Method for producing calcium phosphate crystal, method for producing block material, method for producing porous body, calcium phosphate crystal, block material, porous body, bone prosthetic material, oral bone prosthetic material, and oral care product

Abstract

To provide a crystal, a powder, a block material, a porous body, a bone prosthetic material, an oral cavity bone prosthetic material and an oral cavity care article of calcium phosphate which exhibits antibacterial properties and does not cause blackening by silver, and to provide a method for producing the calcium phosphate crystal, a method for producing the block material and a method for producing the porous body.SOLUTION: A method for producing a calcium phosphate crystal according to the present invention includes a S11 step of preparing a weakly basic phosphate containing a complex composed of a rare-earth element ion and a coordination complex having a ligand that coordinates to the rare-earth element ion, and a S12 step of adding a calcium-containing compound to the weakly basic phosphate and hydrolyzing the calcium-containing compound, wherein a part of a plurality of calcium ions contained in a crystal structure of the calcium phosphate is substituted with the rare-earth element ion.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] The present invention relates to a method for producing calcium phosphate crystals, a method for producing a block material, a method for producing a porous body, and to calcium phosphate crystals, a block material, a porous body, a bone filling material, an oral bone filling material, and an oral care product. [Background technology]

[0002] Materials made of calcium phosphate are used as artificial bone substitutes in oral surgery, orthopedic surgery, and other fields. Examples of calcium phosphate materials include anhydrous calcium hydrogen phosphate (DCPA, CaHPO4), dihydrate calcium hydrogen phosphate (DCPD, CaHPO4·2H2O), octacalcium phosphate (OCP, Ca8(HPO4)2(PO4)4·5H2O), α-tricalcium phosphate (α-TCP, Ca3(PO4)2), β-tricalcium phosphate (β-TCP, Ca3(PO4)2), hydroxyapatite (HAp, Ca 10 (PO4)6(OH)2), tetracalcium phosphate (TTCP, Ca4(PO4)2O), etc. These calcium phosphates have different properties (ease of molding, bone replacement, etc.) and are appropriately selected and used depending on the application.

[0003] In orthopedics and oral surgery, where bone fillers are primarily used, infection of the surgical field, i.e., postoperative infection, is known to be a serious complication. Because the bone filler itself is powerless against infection, once an infection occurs, the only option is to remove the affected area, resulting in a poor prognosis. This disease occurs with a probability of approximately a few percent in all surgical procedures.

[0004] One method known for imparting antibacterial properties to bone fillers made of calcium phosphate is to coat the bone filler with an antibacterial agent (Non-Patent Document 1). However, with the method described in Non-Patent Document 1, it is difficult to maintain the antibacterial properties for a long period of time due to the desorption of the antibacterial agent, etc.

[0005] One known method for maintaining the antibacterial properties of bone fillers for a long period of time is to replace some of the calcium ions contained in the calcium phosphate that constitutes the bone filler with antibacterial elements such as silver ions (Patent Document 1). However, the method described in Patent Document 1 cannot completely prevent the blackening of the bone filler caused by the use of silver ions.

[0006] When bone fillers are used in oral surgery, it is undesirable for the bone filler to discolor after surgery from the viewpoint of aesthetics. [Prior art documents] [Non-patent literature]

[0007] [Non-Patent Document 1] Akiyama T et al. “Silver oxide-containing hydroxyapatite coating has in vivo antibacterial activity in the rat tibia” Journal of Orthopedic Research 2013, 31:1195 [Patent documents]

[0008] [Patent Document 1] International Publication No. 2021 / 157662 Summary of the Invention [Problem to be solved by the invention]

[0009] The present invention has been made in view of the above circumstances, and aims to provide calcium phosphate crystals, powders, blocks, porous bodies, bone filling materials, oral bone filling materials and oral care products that exhibit antibacterial properties and do not become blackened by silver, as well as methods for producing calcium phosphate crystals, methods for producing blocks and methods for producing porous bodies. [Means for solving the problem]

[0010] In order to solve the above problems, the present invention employs the following means.

[0011] (1) A method for producing calcium phosphate crystals according to one embodiment of the present invention comprises the steps of preparing a weakly basic phosphoric acid solution containing a complex consisting of a rare earth element ion and a coordination compound having a ligand that coordinates to the rare earth element ion, and adding a calcium-containing compound to the weakly basic phosphoric acid solution and hydrolyzing the compound, in which some of the multiple calcium ions contained in the structure of the calcium phosphate crystal are substituted with the rare earth element ion.

[0012] The rare earth element ions in the weakly basic phosphoric acid solution form complexes with ligands and are stabilized in the weakly basic phosphoric acid solution, thereby preventing the precipitation of rare earth element ion phosphates. Because these stabilized rare earth element ions have an ionic radius similar to that of calcium ions, they efficiently replace some of the calcium ions in the calcium phosphate crystals and are incorporated into the calcium phosphate.

[0013] By coordinating an antibacterial agent (e.g., a quaternary ammonium cation compound such as benzalkonium chloride, cetylpyridium chloride, benzethonium chloride, trimethylglycine, or didecyldimethylammonium chloride) with the rare earth element ions incorporated into the calcium phosphate crystals, antibacterial properties can be imparted to the rare earth element-substituted calcium phosphate. Rare earth element-substituted calcium phosphate with antibacterial properties does not contain silver atoms, which cause discoloration of bone filling materials, so aesthetics are not impaired even when it is used in oral surgery.

[0014] Even if the antibacterial agent is released from the rare earth element-substituted calcium phosphate after a certain period of time or due to a process such as washing, the antibacterial agent can be brought into contact with the rare earth element-substituted calcium phosphate again and coordinated with the rare earth element ions, thereby imparting antibacterial properties to the rare earth element-substituted calcium phosphate.

[0015] When the ligand functions as an antibacterial agent, the ligand used in the preparation may be directly used as the antibacterial agent and coordinated to the rare earth element ion in the rare earth element-substituted calcium phosphate. Furthermore, an antibacterial agent consisting of a molecular species different from the ligand may be coordinated to the rare earth element ion in the rare earth element-substituted calcium phosphate.

[0016] (2) In the method for producing calcium phosphate crystals described in (1) above, the calcium phosphate may be any one selected from the group consisting of octacalcium phosphate, hydroxyapatite, fluoroapatite, chloroapatite, and carbonate apatite.

[0017] (3) In the method for producing calcium phosphate crystals according to either (1) or (2) above, the rare earth element ions may be one or more selected from the group consisting of yttrium ions, lanthanum ions, cerium ions, praseodymium ions, neodymium ions, samarium ions, europium ions, gadolinium ions, terbium ions, dysprosium ions, holmium ions, thulium ions, ytterbium ions, and lutetium ions.

[0018] (4) In the method for producing calcium phosphate crystals according to any one of the above (1) to (3), the coordination compound may be a quaternary ammonium cation compound.

[0019] (5) In the method for producing calcium phosphate crystals according to any one of (1) to (4) above, the quaternary ammonium cation compound may be one or more selected from the group consisting of benzalkonium chloride, cetylpyridium chloride, benzethonium chloride, trimethylglycine, and didecyldimethylammonium chloride.

[0020] (6) In the method for producing calcium phosphate crystals according to any one of (1) to (5) above, the weakly basic phosphoric acid solution may have a phosphoric acid concentration of 0.1 mol / L to 3.0 mol / L, and a pH of 7.0 to 12.0.

[0021] (7) In the method for producing calcium phosphate crystals described in (1) to (6) above, the calcium-containing compound may be a readily soluble calcium phosphate consisting of calcium hydrogen phosphate dihydrate, calcium monohydrogen phosphate (anhydrous), calcium dihydrogen phosphate hydrate, calcium dihydrogen phosphate anhydrate, α-tricalcium phosphate, or a mixture thereof.

[0022] (8) Another aspect of the present invention provides a method for producing a block material containing calcium phosphate crystals, comprising the steps of: preparing a weakly basic phosphoric acid solution containing a complex of one of calcium and phosphoric acid, a rare earth element ion, and a coordination compound having a ligand that coordinates with the rare earth element ion; and immersing a solid composition made of a ceramic containing the other of calcium and phosphoric acid in the weakly basic phosphoric acid solution to convert a portion of the solid composition into octacalcium phosphate crystals, thereby obtaining a block material, in which a portion of the calcium ions contained in the structure of the octacalcium phosphate crystals have been substituted with rare earth element ions.

[0023] (9) Another aspect of the present invention provides a method for producing a porous body containing calcium phosphate crystals, comprising the steps of: preparing a weakly basic phosphoric acid solution containing a complex of one of calcium and phosphoric acid, rare earth element ions, and a coordination compound having a ligand that coordinates with the rare earth element ions; and immersing a solid composition consisting of a ceramic containing the other of calcium and phosphoric acid in the weakly basic phosphoric acid solution to convert a portion of the solid composition into octacalcium phosphate crystals, thereby obtaining a porous body, wherein a portion of the calcium ions contained in the structure of the octacalcium phosphate crystals have been substituted with rare earth element ions.

[0024] (10) Another aspect of the present invention provides calcium phosphate crystals produced by the method for producing calcium phosphate crystals described in (1) to (6) above, wherein the content of rare earth atoms is 0.01 atomic % or more and 13.00 atomic % or less, the calcium phosphate crystals do not contain silicic acid, and the silver content of the calcium phosphate crystals is less than 0.01 atomic %.

[0025] (11) In the calcium phosphate crystal described in (10) above, the content of the rare earth atoms may be 0.10 atomic % or more and 7.00 atomic % or less.

[0026] (12) A block material according to another aspect of the present invention is a block material produced by the method for producing a block material described in (8) above, wherein the content of rare earth atoms is 0.01 atomic % or more and 13.00 atomic % or less, the calcium phosphate crystals do not contain silicic acid, and the silver content of the calcium phosphate crystals is less than 0.01 atomic %.

[0027] (13) In the block material described in (12) above, the content of the rare earth atoms may be 0.10 atomic % or more and 7.00 atomic % or less.

[0028] (14) Another aspect of the present invention provides a porous body manufactured by the method for manufacturing a porous body described in (9) above, wherein the content of rare earth atoms is 0.01 atomic % or more and 13.00 atomic % or less, the calcium phosphate crystals do not contain silicic acid, and the silver content of the calcium phosphate crystals is less than 0.01 atomic %.

[0029] (15) In the porous body according to (14) above, the content of the rare earth atoms may be 0.10 atomic % or more and 7.00 atomic % or less.

[0030] (16) A bone filler according to another aspect of the present invention contains the calcium phosphate crystals described in (10) above.

[0031] (17) An oral bone filler according to another aspect of the present invention contains the calcium phosphate crystals described in (10) above.

[0032] (18) An oral care product according to another aspect of the present invention comprises the calcium phosphate crystals described in (10) above. [Effects of the Invention]

[0033] The calcium phosphate crystals, powder, block material, porous body, bone filler, oral bone filler and oral care product according to the embodiments of the present invention can impart long-term antibacterial properties to the bone filler, oral bone filler and oral care product and prevent blackening due to silver. Furthermore, according to the methods for producing calcium phosphate crystals, powders, blocks, porous bodies, bone fillers, oral bone fillers, and oral care products according to the embodiments of the present invention, it is possible to produce bone fillers, oral bone fillers, and oral care products that have antibacterial properties and do not turn black. [Brief explanation of the drawings]

[0034] [Figure 1] 1 is a flowchart of a method for producing calcium phosphate crystals according to a first embodiment of the present invention. [Figure 2] 10 is a flowchart of a method for manufacturing a block material according to a second embodiment of the present invention. [Figure 3] 10 is a flowchart of a method for producing a porous body according to a third embodiment of the present invention. [Figure 4] 1 is a graph showing an XRD pattern of the low-angle portion of the powder of OCP supporting a rare earth element obtained in Example 1. [Figure 5] 1 is a graph showing an FT-IR spectrum of the OCP-based powder supporting a rare earth element obtained in Example 1. [Figure 6] 1 is a graph showing the XRD pattern of the low-angle part of the powder of OCP carrying La. [Figure 7] 1 is a graph showing XRD patterns of the rare earth element-containing HAp and CO3Ap powders obtained in Example 2. [Figure 8] 1 is a graph showing FT-IR spectra of the HAp and CO3Ap powders supporting rare earth elements obtained in Example 2. [Figure 9] 10 is a photograph showing the results of evaluating the antibacterial properties of the rare earth element-supported OCP powder treated with CPC in Example 3. DETAILED DESCRIPTION OF THE INVENTION

[0035] Hereinafter, the methods for producing calcium phosphate crystals, the methods for producing block materials, and the methods for producing porous bodies according to embodiments of the present invention, as well as calcium phosphate crystals, block materials, porous bodies, bone fillers, oral bone fillers, and oral care products will be described in detail with reference to the drawings. In addition, the drawings used in the following description may show characteristic portions enlarged for convenience in order to make the features easier to understand, and the dimensional ratios of each component may not be the same as in reality. Furthermore, the materials, dimensions, etc. exemplified in the following description are merely examples, and the present invention is not limited to them and can be implemented with appropriate changes within the scope of the present invention.

[0036] First Embodiment FIG. 1 is a flowchart of a method for producing calcium phosphate crystals according to a first embodiment of the present invention.

[0037] As shown in FIG. 1, the method for producing calcium phosphate crystals according to the first embodiment includes a weakly basic phosphoric acid solution preparation step S11 and a calcium-containing compound addition / hydrolysis step S12. In the weakly basic phosphoric acid solution preparation step S11, a weakly basic phosphoric acid solution containing a complex made of a rare earth element ion and a coordination compound having a ligand that coordinates with the rare earth element ion is prepared. In the calcium-containing compound addition / hydrolysis step S12, a calcium-containing compound is added to the weakly basic phosphoric acid solution and hydrolyzed. After the calcium-containing compound addition / hydrolysis step S12, calcium phosphate crystals are obtained. In the obtained calcium phosphate crystals, some of the calcium ions contained in the structure of the calcium phosphate crystals are substituted with the rare earth element ions.

[0038] [Weakly basic phosphoric acid solution preparation step S11] The weakly basic phosphoric acid solution can be prepared, for example, by adding phosphoric acid (e.g., diammonium hydrogen phosphate), a coordination compound (e.g., benzalkonium chloride), and a rare earth element nitrate (e.g., lanthanum nitrate or cerium nitrate) to pure water, and continuing to stir while maintaining a predetermined temperature.

[0039] The stirring may be carried out in a sealed container, or in a container whose upper part is open to the outside air. The predetermined temperature may be within the range of 0°C to 99°C, preferably 20°C to 90°C, more preferably 30°C to 80°C, and particularly preferably 40°C to 70°C. The stirring speed may be in the range of 0 to 2000 rpm, 10 to 1000 rpm, or 50 to 500 rpm. The stirring time may be within a range of 0 to 72 hours, 0.5 to 48 hours, or 1 to 24 hours.

[0040] Examples of phosphoric acid used to prepare the weakly basic phosphoric acid solution include diammonium hydrogen phosphate, dipotassium hydrogen phosphate, disodium hydrogen phosphate, discesium hydrogen phosphate, triammonium phosphate, tripotassium phosphate, trisodium phosphate, and tricesium phosphate. These may be used alone or in combination. The concentration of the phosphoric acid contained in the weakly basic phosphoric acid solution may be 0.1 mol / L to 3.0 mol / L, 0.2 mol / L to 2.0 mol / L, or 0.5 mol / L to 1.0 mol / L. The pH of the prepared weakly basic phosphoric acid solution may be 7.0 to 12.0, 7.5 to 11.0, or 8.0 to 10.0.

[0041] Even if a precipitate forms immediately after adding phosphoric acid, a coordination compound, and a rare earth element salt to pure water, a transparent, weakly basic phosphoric acid solution can be obtained by continuing to stir.

[0042] The term "rare earth elements" (sometimes referred to as "REEs") is a collective term for the following elements: lanthanoids, which are 17 elements: lanthanum (La), cerium (Ce), praseodymium (Pr), neodymium (Nd), promethium (Pm), samarium (Sm), europium (Eu), gadolinium (Gd), terbium (Tb), dysprosium (Dy), holmium (Ho), erbium (Er), thulium (Tm), ytterbium (Yb), lutetium (Lu), and yttrium (Y) and scandium (Sc), which have similar chemical properties. These elements may be used alone, or multiple rare earth elements may be used simultaneously.

[0043] The compound to be added to the weakly basic phosphoric acid solution as a coordination compound (dispersant for rare earth elements) that coordinates with rare earth elements is not particularly limited. The coordination compound to be selected is one that forms a complex well with the rare earth element ion, disperses in an aqueous solution, inhibits the formation of a phosphate salt of the rare earth element ion, and allows the rare earth element ion to be released from the coordination compound and incorporated into calcium phosphate in response to the calcium phosphate formation reaction.

[0044] Examples of coordination compounds include aqueous pyridine derivatives such as cetylpyridinium chloride (CPC), pyridine, and hydroxypyridinedicarboxylic acid; quaternary ammonium cation compounds such as benzalkonium chloride, benzethonium chloride, N,N,N-trimethylglycine, phosphatidylcholine, choline chloride, choline hydroxide, tetraethylammonium chloride, tetramethylammonium chloride, tetrabutylammonium chloride, polydronium chloride, benzyltriethylammonium chloride, phosphocholine, acetylcholine, L-α-glycerylphosphorylcholine, lecithin, pentolinium, muscarine, and ergothioneine; β-diketonates and their derivatives; and nitrogen-containing cyclic compounds such as porphyrins and phthalocyanines. However, other compounds may also be selected. As the coordination compound, one of these compounds may be used alone, or a mixture of two or more compounds may be used.

[0045] The term "complex" as used herein refers to the general meaning of a complex used in the field of chemistry, i.e., a molecule formed by a coordinate bond, in which a metal and a nonmetallic ligand are bonded together via a coordinate bond.

[0046] [Calcium-containing compound addition / hydrolysis step S12] In the calcium-containing compound addition / hydrolysis step S12, a predetermined calcium-containing compound is added to the weakly basic phosphoric acid solution prepared in the weakly basic phosphoric acid solution preparation step S11, and the added calcium-containing compound is hydrolyzed in the weakly basic phosphoric acid solution under predetermined conditions. In the calcium-containing compound addition / hydrolysis step S12, calcium phosphate (e.g., octacalcium phosphate (OCP)) is formed by a chemical reaction between compounds contained in the system, and some of the calcium ions contained in the calcium phosphate are further substituted with rare earth element ions contained in the weakly basic phosphoric acid solution.

[0047] Calcium phosphate in which some of the calcium ions have been substituted with rare earth element ions (rare earth element-substituted calcium phosphate) precipitates as a solid (e.g., precipitate of crystal grains, etc.) in the solution after the calcium-containing compound addition / hydrolysis step S12. The rare earth element-substituted calcium phosphate precipitated as a solid can be separated and collected by a conventional solid-liquid separation method such as decantation, filtration, or centrifugation.

[0048] The separated rare earth element-substituted calcium phosphate is thoroughly washed with pure water or the like, and then dried at a predetermined temperature, thereby reducing the content of unnecessary impurities to a predetermined value or less.

[0049] In the calcium-containing compound addition / hydrolysis step S12, the calcium-containing compound to be added to the weakly basic phosphoric acid solution may be calcium hydrogen phosphate dihydrate, calcium monohydrogen phosphate (anhydrous), calcium dihydrogen phosphate hydrate, calcium dihydrogen phosphate anhydrate, α-tricalcium phosphate, or a readily soluble calcium phosphate consisting of a mixture thereof.

[0050] The calcium-containing compound may be in a solid or liquid form. The amount of calcium-containing compound to be added to the weakly basic phosphoric acid solution can be determined based on the phosphoric acid concentration contained in the weakly basic phosphoric acid solution. Specifically, the molar ratio between the calcium-containing compound and phosphoric acid (calcium-containing compound / phosphoric acid) in the weakly basic phosphoric acid solution may be within a range of 0.5 to 1.0, 0.6 to 1.0, or 0.6 to 0.8.

[0051] The calcium-containing compound can be hydrolyzed, for example, by stirring for a predetermined time and then leaving to stand at a predetermined temperature.

[0052] The hydrolysis may be carried out in a sealed container, or in a container with the top open to the outside air.

[0053] The stirring speed may be in the range of 0 to 2000 rpm, 10 to 1000 rpm, or 50 to 500 rpm. Alternatively, the mixture may be left to stand without stirring. The stirring time may be within a range of 0 to 72 hours, 0.5 to 48 hours, or 1 to 24 hours. The predetermined temperature may be in the range of 0°C to 99°C, 20°C to 90°C, or 30°C to 80°C.

[0054] The chemical groups contained in the calcium-containing composition hydrolyzed in the calcium-containing compound addition / hydrolysis step S12 react with the chemical groups contained in the weakly basic phosphoric acid solution to form rare earth element-substituted calcium phosphate.

[0055] In the calcium-containing compound addition / hydrolysis step S12, a calcium-containing composition must be added to the basic solution prepared in the weakly basic phosphoric acid solution preparation step S11, and then hydrolyzed. If a phosphoric acid solution that does not contain a complex consisting of rare earth ions and a coordination compound is used, the rare earth ions and phosphoric acid will form a salt and precipitate. The precipitated rare earth ions and phosphoric acid cannot contribute to the formation of rare earth-substituted calcium phosphate in the calcium-containing compound addition / hydrolysis step S12. Therefore, even if a phosphoric acid solution that does not contain a complex consisting of rare earth element ions and a coordination compound is used, it is not possible to obtain rare earth element-substituted calcium phosphate.

[0056] The content of rare earth atoms contained in the calcium phosphate crystal may be 0.01 atomic % or more and 13 atomic % or less, or 0.10 atomic % or more and 10.0 atomic % or less, or 1.00 atomic % or more and 7.0 atomic % or less, or 2.00 atomic % or more and 5.00 atomic % or less.

[0057] The concentration of the rare earth salt used in the reaction can be arbitrarily determined between 0.0001 mol / L and 1.0 mol / L. The content may be 0.001 mol / L or more and 0.5 mol / L or less, 0.01 mol / L or more and 0.2 mol / L or less, or 0.02 mol / L or more and 0.1 mol / L or less. Furthermore, if the concentration exceeds 0.1 mol / L, precipitation may occur regardless of the concentration of the added coordination compound.

[0058] The rare earth element salt used in the reaction is not particularly limited, but usually, a salt is selected that dissolves well in a solvent such as distilled water and liberates rare earth element ions when brought into contact with the solvent. For example, nitrates such as lanthanum nitrate, cerium nitrate, yttrium nitrate, praseodymium nitrate, neodymium nitrate, samarium nitrate, and dysprosium nitrate; chlorides such as lanthanum chloride, cerium chloride, yttrium chloride, praseodymium chloride, neodymium chloride, samarium chloride, and dysprosium chloride; acetates such as lanthanum acetate, cerium acetate, yttrium acetate, praseodymium acetate, neodymium acetate, samarium acetate, and dysprosium acetate; sulfates such as lanthanum sulfate, cerium sulfate, yttrium sulfate, praseodymium sulfate, neodymium sulfate, samarium sulfate, and dysprosium sulfate; acetates such as lanthanum acetate, cerium acetate, praseodymium acetate, neodymium acetate, samarium acetate, and yttrium acetate; but other salts may also be used. In addition, either hydrates or anhydrides may be used, and multiple different salts may be mixed and used.

[0059] The rare earth element-substituted OCP crystals obtained after the calcium-containing compound addition / hydrolysis step S12 can be converted into rare earth element-substituted hydroxyapatite (rare earth element-substituted HAp) crystals or rare earth element-substituted carbonate apatite (rare earth element-substituted CO3Ap) crystals by subjecting them to a specified process.

[0060] [Phase transformation to HAp] In the phase conversion from OCP to HAp, the OCP crystals are converted into HAp crystals while maintaining their solid state by hydrolysis or hydrothermal reaction in a phase conversion solution. Most of the rare earth element ions that were inserted into the crystals of rare earth element-substituted OCP used as the starting material for the phase transformation are retained in the crystals of rare earth element-substituted HAp even after the phase transformation.

[0061] [Phase conversion to CO3Ap] In the phase conversion from OCP to CO3Ap, the OCP crystals are converted into CO3Ap crystals while maintaining their solid state by carbonation treatment in a phase conversion solution. Most of the rare earth ions inserted into the crystals of rare earth-substituted OCP used as the starting material for the phase transformation are retained in the crystals of rare earth-substituted CO3Ap after the phase transformation.

[0062] Second Embodiment FIG. 2 is a flowchart of a method for manufacturing a block according to a second embodiment of the present invention.

[0063] As shown in FIG. 2, the method for producing a block according to the second embodiment includes a weakly basic phosphoric acid solution preparation step S21 and a solid immersion / OCP conversion step S22. In the weakly basic phosphoric acid solution preparation step S21, a weakly basic phosphoric acid solution is prepared containing a complex consisting of one of calcium and phosphoric acid, a rare earth element ion, and a coordination compound having a ligand that coordinates with the rare earth element ion. In the solid immersion / OCP conversion step S22, a solid composition consisting of a ceramic containing the other of calcium and phosphate is immersed in the weakly basic phosphoric acid solution, and a portion of the solid composition is converted into octacalcium phosphate crystals. After the solid immersion / OCP conversion step S22, a rare earth element-substituted block material is obtained. In the obtained block material, some of the calcium ions contained in the crystalline structure of the octacalcium phosphate are substituted with rare earth element ions.

[0064] In the description of the second embodiment, only the differences from the first embodiment will be described, and a description of the same configuration as the first embodiment will be omitted.

[0065] [Weakly basic phosphoric acid solution preparation step S21] The weakly basic phosphoric acid solution used in the second embodiment can be prepared, for example, by adding calcium and phosphoric acid, a coordination compound, and a rare earth element nitrate to pure water, and continuing to stir the mixture while maintaining a predetermined temperature. Other conditions for preparing the weakly basic phosphoric acid solution are the same as those in the first embodiment.

[0066] [Solid immersion / OCP conversion process S22] As the solid composition made of ceramics containing the other of calcium and phosphate, a hardened body of DCPA can be used. In the solid immersion / OCP conversion step S22, the solid composition consisting of ceramics containing at least one of calcium and phosphate is immersed in a weakly basic phosphoric acid solution containing one of calcium and phosphate, and a complex consisting of a rare earth element ion and a coordination compound having a ligand that coordinates with the rare earth element ion.

[0067] For example, when the DCPA cured body is used as a ceramic solid composition, the DCPA cured body is immersed in a mixed solution containing 0.1 mol / L to 2.0 mol / L ammonium hydrogen phosphate, 0.0001 mol / L to 0.1 mol / L lanthanum nitrate, 0.1 mol / L to 2.0 mol / L cetylpyridinium chloride, and 0 mol / L to 5 mol / L sodium nitrate at a predetermined temperature for a predetermined time. The mixture contains a complex in which cetylpyridinium chloride is coordinated to a lanthanum ion. The temperature condition is preferably 0°C to 99°C, more preferably 35°C to 85°C. The immersion time is preferably 0.5 to 14 days, more preferably 1 to 7 days.

[0068] During the immersion of the ceramic solid composition in the solution, DCPA is converted to OCP, and lanthanum ions present in the immersion solution in a complex state are incorporated into the OCP crystal structure and intercalated, substituting for some of the calcium ions of the OCP. As a result, a block material containing OCP crystals characterized in that some of the calcium ions are replaced by lanthanum ions is obtained. After immersion, excess reaction solution is removed with, for example, distilled water, and the substrate is completely dried, for example, in a dryer at 40°C.

[0069] The OCP block material, which has been subjected to a compositional change from the precursor ceramic block to a molded body made of OCP by immersing it in the above solution, maintains the outer shape of the precursor ceramic block used. The dimensions of the precursor ceramic block are reproducibly inherited almost identically to the dimensions of the OCP-based block material whose composition is converted to OCP, so OCP blocks with specified dimensions can be easily obtained without having to consider dimensional changes from the precursor.

[0070] The obtained OCP block material can be further subjected to a phase conversion treatment (thermal decomposition or hydrothermal reaction, carbonation treatment) to produce a HAp block material, a CO3Ap block material, or the like. Rather than directly performing ion substitution in the stable calcium phosphate Ap state, ion substitution can be performed in the state of OCP, which is a calcium phosphate less stable than Ap, and then the resulting OCP-based block is subjected to phase conversion to an Ap block, thereby enabling the efficient production of a block containing Ap crystals in which some of the multiple calcium ions have been substituted with rare earth element ions.

[0071] <Third embodiment> FIG. 3 is a flowchart of a method for producing a porous body according to a third embodiment of the present invention.

[0072] As shown in FIG. 3, the method for producing a porous body according to the third embodiment includes a weakly basic phosphoric acid solution preparation step S31 and a solid immersion / OCP conversion step S32. In the weakly basic phosphoric acid solution preparation step S31, a weakly basic phosphoric acid solution is prepared containing a complex consisting of one of calcium and phosphoric acid, a rare earth element ion, and a coordination compound having a ligand that coordinates with the rare earth element ion. In the solid immersion / OCP conversion step S32, a solid composition consisting of a ceramic containing the other of calcium and phosphate is immersed in the weakly basic phosphoric acid solution, and a portion of the solid composition is converted into octacalcium phosphate crystals. After the solid immersion / OCP conversion step S22, a rare earth element-substituted porous body is obtained. In the resulting porous body, some of the calcium ions contained in the crystalline structure of the octacalcium phosphate are substituted with rare earth element ions.

[0073] In the description of the third embodiment, only the differences from the first and second embodiments will be described, and a description of the same configuration as the first and second embodiments will be omitted.

[0074] The solid immersion / OCP conversion step S32 is almost the same as the solid immersion / OCP conversion step S22 in the second embodiment. The main difference between the third embodiment and the second embodiment is that the third embodiment uses a porous material as the solid composition, while the second embodiment uses a block material.

[0075] A porous material (porous precursor ceramic block) can be obtained, for example, by dropping an appropriate amount of calcium dihydrogen phosphate saturated H3PO4 solution onto a compact of brushite cement powder classified to a predetermined size, and then allowing it to harden.

[0076] <Fourth embodiment> A fourth embodiment of the present invention is a bone substitute material. The bone filler of this embodiment is made of calcium phosphate powder containing crystals of rare earth element-substituted calcium phosphate of the first embodiment, the block material of the second embodiment, or the porous body of the third embodiment. By using the bone substitute material of this embodiment, it is possible to obtain the technical effects that can be obtained in each of the above-mentioned embodiments.

[0077] Fifth Embodiment A fifth embodiment of the present invention is an oral bone substitute material. The oral bone filling material of this embodiment is made of calcium phosphate powder containing crystals of rare earth element-substituted calcium phosphate of the first embodiment, the block material of the second embodiment, or the porous body of the third embodiment. By using the oral bone filler of this embodiment, it is possible to obtain the technical effects that can be obtained in each of the above-mentioned embodiments.

[0078] Sixth Embodiment A sixth embodiment of the present invention is an oral care product. Examples of oral care products include tooth strengtheners, mouthwashes, dentifrices, and bone filling materials. The oral care product of this embodiment comprises calcium phosphate powder containing crystals of rare earth element-substituted calcium phosphate of the first embodiment, the block material of the second embodiment, or the porous body of the third embodiment. When the oral care product of this embodiment is used, the technical effects that can be obtained in each of the above-mentioned embodiments can be obtained. [Example]

[0079] The effects of the present invention will be more clearly understood from the following examples. Note that the present invention is not limited to the following examples and can be practiced with appropriate modifications within the scope of the present invention.

[0080] Example 1 A powder containing crystals of rare earth element-substituted OCP (hereinafter, sometimes referred to as "powder of rare earth element-containing OCP") was prepared by the method described below. In the examples (and comparative examples described later), special grade reagents purchased from Fujifilm Wako Pure Chemical Industries were used.

[0081] To 20 mL of pure water, 1.0 mol / L of diammonium hydrogen phosphate and 0.5 wt% of benzalkonium chloride were added. To the solution thus obtained, lanthanum nitrate, cerium nitrate, praseodymium nitrate, and dysprosium nitrate were added so that the concentrations were 0.05 mol / L, 0.05 mol / L, and 0.05 mol / L, respectively. Thereafter, the added rare earth element nitrate was completely dissolved at 60°C in a sealed container.

[0082] Immediately after the dissolution reaction, a precipitate was formed which was thought to be due to the formation of phosphates of the rare earth elements, but by continuing to stir at 60°C, a clear liquid was obtained.

[0083] 2.39 g of calcium hydrogen phosphate dihydrate (DCPD) powder was added to each of the prepared solutions containing rare earth element nitrates, and the solution was stirred for 10 minutes, then sealed and allowed to stand at 60°C for 24 hours. The resulting precipitate was separated from the liquid phase by decantation, washed thoroughly with pure water, and then completely dried in a dryer set at 40°C.

[0084] The resulting product was white in the lanthanum nitrate and cerium nitrate systems, pale green in the praseodymium nitrate system, and pale yellow in the dysprosium nitrate system.

[0085] The precipitate was identified by X-ray powder structural analysis. Figure 4 is a graph showing the XRD pattern of the OCP powder carrying the rare earth elements. In the system containing rare earth element nitrates, the relative intensity of the peak around 4.7° characteristic of OCP was confirmed to be increased compared to the system without rare earth element nitrates (Law), indicating that the formation of an OCP crystal structure was induced.

[0086] To evaluate the state of rare earth elements supported on the precipitate crystals identified as OCP by XRD, the state of functional groups of the precipitate was evaluated by infrared spectroscopy (FT-IR: Nicolet NEXUS 670 FTIR, manufactured by Thermo Fisher Scientific). The unit cell of OCP contains 12 PO4 groups, which exist in six different chemical states. These PO4 groups are all in conjugation with different Ca ions or OH groups, and when the state or type of the conjugated ions changes, the chemical state of the PO4 group also changes accordingly. Therefore, by detecting the change in the chemical state of the PO4 group, it is possible to estimate the type of cation conjugated with the PO4 group.

[0087] FIG. 5 is a graph showing the FT-IR spectrum of the OCP-based powder supporting a rare earth element. In systems containing rare earth element nitrates, the chemical state of the PO4 group at the base of the HPO4-OH layer structure, called P5 PO4, changed (Fig. 5(b)). This indicates that the rare earth elements are supported in the OCP-based crystal structure by partially substituting the Ca ions that are in a conjugated relationship with P5 PO4 at the base of the HPO4-OH layer structure.

[0088] (Comparative Example 1) In Comparative Example 1, lanthanum loading on OCP was investigated in a system in which the weakly basic phosphoric acid solution did not contain a ligand.

[0089] Phosphoric acid was diluted with distilled water to a concentration of 1.0 mol / L. Lanthanum nitrate was also dissolved in distilled water to prepare a 1.0 mol / L solution. 4 mL of 1.0 mol / L phosphoric acid, 1.0 mol / L lanthanum nitrate solution, and distilled water were mixed in arbitrary ratios in a 50 mL centrifuge tube to prepare a 0.0 to 0.1 mol / L lanthanum nitrate mixed solution in 20 mL of 0.2 mol / L phosphoric acid. 1.0 g of calcium carbonate powder was gradually added thereto, and after the foaming caused by the reaction had subsided, the screw cap was reinforced with Teflon (registered trademark) tape and then sealed. The sealed centrifuge tube was placed in a thermostatic bath set at 60°C and reacted for 24 hours. After the reaction, the supernatant was removed, and the precipitate was washed multiple times with distilled water and then completely dried in a thermostatic bath set at 40°C.

[0090] The precipitate was identified by X-ray powder structural analysis. Figure 6 is a graph showing the XRD pattern of the low-angle part of the La-loaded OCP powder. As the lanthanum nitrate concentration increased, the OCP peak weakened and instead a peak of low-crystalline lanthanum phosphate was observed, indicating that the OCP phase did not become a single phase, but that lanthanum phosphate was being formed.

[0091] Example 2 Rare earth element-containing apatite was prepared from rare earth element-containing OCP by the method described below.

[0092] As a powder containing HAp crystals, a powder of HAp containing a rare earth element (hereinafter referred to as "rare earth element-containing HAp powder") was prepared by the method shown below. At the same time, a powder of CO3Ap containing rare earth elements (hereinafter referred to as "rare earth element-containing CO3Ap powder") was prepared as a powder containing CO3Ap crystals by the method described below.

[0093] 0.4 g of the rare earth element-containing OCP powders (La-containing OCP powder, Pr-containing OCP powder, Ce-containing OCP powder) (rare earth element nitrate concentration: 0.05 mol / L) prepared in Example 1 was immersed in 20 ml of distilled water (CO3 - 0.0 mol / L) and 20 ml of (NH4)2CO3 solutions of different concentrations (0.1 mol / L, 0.2 mol / L, 0.5 mol / L, 1.0 mol / L) at 80°C for 3 days. After immersion, the solid phase component was washed several times with distilled water and dried in a dry oven at 80°C for one day to obtain powders of rare earth element-containing HAp and CO3Ap.

[0094] The obtained rare earth element-containing HAp and CO3Ap powders were analyzed in the same manner as in Example 1. FIG. 7 is a graph showing the XRD patterns of rare earth element-containing HAp and CO3Ap powders. In all samples, the peak at around 4.7° characteristic of OCP disappeared, and the XRD patterns were similar to those of the reference HAp standard. Furthermore, when the obtained sample was observed by SEM, no significant change was observed in the microscopic morphology of the powder (photographs not shown).

[0095] The obtained samples were analyzed for the incorporation of CO3 ions into the crystal lattice by measuring the change in d-spacing and IR analysis. As a result, the incorporation of CO3 ions into the crystal lattice was observed in the sample immersed in (NH4)2CO3 solution (the results of the change in d-spacing are not shown). FIG. 8 is a graph showing the FT-IR spectra of HAp and CO3Ap powders carrying rare earth elements. In the sample immersed in (NH4)2CO3 solution, the absorption band of CO3 was 1400-1500 cm -1 On the other hand, in the sample that had been immersed in distilled water and had undergone phase transformation treatment (CO3-0.0 mol / L), no CO3 absorption band was observed, indicating that it was HAp.

[0096] Example 3 The antibacterial test of the rare earth element-containing OCP powder was carried out by the following method.

[0097] The minimum inhibitory concentration against S. aureus (Staphylococcus aureus) was evaluated. The type culture strain (Streptococcus mutans Clark 1924, ATCC 25175) was inoculated into Heart Infusion Broth Medium (Eiken Chemical Co., Ltd., product number: E-MC04 110929). Five milliliters of the broth medium was placed in an L-shaped tube and cultured at 37°C for 24 hours with shaking at 100 rpm. After confirming that S. mutans was in the logarithmic growth phase by measuring the absorbance at 630 nm using an absorption spectrophotometer, 0.1 mL of the bacterial solution was taken and inoculated into 5 mL of a new bouillon medium.

[0098] 0.4 g of rare earth element-supported OCP powders (La-containing OCP powder, Pr-containing OCP powder, Ce-containing OCP powder, Dy-containing OCP powder) and OCP powder were immersed in 40 mL of 0.01 mol / L cetylpyridinium chloride (CPC) solution and shaken at 60 rpm for 10 minutes at 37°C. After that, they were washed with distilled water three times or more and then completely dried at 40°C. The rare earth element-supported OCP powder treated with CPC and the OCP powder treated with CPC were added to the bacterial solution prepared in the previous section to a concentration of 0.01 g / mL. This was left to act at 37°C and a shaking speed of 100 rpm for 24 hours, and the antibacterial properties of the rare earth element-supported OCP powder were evaluated.

[0099] After 24 hours of action, the mixture was left to stand at room temperature for 5 minutes to allow the powder of rare earth element-loaded OCP (La-containing OCP powder, Pr-containing OCP powder, Ce-containing OCP powder, Dy-containing OCP powder) suspended in the broth medium to settle, and the supernatant was diluted appropriately with PBS solution and inoculated in 0.1 mL onto an agar medium (φ100). After culturing at 37°C for 3 days, the number of colonies formed on the agar medium was counted to evaluate the antibacterial activity.

[0100] FIG. 9 is a photograph showing the results of evaluating the antibacterial properties of rare earth element-supported OCP powders that have been treated with CPC. As shown in FIG. 9, the number of colonies formed was significantly reduced in the rare earth element-supported OCP powders (La-containing OCP powder, Pr-containing OCP powder, Ce-containing OCP powder, and Dy-containing OCP powder). In particular, the number of colonies in the La-containing OCP powder was about 1 / 100 of that in the OCP powder without rare earth elements, demonstrating a remarkable antibacterial effect. In other words, it was suggested that the antibacterial properties were exhibited by the remarkable adsorption and retention of CPC on the surface. [Industrial Applicability]

[0101] It can impart long-lasting antibacterial properties to bone prosthesis materials, oral bone prosthesis materials, and oral care products, and can also prevent blackening caused by silver.

Claims

1. A step of preparing a weakly basic phosphoric acid solution containing a complex formed of a rare earth element ion and a coordination compound having a ligand that coordinates with the rare earth element ion; and adding a calcium-containing compound to the weakly basic phosphoric acid solution and hydrolyzing the compound, A method for producing calcium phosphate crystals, characterized in that a portion of a plurality of calcium ions contained in the structure of the calcium phosphate crystals is substituted with the rare earth element ions.

2. 2. The method for producing calcium phosphate crystals according to claim 1, wherein the calcium phosphate is any one selected from the group consisting of octacalcium phosphate, hydroxyapatite, fluoroapatite, chloroapatite, and carbonate apatite.

3. 2. The method for producing calcium phosphate crystals according to claim 1, wherein the rare earth element ion is one or more selected from the group consisting of yttrium ion, lanthanum ion, cerium ion, praseodymium ion, neodymium ion, samarium ion, europium ion, gadolinium ion, terbium ion, dysprosium ion, holmium ion, thulium ion, ytterbium ion and lutetium ion.

4. 2. The method for producing calcium phosphate crystals according to claim 1, wherein the coordination compound is a quaternary ammonium cation compound.

5. 5. The method for producing calcium phosphate crystals according to claim 4, wherein the quaternary ammonium cationic compound is one or more selected from the group consisting of benzalkonium chloride, cetylpyridium chloride, benzethonium chloride, trimethylglycine and didecyldimethylammonium chloride.

6. The weakly basic phosphoric acid solution has a phosphoric acid concentration of 0.1 mol / L to 3.0 mol / L; 2. The method for producing calcium phosphate crystals according to claim 1, wherein the weakly basic phosphoric acid solution has a pH of 7.0 to 12.

0.

7. 2. The method for producing calcium phosphate crystals according to claim 1, wherein the calcium-containing compound is a readily soluble calcium phosphate consisting of calcium hydrogen phosphate dihydrate, calcium monohydrogen phosphate (anhydrous), calcium dihydrogen phosphate hydrate, calcium dihydrogen phosphate anhydrate, α-tricalcium phosphate, or a mixture thereof.

8. A method for producing a block material containing calcium phosphate crystals, comprising: preparing a weakly basic phosphoric acid solution containing a complex of one of calcium and phosphoric acid, rare earth element ions, and a coordination compound having a ligand that coordinates with the rare earth element ions; a step of immersing a solid composition made of a ceramic containing the other of calcium and phosphate in the weakly basic phosphoric acid solution to convert a part of the solid composition into octacalcium phosphate crystals to obtain a block material; A method for producing a block material, characterized in that a portion of the calcium ions contained in the crystal structure of the octacalcium phosphate are substituted with rare earth element ions.

9. A method for producing a porous body containing calcium phosphate crystals, comprising: preparing a weakly basic phosphoric acid solution containing a complex of one of calcium and phosphoric acid, rare earth element ions, and a coordination compound having a ligand that coordinates with the rare earth element ions; a step of immersing a solid composition made of a ceramic containing the other of calcium and phosphate in the weakly basic phosphoric acid solution to convert a part of the solid composition into octacalcium phosphate crystals and obtain a porous body, A method for producing a porous body, characterized in that a portion of the calcium ions contained in the crystal structure of the octacalcium phosphate are substituted with rare earth element ions.

10. Calcium phosphate crystals produced by the method for producing calcium phosphate crystals according to claim 1, the content of rare earth atoms is 0.01 atomic % or more and 13.00 atomic % or less, The calcium phosphate crystals do not contain silicic acid, The calcium phosphate crystal has a silver content of less than 0.01 atomic %.

11. 11. The calcium phosphate crystal according to claim 10, wherein the content of the rare earth atoms is 0.10 atomic % or more and 7.00 atomic % or less.

12. A block material manufactured by the method for manufacturing a block material according to claim 8, the content of rare earth atoms is 0.01 atomic % or more and 13.00 atomic % or less, The calcium phosphate crystals do not contain silica, The calcium phosphate block has a silver content of less than 0.01 atomic %.

13. 13. The block material according to claim 12, wherein the content of the rare earth atoms is 0.10 atomic % or more and 7.00 atomic % or less.

14. A porous body manufactured by the method for manufacturing a porous body according to claim 9, the content of rare earth atoms is 0.01 atomic % or more and 13.00 atomic % or less, The calcium phosphate crystals do not contain silica, The porous body has a silver content of less than 0.01 atomic % in the calcium phosphate crystals.

15. 15. The porous body according to claim 14, wherein the content of the rare earth atoms is 0.10 atomic % or more and 7.00 atomic % or less.

16. A bone filler comprising the calcium phosphate crystals according to claim 10.

17. An oral bone filler comprising the calcium phosphate crystals according to claim 10.

18. An oral care product comprising the calcium phosphate crystals according to claim 10.

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