

[0022]

[12] The metal-containing compound particles according to any one of [9] to

[11] , which have a circularity of 0.80 or more.

[0023]

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

[12] , characterized in that they have a hollow shell structure, and the shell gaps formed by agglomeration of a plurality of the primary granules, sintered necks, or both constitute interconnected pores, which are interconnected to the hollow interior.

[0024]

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

[13] , which contain hydroxyapatite and β-tricalcium phosphate.

[0025]

[15] The metal-containing compound particles according to

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

[0026] The method for producing metal-containing compound particles of the present invention is a method that can produce metal-containing compound particles having nanoscale and microscale irregularities on their surfaces while controlling with high precision the size and variation of the irregularities, shape, and crystallinity of the irregularities on the surface. Therefore, the method can be suitably used as a method for producing hydroxyapatite, etc., used in bone regeneration. [Brief explanation of the drawings]

[0027] [Figure 1] FIG. 2 is a SEM image of primary granules obtained by spray drying under Condition No. 1 in the primary granulation step of hydroxyapatite particles in Example 1. [Figure 2] FIG. 2 is a diagram showing an analytical image of the circularity analyzed from an SEM image of primary granules obtained by spray drying under Condition No. 1 in the production of hydroxyapatite particles in Example 1. [Figure 3] FIG. 1 is a diagram showing an SEM image (protrusion spherical scale analysis image) of the hydroxyapatite particles obtained in Example 1 and the size of the spherical protrusions on the particle surface. [Figure 4] FIG. 2 is a diagram showing an analytical image of the circularity of the hydroxyapatite of Comparative Example 1 analyzed from an SEM image. [Figure 5] FIG. 2 is a SEM image of the hydroxyapatite particles obtained in Comparative Example 2. [Figure 6] FIG. 1 is a SEM image of the hydroxyapatite particles obtained in Comparative Example 3. [Figure 7] FIG. 1 is a diagram showing a three-dimensional scanned image of the hydroxyapatite particles obtained in Example 1. [Figure 8] FIG. 1 shows a three-dimensional scanned image of the hydroxyapatite particles obtained in Comparative Example 3. [Figure 9] FIG. 1 is a diagram showing a three-dimensional scanned image of the hydroxyapatite particles obtained in Comparative Example 2. [Figure 10] FIG. 1 is a diagram showing 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] FIG. 10 is a SEM image of the hydroxyapatite particles obtained in Comparative Example 15. [Figure 12] FIG. 10 is a SEM image of the hydroxyapatite particles obtained in Comparative Example 20. [Figure 13] FIG. 1 is a diagram showing 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] FIG. 1 is a diagram showing 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 particle surface. [Figure 15] FIG. 1 is a diagram showing 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] FIG. 2 is a diagram showing an SEM image of the interior of a hydroxyapatite particle obtained in Example 3 (the area surrounded by a dotted line is the interior of the particle). [Figure 17] FIG. 1 is a diagram showing an SEM image of the interior of a hydroxyapatite particle obtained in Example 4 (the area surrounded by a dotted line is the interior of the particle). [Figure 18] FIG. 1 is a diagram showing an SEM image of the interior of a hydroxyapatite particle obtained in Example 5 (the area surrounded by a dotted line is the interior of the particle). [Figure 19] FIG. 1 is a diagram showing a three-dimensional scanned image of the hydroxyapatite particles obtained in Example 3. [Figure 20] FIG. 10 is a diagram showing a three-dimensional scanned image of the hydroxyapatite particles obtained in Comparative Example 15. [Figure 21]FIG. 10 is a diagram showing a three-dimensional scanned image of the hydroxyapatite particles obtained in Comparative Example 20. [Figure 22] 1 shows the surface roughness distribution of the hydroxyapatite particles obtained in Example 1. [Figure 23] 1 shows the surface roughness distribution of hydroxyapatite particles obtained in Example 3. [Figure 24] 1 shows the surface roughness distribution of the hydroxyapatite particles obtained in Example 4. [Figure 25] 1 shows the surface roughness distribution of the hydroxyapatite particles obtained in Example 5. [Figure 26] 1 shows the surface roughness distribution of the hydroxyapatite particles obtained in Example 6. [Figure 27] 1 shows the surface roughness distribution of hydroxyapatite particles obtained in Comparative Example 3. [Figure 28] FIG. 1 is a schematic diagram showing the definitions of nanoprotrusions and microprotrusions. [Figure 29] FIG. 2 is a diagram showing the results of an analysis of the circularity of the hydroxyapatite particles obtained in Example 1. [Figure 30] FIG. 1 shows the results of analysis of the circularity of the hydroxyapatite particles obtained in Example 3 and Comparative Example 25. [Figure 31] FIG. 10 is a diagram showing an SEM image of Comparative Example 25. [Figure 32] 1 is a graph showing the relationship between the firing temperature and the BET specific surface area of ​​the hydroxyapatite particles of Examples 2 to 4 and Comparative Examples 14 to 16 and 19 to 21. FIG. [Figure 33] FIG. 1 shows the results of X-ray diffraction spectrum measurement of the hydroxyapatite particles of Examples 2 to 5. [Figure 34] FIG. 2 is a diagram showing the results of X-ray diffraction spectrum measurement of the hydroxyapatite particles of Example 1 and the samples of Comparative Examples 24 and 25. [Figure 35] 1 is a diagram showing a structural image of secondary granules of metal-containing compound particles according to the present invention. DETAILED DESCRIPTION OF THE INVENTION

[0028] Preferred embodiments of the present invention will be specifically described below, but the present invention is not limited to the following description and can be appropriately modified and applied within the scope that does not change the gist of the present invention.

[0029] 1.Method for producing metal-containing compound particles The method for producing metal-containing compound particles of the present invention includes 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. Spray-drying granulation refers to a method of forming a slurry into droplets and applying hot air to the droplets to obtain dried granules. By producing metal-containing compound particles using this production method, it is possible to produce metal-containing compound particles having surface irregularities of different sizes, with sizes differing by more than 100 times. Using this production method, a fine metal-containing compound raw material having a primary particle diameter on the order of nanometers is made into a slurry, and then spray-dried and granulated to obtain primary granules having microscale particle sizes and nanoscale irregularities on the surface. These primary granules can be made into a slurry again, and then spray-dried and granulated to obtain metal-containing compound particles having both nanoscale and microscale irregularities on the surface. Regarding the properties of the particles obtained by spray drying granulation, there are many variable parameters, such as the solids concentration of the raw material liquid, the hot air temperature, the atomizer disk rotation speed, and the mixture ratio of atomizing air and liquid. However, these are easy to control artificially or mechanically, and therefore granulated products can be produced with high quality stability. In this manufacturing method, it is possible to adjust the size and variation of the 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, sintering necks can be formed between nanoscale or macroscale irregularities, making it possible to adjust the size and variation of the irregularities, as well as their shape and the crystalline structure of the material.

[0030] <Slurry containing metal-containing compound raw material> The metal-containing compound raw material in the slurry containing the metal-containing compound raw material preferably has an average primary particle diameter (D50) of 10 to 900 nm. By using a particle diameter of this size, it becomes easy to obtain metal-containing compound particles having nanoscale irregularities on the surface of secondary granules. Furthermore, even after the calcination step in the method for producing metal-containing compound particles, the particles have a high specific surface area, and when used in vivo as a biomaterial, they have sites to which many 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] The average secondary particle size of the metal-containing compound raw material in the slurry containing the metal-containing compound raw material is preferably 0.1 to 40 μm. The use of such particle sizes results in an aggregated slurry, making it easy to adjust the circularity of the primary granules to 0.80 or more. Furthermore, a slurry with such an average secondary particle size has strong interparticle cohesion, which reduces the uneven distribution of particles within the droplets that occurs when the droplets are dried with hot air. This makes it easy to produce granules with high circularity when spray-dried and granulated in the subsequent primary granulation step. 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 size and average secondary particle size of the metal-containing compound raw material can be measured by the method described in the examples below. The average primary particle size in the present invention refers to the average particle size (D50) measured in a state where the metal-containing compound in the slurry is secondarily agglomerated due to van der Waals forces generated mainly during liquid phase synthesis or wet pulverization, crosslinking due to the addition of an organic binder, and the like, and the secondary agglomeration is weakened by physical stimulation such as mixing and dispersing with a dispersant such as sodium hexametaphosphate or ultrasonic dispersion. The average secondary particle diameter in the present invention refers to the average particle diameter (D50) measured in an environment similar to the state in which the metal-containing compound in the slurry remains in secondary agglomerated form, as opposed to the state in which the metal-containing compound in the slurry is secondary agglomerated due to van der Waals forces generated mainly during liquid phase synthesis or wet pulverization, or crosslinking due to the addition of an organic binder.

[0032] There are no particular limitations on the method for obtaining a slurry containing a metal-containing compound raw material having the above average particle size, but a method of wet-pulverizing 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 may be prepared by generating the metal-containing compound raw material through a chemical reaction in the solvent.

[0033] The solvent used for the slurry containing the 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 the solvent used is preferably 50 to 10,000 mass % relative to 100 mass % of the solid content of the metal-containing compound raw material, more preferably 100 to 8,000 mass %, and even more preferably 200 to 5,000 mass %.

[0034] When preparing a slurry containing the metal-containing compound raw material, components other than the solvent may be added. Examples of components other than the solvent include a polymeric organic binder and a polymeric dispersant. Examples of the organic binder include carboxymethyl cellulose (CMC) and polyvinyl alcohol (PVA), and examples of the polymeric dispersant include one or more of polyacrylates, naphthalene sulfonates, nitrohumates, polyethylene glycols, and the like. By adding the polymeric organic binder or polymeric dispersant, the slurry becomes an aggregated system due to crosslinking between primary particles, making it easier to obtain primary granules with high circularity in the spray-drying granulation step in the primary granulation process.

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

[0036] The method of wet pulverization for obtaining the slurry containing the metal-containing compound raw material is not particularly limited, but it is preferable to use a bead mill or a ball mill using fine media. The media used here are preferably made of ceramics such as zirconia and have a diameter of 0.05 to 2 mm, and more preferably have a diameter of 0.1 to 0.5 mm. By using fine media in this range, it is possible to reduce the primary particle size while suppressing changes in the crystal 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 containing a metal element as a constituent element, and there are no limitations on the type or number of metal elements contained or the type of compound, but it is preferably a bioceramic. More preferably, the bioceramic is made of one or more of hydroxyapatite, β-tricalcium phosphate, bioglass, alumina, and zirconia, and particularly preferably, it is made 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, the metal-containing compound raw material preferably contains hydroxyapatite.

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

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

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

[0041] When reacting an aqueous solution of calcium nitrate with an aqueous solution of trisodium phosphate, the method for mixing them is not particularly limited, but it is preferable to dropwise add the aqueous solution of trisodium phosphate while stirring the aqueous solution of calcium nitrate, thereby allowing the reaction to occur. This makes it easy to obtain hydroxyapatite with a crystallinity of 40 to 80.

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

[0043] When an aqueous solution of calcium nitrate and an aqueous solution of trisodium phosphate are reacted, it is preferable to dropwise add the aqueous solution of trisodium phosphate to the aqueous solution of calcium nitrate to cause the reaction. In this case, the rate at which the trisodium phosphate aqueous solution is dropped into the calcium nitrate aqueous solution is preferably 4 to 30 kg / h. By adjusting the dropping rate to this level 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 liquid temperature when reacting the calcium nitrate aqueous solution with the trisodium phosphate aqueous solution is preferably 30 to 90°C, and more preferably 80 to 90°C. By setting the temperature within this range, it becomes easy to obtain hydroxyapatite with a crystallinity of 40 to 80.

[0045] The end point of the reaction is controlled by pH measurement, and the pH value is preferably 5.0 to 10.0, and more preferably 7.0 to 9.0, at a liquid temperature of 80 to 90° C. By setting the pH within this range, it becomes easy to obtain hydroxyapatite with a crystallinity of 40 to 80.

[0046] The average primary particle size and average secondary particle size of the hydroxyapatite obtained after the reaction between the aqueous calcium nitrate solution and the aqueous trisodium phosphate solution are both preferably 0.1 to 20 μm, more preferably 1 to 10 μm. By setting the particle size within this range, it becomes possible to efficiently grind the powder in the subsequent wet grinding step with less settling and clogging of the screen inside the mill. The primary average particle size and secondary average particle 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 filtering device such as a filter press or a centrifugal dehydrator, and after recovering the dehydrated cake, it is washed with a polar solvent such as ion-exchanged water. This operation removes sodium nitrate, a by-product of synthesis, and makes it possible to increase the purity of the synthesized hydroxyapatite.

[0048] Next, the dehydrated cake of hydroxyapatite is dispersed in a solvent, and the hydroxyapatite in the slurry is physically pulverized. By pulverizing the hydroxyapatite dispersed in the solvent in this manner, the primary particles are reduced in size, making it easier to form nanoscale irregularities on the surface of the granules in the subsequent primary granulation step.

[0049] The method for physically pulverizing the hydroxyapatite dispersed in the solvent is not particularly limited, but a method similar to the wet pulverization method used to obtain the slurry containing the metal-containing compound raw material described above can be used.

[0050] <Primary granulation process> The primary granulation step is a step in which a slurry containing a metal-containing compound raw material is spray-dried and granulated to obtain primary granules. The primary granules obtained in the primary granulation step 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 micro-scale irregularities (spherical protrusions of 1.0 to 5.0 μm) on the surface of the secondary granules obtained through the secondary granulation step. 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, and D95 ​​(the particle size at which 95% of particles in a cumulative distribution are equal to or smaller than the specified particle size) is 10.0 μm or smaller. The average particle size (D50) and D95 ​​of the primary granules can be measured by the method described in the Examples below.

[0051] The primary granules preferably have a circularity of 0.80 or more. More preferably, the average circularity measured for 100 or more particles is 0.80 or more, and even more preferably, the average circularity measured for 100 or more particles is 0.80 or more and the standard deviation is 0.08 or less. When the circularity of 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 than, for example, a plate-like shape. Particles with a larger surface area are preferred because they provide more surface area for cells to adhere to when used in vivo. Furthermore, compared to sharp protrusions with a low circularity, they are expected to reduce stress concentration and suppress membrane perforation during cell adhesion. Primary granules with a circularity of 0.80 or more can be easily obtained by carrying out the primary granulation step by spray-drying granulation. The circularity of the primary granules can be determined by analysis using the method described in the Examples section below.

[0052] The primary granulation step is not particularly limited to the apparatus used for spray-drying granulation as long as it is performed by spray-drying granulation, but the atomization method for converting the slurry into droplets is preferably performed using a collision-type two-fluid nozzle. By using a collision-type two-fluid nozzle, it becomes easy to adjust the average particle size of the primary granules to the range of 1.0 to 10.0 μm. In the manufacturing method of the present invention, in the step of spray-drying and granulating the liquid raw material, it is preferable to use a two-fluid nozzle (hereinafter referred to as a "collision-type two-fluid nozzle") that has an edge where the liquid raw material and a gas (e.g., compressed air or nitrogen) come into contact and mix, and that includes 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 to be 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 between droplets formed by mixing liquid and gas," it is included in 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) sent to the collision-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 in this range, it is possible to efficiently granulate particles with a D50 in 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 primary granulation step is not particularly limited, but it is preferable that the hot air inlet temperature be 150° C. to 400° C. and the exhaust air temperature be 50 to 140° C. By setting the temperature within these ranges, the water in the droplets can be efficiently evaporated, the amount of residual solvent in the particles after drying can be reduced to 10 wt % or less, and primary granules can be easily obtained as dry powder. More preferably, the hot air inlet temperature is 200 to 300°C and the exhaust air temperature is 80 to 130°C.

[0055] <Secondary granulation process> In the secondary granulation step, the primary granules obtained in the primary granulation step are dispersed in a solvent to form a slurry, which is then spray-dried and granulated again to obtain secondary granules having a more porous and multi-layered structure. By performing the granulation step twice using spray-drying granulation in this way, metal-containing compound particles having uneven surfaces of different sizes can be obtained.

[0056] The solvent used to prepare the slurry in which the primary granules are dispersed can be one or more low-boiling solvents having a boiling point of 100°C or less at 1 atmosphere, such as water, ethyl alcohol, methanol, isopropanol, and acetone. The amount of the solvent used is preferably 50 to 10,000% by mass, more preferably 100 to 8,000% by mass, and even more preferably 200 to 5,000% by mass, relative to 100% by mass of the solid content of the primary granules. By setting the amount of solvent used in this way, the void ratio within the particles after spray drying granulation increases, It becomes easy to form the secondary granules into a hollow shell structure.

[0057] When preparing a slurry in which the primary granules are dispersed, components other than the solvent may be added. Examples of the components other than the solvent include an organic binder. As the organic binder, one or more of carboxymethyl cellulose (CMC), polyvinyl alcohol (PVA), and the like can be used.

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

[0059] The secondary granules preferably have an average particle size (D50) of 10 to 500 μm. By adjusting the average particle size to such a value, it becomes easy to obtain granules that are sufficiently dried for use as a powder and have high fluidity. The average particle size of the secondary granules is more preferably 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 preferably have a circularity of 0.80 or more, which allows the irregularities derived from the primary granules to be uniformly arranged on the surface, and is expected to facilitate the multivalent effect (synergistic improvement in adhesive ability due to simultaneous contact of multiple irregularities) when used in vivo. Furthermore, when the circularity of the secondary granules is 0.80 or more, the entire surface becomes a continuously curved surface, and when the metal compound granules are used as a bone regeneration material, the resistance to the extension of the osteoblast body and lamellibodia is reduced, making it easier for them to spread smoothly along the adhesive surface, which is expected to facilitate promotion of bone regeneration. The circularity of the secondary granules is more preferably 0.80 or more on average when measuring the circularity of 100 or more particles, and even more preferably 0.80 or more on average with a standard deviation of 0.09 or less when measuring the circularity of 100 or more particles. The circularity of the secondary granules can be determined by analysis using the method described in the Examples section below.

[0061] The secondary granules obtained in the secondary granulation process were measured by XRD to determine the crystallinity ((1-V 112 / 300 / I 300 ) × 100 is preferably 40 to 80. When the degree of crystallinity is within this range, the secondary granules can be said to be chemically stable, and even when used in vivo, the uneven surface structure does not easily dissolve in the body, and the phase transition to β-tricalcium phosphate is facilitated during firing. The crystallinity is more preferably 45-70, and further preferably 50-60.

[0062] The secondary granulation step is carried out by spray-drying a slurry of primary granules, and the type of spray-drying granulation equipment is not particularly limited. However, the atomization method for turning the slurry into droplets is preferably a disk atomizer, a two-fluid nozzle, or a one-fluid nozzle. By using such an atomizer, it is possible to efficiently produce granules with an average diameter in the range of 10 to 500 μm.

[0063] In the above disk atomizer system, the disk rotation speed is preferably 1,000 to 40,000 rpm. By using this disk rotation speed, the average diameter of the granules is 10 to 500 μm. This makes it easier. More preferably, it is 5,000 to 20,000 rpm.

[0064] The temperature during spray-drying granulation in the secondary granulation step 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 these ranges, the water in the droplets can be efficiently evaporated, the amount of residual solvent in the particles after drying can be reduced to 10 wt % or less, and secondary granules can be easily obtained as dry powder with good flowability. More preferably, the hot air inlet temperature is 200 to 300°C, and the exhaust air temperature is 80 to 130°C.

[0065] <Firing process> The method for producing metal-containing compound particles of the present invention preferably further includes a step of firing the secondary granules at 400 to 1300° C. In particular, when the metal-containing compound particles contain hydroxyapatite, the firing step can convert a portion of the hydroxyapatite crystal phase to β-tricalcium phosphate, which has high bone resorption, to obtain secondary granules of BCP (biphase calcium phosphate), which is a mixture of hydroxyapatite and β-tricalcium phosphate, and can also reduce the amount of organic binder added during granulation, thereby increasing the purity of the BCP. Furthermore, the formation of sintered necks also makes it possible to adjust the unevenness and average surface roughness (Ra). The temperature for firing the secondary granules is more preferably 500 to 1250°C, and even more preferably 700 to 1100°C. The time for firing the secondary granules within the above temperature range is preferably 2 to 20 hours, more preferably 3 to 10 hours, and even more preferably 4 to 7 hours.

[0066] The atmosphere for the firing step is not particularly limited, but an oxidizing atmosphere such as air or an oxygen atmosphere that readily promotes the elimination of hydroxyl groups is preferred.

[0067] The method for producing metal-containing compound particles of the present invention may include other steps in addition to the primary granulation step, secondary granulation step, and calcination step. Examples of other steps include a pulverization step using a dry pulverizer or the like, a synthesis step using a liquid phase method, a solid phase method, or a hydrothermal method, a filtration step using a filter press or a centrifugal dehydrator, a solid-liquid separation step using a centrifuge or the like, a step of removing impurities by washing with a polar solvent or the like, a drying step using a dryer or the like, a dissolution step using an acid or a base, a step of mixing or coating different materials using a blender or a stirrer or the like, a neutralization step using an acid or a base, and a flocculation step using a polymeric dispersant or an organic binder.

[0068] 2. Metal-containing compound particles The metal-containing compound particles of the present invention are characterized in that the surface roughness measured by a laser microscope has an Ra of 0.1 to 5.0 μm and an RSm of 1.0 to 2.0 μm, and the particles have nanoprotrusions with a diameter of 0.01 to 0.9 μm and microprotrusions with a diameter of 1.0 to 5.0 μm on the surface. The metal-containing compound particles of the present invention, which have these characteristics, are suitable for use in vivo, particularly as materials for bone regeneration and artificial bone. By measuring the surface roughness, the Ra of the metal-containing compound particles is 0.1 to 5.0 μm, resulting in a textured structure that facilitates adhesion of filipodia and lamellipodia in osteoblasts. Furthermore, by having a surface roughness (RSm) of 1.0 to 2.0 μm and a multi-layered structure with nanoprotrusions of 0.01 to 0.9 μm in diameter and microprotrusions of 1.0 to 5.0 μm in diameter on the surface, a strong double interlocking action occurs between the lamellipodia extending from osteoblasts in a membrane-like manner and the microprotrusions of the present invention, and between the filipodia on the lamellipodia surface and the nanoprotrusions on the microprotrusion surface, which is expected to provide a more stable cell scaffold. Furthermore, by controlling the surface roughness (Rz) to 0.1 to 5.0 μm and making the shape of the microprotrusions spherical, it is possible to prevent cells from being subjected to stress due to extreme roughness or sharpness, and it is expected that the possibility of cell death will be reduced.

[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, and more preferably 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, and more preferably 0.8 to 5.0 μm. The diameter of the nanoprotrusions having 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 microprotrusions of the metal-containing compound particles of the present invention having a diameter of 1.0 to 5.0 μm 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 protrusion diameter 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 have a BET specific surface area of ​​1.0 to 100 m 2 / g. Materials having such a BET specific surface area are preferred because they have sites for cell adhesion when used in vivo as biomaterials. The BET specific surface area of ​​the metal-containing compound particles is more preferably 2.0 to 80 m 2 / g, and more preferably 5.0 to 50m 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 continuously curved surface. This continuous curved surface reduces resistance to the extension of osteoblast bodies and lamellibodia, making it easier for them to slide along the adhesive surface, which is expected to promote bone regeneration. In addition, it is now possible to uniformly arrange the irregularities derived from the primary granules on the entire surface, which is expected to make it easier for the multivalent effect (synergistic improvement in adhesive ability due to simultaneous contact of multiple irregularities) to be achieved when used in vivo. The circularity of the metal-containing compound particles can be determined by analysis using the method described in the Examples section below.

[0072] It is preferable that the metal-containing compound particles of the present invention have a hollow shell structure, and the shell gaps formed by agglomeration of a plurality of the primary granules, sintered necks, or both constitute interconnected pores, which are connected to the hollow interior. Hollow-shell structure particles refer to particles with 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 bodily fluids, nutrients, and cytokines to penetrate and diffuse through the gaps in the shell on the particle surface, making them more suitable as biomaterials because they help promote cell growth. In the method for producing metal-containing compound particles of the present invention, metal-containing compound particles are produced by spray-drying granulation. In spray-drying granulation, after droplets are formed, drying proceeds from the droplet surface to form an outer shell. As the internal pressure inside the droplets increases due to steam, the constituent particles concentrate at the interface and take on a compacted form. Therefore, 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, which makes the metal-containing compound particles suitable as a biomaterial for bone regeneration, artificial bone material, and the like. By combining the highly chemically stable hydroxyapatite crystalline phase with the highly absorbable β-tricalcium phosphate (β-TCP) crystalline phase, it is possible to maintain the nano-roughness of the powder surface in the body while increasing its absorbability by osteoclasts. This composite crystalline phase is called biphase calcium phosphate (BCP), and is considered ideal for artificial bone applications because it is gradually absorbed in the body and replaced by new bone.

[0074] When the metal-containing compound particles of the present invention contain hydroxyapatite and β-tricalcium phosphate (β-TCP), the content ratio of β-tricalcium phosphate to hydroxyapatite is preferably 1 to 80 mass%. When β-tricalcium phosphate is contained in such a ratio, it is expected that the stability derived from hydroxyapatite and the absorbability derived from β-TCP can be more fully obtained. The content ratio of β-tricalcium phosphate to hydroxyapatite is more preferably 20 to 70 mass%, and even more preferably 25 to 60 mass%. In the present invention, the β-TCP crystalline phase refers to a crystalline phase in which specific diffraction peaks are observed at 2θ of approximately 31 degrees and 34.5 degrees in XRD measurement. The hydroxyapatite content (wt%) and the β-TCP content (wt%) were calculated from the X-ray diffraction spectrum using the following formula. β-TCP content (wt%) = {Integrated intensity of 0210 plane (near 2θ = 31 degrees) ÷ Integrated intensity of 211 plane (near 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-tricalcium phosphate, the total content of hydroxyapatite and β-tricalcium phosphate relative to the entire metal-containing compound particles is preferably 10% by mass or more, more preferably 50% by mass or more, and even more preferably 70% by mass or more, particularly preferably 90% by mass or more, and most preferably 100% by mass, i.e., the metal-containing compound particles are composed only of hydroxyapatite and β-tricalcium phosphate. [Example]

[0076] Specific examples are given below to explain 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 trisodium phosphate solution (1.01 mol / L) was added dropwise at a rate of 20 kg / h until the pH of the mixture reached 8.9. After 19 hours of aging and stirring, the final pH of the mixture was 8.6. The tank was covered during the dropwise addition and aging and stirring, and nitrogen gas was flowed into the headspace above the liquid surface to maintain the liquid temperature at 80-90°C. The rotation speed for stirring the mixture was maintained at 800-900 rpm (circumferential speed: 13.8-15.5 m / s), and the stirring power was 10-70 W per 1 kg of the mixture. The molar ratio of calcium nitrate to trisodium phosphate in the above synthesis was 1.3 mol of trisodium phosphate per 1 mol of calcium nitrate. Next, the obtained slurry was filtered and dehydrated using a filter press (Nihon Toro Kikizai, Model 600) in which a P89C filter cloth manufactured by Shikishima Campus Co., Ltd. was set in a filter frame with a thickness of 15 mm. After that, the filter cake filled in the machine was washed with ion-exchanged water. The end point of the washing was determined to be the time when the electrical conductivity of the discharged washing filtrate reached 0.4 mS / cm. (Wet grinding process) Next, 25.3 kg of the obtained dehydrated cake (11.39 kg on a dry powder basis) and 77.5 kg of ion-exchanged water were mixed in a disper (manufactured by Asada Iron Works, model: MH-1200), and 92.7 kg of the resulting pre-dispersion was circulated in a bead mill (manufactured by Asada Iron Works, model: PCMH-C20M) at a flow rate of 7 kg / min for 400 minutes, whereupon wet grinding was carried out. The peripheral speed of the bead mill during circulation was set to 12 m / s. As grinding media, 24.4 kg (78% capacity of the bead mill vessel) of zirconia beads (manufactured by Nikkato, model: YTZ-01) having a diameter of 0.1 mm was packed into the bead mill. The particle size distribution of the aggregates contained in the slurry before pulverization and the aggregates contained in the slurry at each specified circulation time 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 diameter is the volume average particle diameter (D50) measured immediately after dispersing the sample in a 0.5 wt% sodium hexametaphosphate solution placed in a particle size distribution analyzer and dispersing it with ultrasound (output setting: 7) for 1 minute. The average secondary particle diameter is the volume average particle diameter (D50) when a sample is dispersed in ion-exchanged water placed inside a particle size distribution analyzer and measured without ultrasonic dispersion. The moisture content of the slurry containing the crushed aggregates was measured to be 88.92%. The moisture content is the weight loss rate (%) measured using an infrared moisture meter (AND, model: MX-50) under the following conditions: set temperature: 105°C, drying end point setting: 0.05% / min, sample weight: 6g.

[0078] [Table 1]

[0079] (Primary granulation process) Next, the slurry containing the pulverized aggregates was spray-dried and granulated using a spray-drying granulator equipped with a collision-type two-fluid nozzle (GF Micromist Spray Dryer, Model: MDP-050) to obtain primary hydroxyapatite granules. Table 2 shows the spray-drying granulation conditions 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 (manufactured by Horiba, Ltd., model: LA-960), and was the volume average particle size (D50) measured without ultrasonic dispersion after dispersing the sample in a 0.05 wt% sodium hexametaphosphate solution placed inside the particle size distribution analyzer. The D95 of the primary granules is D95 (the particle size at which 95% of particles in the cumulative volume distribution are equal to or smaller than the specified particle size) calculated from the particle size distribution when the D50 is measured. The D10 of the primary granules is the D10 (10% of particles in the cumulative volume distribution have a particle size equal to or smaller than the specified particle size) calculated from the particle size distribution when the D50 is measured. The moisture content of the primary granules is the weight loss rate (%) measured using an infrared moisture meter (AND, model: MX-50) under the following conditions: a set temperature of 105°C, a drying end point setting of 0.05% / min, and a sample weight of 2 g.

[0080] [Table 2]

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

[0082] (Secondary granulation process) Next, 100 g of the obtained primary granules under condition No. 1 was mixed with 476.7 g of ion-exchanged water and 100 g of a 1.5 wt % aqueous solution of sodium carboxymethylcellulose (1.5 to 1.6% by dry powder weight relative to the dry hydroxyapatite powder), and the resulting slurry was spray-dried and granulated using a spray dryer equipped with a disk atomizer (IS Japan, research and development spray dryer, model RDS-1R, disk atomizer system) to obtain secondary hydroxyapatite granules. The 1.5 wt % aqueous solution of sodium carboxymethyl cellulose was prepared by dissolving sodium carboxymethyl cellulose (manufactured by Marugo Corporation, product name: CMC) in ion-exchange water to a concentration of 1.5 mass percent. The spray drying conditions were a hot air inlet temperature of 210°C, a hot air outlet temperature of 85 to 109°C, a disk rotation speed of 20,000 rpm, and a liquid flow rate of 23.7 g / min, and the secondary granule powder was collected from the bottom of the dryer body. The moisture content of the secondary granule powder was measured using an infrared moisture meter (manufactured by AND, model: MX-50) and was found to be 4.06%. The moisture content was measured under the same conditions as in the measurement of the moisture content of one granule. The average particle size (D50) of the secondary granules was measured and found to be 35.2 μm. The average particle size (D50) of the secondary granules was measured using a particle size distribution analyzer (manufactured by Horiba, Ltd., Model: LA-960). The method for measuring the average particle size (D50) of the secondary granules was the same as the method for measuring D50 of the primary granules described above. The angle of repose of the secondary granule powder was measured using a repose angle measuring instrument (AS ONE, ASK-01) and found to be 30 degrees. The bulk density of 30 ml of the secondary granule powder was measured using a 50 ml measuring cylinder, and the static bulk density was 0.61 g / ml and the density after 100 taps was 0.64 g / ml. In addition, SEM images of the secondary granules were observed using a scanning electron microscope (manufactured by JEOL, model: JCM-7000), and images of the particles were taken and the sizes of the spherical protrusions on the surface were measured. The conditions of the scanning electron microscope when taking SEM images were set to a magnification of 1700 times and an acceleration voltage of 10 kV. 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 more, and therefore have spherical irregularities on the particle surfaces. FIG. 3 shows an SEM image (spherical protrusion scale analysis image) of the secondary granules obtained in Example 1 and the results of measuring the spherical protrusion size. The size of the spherical protrusions measured by the above method was 2.80 μm (σ=0.764) on average at 10 points, which indicates that they are microscale (1.0 to 5.0 μm) protrusions. The size of the spherical protrusions was determined by measuring the length of the spherical protrusions on the particle surface using the scale of a scanning electron microscope, as observed in the SEM image of the particle.

[0083] Comparative Example 1 500 g of the hydroxyapatite filtered and dehydrated cake obtained in Example 1 (metal-containing compound particle raw material synthesis step) was dried for 24 hours at a set temperature of 105°C using a dryer (Yamato Scientific, low-temperature incubator with air blower, model: DKM300), and dried hydroxyapatite powder was recovered. This was designated as the hydroxyapatite of Comparative Example 1. The moisture content of this dry powder was measured using an infrared moisture meter (manufactured by AND, model: MX-50) and was found to be 0.36%. The moisture content is the weight loss rate (%) measured using an infrared moisture meter (AND, model: MX-50) under the following conditions: set temperature: 105°C, drying end point setting: 0.05% / min, sample weight: 4g. 100 g of this dry powder was dispersed in 476.7 g of ion-exchanged water to prepare a slurry, which was then measured using a particle size distribution analyzer (HORIBA, Model: LA-960). The volume average particle diameter (D50) measured was 4.34 μm. The D50 measurement conditions were the same as those for the primary granules and secondary granules in Example 1.

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

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

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

[0087] <3D scan image capture> Three-dimensional scanned images of the secondary granules of Example 1 and Comparative Examples 2 and 3 were taken using a white light interference laser microscope (manufactured by Keyence, model: VK-X3000). The 3D scan image revealed that the secondary granules of Example 1 were spherical particles composed of micro-scale spherical particles with a surface condition that was clearly different from the particles of Comparative Example 3 and the particles of Comparative Example 2. A three-dimensional scanned image of Example 1 is shown in Fig. 7. A three-dimensional scanned image of the particles of Comparative Example 3 is shown in Fig. 8, and a three-dimensional scanned image of the particles of Comparative Example 2 is shown in Fig. 9.

[0088] Examples 2 to 5 2.00 g of the secondary granules of Example 1 were weighed into an alumina porcelain dish and fired in an electric muffle furnace (manufactured by Yamato Scientific, model: FO510). The heating rate was set to 16°C / min, and the sample fired at 400°C for 4 hours was designated Example 2, the sample fired at 700°C for 4 hours was designated Example 3, the sample fired at 900°C for 4 hours was designated Example 4, and the sample fired at 1,100°C for 4 hours was designated Example 5.

[0089] Example 6 The secondary granules of Example 1 were calcined at 1,250°C for 4 hours using a thermal analyzer (Shimadzu Corporation, model: DTG-60H) with a temperature increase rate set to 16°C / min to obtain a sample of Example 6.

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

[0091] Comparative Example 9 The primary granules obtained under the spray drying conditions of Condition No. 1 in the primary granulation step of Example 1 were calcined at 1,250°C for 4 hours using a thermal analyzer (Shimadzu Corporation, DTG-60H) with a temperature rise rate set to 16°C / min to obtain a sample used as Comparative Example 9.

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

[0093] Comparative Examples 14 to 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 Comparative Example 14, those fired at 700 °C for 4 h were Comparative Example 15, those fired at 900 °C for 4 h were Comparative Example 16, and those fired at 1,100 °C for 4 h were Comparative Example 17.

[0094] Comparative Example 18 The primary granule of Comparative Example 3 was fired at 1,250 °C for 4 h with a heating rate of 16 °C / min set using a thermal analyzer (manufactured by Shimadzu Corporation, DTG-60H), and the sample 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 Comparative Example 19, those fired at 700 °C for 4 h were Comparative Example 20, those fired at 900 °C for 4 h were Comparative Example 21, and those fired at 1,100 °C for 4 h were Comparative Example 22.

[0096] Comparative Example 23 The primary granule of Comparative Example 2 was fired at 1,250 °C for 4 h with a heating rate of 16 °C / min set using a thermal analyzer (manufactured by Shimadzu Corporation, DTG-60H), and the sample 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 during SEM image taking were in accordance with Example 1. An SEM image (protrusion scale analysis image) and spherical protrusion size of Example 3, which was fired at 700°C for 4 hours, are shown in Fig. 10, an SEM image of Comparative Example 15 is shown in Fig. 11, and an SEM image of Comparative Example 20 is shown in Fig. 12. Comparing these SEM images, it can be seen that Example 3 has become a secondary granule composed of micro-scale spherical particles, just like before firing. Furthermore, an SEM image (spherical protrusion scale analysis image) and spherical protrusion size of Example 4, which was fired at 900°C for 4 hours, is shown in Figure 13, an SEM image (protrusion scale analysis image) and spherical protrusion size of Example 5, which was fired at 1,100°C for 4 hours, is shown in Figure 14, and an SEM image (spherical protrusion scale analysis image) and spherical protrusion size of Example 6, which was fired at 1,250°C for 4 hours, is shown in Figure 15. These SEM images show that neck formation begins at the grain boundaries between spherical particles on the surface from a firing temperature of around 1,100°C. This phenomenon is the reason why the specific surface area tends to decrease as the firing temperature increases. The spherical protrusion size was measured in the same manner as in Example 1. The results of measuring 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, just like those before firing.

[0098] The interior of the particles of the secondary granules obtained in Example 3 was observed with a scanning electron microscope (manufactured by JEOL Ltd., model: JCM-7000, accelerating voltage 15 kV, 3000x magnification), and an image was taken. The resulting SEM image is shown in FIG. In the SEM image of FIG. 16, the area surrounded by the dotted line is the inside of the particle. The interior of the particles of the secondary granules obtained in Example 4 was observed with a scanning electron microscope (manufactured by JEOL Ltd., model: JCM-7000, accelerating voltage 10 kV, 3500x magnification), and an image was taken. The resulting SEM image is shown in FIG. In the SEM image of FIG. 17, the area surrounded by the dotted line is the inside of the particle. The interior of the particles of the secondary granules obtained in Example 5 was observed using a scanning electron microscope (manufactured by JEOL Ltd., model: JCM-7000, accelerating voltage 10 kV, 3000x magnification), and images were taken. The resulting SEM image is shown in FIG. In the SEM image of FIG. 18, the area surrounded by the dotted line is the intra-particle image. The particles of Examples 3, 4, and 5 have hollow interiors, which indicates that they have a core-shell structure (hollow shell structure) consisting of an air core (hollow) and a shell (shell) made of primary granules. The SEM image also shows that there are gaps within the shell, which means that the gaps between the shells made up of primary granules form interconnected pores that are connected to the internal air core (hollow).

[0099] <Surface roughness distribution measurement> Three-dimensional scanned images of the secondary granules and measurements of the surface roughness distribution were performed using a white light interference laser microscope (Keyence, model: VK-X3000). A 3D scan image of Example 3, which was fired at 700°C for 4 hours, is shown in Figure 19, a 3D scan image of Comparative Example 15 in Figure 20, and a 3D scan image of Comparative Example 20 in Figure 21. Comparison of these 3D scan images reveals that the fired body of Example 3 is a secondary granule composed of microscale spherical particles. The surface roughness distribution was measured by measuring the line roughness distribution using the evaluation length between two points on a particle in a 3D scanned particle image captured with a white light interference laser microscope (Keyence, model: VK-X3000). The surface roughness distribution of Example 1 is shown in FIG. 22, and the surface roughness distribution of Example 3 is shown in FIG. 23. The surface roughness distribution of Example 4 is shown in FIG. 24, and the surface roughness distribution of Example 5 is shown in FIG. The surface roughness distribution of Example 6 is shown in FIG. 26, and the surface roughness distribution of Comparative Example 3 is shown in FIG.

[0100] <Confirmation of micro- and nano-protrusions based on surface roughness distribution> From the surface roughness distribution, it was confirmed that the secondary granules had micro-projections (1.0 to 5.0 μm) and nano-projections (0.01 to 0.9 μm) on their surfaces. In the present invention, microprotrusions refer to peaks (waviness roughness) in the particle surface roughness distribution that have a peak width of 1.0 to 5.0 μm, and both the convex side height and the concave side height relative to the peak top are 1.0 to 5.0 μm, and have multiple nanoprotrusions inside. The nanoprotrusions refer to peaks that exist in multiple locations within the microprotrusions, and either the height of the convex side or the height of the concave side relative to the peak top is 0.01 to 0.9 μm. A schematic diagram showing the definitions of nanoprotrusions and microprotrusions is shown in FIG. 22 to 27, it can be seen that the surface of the secondary granules has microprotrusions (1.0 to 5.0 μm) and nanoprotrusions (0.01 to 0.9 μm). Furthermore, it can be seen that the primary granules of Comparative Example 3 have nanoprotrusions but no microprotrusions.

[0101] <Surface roughness> Table 3 shows the surface roughness indices Ra, RSm, and Rz calculated using a laser microscope when measuring the surface roughness distribution. <Variations in unevenness> Table 3 shows the variation in unevenness (standard deviation of Z value of surface roughness distribution) calculated from the surface roughness distribution.

[0102] [Table 3]

[0103] <Comparison of surface roughness> Comparison of Examples 3 to 6 with Comparative Examples 6, 11, and 15 As can be seen from Table 3, Examples 3 to 6 have higher RSm values ​​than Comparative Examples 6, 11, and 15, falling within the range of 1.0 to 2.0 μm. Comparing Example 3 and Comparative Example 6, which were fired at the same temperature, it can be seen that despite the Ra being nearly the same (0.37 μm for Example 3 and 0.38 μm for Comparative Example 6), there is a significant difference in RSm value (RSm for Example 3 is 1.78 μm, while for Comparative Example 6 it is 0.63 μm). This means that Comparative Examples 6, 11, and 15 are aggregates of densely packed nanostructured irregularities, whereas Examples 3 to 6 have large undulating waveforms due to the combination of microscale irregularities. This comparison reveals that Examples 3 to 6 form a multi-hierarchical structure consisting of nano- and micro-irregularities. Comparison of Examples 3 to 6 and Comparative Example 20 From Table 3, it can be seen that Comparative Example 20 has an RSm of 2.61 μm, which suggests the presence of smooth, wide protrusions compared to secondary granules with RSm values ​​of 1.03 to 1.78 μm, and it is inferred that the surface is poorly three-dimensional and is difficult for lamellipodia, the microprotrusion sensing structures of osteoblasts, to recognize. Comparison of the SEM images in Figures 12 and 13 and comparison of the 3D scanned images in Figures 19 and 21 also reveals that Comparative Example 20 has smoother protrusions with less three-dimensionality than the secondary granules of the Examples. This is presumably because the constituent particles are flat, plate-like particles with a relatively low degree of circularity.

[0104] <Comparison of firing temperature ranges> From Table 3, it can be seen that the standard deviation of the Z value in Examples 3 to 6 tends to decrease as the firing temperature increases. This is presumably because sintering necks are formed between particles during firing, making the particle surfaces smoother. A comparison of the particle surface conditions in SEM images of secondary granules obtained at different firing temperatures in Figures 13, 14, and 15 reveals that sintering neck formation is progressing. Similarly, Ra tends to decrease in the high temperature range of 1,100 to 1,250°C due to the formation of sintering necks. From the above, it is possible to control the roughness and variation of the unevenness by adjusting the firing temperature.

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

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

[0107] <Measurement of BET specific surface area> The BET specific surface area was measured using a specific surface area measuring device (manufactured by Mountec, model Marcsorb-1201). The measurement results of the obtained specific surface area are shown in Table 4. 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 is shown in Fig. 32.

[0108]

Table 4

[0109] Comparison between Examples 2 to 4 and Comparative Examples 14 to 16 All particles were subjected to wet grinding 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 a firing temperature of 700 to 900 °C, secondary granulates with microscale irregularities on the surface have a higher specific surface area, indicating that they have many cell adhesion sites.

[0110] Comparison between Examples 2 to 4 and Comparative Examples 19 to 21 In Examples 2 to 4, due to wet grinding before primary granulation to a D50 of 80 nm or less, more nano-scale irregularities are formed compared to Comparative Examples 19 to 21. Therefore, at the same firing temperature, they have a higher specific surface area. It can be seen that secondary granulates with nano-scale irregularities on the surface have a higher specific surface area and have many cell adhesion sites.

[0111] <Measurement of the weight ratio of β-TCP in hydroxyapatite> An X-ray diffractometer (Shimadzu Corporation, model: XRD-6100) was used to measure the X-ray diffraction spectra of Examples 1 to 5 and Comparative Examples 6, 15, and 20. The results of measuring the X-ray diffraction spectra of Examples 2 to 5 are shown in FIG. [X-ray diffraction spectrum measurement conditions] ·X-ray tube: Cu (1.54060Å) Tube voltage: 40.0 kV ·Tube current: 30.0mA Step width: 0.020 degrees

[0112] <Mass ratio of β-TCP in hydroxyapatite> The mass ratio of β-TCP in hydroxyapatite (HAP) was calculated by dividing the integral intensity of the 0120 plane by the integral intensity of the 211 plane + the 0210 plane × 100 of the measured X-ray diffraction spectrum. The results are shown in Table 5. The β-TCP mass ratio (wt%) is calculated as follows: "Integrated intensity of 0210 plane (near 2θ = 31 degrees) ÷ {Integrated intensity of 211 plane (near 2θ = 31.8 degrees) + Integrated intensity of 0210 plane} × 100" Calculated from. 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 Examples and Comparative Examples, which have different pretreatments. However, as the firing temperature increases, the X-ray diffraction spectrum gradually changes, and the β-TCP ratio increases.

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

[0116] [Table 6]

[0117] Table 7 shows the calcination temperatures, outlines, and particle shape classifications of the samples of the present invention in Examples and Comparative Examples.

[0118] [Table 7]

Claims

1. Metal-containing compound particles comprising hydroxyapatite and beta-tricalcium phosphate, having a surface roughness measurement using a laser microscope of Ra of 0.1 to 5.0 μm and RSm of 1.0 to 2.0 μm, and having microprotrusions on the surface with a diameter of 1.0 to 5.0 μm, and having nanoprotrusions of 0.01 to 0.9 μm on the surface of the microprotrusions.

2. The metal-containing compound particles according to claim 1 , wherein the microprotrusions are spherical particles having a circularity of 0.80 or more.

3. BET specific surface area is 1.0 to 100m ２ The metal-containing compound particles according to claim 1, wherein the metal-containing compound particles have a molecular weight of 1 / g.

4. 2. The metal-containing compound particles according to claim 1, having a circularity of 0.80 or more.

5. The metal-containing compound particles according to claim 1, characterized in that they have a hollow shell structure, and the shell gaps formed by the aggregation of a plurality of the primary granules, sintered necks, or both constitute interconnected pores, which are connected to the hollow interior.

6. 2. The metal-containing compound particles according to claim 1, wherein the content of β-tricalcium phosphate relative to the hydroxyapatite is 1 to 80 mass %.

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