Medical calcium carbonate compositions and related medical compositions, and methods for their manufacture

Abstract

This invention provides medical-grade calcium carbonate compositions that highly meet the requirements for implantable medical materials in vivo, including: 1) tissue affinity, 2) bioavailability, 3) reactivity, and 4) mechanical strength; related medical-grade calcium phosphate compositions; medical-grade carbonate apatite compositions; medical-grade porous calcium hydroxide; medical-grade solidified calcium sulfate granules; a reagent kit for bone defect regeneration therapy; and methods for manufacturing the same. By controlling the polymorphism and structure of calcium carbonate, it is possible to manufacture medical-grade calcium carbonate compositions and related medical compositions that highly meet the aforementioned requirements.

Description

Technical Field

[0001] This invention relates to medical compositions and methods of manufacturing the same. Specifically, it relates to medical calcium carbonate compositions implanted in living organisms, cell culture scaffolds used in vitro, and related medical calcium sulfate curing compositions, medical calcium phosphate compositions, medical calcium hydroxide compositions, bone defect reconstruction treatment kits, and methods of manufacturing the same.

[0002] More specifically, it relates to medical calcium carbonate compositions that highly satisfy 1) tissue affinity, 2) bioavailability, 3) reactivity, and 4) mechanical strength, as well as related medical compositions and methods for manufacturing them. Background Technology

[0003] The skeletons of invertebrates are composed of calcium carbonate, while the skeletons of vertebrates are composed of apatite (a type of calcium phosphate obtained by adding phosphoric acid to calcium carbonate). Calcium carbonate has been studied as a bone filling material, and calcium phosphate and calcium sulfate, which contain apatite, have been used clinically as bone filling materials.

[0004] (Organizational affinity)

[0005] Medical compositions, such as bone fillers, require different properties than industrial compositions; the biological response is paramount. Implanting powder into a living organism can trigger an inflammatory response. Therefore, medical compositions implanted into a living organism require a certain volume for tissue compatibility. Antibacterial properties are also sometimes necessary for infection prevention. Furthermore, as medical compositions, substantial purity is essential.

[0006] (Absorbability within the organism)

[0007] As bone filling materials, medical-grade calcium carbonate compounds and related medical compositions are sometimes expected to be absorbed within the body to replace desired tissue. For tissue replacement, both material absorption and tissue regeneration are necessary. Calcium carbonate and some calcium phosphate are absorbed by osteoclasts, etc., and for absorption to be effective, materials that are not absorbed within the body are required.

[0008] (Reactivity)

[0009] For medical-grade calcium carbonate compositions, excellent tissue reactivity, such as tissue replacement, or chemical reactivity, is sometimes desired in vivo. Regarding the former, the penetration and dissolution by tissues, cells, and tissue fluid become crucial factors, while porosity control, polymorphism, and crystallite size are important. Regarding the latter, the penetration and dissolution by aqueous solutions become crucial factors, while porosity control, polymorphism, and crystallite size are important.

[0010] Regarding the latter, medical-grade calcium carbonate compositions are not only anticipated as bone-filling materials, but also useful as precursors in the manufacture of medical-grade calcium phosphate compositions such as medical-grade apatite compositions. For example, if a calcium carbonate block is impregnated in a phosphate aqueous solution, the composition transforms into apatite while maintaining its macroscopic shape during the dissolution reaction, enabling the manufacture of apatite blocks (Patent Document 1). However, since the dissolution reaction begins from the surface of the calcium carbonate block, in cases where the calcium carbonate block is large or has low reactivity, the composition may not be completely transformed into apatite, leaving a core. Therefore, a highly reactive medical-grade calcium carbonate composition and a manufacturing method that accelerates the incorporation of phosphate components are desired.

[0011] The reactivity of calcium carbonate compositions is influenced not only by their composition and polymorphism but also significantly by their structure. In particular, interconnected porous structures are preferred due to the internal movement of cells and tissues. While large pores of a certain size are necessary for cell and tissue movement, smaller micropores become important when tissue replacement is desired.

[0012] (Mechanical strength)

[0013] A high porosity, including both large and micropores, is generally desirable, but increased porosity leads to decreased mechanical strength. Therefore, achieving a balance between porosity and mechanical strength is crucial.

[0014] It should be noted that medical calcium phosphate compositions made from medical calcium carbonate compositions, medical calcium hydroxide compositions required for the manufacture of medical calcium carbonate compositions, medical calcium sulfate compositions, and reagent kits for bone defect reconstruction treatment are also important as related medical compositions.

[0015] (Reactivity of calcium carbonate: polymorphism, porosity, and density)

[0016] Polymorphism, porosity, density, and other factors affect the reactivity of calcium carbonate. Aragonite is metastable at room temperature and pressure, does not exist naturally, and is the most reactive form of calcium carbonate. Its density is 2.64 g / cm³. 3 Calcite is a stable phase under normal temperature and pressure, and its reactivity is lower than that of aragonite. Its density is 2.71 g / cm³. 3 Aragonite is a stable phase under high temperature and pressure, and a metastable phase under normal temperature and pressure. Its density is 2.96 g / cm³. 3 If high-density calcium carbonate is used as a raw material to manufacture medical materials, high-density medical materials can be produced, which sometimes results in lower reactivity. Therefore, calcium carbonate with lower density is sometimes desired.

[0017] Furthermore, porosity has the greatest impact on the reactivity of calcium carbonate; generally, higher porosity corresponds to higher reactivity. Based on this relationship, when using calcium carbonate as a raw material to manufacture other materials, or when using calcium carbonate with low density, it is sometimes possible to produce highly reactive materials.

[0018] For the reasons stated above, the present invention is limited to calcium carbonate formed from aragonite and calcite.

[0019] (Background of the aragonite composition)

[0020] Aragonite is a metastable phase, exhibiting higher reactivity not only compared to the stable calcite phase but also compared to the metastable aragonite phase, making it an extremely preferred choice for medical-grade calcium carbonate compositions. Previously, compositions containing more than 20% by mass of aragonite and with a volume of 10... -12 m 3 The above are medical-grade aragonite compositions.

[0021] Regarding aragonite powder, it is known that it can be manufactured by the following methods: adding divalent cations other than calcium to slow down the transformation to calcite when manufacturing calcium carbonate by reacting an aqueous solution of a water-soluble calcium salt and a carbonate (Patent Documents 2 and 3); controlling the Ca concentration, temperature, and pH of the slurry during the carbonation of calcium chloride or calcium nitrate (Patent Documents 4 and 5); reacting an O / W emulsion formed by passing a continuous aqueous phase containing dissolved calcium ions and an organic phase through a porous membrane with an aqueous solution containing carbonate ions (Patent Document 6); introducing carbon dioxide into an alcohol-water suspension of calcium hydroxide (Patent Document 7); adding alkylamine salt-type surfactants (Non-Patent Document 1); adding organic substances such as ethylene glycol (Non-Patent Document 2). However, the powder cannot be used because it induces inflammatory reactions in living organisms.

[0022] The inventors of this application have discovered a method for manufacturing calcite particles containing 17% by mass of aragonite by impregnating anhydrous calcium sulfate particles in 50 mL of a 2 mol concentration sodium carbonate aqueous solution at 4°C for 14 days. However, in this manufacturing method, the aragonite content is 17% by mass because calcite formation cannot be sufficiently suppressed (Patent Document 8). Furthermore, as described in Patent Document 8, it is argued that "when manufacturing an inorganic compound containing calcium carbonate comprising aragonite, the electrolyte temperature must be below 10°C," which presents problems with the product and its manufacturing process (Patent Document 8).

[0023] That is, a medical calcium carbonate composition containing 20% ​​by mass or more of aragonite that satisfies all the conditions of the above-mentioned medical calcium carbonate composition, and its manufacturing method, are unknown. Furthermore, a method for manufacturing aragonite at a temperature above 10°C is also unknown. In other words, a medical material containing 20% ​​by mass or more of aragonite of a certain size or larger that highly suppresses calcite formation is unknown. Of course, sintered bodies containing aragonite are unknown.

[0024] (Background of the calcite composition)

[0025] In calcium carbonate, calcite, which is a stable phase, is relatively easy to manufacture in the form of granules or lumps. Methods for exposing calcium hydroxide powder to carbon dioxide have been reported (Patent Document 9).

[0026] On the other hand, calcite in its stable phase is less reactive than aragonite and spherulite in their metastable phases. When phosphate is added to calcite to produce calcium phosphate, the calcium phosphate formation reaction begins at the surface of the calcite composition. Therefore, there are situations where: a residual calcium carbonate core prevents the production of a calcium phosphate composition; a reaction temperature above 100°C is required; or the production process is time-consuming.

[0027] To increase the apparent reactivity of medical-grade calcium carbonate compositions, interconnected porous structures are effective. For example, when manufacturing medical-grade calcium phosphate compositions from a certain volume or more of medical-grade calcite, a dense structure may leave a core residue or require a long manufacturing time. However, with interconnected porous structures of the same volume, the reaction begins from the surface of the porous structure, thus eliminating core residue or enabling the manufacture of medical-grade calcium phosphate compositions in a shorter time. Interconnected porous structures also allow cells and tissues to penetrate the interior. For example, in the case of interconnected porous carbonate apatite, bone replacement is significantly improved.

[0028] Various studies have been conducted previously on calcium carbonate porous bodies, which serve as precursors to medical-grade apatite porous bodies. For example, a method was proposed that involves mixing pore-forming substances such as sodium chloride into calcium hydroxide, pressing it into powder, carbonating it, and then removing the pore-forming substances to produce a calcium carbonate porous body (Patent Document 9). While the formation of a porous body improves reactivity, further improvements in reactivity are required since it is a calcite porous body. Furthermore, limiting the pore size is extremely important from the perspective of mechanical strength and reactivity, but at that time, the specific pore size was unknown.

[0029] Previously, it was believed that calcium carbonate was difficult to sinter due to its decomposition. A method was proposed to easily manufacture calcium carbonate sintered bodies by adding a foaming agent to a dispersion containing calcium carbonate and a gelling agent, stirring, and then sintering the foamed body (Patent Document 10). This manufacturing method forms interconnected pores, but the sintered pores are large, ranging from hundreds of micrometers to over 1 mm, and the walls are thick, resulting in poor reactivity. Furthermore, the formation of pores due to foaming leads to poor reproducibility. Moreover, as described in Reference Example 1 of Patent Document 10, a porous calcium carbonate sintered body cannot be obtained without adding potassium carbonate and lithium carbonate as sintering aids. Additionally, bone filler materials containing potassium and lithium are not preferred. Although porous calcium carbonate sintered bodies can be manufactured by adding sintering aids or using high-purity calcium carbonate, the mechanical strength is low, lacking clinical practicality.

[0030] Furthermore, a degreasing method for manufacturing porous ceramic bodies has been proposed, characterized in that, during the degreasing process when manufacturing porous ceramic bodies using hot-melt resin beads as pore-forming materials, the temperature is increased at a rate of 30°C / hour or higher to above the decomposition initiation temperature of the hot-melt resin beads (Patent Document 11). While useful in thermally stable ceramics such as alumina, its usefulness is limited in ceramics such as calcium carbonate, which decompose at high temperatures. Moreover, a more sophisticated degreasing method is needed in medical compositions where high reactivity is desired. Although the method of mixing the pore-forming material with the raw ceramic material can accurately adjust the pore size, a relatively large amount of pore-forming material needs to be introduced to form interconnected porous bodies. With the increase in porosity, the mechanical strength of the manufactured porous ceramic body decreases significantly, thus requiring the introduction of a suitable pore-forming material.

[0031] Regarding a method for manufacturing interconnected porous calcium carbonate structures, the inventors of this application have proposed the following method: using calcium hydroxide containing a polymeric material, extruding it through a mold for forming a honeycomb structure, degreasing the polymeric material, and then carbonating it, or simultaneously performing degreasing and carbonation of the polymeric material, to manufacture a calcium carbonate honeycomb structure (Patent Document 12). Furthermore, it has been disclosed that by imparting a phosphoric acid component to the calcium carbonate honeycomb structure of this invention, a carbonate apatite honeycomb structure can be manufactured. Both the calcium carbonate honeycomb structure and the carbonate apatite honeycomb structure exhibit osteoconductivity and excellent properties such as a high degree of orientation of the conducted bone in the direction of the interconnected pores. Further research and development related to this carbonate apatite honeycomb structure revealed that the degreasing of the calcium carbonate honeycomb structure is insufficient, and the possibility of manufacturing highly functional medical calcium carbonate compositions by increasing the level of degreasing was discovered. In other words, in the manufacture of the calcium carbonate honeycomb structure of this invention, high-molecular materials such as wax-based organic binders were used. Therefore, although degreasing was performed, at that time it was determined that the required degree of degreasing varied depending on the desired whiteness. Furthermore, the required level of degreasing for medical-grade calcium carbonate compositions was not clarified, and no method for quantifying the degree of degreasing was devised. Not to mention, it was unimaginable that the acid-dissolving residues resulting from the degree of degreasing would have a significant impact on the reactivity and usability of the calcium carbonate honeycomb structure.

[0032] Therefore, the calcium carbonate honeycomb structure disclosed in Example 1 of Patent Document 12 (Comparative Example 7 of this specification) contains 1.2% by mass of acid-dissolving residue. Furthermore, the carbonate apatite honeycomb structure manufactured by imparting phosphoric acid to this calcium carbonate honeycomb structure (Example 11 of Patent Document 12) also contains 1.2% by mass of acid-dissolving residue. At the time, even though these acid-dissolving residues were a cause of discoloration, it was not anticipated that they would necessarily affect long-term tissue affinity. In fact, even in the carbonate apatite honeycomb structure containing 1.2% by mass of acid-dissolving residue, a certain degree of osteoconductivity and excellent tissue affinity were confirmed.

[0033] Further research was conducted to enhance the functionality of this carbonate apatite honeycomb structure. The results showed that even small amounts of acid-dissolving residue can affect osteoconductivity and bioavailability. Therefore, in-depth research was carried out on medical-grade calcium carbonate honeycomb structures with acid-dissolving residues of less than 1% by mass, and ideally 0% by mass.

[0034] It should be noted that in medical-grade calcium carbonate honeycomb structures, not only are large pores forming interconnected structures important, but micropores are also crucial. This is because large pores are useful not only for the invasion of tissues and cells, but micropores are also useful for promoting the absorption of medical-grade calcium carbonate porous bodies based on cells, body fluids, etc., or for their reaction with aqueous solutions. However, previously, no method for determining the micropores useful in medical-grade calcium carbonate compositions, or the effective range of micropores, had been found.

[0035] Existing technical documents

[0036] Patent documents

[0037] Patent Document 1: Japanese Re-publication Patent No. WO2004 / 112856

[0038] Patent Document 2: Japanese Patent Application Publication No. 57-92520

[0039] Patent Document 3: Japanese Patent Application Publication No. 60-90822

[0040] Patent Document 4: Japanese Patent Application Publication No. 54-150397

[0041] Patent Document 5: Japanese Patent Application Publication No. 2011-126741

[0042] Patent Document 6: Japanese Patent Application Publication No. 2011-157245

[0043] Patent Document 7: Japanese Patent Application Publication No. 11-314915

[0044] Patent Document 8: International Publication No. 2016 / 035751

[0045] Patent Document 9: Japanese Patent Application Publication No. 2016-552061

[0046] Patent Document 10: Japanese Patent Application Publication No. 2018-140890

[0047] Patent Document 11: Japanese Patent Application Publication No. 7-223871

[0048] Patent Document 12: International Publication No. 2018 / 074429

[0049] Non-patent literature 1: Japan Adhesion Association Journal, Vol. 22, No. 11, 1986, pp. 573-579

[0050] Non-Patent Literature 2: Materials, Vol. 30, No. 336, 1986, pp. 6-10 Summary of the Invention

[0051] The problem that the invention aims to solve

[0052] The subject of this invention is to provide a medical calcium carbonate composition that highly satisfies 1) tissue affinity, 2) bioavailability, 3) reactivity, and 4) mechanical strength, and related medical calcium sulfate curing compositions, medical calcium phosphate compositions, medical calcium hydroxide compositions, kits for bone defect reconstruction treatment, and methods for manufacturing the same.

[0053] Methods for solving problems

[0054] The inventors of this application have conducted repeated and in-depth research and have discovered that they can provide medical calcium carbonate compositions that highly satisfy 1) tissue affinity, 2) bioavailability, 3) reactivity, and 4) mechanical strength, as well as medical calcium sulfate hemihydrate compositions, medical calcium phosphate compositions, medical calcium hydroxide compositions, bone defect reconstruction treatment kits, and methods for manufacturing them, thereby completing this invention.

[0055] That is, the present invention is as follows. [1]

[0057] A medical calcium carbonate composition, characterized in that it satisfies all of the conditions in (A) to (C) below, and at least one condition selected from the group consisting of (D) to (K).

[0058] (A) Volume is 10 -12 m 3 above.

[0059] (B) The acid-dissolved residue is less than 1% by mass.

[0060] (C) As a medical composition mainly formed from aragonite or calcite, it is essentially pure calcium carbonate.

[0061] (D) Contains more than 20% by mass of aragonite.

[0062] (E) is a honeycomb structure with multiple through-holes extending in one direction, and in the fine pore distribution measurement based on mercury intrusion porosimetry, the pore volume with a pore diameter of 10 μm or less relative to the mass of the honeycomb structure is greater than 0.02 cm³. 3 / g.

[0063] (F) is a particle-bonded porous body formed by the bonding of multiple particles with a maximum diameter of 50 μm to 500 μm, possessing multiple through pores extending in multiple directions, and the pore volume of the particle-bonded porous body with a diameter of 10 μm or less, as determined by mercury porosimetry, is 0.05 cm³. 3 / g or more.

[0064] (G) is a porous material with aggregated pores having a maximum diameter of 50 μm to 400 μm, but not including pores with a maximum diameter of 800 μm or more, in the overall medical composition. Furthermore, the volume of fine pores of 10 μm or less in this porous material, as determined by mercury porosimetry, is 0.05 cm³. 3 / g or more.

[0065] (H) In the mercury porosimetry determination, the ratio of the volume of pores with a diameter of 1 μm or more but less than 6 μm to the volume of pores with a diameter of 6 μm or less is 10% or more.

[0066] (I) The maximum compressive strength obtained in any direction is greater than or equal to the reference compressive strength [S] calculated by the following formula (wherein, excluding honeycomb structures having multiple through holes extending in one direction, and pore volumes of 0.02 cm³ with a pore diameter of 10 μm or less relative to the mass of the honeycomb structure in mercury porosimetry determination). 3 The following are examples of / g.

[0067] S = S0 × C × exp(-b × P)

[0068] (Where, S0 and b are constants, S0 is 500, b is 0.068, C is a constant determined according to the polymorphism of calcium carbonate, which is 0.01 when it contains more than 20% by mass of aragonite, and 1 when it does not contain more than 20% by mass of aragonite, and P is the percentage of porosity of the composition.)

[0069] (J) Honeycomb structure particles with a minor diameter of 1 mm or more and less than 5 mm, and which do not have the following points in the projection diagram of the composition: the points are the points of triangles formed by three points where a circle with a radius of 0.2 mm is drawn from any point on the perimeter line of the projection diagram and the perimeter line of the projection diagram intersects the circle, and the angle with any point on the perimeter line of the projection diagram as the vertex is 90° or less.

[0070] (K) Multiple composition particles are connected by fibers. [2]

[0072] The medical calcium carbonate composition as described in [1] is characterized in that it is medical calcium carbonate that satisfies the aforementioned condition (D) and is a sintered body. [3]

[0074] The medical calcium carbonate composition as described in [1] or [2] is characterized in that calcium carbonate powder satisfying any one of the following conditions (AJ1) to (AJ4) is combined to form the calcium carbonate composition.

[0075] (AJ1) has an average particle size of 2 μm to 8 μm.

[0076] (AJ2) Sphericity is 0.9 or higher.

[0077] (AJ3)Mg content is 5×10 -4 3×10 of the above % by mass -3 Less than % of the mass.

[0078] The (AJ4)Sr content is 3×10 -3 1.5 × 10⁻⁶ (by weight) or more -2 Less than % of the mass. [4]

[0080] The medical calcium carbonate composition as described in [1] or [3] satisfies the aforementioned condition (E), and,

[0081] The medical calcium carbonate composition is characterized in that it is a curved honeycomb structure with a diameter of 1 cm to 50 cm, formed by the three points passing through the two ends and the center of any through hole. [5]

[0083] A method for manufacturing a medical calcium carbonate composition, characterized in that it is a method for manufacturing a medical calcium carbonate composition as described in [1] or [3] that satisfies the aforementioned condition (D), wherein in the manufacturing method,

[0084] With a volume of 10 -12 m 3 In the process of exposing the above-mentioned raw material calcium composition to carbon dioxide or carbonate ions, at least one condition selected from the group consisting of (D1) to (D8) below is satisfied, and (D9) to (D12) are optional processes.

[0085] (D1) includes the process of inhibiting the formation of calcite or the growth of calcite crystals and relatively promoting the formation of aragonite.

[0086] (D2) includes the step of exposing the raw calcium composition to carbon dioxide or carbonate ions and at least one selected from the group consisting of organic solvents, water-soluble organics, ammonia and ammonium salts.

[0087] (D3) includes the step of exposing a raw material calcium composition comprising at least one of the group consisting of organic solvents, water-soluble organics, ammonia and ammonium salts to carbon dioxide or carbonate ions, and the step of exposing a raw material calcium composition comprising at least one of the group consisting of organic solvents, water-soluble organics, ammonia and ammonium salts to carbon dioxide or carbonate ions.

[0088] (D4) includes the step of exposing the raw calcium composition to carbon dioxide or carbonate ions and at least one selected from the group consisting of methanol, ethanol, glycerol, ethylene glycol and ammonium carbonate.

[0089] (D5) includes the steps of exposing a raw material calcium composition comprising at least one of methanol, ethanol, glycerol, ethylene glycol and ammonium carbonate to carbon dioxide or carbonate ions, and at least one of methanol, ethanol, glycerol, ethylene glycol and ammonium carbonate.

[0090] (D6) includes a process to suppress the transformation from aragonite to calcite.

[0091] (D7) includes the process of removing water from the raw calcium composition.

[0092] (D8) includes a step of causing carbon dioxide or carbonate ions containing an organic solvent to flow around the raw calcium composition.

[0093] (D9) includes the steps of partially carbonating a raw calcium composition by exposing it in the gas phase to carbon dioxide or carbonate ions, and then exposing the raw calcium composition in the liquid phase to carbon dioxide or carbonate ions.

[0094] (D10) includes a process of exposing a raw calcium composition contained in a mold to carbon dioxide or carbonate ions.

[0095] (D11) includes a process of exposing a raw calcium composition containing a pore-forming material to carbon dioxide or carbonate ions.

[0096] (D12) includes a process of exposing the fiber-linked raw material calcium composition to carbon dioxide or carbonate ions. [6]

[0098] A method for manufacturing a medical aragonite sintered body, characterized in that it is a method for manufacturing a medical calcium carbonate composition as described in [1] or [2] that satisfies the aforementioned condition (D), wherein the calcium carbonate powder containing aragonite of 20% by mass or more is pressed and sintered. [7]

[0100] A method for manufacturing a medical calcium carbonate composition, characterized in that it is a method for manufacturing a medical calcium carbonate composition as described in [1], [3] or [4] that satisfies the aforementioned condition (E), wherein in the manufacturing method,

[0101] Choose one of the following (E1) and one of the groups (E5) to (E9) as a required process, and (E2) to (E4) and (E10) as optional processes.

[0102] (E1) Extrusion process

[0103] A calcium composition containing polymer materials is extruded through a mold used to form a honeycomb structure to produce a volume of 3 × 10⁻⁶. -11 m 3The above process, and the process of constructing a raw material honeycomb structure with multiple through holes extending in one direction.

[0104] (E2) Molding process after extrusion

[0105] The process involves softening a honeycomb structure composed of a calcium-based raw material containing polymer materials through heat treatment, then subjecting it to pressure and molding it into the desired shape.

[0106] (E3) External peripheral sidewall removal process

[0107] The process of removing the outer peripheral sidewalls after the extrusion process or the molding process following the extrusion process, and before the degreasing and carbonation process.

[0108] (E4) Molding process after removing the outer peripheral sidewall

[0109] After the outer peripheral sidewall removal process, the honeycomb structure, composed of a calcium-based raw material containing polymer materials, is softened by heat treatment and then subjected to pressure to be molded into the desired shape.

[0110] (E5) Degreased calcium carbonate sintering process

[0111] The degreasing and sintering process involves heating the calcium carbonate containing polymeric materials to remove the residue by acid dissolution, reducing it to less than 1% by mass, and then sintering the calcium carbonate.

[0112] (E6) Degreasing and Carbonation Process

[0113] The process involves heating and degreasing a porous calcium hydroxide containing polymer materials by dissolving the residue with acid to a concentration of less than 1% by mass under conditions of oxygen concentration less than 30%, while simultaneously performing carbonation.

[0114] (E7) via calcium oxide degreasing and carbonation process

[0115] The process involves heating and degreasing calcium hydroxide porous bodies or calcium carbonate porous bodies containing polymeric materials by dissolving the residue with acid to a concentration of less than 1% by mass, thereby producing calcium oxide porous bodies. Then, the calcium oxide porous bodies are exposed to carbon dioxide to produce calcium carbonate porous bodies.

[0116] (E8) Degreasing and carbonation process using calcium carbonate and calcium oxide

[0117] Calcium hydroxide containing polymeric materials is heat-treated in the presence of carbon dioxide to produce porous calcium carbonate containing polymeric materials. Then, the residue is dissolved in acid and degreased by heating to a concentration of less than 1% by mass, producing porous calcium oxide. Finally, the porous calcium oxide is exposed to carbon dioxide to produce porous calcium carbonate through a carbonation process involving degreasing calcium oxide.

[0118] (E9) Calcium sulfate defatting and carbonation process

[0119] The calcium sulfate containing polymeric materials is degreased by heating to dissolve the residue in acid to less than 1% by mass. Then, carbon dioxide or carbonate ions are introduced into the resulting porous calcium sulfate to produce calcium carbonate. This is a degreasing and carbonation process.

[0120] (E10) Shaping process performed after the defatting and carbonation process. [8]

[0122] The method for manufacturing the medical calcium carbonate composition as described in [7] is characterized in that at least one condition selected from the group consisting of (E11) to (E14) below is satisfied.

[0123] (E11) In the aforementioned "(E1) extrusion process", the thickness of the outer peripheral sidewall of the honeycomb structure is greater than the thickness of the partition wall, and the cross-sectional area of ​​the surface perpendicular to the through hole is 1 cm². 2 Extrusion is performed using the methods described above.

[0124] (E12) In at least one of the aforementioned “(E1) extrusion process”, “(E2) molding process after extrusion process”, “(E4) molding process after outer peripheral sidewall removal process” and “(E10) shape finishing process after degreasing and carbonation process”, a heat-softened honeycomb structure composed of a raw material calcium composition containing polymer materials is subjected to pressure and bent in such a way that the diameter of the circle passing through the two ends of the through hole and the center of the through hole is 1 cm or more and 50 cm or less.

[0125] (E13) The aforementioned “(E3) peripheral sidewall removal process” is performed by grinding, and the aforementioned “(E10) shape finishing process after degreasing and carbonation process” is performed by polishing.

[0126] (E14) The raw material calcium composition for the aforementioned “(E1) extrusion process” is anhydrous calcium sulfate. [9]

[0128] A method for manufacturing a medical calcium carbonate composition, characterized in that it is a method for manufacturing a medical calcium carbonate composition that satisfies the aforementioned conditions (F) [1] using calcium oxide particles as raw materials.

[0129] The manufacturing method includes the steps (F1) and (F2) below, and includes at least one of the steps (F3) and (F4).

[0130] (F1) Introduce the closed process

[0131] The process of loading calcium oxide particles into a reaction vessel and sealing the opening of the reaction vessel in a manner that prevents the calcium oxide particles from being discharged from the reaction vessel.

[0132] (F2) Porous body formation process

[0133] The process of adding water or acetic acid to calcium oxide particles inside a reaction vessel to produce calcium hydroxide or calcium acetate, and then expanding the particles to create a porous body.

[0134] (F3) Carbonation process

[0135] A carbonation process that involves imparting carbon dioxide to calcium hydroxide porous bodies to produce calcium carbonate porous bodies, either simultaneously with or after the porous body formation process; or a carbonation process that involves heat-treating calcium acetate after the porous body formation process to produce calcium carbonate porous bodies.

[0136] (F4) Calcium oxide carbonation process

[0137] A carbonation process starting from a calcium oxide porous body involves heat-treating at least one porous body selected from the group consisting of calcium hydroxide porous bodies, calcium carbonate porous bodies, and calcium acetate porous bodies to produce a calcium oxide porous body, and exposing the calcium oxide porous body to carbon dioxide to produce a calcium carbonate porous body.

[10]

[0139] A method for manufacturing a medical calcium carbonate composition, characterized in that it is a method for manufacturing a medical calcium carbonate composition that satisfies the aforementioned conditions (F) [1] using calcium sulfate particles as a raw material.

[0140] The manufacturing method includes steps (F5) and (F6) below, or includes steps (F5), (F7) and (F9) below, with step (F8) as an optional step.

[0141] (F5) Introduction Process

[0142] The process of loading calcium sulfate granules into the reaction vessel

[0143] (F6) Porous body formation carbonation process

[0144] The process involves reacting calcium sulfate particles inside the reaction vessel with carbonate ions to convert the composition into calcium carbonate, and then solidifying the particles to create a porous structure.

[0145] (F7) Porous body formation process

[0146] The process of adding water to calcium sulfate hemihydrate particles or calcium sulfate anhydrous particles to manufacture porous calcium sulfate dihydrate bodies.

[0147] (F8) Heat treatment process

[0148] The process of heat-treating porous calcium sulfate dihydrate to manufacture porous calcium sulfate anhydrous materials.

[0149] (F9) Carbonation process

[0150] The process of exposing porous calcium sulfate dihydrate or porous calcium sulfate anhydrous material to water containing carbonate ions to convert its composition into calcium carbonate.

[11]

[0152] A method for manufacturing a medical calcium carbonate composition, characterized in that it is a method for manufacturing a medical calcium carbonate composition [1] that satisfies the aforementioned conditions (F), wherein,

[0153] Choose one of the following steps (F10) and (F11) and one of the groups selected from (F12) to (F16) as a required step, and (F17) as an optional step.

[0154] (F10) Introduction Process

[0155] With a volume of 10 -12 m 3 The above steps involve loading the raw material calcium composition granules containing polymer materials into the reaction vessel.

[0156] (F11) Porous body formation process

[0157] By employing any one of the following steps—heating and fusing the particles inside the reaction vessel, dissolving the surface of the particles to bond their surfaces together, and fusing the surfaces of the particles together using a plasticizer—a volume of 3 × 10⁻⁶ particles can be manufactured. -11 m 3 The process of forming a particle-bonded porous body with multiple through-holes extending in multiple directions by combining multiple particles with a maximum diameter length of 50μm to 500μm.

[0158] (F12) Degreased calcium carbonate sintering process

[0159] The degreasing and sintering process involves heating the calcium carbonate containing polymeric materials to remove the residue by acid dissolution, reducing it to less than 1% by mass, and then sintering the calcium carbonate.

[0160] (F13) Degreasing and Carbonation Process

[0161] The process involves heating and degreasing a porous calcium hydroxide containing polymer materials by dissolving the residue with acid to a concentration of less than 1% by mass under conditions of oxygen concentration less than 30%, while simultaneously performing carbonation.

[0162] (F14) via calcium oxide degreasing and carbonation process

[0163] The process involves heating and degreasing calcium hydroxide porous bodies or calcium carbonate porous bodies containing polymeric materials by dissolving the residue with acid to a concentration of less than 1% by mass, thereby producing calcium oxide porous bodies. Then, the calcium oxide porous bodies are exposed to carbon dioxide to produce calcium carbonate porous bodies.

[0164] (F15) is produced through a degreasing and carbonation process using calcium carbonate and calcium oxide.

[0165] Calcium hydroxide containing polymeric materials is heat-treated in the presence of carbon dioxide to produce porous calcium carbonate containing polymeric materials. Then, the residue is dissolved in acid and degreased by heating to a concentration of less than 1% by mass, producing porous calcium oxide. Finally, the porous calcium oxide is exposed to carbon dioxide to produce porous calcium carbonate through a carbonation process involving degreasing calcium oxide.

[0166] (F16) Calcium sulfate defatting and carbonation process

[0167] The calcium sulfate containing polymeric materials is degreased by heating to dissolve the residue in acid to less than 1% by mass. Then, carbon dioxide or carbonate ions are introduced into the resulting porous calcium sulfate to produce calcium carbonate. This is a degreasing and carbonation process.

[0168] (F17) Shaping process performed after the defatting and carbonation process.

[12]

[0170] A method for manufacturing a medical calcium carbonate composition, characterized in that it is a method for manufacturing a medical calcium carbonate composition [1] that satisfies the aforementioned condition (G), wherein,

[0171] At least one of the following (G1) and selected from (D1) to (D10) and (E5) to (E9) is a required step, and (G2) and (G3) and (E10) are optional steps.

[0172] (G1) Mixing process

[0173] The process of mixing raw calcium composition powder or raw calcium composition paste with pore-forming material.

[0174] (G2) Powder pressing process

[0175] The process of pressing powdered raw calcium composition or a mixture of raw calcium composition paste and pore-forming material into powder.

[0176] (G3) Hole-forming material removal process

[0177] The process of removing pore-forming materials by dissolving them in a solvent.

[0178] (D1) includes the process of inhibiting the formation of calcite or the growth of calcite crystals and relatively promoting the formation of aragonite.

[0179] (D2) includes the step of exposing the raw calcium composition to carbon dioxide or carbonate ions and at least one selected from the group consisting of organic solvents, water-soluble organics, ammonia and ammonium salts.

[0180] (D3) includes the step of exposing a raw material calcium composition comprising at least one of the group consisting of organic solvents, water-soluble organics, ammonia and ammonium salts to carbon dioxide or carbonate ions, and the step of exposing a raw material calcium composition comprising at least one of the group consisting of organic solvents, water-soluble organics, ammonia and ammonium salts to carbon dioxide or carbonate ions.

[0181] (D4) includes the step of exposing the raw calcium composition to carbon dioxide or carbonate ions and at least one selected from the group consisting of methanol, ethanol and ammonium carbonate.

[0182] (D5) includes the step of exposing a raw material calcium composition comprising at least one of methanol, ethanol and ammonium carbonate to carbon dioxide or carbonate ions, and at least one of methanol, ethanol and ammonium carbonate.

[0183] (D6) includes a process to suppress the transformation from aragonite to calcite.

[0184] (D7) includes the process of removing water from the raw calcium composition.

[0185] (D8) includes a step of causing carbon dioxide or carbonate ions containing an organic solvent to flow around the raw calcium composition.

[0186] (D9) includes the steps of partially carbonating a raw calcium composition by exposing it in the gas phase to carbon dioxide or carbonate ions, and then exposing the raw calcium composition in the liquid phase to carbon dioxide or carbonate ions.

[0187] (D10) includes a process of exposing a raw calcium composition contained in a mold to carbon dioxide or carbonate ions.

[0188] (E5) Degreased calcium carbonate sintering process

[0189] The degreasing and sintering process involves heating the calcium carbonate containing polymeric materials to remove the residue by acid dissolution, reducing it to less than 1% by mass, and then sintering the calcium carbonate.

[0190] (E6) Degreasing and Carbonation Process

[0191] The process involves heating and degreasing a porous calcium hydroxide containing polymer materials by dissolving the residue with acid to a concentration of less than 1% by mass under conditions of oxygen concentration less than 30%, while simultaneously performing carbonation.

[0192] (E7) via calcium oxide degreasing and carbonation process

[0193] The process involves heating and degreasing calcium hydroxide porous bodies or calcium carbonate porous bodies containing polymeric materials by dissolving the residue with acid to a concentration of less than 1% by mass, thereby producing calcium oxide porous bodies. Then, the calcium oxide porous bodies are exposed to carbon dioxide to produce calcium carbonate porous bodies.

[0194] (E8) Degreasing and carbonation process using calcium carbonate and calcium oxide

[0195] Calcium hydroxide containing polymeric materials is heat-treated in the presence of carbon dioxide to produce porous calcium carbonate containing polymeric materials. Then, the residue is dissolved in acid and degreased by heating to a concentration of less than 1% by mass, producing porous calcium oxide. Finally, the porous calcium oxide is exposed to carbon dioxide to produce porous calcium carbonate through a carbonation process involving degreasing calcium oxide.

[0196] (E9) Calcium sulfate defatting and carbonation process

[0197] The calcium sulfate containing polymeric materials is degreased by heating to dissolve the residue in acid to less than 1% by mass. Then, carbon dioxide or carbonate ions are introduced into the resulting porous calcium sulfate to produce calcium carbonate. This is a degreasing and carbonation process.

[0198] (E10) Shaping process performed after the defatting and carbonation process.

[13]

[0200] The method for manufacturing a medical calcium carbonate composition as described in any one of [7], [8],

[11] , and

[12] is characterized in that the aforementioned heat degreasing is carried out at a temperature above 200°C, and the mass reduction of the polymer material in the calcium composition containing polymer material during the heat degreasing is less than 1 wt% per minute.

[14]

[0202] A method for manufacturing a medical calcium carbonate composition as described in any one of [5] to

[13] is characterized by comprising at least one step selected from the group consisting of (L) to (Q) below.

[0203] (L) Degreasing process using an oxygen partial pressure of 30 kPa or higher.

[0204] (M) Degreasing or carbonation process using carbon dioxide partial pressure above 30 kPa

[0205] (N) Degreasing or carbonation processes carried out in a gas containing oxygen or carbon dioxide at a pressure of 150 kPa or higher.

[0206] (O) The process of replacing part or all of the air in the reaction vessel with carbon dioxide, and then introducing carbon dioxide into the reaction vessel, thereby increasing the carbon dioxide concentration in the reaction vessel.

[0207] (P) Carbonation process in which carbon dioxide is supplied in a closed reaction vessel at a constant pressure.

[0208] (Q) Carbonation process in which carbon dioxide in the reaction vessel is stirred or circulated.

[15]

[0210] The method for manufacturing a medical calcium carbonate composition as described in any one of [5] to [9] and

[11] to

[14] is characterized in that the composition of the raw calcium composition is selected from the group consisting of calcium oxide, calcium hydroxide and calcium carbonate.

[16]

[0212] The method for manufacturing a medical calcium carbonate composition as described in any one of [5] to

[15] is characterized in that at least one of the following conditions (R1) to (R4) is satisfied.

[0213] (R1) Use calcium carbonate powder with an average particle size of 2 μm to 8 μm.

[0214] (R2) Use calcium carbonate powder with a sphericity of 0.9 or higher.

[0215] (R3) Uses a Mg content of 5×10 -4 3×10 of the above % by mass -3 Calcium carbonate powder with a mass percentage of less than 5%.

[0216] (R4) Uses an Sr content of 3×10 -3 1.5 × 10⁻⁶ (by weight) or more -2 Calcium carbonate powder with a mass percentage of less than 5%.

[17]

[0218] A medical-grade calcium sulfate curing composition, characterized in that it satisfies all of the conditions (T1) to (T5) below.

[0219] (T1) The acid-dissolved residue is less than 1% by mass.

[0220] (T2) has a volume of 5×10 -13 m 3 above.

[0221] (T3) is a medical composition that is essentially pure calcium sulfate.

[0222] (T4) The content of calcium sulfate hemihydrate is 50% or more by mass.

[0223] (T5) When the composition is brought into contact with each other and immersed in water, it is cured to form a porous body with a compressive strength of 0.3 MPa or more. [8]

[0225] A method for manufacturing medical calcium sulfate hemihydrate particles, characterized in that it is a method for manufacturing the medical calcium sulfate curable composition described in

[17] , wherein the manufacturing method includes (U2) and (U3) as necessary steps and (U1) and (U4) as optional steps.

[0226] (U1) Degreasing process of polymer materials

[0227] The process involves degreasing calcium sulfate particles or lumps containing polymeric materials through heat treatment, thereby reducing the acid-dissolved residue to less than 1% by mass.

[0228] (U2) Manufacturing process of calcium sulfate dihydrate

[0229] The process of adding water to anhydrous calcium sulfate or calcium sulfate hemihydrate particles or blocks formed through a polymer degreasing process, or adding water to calcium sulfate hemihydrate powder to solidify it, thereby manufacturing calcium sulfate dihydrate particles or blocks.

[0230] (U3) Manufacturing process of calcium sulfate hemihydrate

[0231] The process of dehydrating calcium sulfate dihydrate particles or lumps in the gas phase to produce calcium sulfate hemihydrate particles or lumps.

[0232] (U4) Particle size adjustment process

[0233] To form a volume of 5×10 -13 m 3 The above process for adjusting the size of particles

[19]

[0235] A medical calcium phosphate composition, characterized in that it satisfies all of the conditions (V1) to (V3) below, and at least one condition selected from the group consisting of (V4) to (V10), with (V11) or (V12) as optional conditions.

[0236] (V1) has a volume of 10 -12 m 3 above.

[0237] (V2) The acid-dissolved residue is less than 1% by mass.

[0238] (V3) is a substantially pure calcium phosphate composition selected from the group consisting of carbonate apatite, apatite containing HPO4 groups, tricalcium phosphate, leucite, and dicalcium phosphate.

[0239] (V4) A honeycomb structure having multiple through-holes extending in a unidirectional direction (excluding honeycomb structures that do not meet any of the following conditions: composed of tricalcium phosphate, and having a pore volume of 0.01 cm³ relative to the mass of the honeycomb structure as determined by mercury porosimetry). 3 / g or more; the diameter of the circle passing through the two ends and the center of any through hole is 1cm or more and less than 50cm; the arithmetic mean roughness (Ra) of the partition wall surface in the direction of the through hole in the honeycomb structure is 0.7μm or more.

[0240] (V5) is a particle-bonded porous body formed by the bonding of multiple particles with a maximum diameter of 50 μm to 500 μm, possessing multiple through pores extending in multiple directions. Furthermore, the pore volume of this particle-bonded porous body with a diameter of 10 μm or less, as determined by mercury porosimetry, is 0.05 cm³. 3 / g or more.

[0241] (V6) is a porous body with aggregated pores having a maximum diameter of 50 μm to 400 μm within the overall composition of a medical application, but excluding pores with a maximum diameter of 800 μm or more. Furthermore, the pore volume of this particle-bonded porous body with a diameter of 10 μm or less, as determined by mercury porosimetry, is 0.05 cm³. 3 / g or more (excluding cases where the composition is tricalcium phosphate).

[0242] (V7) In mercury porosimetry, the pore volume with a pore size of 1 μm or more and 6 μm or less is 5% or more relative to the pore volume with a pore size of 6 μm or less.

[0243] (V8) The maximum compressive strength obtained in any direction is greater than or equal to the reference compressive strength [S] calculated by the following formula (wherein, excluding honeycomb structures having multiple through holes extending in one direction, and pore volumes of 0.02 cm³ with a pore diameter of 10 μm or less relative to the mass of the honeycomb structure in mercury porosimetry determination). 3 The following are examples of / g.

[0244] S = S0 × C × exp(-b × P)

[0245] (Where, S0 and b are constants, S0 is 500, b is 0.068, C is a constant determined according to the composition, which is 1 in the case of carbonate apatite or apatite containing HPO4 groups or tricalcium phosphate, 0.5 in the case of leucobrycete, and 0.1 in the case of dicalcium phosphate, and P is the percentage of porosity of the composition.)

[0246] (V9) Honeycomb structure particles with a minor diameter of 1 mm or more and less than 5 mm, and which do not have the following points in the projection diagram of the composition: points formed by drawing a circle with a radius of 0.2 mm from any point on the perimeter line of the projection diagram, and forming a triangle with three points where the circle intersects the perimeter line of the projection diagram, and the angle with any point on the perimeter line of the projection diagram as the vertex is 90° or less.

[0247] (V10) Multiple composition particles are connected by fibers.

[0248] (V11) is composed of apatite with a carbonate content of 10% or more by mass.

[0249] (V12) is composed of apatite with a carbonate content of less than 10% by mass.

[20]

[0251] A medical calcium phosphate composition, characterized in that it satisfies (AG1) or (AG2) below, with (AG3) to (AG10) below as optional conditions.

[0252] (AG1) is composed of one of the following groups: carbonate apatite, apatite containing HPO4 groups, leucobite, and dicalcium phosphate, and has a volume of 10. -12 m 3 The particles or blocks mentioned above contain more than 0.01% by mass and less than 3% by mass of silver or silver compounds.

[0253] (AG2) comprises one of the following groups: hydroxyapatite sintered body, tricalcium phosphate sintered body, carbonate apatite, apatite containing HPO4 groups, leucobite, and dicalcium phosphate, and in a volume of 10 -12 m 3 The particles or blocks mentioned above contain silver phosphate crystals bonded to the surface of calcium phosphate, and the silver phosphate content is more than 0.01% by mass and less than 3% by mass.

[0254] (AG3) The aforementioned silver compound is silver phosphate.

[0255] (AG4) The calcium phosphate composition contains silver or a silver compound in the surface and interior portions, wherein the ratio of the silver concentration in the surface portion to the silver concentration in the portion at least 50 μm from the surface toward the center is 1.2 or more.

[0256] (AG5) is a honeycomb structure with multiple through holes extending in one direction.

[0257] (AG6) is a particle-bonded porous body formed by the combination of multiple particles with a maximum diameter length of 50μm to 500μm, and having multiple through holes extending in multiple directions.

[0258] (AG7) is a porous material with aggregated pores having a maximum diameter length of 50 μm to 400 μm in the whole medical composition, but without pores having a maximum diameter length of 800 μm or more.

[0259] (AG8) In mercury porosimetry, the pore volume with a pore size of 1 μm or more and 6 μm or less is 5% or more relative to the pore volume with a pore size of 6 μm or less.

[0260] (AG9) The maximum compressive strength obtained in any direction is greater than or equal to the reference compressive strength [S] calculated by the following formula.

[0261] S = S0 × C × exp(-b × P)

[0262] (Where, S0 and b are constants, S0 is 500, b is 0.068, C is a constant determined according to the composition, which is 1 in the case of carbonate apatite or apatite containing HPO4 groups, 0.5 in the case of white phosphogypsum, 0.1 in the case of dicalcium phosphate, and 2 in the case of hydroxyapatite sintered body and tricalcium phosphate sintered body, and P is the percentage of porosity of the composition.)

[0263] (AG10) Honeycomb structure particles with a minor diameter of 1 mm or more and less than 5 mm, and which do not have the following points in the projection diagram of the composition: the points are the points of triangles formed by drawing a circle with a radius of 0.2 mm from any point on the perimeter line of the projection diagram, and the angle of the triangle formed by the intersection of the circle and the perimeter line of the projection diagram with any point on the perimeter line of the projection diagram as the vertex is 90° or less. [twenty one]

[0265] The medical calcium phosphate composition as described in

[19] or

[20] is characterized in that it satisfies at least one of the following conditions (W1) to (W7).

[0266] (W1) is a honeycomb structure with multiple through-holes extending in one direction, and in mercury porosimetry, the pore volume with a pore diameter of less than 10 μm relative to the mass of the honeycomb structure is 0.01 cm³. 3 / g or more.

[0267] (W2) is a honeycomb structure having multiple through holes extending in one direction, and the diameter of the circle passing through the two ends and the center of any one through hole is more than 1 cm and less than 50 cm.

[0268] (W3) is a honeycomb structure, and the arithmetic mean roughness (Ra) of the partition surface in the direction of the through hole is greater than 0.7 μm.

[0269] (W4) is an aggregate of calcium phosphate with an average particle size of more than 2 μm and less than 8 μm.

[0270] (W5) is an aggregate of calcium phosphate with a sphericity of 0.9 or higher.

[0271] (W6)Mg content is 5×10 -4 3×10 of the above % by mass -3 Less than % of the mass.

[0272] (W7)Sr content is 3×10 -3 1.5 × 10⁻⁶ (by weight) or more -2 Less than % of the mass. [twenty two]

[0274] A method for manufacturing a medical calcium phosphate composition, characterized in that the following conditions (AH1) or (AH2) are met, and (AH3) to (AH9) are optional conditions.

[0275] (AH1) uses silver or a silver compound containing 0.01% to 3% by mass, and is composed of one selected from the group consisting of calcium carbonate, calcium hydroxide, calcium oxide, calcium sulfate, and calcium hydrogen phosphate, and has a volume of 10. -12 m 3 The above-mentioned granular or block-shaped calcium raw material composition,

[0276] Furthermore, when the raw material calcium composition is composed of a substance other than calcium carbonate, the process includes the step of imparting a carbonate group to the composition.

[0277] Furthermore, it includes a process of exposing the sample to an aqueous solution of phosphate or a mixed aqueous solution of phosphate and magnesium salt, thereby converting its composition to include silver or silver compounds, selected from the group consisting of carbonate apatite, apatite containing HPO4 groups, leucobrycete, and dicalcium phosphate.

[0278] (AH2) includes the step of exposing a raw calcium composition to an aqueous solution containing silver ions to form silver phosphate in the raw calcium composition, wherein the raw calcium composition is selected from the group consisting of apatite, tricalcium phosphate, leucite, octacalcium phosphate, and calcium hydrogen phosphate, and is in a volume of 10 -12 m 3 The above particles or blocks.

[0279] (AH3) includes the steps of exposing a raw calcium compound consisting of calcium phosphate to a first aqueous solution containing silver ions to form silver phosphate in the raw calcium composition, and then exposing it to a second aqueous solution with a higher concentration of silver ions than the first aqueous solution.

[0280] (AH4) The calcium raw material composition is a honeycomb structure with multiple through holes extending in one direction.

[0281] (AH5) The raw material calcium composition is a particle-bonded porous body formed by combining multiple particles with a maximum diameter length of 50 μm to 500 μm, and having multiple through pores extending in multiple directions.

[0282] (AH6) is a porous material composed of calcium raw materials that contains multiple pores with a maximum diameter length of 50 μm to 400 μm in the whole medical composition, but does not contain pores with a maximum diameter length of 800 μm or more.

[0283] (AH7) A raw material calcium composition used in mercury porosimetry determination, having a pore size of 1 μm or more and a pore volume of 6 μm or less relative to the pore volume of 6 μm or less.

[0284] (AH8) uses a raw calcium composition whose maximum compressive strength obtained in any direction is greater than the reference compressive strength [S] calculated by the following formula.

[0285] S = S0 × C × exp(-b × P)

[0286] (Where, S0 and b are constants, S0 is 500, b is 0.068, C is a constant determined according to the composition, which is 1 in the case of carbonate apatite or apatite containing HPO4 groups, 0.5 in the case of white phosphogypsum, 0.1 in the case of dicalcium phosphate, and 2 in the other cases, and P is the percentage of porosity of the composition.)

[0287] (AH9) is used as a raw material calcium composition. The honeycomb structure particles have a minor diameter of 1 mm or more and less than 5 mm and do not have the following points in the projection diagram of the composition. The points are the triangles formed by drawing a circle with a radius of 0.2 mm from any point on the perimeter line of the projection diagram and the intersection of the circle with the perimeter line of the projection diagram, and the angle with any point on the perimeter line of the projection diagram as the vertex is 90° or less. [twenty three]

[0289] The method for manufacturing a medical calcium phosphate composition according to any one of

[19] to

[21] is characterized in that it satisfies any one of the following conditions (AI1) to (AI4).

[0290] (AI1) Use calcium carbonate powder with an average particle size of 2 μm to 8 μm.

[0291] (AI2) Use calcium carbonate powder with a sphericity of 0.9 or higher.

[0292] (AI3) uses a Mg content of 5×10 -4 3×10 of the above % by mass-3 Calcium carbonate powder with a mass percentage of less than 5%.

[0293] (AI4) uses an Sr content of 3×10 -3 1.5 × 10⁻⁶ (by weight) or more -2 Calcium carbonate powder with a mass percentage of less than 5%. [twenty four]

[0295] A method for manufacturing a medical calcium phosphate composition, characterized in that a phosphoric acid component is imparted to the medical calcium carbonate composition described in any one of [1] to [4], or to a medical calcium carbonate composition manufactured by any one of the manufacturing methods described in any one of [5] to

[16] , thereby manufacturing the medical calcium phosphate composition described in any one of

[19] to

[21] , wherein in the manufacturing method,

[0296] The aforementioned medical calcium carbonate composition is impregnated in at least one aqueous solution selected from the group consisting of (X1) to (X5) to impart a phosphoric acid component to the medical calcium carbonate composition.

[0297] (X1) An aqueous solution containing phosphoric acid with a pH of 8.5 or higher.

[0298] (X2) An aqueous solution containing phosphoric acid with a pH less than 8.5.

[0299] (X3) An aqueous solution containing both phosphoric acid and carbonic acid at a concentration of less than 0.5 moles, with a pH of 8.5 or higher.

[0300] (X4) An aqueous solution containing both phosphoric acid and carbonic acid at a concentration of less than 0.5 moles, with a pH less than 8.5.

[0301] (X5) An aqueous solution containing both phosphoric acid and magnesium.

[25]

[0303] A method for manufacturing a medical calcium phosphate composition, characterized in that a phosphoric acid component is imparted to the medical calcium carbonate composition described in any one of [1] to [4], or to a medical calcium carbonate composition manufactured by any one of the manufacturing methods described in any one of [5] to

[16] , thereby manufacturing the medical calcium phosphate composition described in any one of

[19] to

[21] , wherein in the manufacturing method,

[0304] A process comprising a step of making the aforementioned medical calcium carbonate composition satisfy at least one condition selected from the group consisting of (Y1) to (Y6).

[0305] (Y1) A process of replacing part or all of the gas in the pores of a medical calcium carbonate composition that has been impregnated in an aqueous solution containing phosphoric acid with an aqueous solution containing phosphoric acid.

[0306] (Y2) A process of applying vibration to a medical calcium carbonate composition impregnated in an aqueous solution containing phosphoric acid, thereby replacing part or all of the gas in the pores of the medical calcium carbonate composition with the aqueous solution containing phosphoric acid.

[0307] (Y3) A process of flowing an aqueous solution containing phosphoric acid around the medical calcium carbonate composition to replace part or all of the gas in the internal pores of the medical calcium carbonate composition with an aqueous solution containing phosphoric acid.

[0308] (Y4) A process of degassing a container containing an aqueous solution of phosphoric acid impregnated with a medical-grade calcium carbonate composition under reduced pressure, thereby replacing part or all of the gas in the pores of the medical-grade calcium carbonate composition with the aqueous solution containing phosphoric acid.

[0309] (Y5) A process of replacing part or all of the gas in the pores of a medical-grade calcium carbonate composition with a gas that has a higher solubility in an aqueous solution containing phosphoric acid than air.

[0310] (Y6) A process of replacing part or all of the gas in the pores of a medical calcium carbonate composition with a solvent having a contact angle smaller than that of water and a boiling point lower than that of water.

[26]

[0312] A method for manufacturing a medical calcium phosphate composition, characterized in that the following steps (Z1) to (Z4), or (Z1), (Z3), (Z4), or (Z1), (Z3) are carried out continuously in the order described, and all are carried out in the same container.

[0313] (Z1) The process of imparting carbonic acid to a raw calcium composition to manufacture a medical-grade calcium carbonate composition.

[0314] (Z2) Cleaning process for medical-grade calcium carbonate composition

[0315] (Z3) Process of imparting phosphoric acid component to medical calcium carbonate composition

[0316] (Z4) Cleaning process for medical-grade calcium phosphate composition

[27]

[0318] A medical calcium hydroxide composition, characterized in that it satisfies all of the conditions below (AB1) to (AB3) and at least one condition selected from the group consisting of (AB4) to (AB8).

[0319] (AB1) has a volume of 10. -12 m 3 above.

[0320] (AB2) The acid-dissolved residue is less than 1% by mass.

[0321] (AB3) is a medical composition that is essentially pure calcium hydroxide.

[0322] (AB4) A honeycomb structure with multiple through holes extending in one direction.

[0323] (AB5) is a particle-bonded porous body formed by the combination of multiple particles with a maximum diameter length of 50μm to 500μm, and having multiple through holes extending in multiple directions.

[0324] (AB6) is a porous material with aggregated pores having a maximum diameter length of 50 μm to 400 μm in the whole medical composition, but not including pores with a maximum diameter length of 800 μm or more.

[0325] (AB7) Honeycomb structure particles with a minor diameter of 1 mm or more and less than 5 mm, and which do not have the following points in the projection diagram of the composition: the points are the points of triangles formed by drawing a circle with a radius of 0.2 mm from any point on the perimeter line of the projection diagram, and the angle of the triangle formed by the intersection of the circle and the perimeter line of the projection diagram with any point on the perimeter line of the projection diagram as the vertex is 90° or less.

[0326] (AB8) Multiple composition particles are connected by fibers.

[28]

[0328] A method for manufacturing a medical calcium hydroxide composition, characterized in that it is a method for manufacturing a medical calcium hydroxide composition that satisfies the aforementioned conditions (AB4)

[27] , wherein in the manufacturing method,

[0329] The raw material calcium composition is calcium hydroxide, and one of the following (AD1) and selected from (AD2) to (AD5) is a required step, and (AD6) to (AD8) are optional steps.

[0330] (AD1) Extrusion process

[0331] A calcium composition containing polymer materials is extruded through a mold used to form a honeycomb structure to produce a volume of 3 × 10⁻⁶. -11 m 3 The above process, and the process of constructing a raw material honeycomb structure with multiple through holes extending in one direction.

[0332] (AD2) Degreasing process

[0333] The process involves degreasing the porous calcium hydroxide containing polymer materials by dissolving the residue in acid to a concentration of less than 1% by mass.

[0334] (AD3) via the calcium oxide hydration process

[0335] The process involves degreasing a porous calcium hydroxide containing polymer materials by dissolving the residue in acid to a concentration of less than 1% by mass, thus producing a porous calcium oxide. The process then involves hydrating the porous calcium oxide to produce a porous calcium hydroxide.

[0336] (AD4) via the hydration process of calcium carbonate and calcium oxide

[0337] Calcium hydroxide containing polymeric materials is heat-treated in the presence of carbon dioxide to produce porous calcium carbonate containing polymeric materials. Then, the residue is degreased by acid dissolution to less than 1% by mass, producing porous calcium oxide. Finally, the porous calcium oxide is hydrated to produce porous calcium hydroxide through a carbonation-degreasing and calcium oxide hydration process.

[0338] (AD5) Manufacturing process starting from calcium carbonate porous bodies

[0339] The process involves degreasing a porous calcium carbonate containing polymer materials by dissolving the residue in acid to a concentration of less than 1% by mass, thus producing a porous calcium oxide. The porous calcium oxide is then hydrated to produce a porous calcium hydroxide.

[0340] (AD6) Molding process after extrusion

[0341] The process involves softening a honeycomb structure composed of a calcium-based raw material containing polymer materials through heat treatment, then subjecting it to pressure and molding it into the desired shape.

[0342] (AD7) External peripheral sidewall removal process

[0343] The process of removing the outer peripheral sidewalls after the extrusion process or the molding process following the extrusion process, and before the degreasing and carbonation process.

[0344] (AD8) Molding process after removing the outer peripheral sidewall

[0345] After the outer peripheral sidewall removal process, the honeycomb structure, composed of a calcium-based raw material containing polymer materials, is softened by heat treatment and then subjected to pressure to be molded into the desired shape.

[29]

[0347] A method for manufacturing a medical calcium hydroxide composition, characterized in that it is a method for manufacturing a medical calcium hydroxide composition that satisfies the aforementioned conditions (AB5)

[27] , wherein in the manufacturing method,

[0348] The following (AE1) and (AE2) and at least one of the above (AD2) to (AD5) are required steps.

[0349] (AE1) Introduction Process

[0350] With a volume of 10 -12 m 3 The above steps involve loading calcium hydroxide granules containing polymeric materials into the reaction vessel.

[0351] (AE2) Particle bonding process

[0352] A volume of 3 × 10⁻⁶ is manufactured by any one of the following steps: heat-treating the particles inside the reaction vessel to soften and fuse their surfaces together; dissolving the surface of the particles to bond their surfaces together; or using a plasticizer to fuse the surfaces of the particles together. -11 m 3 The process of forming a particle-bonded porous body with multiple through-holes extending in multiple directions by combining multiple particles with a maximum diameter length of 50μm to 500μm.

[0353] (AD2) Degreasing process

[0354] The process involves degreasing the porous calcium hydroxide containing polymer materials by dissolving the residue in acid to a concentration of less than 1% by mass.

[0355] (AD3) via the calcium oxide hydration process

[0356] The process involves degreasing a porous calcium hydroxide containing polymer materials by dissolving the residue in acid to a concentration of less than 1% by mass, thus producing a porous calcium oxide. The process then involves hydrating the porous calcium oxide to produce a porous calcium hydroxide.

[0357] (AD4) via the hydration process of calcium carbonate and calcium oxide

[0358] Calcium hydroxide containing polymeric materials is heat-treated in the presence of carbon dioxide to produce porous calcium carbonate containing polymeric materials. Then, the residue is degreased by acid dissolution to less than 1% by mass, producing porous calcium oxide. Finally, the porous calcium oxide is hydrated to produce porous calcium hydroxide through a carbonation-degreasing and calcium oxide hydration process.

[0359] (AD5) From the manufacturing process of calcium carbonate porous bodies

[0360] The process involves degreasing a porous calcium carbonate containing polymer materials by dissolving the residue in acid to a concentration of less than 1% by mass, thus producing a porous calcium oxide. The porous calcium oxide is then hydrated to produce a porous calcium hydroxide.

[30]

[0362] A method for manufacturing a medical calcium hydroxide composition, characterized in that it is a method for manufacturing the medical calcium hydroxide composition described in

[27] using porous calcium hydroxide or porous calcium carbonate as raw materials, wherein in the manufacturing method,

[0363] Calcium hydroxide porous bodies or calcium carbonate porous bodies are converted into calcium oxide porous bodies, and then the calcium oxide porous bodies are hydrated to produce calcium hydroxide porous bodies.

[31]

[0365] The method for manufacturing a medical calcium composition as described in any one of [9] to

[11] ,

[14] and

[29] is characterized in that, in the aforementioned introduction sealing step or introduction step, at least one of the following conditions (AF1) to (AF3) is satisfied.

[0366] The sphericity of (AF1) particles is 0.9 or higher.

[0367] (AF2) particles are hollow.

[0368] (AF3) Particles with a loose volume of more than 105% of the reaction vessel volume are loaded into the reaction vessel.

[32]

[0370] The kit for bone defect reconstruction therapy comprises a solid portion containing aragonite and tricalcium alpha-phosphate, and a solution portion containing phosphate. When the solid portion and the solution portion are mixed, carbonate apatite is formed and solidified.

[33]

[0372] The bone defect reconstruction treatment kit as described in

[32] is characterized in that the content of aragonite in the aforementioned solid part is more than 10% by mass and less than 60% by mass.

[34]

[0374] The bone defect reconstruction treatment kit as described in any one of

[32] or

[33] is characterized in that the aforementioned solution portion contains at least one of an acid having multiple carboxyl groups, a bisulfite, a cellulose derivative, a dextran sulfate, a chondroitin sulfate, an alginate, and glucomannan.

[35]

[0376] The bone defect reconstruction treatment kit as described in

[32] to

[34] is characterized in that the aforementioned solid part contains a volume of 10 -12 m 3 The above are garnets.

[36]

[0378] The bone defect reconstruction treatment kit as described in

[32] to

[34] is characterized in that the average particle size of the aforementioned aragonite is less than 6 μm. Attached Figure Description

[0379] [ Figure 1 [This is a schematic diagram of a honeycomb structure with outer peripheral sidewalls.]

[0380] [ Figure 2 [This refers to the pore distribution determination results based on mercury intrusion porosimetry for the medical calcite composition manufactured in Example 7 at a final temperature of 480°C.]

[0381] [ Figure 3 [Image shows the powder X-ray diffraction (XRD) pattern of the medical aragonite composition involved in Example 1.]

[0382] [ Figure 4 [Image shows the XRD pattern of the medical carbonate apatite composition involved in Example 1.]

[0383] [ Figure 5 [Image is an electron microscope (SEM) image of the honeycomb structure involved in Example 7.]

[0384] [ Figure 6 [This refers to the particle size distribution analysis results involved in Example 8.]

[0385] [ Figure 7 [Image of pathological tissue during histopathological examination using the medical carbonate apatite honeycomb structure described in Example 9.]

[0386] [ Figure 8 [Image is a SEM image of the medical carbonate apatite honeycomb structure involved in Example 12.]

[0387] [ Figure 9 [Image of pathological tissue from a pathological histological examination at week 4 of implantation of the medical carbonate apatite honeycomb structure involved in Example 14.]

[0388] [ Figure 10 [Image of pathological tissue during histopathological examination of the medical carbonate apatite honeycomb structure involved in Example 14 at week 12.]

[0389] [ Figure 11 [Images are pathological tissue images from the 4th and 12th weeks after implantation of the medical carbonate apatite composition of Example 15 and the hydroxyapatite composition of Comparative Example 10.]

[0390] [ Figure 12 [Image is a SEM image of the medical spheroidal porous body involved in Example 16.]

[0391] [ Figure 13[Image of pathological tissue from a pathological histological examination at week 4 of implantation of the medical carbonate porous body involved in Example 16.]

[0392] [ Figure 14 [Image is a SEM image of the porous calcite material for medical use involved in Example 17.]

[0393] [ Figure 15 [Image is a SEM image of the medical carbonate apatite honeycomb structure involved in Example 22.]

[0394] [ Figure 16 [Image of pathological tissue from a pathological histological examination at week 4 of implantation of the medical carbonate apatite honeycomb structure involved in Example 22.]

[0395] [ Figure 17 [Image is a SEM image of the medical carbonate apatite honeycomb structure involved in Example 24.] Detailed Implementation

[0396] (Definition of the term)

[0397] The terms used in this invention are defined as follows.

[0398] The "medical calcium carbonate composition" referred to in this invention is a calcium carbonate composition that can be used as a medical composition (medical material) or a calcium carbonate composition that can be used as a raw material for a medical composition. Bone filling materials and drug delivery carriers implanted in biological tissues are, of course, medical materials, but cell culture scaffolds used outside biological tissues are also included in the category of medical materials. It should be noted that when the composition is porous, it is sometimes described as a porous medical calcium carbonate composition; when the porous structure is a honeycomb structure, it is sometimes described as a honeycomb medical calcium carbonate composition, etc.

[0399] The "medical calcium carbonate composition" referred to in this invention is sometimes also used in the manufacture of other medical compositions. Due to this relationship, it sometimes contains pore-forming materials such as sodium chloride. Furthermore, to improve the workability of medical calcium carbonate and other medical compositions, fibers are sometimes used to bind the composition particles together. Such a material, containing these pore-forming materials and fibers, is also defined as a "medical calcium carbonate composition."

[0400] In this invention, the term "volume" refers to the loose volume, also known as the total volume. It includes the volume of pores and is also called loose capacity or total volume.

[0401] In this invention, "spherulite," "aragonite," and "calcite" refer to various polymorphs of calcium carbonate crystals.

[0402] The "medical aragonite composition" referred to in this invention is a medical calcium carbonate composition containing 20% ​​by mass or more aragonite. Here, the mass of the pore-forming material and fibers is excluded from the calculation of the aragonite content.

[0403] The contents of aragonite and calcite in the medical calcium carbonate composition were calculated by the respective peak area ratios in powder X-ray diffraction (XRD) analysis using the method described later.

[0404] The "medical calcium phosphate composition" mentioned in this invention refers to a calcium phosphate composition that can be used in medicine as an artificial bone filling material, etc.

[0405] In this invention, "calcium phosphate" refers to a compound comprising phosphoric acid and calcium, such as condensed calcium phosphate compounds like orthophosphate, calcium metaphosphate, amorphous calcium phosphate, and calcium pyrophosphate. Orthophosphate is a salt of orthophosphate and calcium. Examples include tetracalcium phosphate, apatite containing hydroxyapatite and carbonate apatite, tricalcium α-phosphate, tricalcium β-phosphate, and calcium hydrogen phosphate. It should be noted that tricalcium β-phosphate sometimes includes leucobrine, but in this invention, substances without HPO4 are distinguished as tricalcium phosphate, and substances containing HPO4 are distinguished as leucobrine. Tricalcium α-phosphate is sometimes abbreviated as αTCP, and tricalcium β-phosphate is sometimes abbreviated as βTCP.

[0406] The "medical apatite composition" mentioned in this invention is a type of medical calcium phosphate composition, which is an apatite composition used as a medical material in the form of artificial filler materials, etc.

[0407] Furthermore, the "medical-grade apatite composition" referred to in this invention is a apatite composition used for medical purposes. The carbonate group content of the apatite is not particularly limited, but is preferably 0.5% by mass or more, more preferably 3% by mass or more, and even more preferably 6% by mass or more. The apatite referred to in this invention is defined as apatite containing carbonate groups. Typically, it is apatite formed by replacing part or all of the phosphate groups or hydroxyl groups of calcium phosphate apatite with carbonate groups. It should be noted that, along with the substitution of carbonate groups, in order to achieve charge balance in the apatite, elements such as Na and K are often included in the crystal structure. In this invention, apatite formed by replacing a portion of the apatite with other elements or voids is also defined as apatite.

[0408] As the carbonate content increases, it becomes more susceptible to absorption by osteoclasts, accelerating bone replacement. However, depending on the condition, medical materials may be desired for slow bone replacement or for non-bone replacement. For medical materials where slow bone replacement is desired, carbonated apatite with a low carbonate content is ideal; for medical materials where non-bone replacement is desired, apatite with a carbonate content of less than 0.2% by mass is ideal.

[0409] The "honeycomb structure" referred to in this invention is a porous body described in Japanese Patent Application Publication Nos. 2004-298407 and 2005-152006, which has a plurality of through holes with polygonal or circular cross-sectional shapes extending in one direction. These through holes are arranged substantially without gaps through partitions, but some through holes may be missing.

[0410] It should be noted that the term "unidirectional" in this invention is not limited to a straight line, but refers to substantially the same direction. Although the through holes of the curved honeycomb structure described later are not one-dimensional, they are honeycomb structures with a shape having multiple through holes extending substantially in the same direction.

[0411] Here, use Figure 1 An example of the honeycomb structure of the present invention will be described. For example... Figure 1 As shown, the honeycomb structure 14 is a structure having a plurality of through holes 11 extending in one direction and partition walls 12 separating the through holes. The honeycomb structure includes a honeycomb structure having an outer peripheral sidewall 13 surrounding the honeycomb structure portion formed by the through holes, and a honeycomb structure having part or all of the outer peripheral sidewall removed, but both are honeycomb structures.

[0412] The mercury intrusion porosimetry method described in this invention is one type of pore distribution determination method. It involves applying pressure to allow the mercury to penetrate the fine pores of the powder, utilizing the high surface tension of mercury. The pore distribution is then determined by the pressure and the amount of mercury intruded. It should be noted that in this invention, the advancing and receding contact angles between the mercury and the material are set to 130°, and the surface tension of the mercury is set to 485 mN / m for the pore size calculation.

[0413] To visualize the pore distribution, a graph is shown that plots the common logarithm of the differential pore volume relative to the pore diameter at the measurement point. The pore volume is calculated as the difference between the cumulative data of mercury injected at different pore diameters.

[0414] The fine pore size is sometimes also called the pore diameter, but it is basically unrelated to the shape of the pore. It is a value calculated based on the results of mercury intrusion porosimetry analysis, assuming that mercury is pressed into a cylindrical pore.

[0415] In this invention, the "average particle size" refers to the particle size that accounts for 50% of the cumulative particle size distribution determined by laser diffraction and scattering. The powder is dispersed in 100 mL of distilled water and cleaned for 30 seconds using an ultrasonic cleaner with a frequency of 45 kHz-100 W. The particle size is then measured within one minute.

[0416] The "surface roughness (arithmetic mean roughness Ra)" mentioned in this invention refers to the surface roughness (arithmetic mean roughness Ra) measured using a 3D laser microscope.

[0417] The "sphericity" referred to in this invention is Wadell's practical sphericity. Wadell's practical sphericity is the value obtained by dividing the diameter of the circle with the same projected area as the material by the diameter of the smallest circle circumscribed to the projected image of the material.

[0418] In this invention, the so-called "compressive strength" is defined as follows: the value obtained by dividing the original cross-sectional area of ​​the cylindrical test specimen supplied for the compression test by the maximum load, with the crosshead speed at 10 mm per minute. In this invention, the specimen is not cylindrical, and the specimen volume is 1 × 10⁻⁶. -8 m 3 In the above cases, the specimen is processed into a cylindrical shape for compression testing. When the specimen is not cylindrical and its volume is less than 1 × 10⁻⁶, the compression test is performed. -8 m 3 In this case, the area of ​​the projected image of the sample is taken as the original cross-sectional area of ​​the test piece.

[0419] It should be noted that the medical calcium carbonate composition of the present invention is sometimes anisotropic. Anisotropic materials have different compressive strengths depending on the direction. In the present invention, the maximum compressive strength obtained in any direction is defined as the compressive strength of the composition.

[0420] Furthermore, since medical calcium carbonate compositions and the like are ceramic materials, indirect tensile strength can also be measured, and five times the indirect tensile strength can be taken as the compressive strength. If the compressive strength differs from five times the indirect tensile strength, the higher value is taken as the compressive strength value in this invention.

[0421] The gas pressure used in this invention is an absolute pressure of 101.3 kPa near the sea surface, rather than a relative pressure based on atmospheric pressure. Therefore, at pressures above 101.3 kPa, the gas is pressurized relative to atmospheric pressure, and at pressures below 101.3 kPa, it is depressurized relative to atmospheric pressure.

[0422] In this invention, "aggregation" is defined as the aggregation of multiple objects. Pore aggregation refers to the aggregation of multiple pores, which may or may not be connected. Therefore, it is not necessary for the pores to be in contact with each other.

[0423] In this invention, the term "minor diameter" is a morphology-related term, defined as the size related to whether or not the material passes through a sieve. That is, a minor diameter of 1 mm or more but less than 5 mm is defined as a composition that passes through a sieve with a mesh size of 5 mm but not through a sieve with a mesh size of 1 mm.

[0424] In this invention, a "closed-system reaction vessel" is defined as a non-open-system reaction vessel. For example, when using carbon dioxide to carbonate calcium hydroxide powder in a reaction vessel to produce calcium carbonate, it is necessary to expose the calcium hydroxide powder to carbon dioxide. Carbonation performed using an open-system reaction vessel is considered when carbon dioxide is released from the reaction vessel into the atmosphere; carbonation performed using a closed-system reaction vessel is considered when carbon dioxide is not released from the reaction vessel into the atmosphere.

[0425] From this perspective, even if carbon dioxide is discharged from an outlet or the like, it is defined as carbonation performed in a closed-system reaction vessel if it is not released into the atmosphere. For example, if a pump or the like is used to circulate the carbon dioxide discharged from the outlet within the reaction vessel, it is defined as carbonation performed in a closed-system reaction vessel. Furthermore, if the reaction vessel is connected to a carbon dioxide storage cylinder or the like, it is also defined as carbonation performed in a closed-system reaction vessel.

[0426] In this invention, aqueous methanol, aqueous ethanol, etc., are simply expressed as the volume percentage of solvents other than water. For example, methanol containing 10% by volume of water is referred to as 90% methanol.

[0427] "Particles" are generally considered to be particles larger than powder, especially products obtained by agglomerating powder and shaping it into large particles. In this invention, "particles" also refer to particles larger than powder, particularly those with a short diameter of 50 μm to 500 μm (unspecified when volume or minor diameter is not specified), or particles with a minor diameter of 1 × 10⁻⁶ μm. -13 cm 3 Above 1×10 -7 cm 3 The particle of any of the following.

[0428] [I. Medical-grade calcium carbonate composition: necessary conditions]

[0429] First, let’s explain [1].

[0430] Regarding <(A) volume is 10 -12 m3 above. >

[0431] In the medical calcium carbonate composition of the present invention, the volume is 10 -12 m 3 The above are necessary conditions. Excellent tissue affinity in vivo is required for the medical composition, but both calcium carbonate powder and calcium phosphate powder trigger inflammatory responses. On the other hand, a volume of 10... -12 m 3 The above-mentioned medical calcium carbonate composition, or a product made from the above-mentioned medical calcium carbonate composition with a volume of 10 -12 m 3 The above-mentioned medical calcium phosphate compositions exhibit excellent tissue affinity.

[0432] When using a medical-grade calcium carbonate composition as a bone filler or a raw material for bone fillers, if the volume becomes 10 -11 m 3 The above, preferably 3×10 -11 m 3 The above-mentioned method, when filling the bone defect, facilitates the formation of interconnected pores suitable for cell invasion, and is therefore more preferable. If the volume becomes 10... -10 m 3 The above-mentioned method, when filling the bone defect, creates pores that are effective against tissue invasion, and is therefore further preferred. If the volume is 10... -9 m 3 The above features allow it to easily fill large bone defects, making it a particularly preferred choice in clinical practice.

[0433] There is no particular upper limit to the volume of the medical-grade calcium carbonate composition, but manufacturing takes time and the demand is low when the volume is large, so 10 is preferred. -3 m 3 the following.

[0434] Regarding <(B) acid-dissolved residue is less than 1% by mass>

[0435] (B) This is also related to the point that “as a medical composition, it is substantially pure calcium carbonate”. In particular, the requirement that the acid-dissolving residue be less than 1% by mass is a necessary condition and an extremely important factor related to the usefulness of the medical calcium carbonate composition.

[0436] This is because excellent tissue affinity and bioavailability are desired for the medical calcium carbonate composition of the present invention or for carbonated apatite manufactured from the medical calcium carbonate composition. In vivo, calcium carbonate, carbonated apatite, etc., are absorbed due to the weakly acidic environment formed by osteoclasts, etc. The presence of acid-dissolved residues is equivalent to non-absorption by osteoclasts, etc., and therefore is unsuitable as a medical composition.

[0437] Acid-dissolving residues become a problem when manufacturing medical calcium carbonate compositions from raw materials containing polymers. Since polymers are insoluble in acids, the presence of acid-dissolving residues carries the same implications as residues of the polymer or its decomposition products.

[0438] The acid dissolution residue is the residue left when calcium carbonate or the like is dissolved in hydrochloric acid of 1 mole concentration in an amount equal to 20 moles of the calcium carbonate or the like, and the dried mass relative to the mass of the calcium carbonate or the like is expressed as a percentage.

[0439] It is necessary that the acid-dissolved residue is less than 1% by mass, preferably less than 0.5% by mass, more preferably less than 0.3% by mass with less impact, and even more preferably less than 0.1% by mass with negligible impact. It is ideal that it is practically 0% by mass.

[0440] It should be noted that in cases where the calcium carbonate composition for medical use contains a pore-forming material or where multiple composition particles are connected by fibers, the pore-forming material and the fibers connecting the multiple composition particles are not considered as acid-dissolving residues. That is, a necessary condition of the present invention is that the acid-dissolving residue of the calcium carbonate composition, excluding the pore-forming material and the fibers connecting the multiple composition particles, is less than 1% by mass.

[0441] Regarding <(C), as a medicinal composition mainly formed from aragonite or calcite, it is substantially pure calcium carbonate.>

[0442] The medical calcium carbonate composition of the present invention is a medical material intended for medical use. Compositions containing impurities other than pore-forming materials and fibers connecting multiple composition particles cannot be used as medical materials. Therefore, natural materials are not included in this invention. Furthermore, calcium carbonate compositions manufactured using calcium oxide-containing coal ash discharged from boilers or slag produced in iron and steel manufacturing processes also contain impurities and are therefore not included in this invention. In studies of natural minerals, organic gels, silica-containing gels, metaphosphate gels, etc., are sometimes used; however, calcium carbonate compositions containing these substances also present problems with tissue affinity and are therefore not included in this invention.

[0443] In the medical calcium carbonate composition of the present invention, a necessary condition is that: as a medical calcium carbonate composition mainly formed of aragonite or calcite, it is substantially pure calcium carbonate composition, that is, it is substantially pure calcium carbonate composition, and its polymorph is mainly aragonite or calcite; it is required to be substantially free of impurities other than sodium, strontium, and magnesium. Here, in (C) of the present invention, the amount of impurities other than sodium, strontium, and magnesium is preferably 1% by mass or less, more preferably 0.5% by mass or less, and even more preferably 0.1% by mass or less. Ideally, it is completely free of impurities other than sodium, strontium, and magnesium.

[0444] It should be noted that in medical-grade calcium carbonate compositions, sodium, strontium, and magnesium differ from other impurities and are less likely to cause tissue damage. The mechanism is not fully understood, but invertebrates that live in seas containing sodium, strontium, and magnesium have chosen calcium carbonate containing these elements, thus, from an evolutionary perspective, it can be inferred that organisms capable of containing sodium, strontium, and magnesium have emerged. However, magnesium, strontium, and sodium are also impurities. In the "substantially pure calcium carbonate as a medical-grade composition" of this invention, their content is preferably 2% by mass or less, more preferably 1.0% by mass or less, and even more preferably 0.2% by mass or less.

[0445] It should be noted that, as described above, there are cases where the calcium carbonate composition for medical use contains pore-forming materials and fibers connecting the multiple composition particles. The pore-forming materials and fibers connecting the multiple composition particles are not considered impurities. That is, a necessary condition of the present invention is that the calcium carbonate composition, excluding the pore-forming materials and fibers connecting the multiple composition particles, is substantially pure calcium carbonate.

[0446] As described above, in the polymorphs of calcium carbonate, aragonite is present in addition to aragonite and calcite. Aragonite is essentially calcium carbonate, so even if it is present in mixture, it does not hinder the effect of the present invention. However, from the viewpoint of the reactivity of the medical composition manufactured using the medical calcium carbonate composition of the present invention as a raw material, the content of aragonite is preferably 20% by mass or less, more preferably 10% by mass or less, and even more preferably 5% by mass or less. That is, the present invention's "mainly formed of aragonite or calcite" means that the proportion of aragonite or calcite is preferably higher than 80% by mass, more preferably higher than 90% by mass, even more preferably higher than 95% by mass, and particularly preferably 100% by mass.

[0447] Furthermore, calcium hydroxide and calcium oxide react with carbon dioxide in the air over time to form calcium carbonate, so they do not need to be strictly excluded. Therefore, in the "substantially pure calcium carbonate composition as a medical calcium carbonate composition" of this invention, calcium hydroxide and calcium oxide are not considered impurities. However, it is also preferable that calcium hydroxide and calcium oxide are not present. Therefore, the content of calcium hydroxide and calcium oxide is preferably 3% by mass or less, more preferably 2% by mass or less, and even more preferably 1% by mass or less. Ideally, it should be completely free of calcium hydroxide and calcium oxide.

[0448] Regarding <(D) containing more than 20% by mass of aragonite.>

[0449] Calcium carbonate compositions containing metastable aragonite in calcium carbonate are preferred due to their high reactivity. While reactivity can be effectively improved even when the aragonite content is less than 20% by mass, the effect is limited; therefore, in this invention, aragonite content of 20% by mass or more is specified.

[0450] A content of aragonite of 20% by mass or more is a necessary condition; when it is 30% by mass or more, the active ingredient is close to a sufficient amount, and therefore it is preferred; when it is 50% by mass or more, the active ingredient is a sufficient amount, and therefore it is more preferred; when it is 80% by mass or more, the composition generally exhibits the properties of aragonite, and therefore it is further preferred; and when it is 90% by mass or more, it is particularly preferred.

[0451] It should be noted that, as mentioned above, since it is unrelated to reactivity, the mass of the pore-forming material and the fibers connecting the multiple composite particles are excluded from the calculation of the aragonite content.

[0452] Regarding <(E), it is a honeycomb structure with multiple through-holes extending in one direction, and in the fine pore distribution measurement based on mercury intrusion porosimetry, the fine pore volume with a pore diameter of 10 μm or less relative to the mass of the honeycomb structure is greater than 0.02 cm³. 3 / g. >

[0453] honeycomb structure such as Figure 1 As shown, it is formed by a partition wall, a solid part consisting of an outer peripheral sidewall, and a spatial part that serves as a through hole. Therefore, when the fine pore distribution is measured using the mercury porosimetry method, the fine pore distribution caused by the through hole can certainly be observed. Figure 2 An example is shown of the results of mercury intrusion porosimetry (MIP) determination of the pore size distribution of the medical calcium carbonate honeycomb structure of the present invention. It can be seen that in addition to the peak with a pore size of about 70 μm caused by the large pores of the honeycomb structure, there are also pores with a pore size of less than 1 μm caused by the micropores of the honeycomb septa.

[0454] There are no medical-grade calcium carbonate honeycomb structures with through-pores smaller than 10 μm. Therefore, pores with a fine pore size of less than 10 μm exist in the septa. Tissues and cells do not penetrate into pores with a fine pore size of less than 10 μm, so these pores have not been considered previously. However, tissue fluid and aqueous solutions can penetrate them. Therefore, it can be concluded that pores with a fine pore size of less than 10 μm play an important role in the biological reaction and in the process of imparting phosphate to the medical-grade calcium carbonate honeycomb structure to manufacture the medical-grade calcium phosphate honeycomb structure.

[0455] If the pore size relative to the mass of the honeycomb structure increases, the reactivity increases, but the mechanical strength decreases; therefore, a balance needs to be struck. From a reactivity perspective, the pore volume relative to the mass of the honeycomb structure, with a pore size of less than 10 μm, must be greater than 0.02 cm³. 3 / g, preferably 0.03cm 3 / g or more, more preferably 0.10cm 3 / g or more, further preferably 0.15cm 3 / g or higher. Furthermore, from the viewpoint of compressive strength, 0.15cm is preferred. 3 / g or less, more preferably 0.10cm 3 / g or less, more preferably 0.03cm 3 / g or less.

[0456] Regarding <(F), it is a particle-bonded porous body formed by the aggregation of multiple particles with a maximum diameter of 50 μm to 500 μm, possessing multiple through pores extending in multiple directions, and the pore volume of the particle-bonded porous body with a diameter of 10 μm or less, as determined by mercury porosimetry, is 0.05 cm³. 3 / g or more. >

[0457] Depending on the specific condition, porous materials with three-dimensional through-pores are sometimes desired. In the case of medical bone fillers, pore size is particularly important, as fatty tissue and other substances outside the bone can intrude into large pores; therefore, controlling pore size is crucial.

[0458] Particle-bonded porous bodies formed by the combination of multiple particles with a maximum diameter length of 50μm to 500μm and possessing multiple through-holes extending in multiple directions have the following characteristics: the permeability is as high as that of through-holes formed by a hexagonal dense-filled structure, and osteoblasts, osteoclasts, and bone tissue can easily move and conduct within them.

[0459] Furthermore, in the tissue replacement of this particle-bonded porous body, the fine pores of the granular portion play an important role. The pore volume of the granular portion, measured by mercury porosimetry, must be 0.05 cm³ for pores smaller than 10 μm in this particle-bonded porous body.3 / g or more, the preferred pore volume is 0.1cm³. 3 / g or more, preferably 0.2cm 3 / g or more, further preferably 0.3cm 3 / g or more.

[0460] Regarding <(G), it is a porous material with aggregated pores having a maximum diameter length of 50 μm to 400 μm, but not including pores with a maximum diameter length of 800 μm or more, in the overall medical composition. Furthermore, the pore volume of this porous material with a diameter of 10 μm or less, as determined by mercury porosimetry, is 0.05 cm³. 3 / g or more. >

[0461] The aforementioned particle-bonded porous bodies are extremely useful for bone filling materials from the viewpoint of permeability, but they generally have disadvantages such as low mechanical strength and difficulty in manufacturing. On the other hand, porous bodies with specific pores formed using pore-forming materials, for example, have poor permeability, but they are relatively easy to manufacture using polymeric pore-forming materials and have superior mechanical strength, making them useful as medical-grade calcium carbonate. Specifically, in porous bodies with aggregated pores, pores are aggregated through pore walls formed of calcium carbonate or through-holes formed on a portion of these pore walls. When the through-holes are completely continuous, it becomes a porous body with three-dimensional through-pores, which is particularly useful.

[0462] Furthermore, the stomatal size must be between 50 μm and 400 μm. This stomatal size is useful from the viewpoint of cell and tissue invasion. Preferably, the stomatal size is between 70 μm and 350 μm, more preferably between 90 μm and 300 μm, and even more preferably between 100 μm and 300 μm.

[0463] On the other hand, the absence of pores with a maximum diameter of 800 μm or more is also a necessary condition. As mentioned above, in large pores, adipose tissue moves, rather than bone tissue. Furthermore, compositions with large pores have lower mechanical strength.

[0464] It is also necessary that the pores with a maximum diameter of 800 μm or more are not included, but regarding the pore size to be excluded, it is preferable that the maximum diameter is 700 μm or more, and more preferably that the maximum diameter is 600 μm or more.

[0465] In addition, considering the balance of cell and tissue invasion, absorption and mechanical strength, the porosity is preferably 40% to 80% by volume, more preferably 45% to 78% by volume, and even more preferably 50% to 77% by volume.

[0466] Furthermore, in the tissue replacement of this pore-aggregate porous body, not only the pores themselves, but also the fine pores of calcium carbonate surrounding the pores play an important role. The volume of these fine pores, measured by mercury porosimetry for pores smaller than 10 μm in this pore-aggregate porous body, must be 0.05 cm³. 3 / g or more, the preferred pore volume is 0.1cm³. 3 / g or more, preferably 0.2cm 3 / g or more, further preferably 0.3cm 3 / g or more.

[0467] Porous bodies with aggregated pores are classified into those containing pore-forming materials and those without. In the case of porous bodies containing pore-forming materials, they are used directly as raw materials for manufacturing medical compositions and are removed during the manufacturing process; therefore, the pore-forming material portion is essentially pores. Thus, in the porosity calculation of this porous body, the pore-forming material is calculated as pores.

[0468] Regarding <(H) in mercury porosimetry determination, the ratio of the volume of pores with a diameter of 1 μm to 6 μm to the volume of pores with a diameter of 6 μm or less is 10% or more.

[0469] As mentioned above, for the reactivity of porous calcium carbonate, not only are large pores important, but micropores are also important. The absolute amount of micropores is also important, but sometimes a specific distribution of micropores is useful. That is, in mercury porosimetry, the ratio of the volume of micropores with a diameter of 1 μm or more and 6 μm or less to the volume of micropores with a diameter of 6 μm or less is preferably 10% or more. More preferably, the ratio is 15% or more, and even more preferably 20% or more.

[0470] Regarding <(I) the maximum compressive strength obtained in any direction is the reference compressive strength [S] calculated by the following formula (wherein, it does not include honeycomb structures having multiple through holes extending in one direction, and in the mercury porosimetry determination, the pore size is less than 10 μm relative to the mass of the honeycomb structure and the pore volume is 0.02 cm³). 3 The following are examples of / g.

[0471] S = S0 × C × exp(-b × P)

[0472] (Where, S0 and b are constants, S0 is 500, b is 0.068, C is a constant determined according to the polymorphism of calcium carbonate, which is 0.01 when containing more than 20% by mass of aragonite, and 1 when not containing more than 20% by mass of aragonite, and P is the percentage of porosity of the composition.)

[0473] As described above, the medical calcium carbonate composition of the present invention is preferably porous, and the higher the porosity, the higher its usefulness. On the other hand, as the porosity increases, the mechanical strength of the medical calcium carbonate decreases.

[0474] The relationship between mechanical strength [S] and the percentage of porosity [P] is known through empirical formulas (Duckworth formulas) such as S = S0exp(-bP), cited in academic journals such as the Journal of Biomedical Research, Volume 29, pp. 1537-1543, and the Journal of the American Ceramics Society, Volume 36, Issue 2, p. 68. Here, S0 is the mechanical strength of the compact body, and b is an empirical constant.

[0475] It should be noted that, as mentioned above, reactivity is also affected by composition; therefore, even compositions with low porosity can exhibit high reactivity depending on their composition. This component is set to C, and the requirements for compressive strength are corrected. In the case of containing 20% ​​by mass or more of highly reactive aragonite, it is set to 0.01; in the case of not containing 20% ​​by mass or more of aragonite, it is set to 1. Furthermore, P represents the percentage of porosity of the composition.

[0476] In addition, in this invention, reference is made to the values ​​reported in Volume 29, pp. 1537-1543 of the Journal of Biomedical Research, which is used as a similar ceramic, namely hydroxyapatite.

[0477] That is, S0 is 500, and b is 0.068. As for compressive strength, the higher the value, the better. Therefore, S0 is preferably 700, more preferably 900, and even more preferably 1000.

[0478] It should be noted that, in the case of a honeycomb structure with multiple through-holes extending in one direction, the pore volume with a pore diameter of less than 10 μm relative to the mass of the honeycomb structure, as determined by mercury porosimetry, is 0.02 cm³. 3 Cellular structures with a reactivity of less than / g are low and are therefore excluded from this invention.

[0479] Regarding honeycomb structure particles with a minor diameter of 1 mm or more and less than 5 mm, and which do not have the following points in the projection diagram of the composition: The points are points forming a triangle with three points where a circle of radius 0.2 mm is drawn from any point on the perimeter line of the projection diagram, and the triangle intersects the perimeter line of the projection diagram, with the angle of any point on the perimeter line of the projection diagram as the vertex being 90° or less.

[0480] This relates to the shape of the honeycomb structure particles, and is a condition related to compositions with smooth corners that do not damage surrounding tissues. Compositions with a minor diameter of less than 5 mm are sometimes used as particles to fill bone defects. In the medical calcium carbonate composition of the present invention, the honeycomb structure has high anisotropy. Therefore, if it is pulverized, it becomes spindle-shaped. When the minor diameter is less than 1 mm, the particles are fluid, so the sharp corners are not easily perpendicular to the periosteum and other surrounding tissues covering the defect. However, as the minor diameter increases, it becomes easier to damage surrounding tissues due to reasons such as the limited fluidity of the particles. In addition, if it is 5 mm or more, it is easier to prevent the formation of sharp angles. Therefore, it is sufficient to make the corners of the honeycomb structure particles with a minor diameter of 1 mm or more and less than 5 mm smooth. Specifically, particles with a minor diameter of 1 mm or more and less than 5 mm, and which do not contain the following points in the projection diagram of the composition: The point is a triangle formed by three points where a circle with a radius of 0.2 mm is drawn from any point on the perimeter line of the projection diagram, and the triangle intersects the perimeter line of the projection diagram at any point, with the angle of the triangle being 90° or less, using any point on the perimeter line of the projection diagram as its vertex. The minor diameter is defined based on whether it passes through a sieve. That is, a composition with a minor diameter of 1 mm or more and less than 5 mm is a composition that passes through a sieve with a mesh size of 5 mm but not through a sieve with a mesh size of 1 mm. The minor diameter is preferably 1 mm or more and less than 5 mm, more preferably 1.2 mm or more and less than 4 mm, and even more preferably 1.4 mm or more and less than 3 mm.

[0481] From the perspective of rounded corners, the aforementioned "points that do not form a triangle with three points and whose angle is less than 60° with any point of the perimeter line of the projection map as the vertex" is preferred. In terms of angle, it is more preferred to be less than 80°, and even more preferred to be less than 100°.

[0482] Similarly, in this honeycomb structure particle, not only does it not damage the shape of the particles surrounding the tissue, but the fine pores of the particles also play an important role in tissue response. The volume of these fine pores, preferably 0.02 cm³, is calculated using mercury porosimetry to measure the pore volume of the honeycomb structure particle below 10 μm. 3 / g or more, more preferably 0.05cm 3 / g or more, further preferably 0.1cm 3 / g or more.

[0483] Regarding <(K) multiple compositions being connected by fibers.>

[0484] Medical calcium carbonate compositions, or medical calcium phosphate compositions made from medical calcium carbonate compositions, are sometimes implanted in living organisms as bone fillers. However, when the composition is in the form of particles, implanting these particles into bone defects is cumbersome. Compositions obtained by connecting multiple composition particles with fibers, like beads, are more manipulable. From the viewpoint of tissue affinity and connection strength, it is more preferable for fibers to pass through the interior of the composition particles and connect multiple composition particles.

[0485] There are no particular restrictions on the size of the particles, as long as they are large enough to be connected by fibers. For example, particles with a minor diameter of 1 mm or more but less than 5 mm are preferred.

[0486] There is no limitation on the type of fiber, but in the case of medical compositions manufactured by a firing process, carbon fibers must be used for tissue compatibility and to prevent incineration. Alternatively, when a firing process is not performed, bioabsorbable fibers are preferred. Examples include polyglycolic acid, polylactic acid, polycaprolactone, and copolymers thereof.

[0487] In this composition, the pores also play an important role in tissue response. The volume of these pores, preferably greater than 0.02 cm³, is determined by mercury porosimetry for pores smaller than 10 μm. 3 / g, more preferably 0.05cm 3 / g or more, further preferably 0.1cm 3 / g or more.

[0488] In this invention, satisfying at least one of the groups selected from (D) to (K) is a necessary condition, but it is preferred to satisfy multiple conditions.

[0489] (The shape of the medical calcium carbonate composition)

[0490] The shape of the medical calcium carbonate composition of the present invention is not particularly limited. It can be any shape such as dense body, porous body, block, granules, plate, etc., but is particularly preferred to be the specific porous body described later.

[0491] [I. Medical Grade Calcium Carbonate Composition: Sintered Ornamentite]

[0492] Next, we will explain [2].

[0493] Aragonite is a polycrystalline form of highly reactive calcium carbonate, but it is a metastable phase and a low-temperature stable phase. Therefore, it was completely unexpected that aragonite could be sintered, and no aragonite sintered bodies have been found to date. However, as will be discussed later, it is known that medical-grade aragonite sintered bodies can be manufactured by pressing calcium carbonate powder containing more than 20% by mass of aragonite and then firing it.

[0494] The medical calcium carbonate composition of the present invention, and medical compositions manufactured using the composition as a raw material, are used in humid environments such as in vivo. A sintered body is an object formed from powder agglomeration. If water is applied to a powdered aragonite and rubbed, the powder becomes free; if immersed in water, the powder disintegrates from the powder and collapses, failing to maintain its shape. Therefore, in the present invention, the presence or absence of sintering in the medical aragonite sintered body is determined by the shape retention of the sintered body in water. The composition is immersed in 10 times its volume of calcium carbonate-saturated water in a glass container. The glass container is placed in an ultrasonic cleaner at 28 kHz and 75 W output power, and irradiated with ultrasound for 1 minute. If the dry weight of the composition is 95% or more relative to its dry weight before ultrasonic irradiation, the composition is determined to maintain its shape in water and is defined as a sintered body. It should be noted that in cases where part of the composition is damaged due to ultrasonic irradiation, the dry weight of the largest volume of the composition is used.

[0495] [I. Medical-grade calcium carbonate compositions: specific microstructure and composition]

[0496] Next, we will explain [3].

[0497] Considering the balance between compressive strength and reactivity, the following medical calcium carbonate composition is preferred: [1] or [2] the medical calcium carbonate composition, characterized in that calcium carbonate powders satisfying any one of the conditions selected from (AJ1) to (AJ4) are combined to form the calcium carbonate composition.

[0498] Larger average particle size leads to the formation of interconnected pores and thus higher reactivity, but also lower compressive strength. Furthermore, to maintain compressive strength while forming interconnected pores, particles with high sphericity are preferred because they approach the densest packing.

[0499] From these perspectives, the average particle size is preferably 2 μm or more and 8 μm or less, more preferably 3 μm or more and 7 μm or less, and even more preferably 4 μm or more and 6 μm or less. The sphericity is preferably 0.9 or more, more preferably 0.95 or more, and even more preferably 0.97 or more. It should be noted that the average particle size and sphericity are determined and calculated based on the grain boundaries of the calcium carbonate composition.

[0500] Furthermore, if the calcium carbonate composition is over-sintered, the interconnected pores cannot be maintained. Therefore, it is preferable to contain trace elements in the calcium carbonate particles that can control sintering properties. These elements should not be those that affect biocompatibility. From these perspectives, Mg and Sr are selected, with the Mg content preferably being 5 × 10⁻⁶. -4 3×10 of the above % by mass -3 Less than 1% by mass, more preferably 1×10-3 2.5 × 10⁻⁶ (by weight) or more -3 Less than 1% by mass, more preferably 1.5 × 10⁻⁶. -3 2.5 × 10⁻⁶ (by weight) or more -3 Less than % by mass. The Sr content is preferably 3 × 10⁻⁶. -3 1.5 × 10⁻⁶ (by weight) or more -2 Less than 10% by mass, more preferably 4×10 -3 1.3 × 10⁻⁶ (by weight) or more -2 Less than 5% by mass, more preferably 5×10 -3 1×10 of mass% or more -2 Less than % of the mass.

[0501] It is preferable to satisfy any one of the conditions (AJ1) to (AJ4), more preferably to satisfy multiple conditions, and even more preferably to satisfy all conditions.

[0502] [I: Medical grade calcium carbonate composition: curved honeycomb structure]

[0503] Next, we will explain [4].

[0504] In the aforementioned medical calcium carbonate composition that satisfies condition (E),

[0505] "The diameter of the circle passing through the two ends and the center of any through hole is more than 1 cm and less than 50 cm" is a specific condition related to the morphology of medical carbonate apatite honeycomb structures.

[0506] This includes bones that are not straight columns but curved columns. In bone reconstruction procedures, curved column-shaped medical calcium carbonate honeycomb structures are useful. This is because bone is conducted to the pores within the medical calcium carbonate honeycomb structure, and because even if a curved column-shaped honeycomb structure is manufactured by processing a straight column-shaped honeycomb structure, bone will not be conducted to the pores if the pores do not contact the bone.

[0507] Furthermore, when bone is constructed in a direction perpendicular to the bone surface, it is preferable that the through holes of the honeycomb structure do not open relative to the binding tissue surrounding the bone, but only relative to the bone surface. This is because the binding tissue cannot invade the honeycomb structure of the structure, and only bone tissue is conducted into the honeycomb structure. The honeycomb structure of this structure can be manufactured by bending the honeycomb structure and cutting it as needed so that the through holes open only on one side.

[0508] In cases where it is desirable to make the angle of the rising portion of the curved honeycomb structure small, it is useful to further bend the honeycomb structure along a direction that is not parallel to the surface formed by the circle passing through the two ends and the center of the through hole.

[0509] In a honeycomb structure, it is preferred that the diameter of the circle passing through the two ends and the center of any through hole be 1 cm or more and 50 cm or less. More preferably, the diameter of this circle is 2 cm or more and 20 cm or less, and even more preferably, the diameter of this circle is 3 cm or more and 10 cm or less.

[0510] [II. Method for manufacturing medical-grade calcium carbonate]

[0511] Next, the manufacturing process of the medical calcium carbonate composition of the present invention will be described.

[0512] It should be noted that the raw calcium composition may include pore-forming materials and fibers connecting multiple composition particles. Furthermore, pore-forming materials and fibers connecting multiple composition particles are excluded from calculations such as those involving aragonite content.

[0513] The pore-forming material is the material that is removed to form pores. The pore-forming material does not need to be removed during the manufacturing stage of the medical calcium carbonate composition; it can be removed during the stage of manufacturing other medical compositions using the medical calcium carbonate composition as a raw material. Examples include salts such as sodium chloride, potassium chloride, and disodium hydrogen phosphate, as well as acrylic polymer beads, but from the viewpoint of ease of removal, water-soluble inorganic materials are preferred.

[0514] For example, when sodium chloride is used as the pore-forming material and calcium hydroxide is used as the raw material calcium composition, the two are mixed and pressed into powder. Carbon dioxide is then introduced, causing the calcium hydroxide powder to transform into aragonite. Even when carbon dioxide is introduced into the calcium hydroxide, the sodium chloride does not react and is not removed. Sodium chloride, as the pore-forming material, is present in medical-grade aragonite blocks. For example, to manufacture medical-grade apatite blocks from these blocks, the aragonite is transformed into apatite through an impregnation process in an aqueous solution of disodium hydrogen phosphate, while the pore-forming material dissolves. As a result, a porous medical-grade apatite body is manufactured.

[0515] As described above, fibers are used to connect the particles of the composition in order to improve the operability of the composition. Since fibers are used to improve the operability of medical calcium carbonate granules, or medical calcium phosphate granules manufactured from the composition, they are preferably present within the particles of such granules.

[0516] [II. Method for manufacturing medical-grade calcium carbonate: (D) Ornamentite composition]

[0517] First, let’s explain [5].

[0518] For the manufacture of metastable aragonite compositions, the following manufacturing method is useful: by suppressing the formation of stable calcite, a metastable aragonite composition is relatively formed, thus suppressing the transformation from metastable aragonite to stable calcite. Organic matter suppresses the formation of stable calcite and relatively promotes the formation of aragonite (ammonia and ammonium salts, as inorganic substances, are also useful for suppressing the transformation to calcite, but due to simplicity, organic matter is used in the explanation).

[0519] Water plays a role in promoting both the carbonation of the calcium feedstock composition and the transformation from aragonite to calcite. Without water, the calcium feedstock composition is not ionized. Furthermore, carbon dioxide has limited solubility in organic solvents, and there is no possibility of carbon dioxide dissolving in water to form carbonate ions. In the presence of water, calcium ions formed from the calcium feedstock react with carbonate ions formed from carbon dioxide; therefore, water promotes the formation of calcium carbonate.

[0520] If carbon dioxide is introduced into the raw calcium composition, water is formed in the raw calcium composition. For example, in the process of exposing calcium hydroxide powder to carbon dioxide to manufacture aragonite, the same molar amount of water as aragonite is formed in the calcium hydroxide powder. Water is necessary for the formation of aragonite, but excessive water is undesirable for aragonite production because it promotes the phase transformation from the metastable aragonite to the stable calcite. In the manufacture of aragonite powder using calcium hydroxide powder as a raw material, water easily diffuses to the surrounding area and is therefore not a problem, but the object of the present invention is "(A) a volume of 10 -12 m 3 The above-mentioned medical calcium carbonate composition does not easily diffuse from the composition to the outside. Therefore, the process of draining the water formed in the raw calcium composition to the outside of the raw calcium composition becomes important.

[0521] A medical calcium carbonate composition that satisfies all of the conditions in (A) to (C) above, and condition (D) can be made to have a volume of 10 under specific conditions. -12 m 3 The above-mentioned raw material calcium composition (which may include pore-forming materials and fibers connecting multiple composition particles) is exposed to carbon dioxide or carbonate ions to manufacture the product.

[0522] That is, the process of “(D1) inhibiting the formation of calcite or the growth of calcite crystals and relatively promoting the formation of calcium carbonate other than calcite” is useful as a method for manufacturing a medical calcium carbonate composition that satisfies condition (D).

[0523] At least one of the group consisting of organic solvents, water-soluble organics, ammonia and ammonium salts inhibits the formation of calcite or the growth of calcite crystals. Therefore, the step of “(D2) exposing the raw calcium composition to carbon dioxide or carbonate ions and at least one of the group consisting of organic solvents, water-soluble organics, ammonia and ammonium salts” is preferred.

[0524] The reaction that forms a medical calcium carbonate composition satisfying condition (D) from the raw calcium composition must also take place inside the raw calcium composition. Therefore, it is sometimes preferable to add the aforementioned substance that inhibits the formation of calcite or the growth of calcite crystals to the raw calcium composition.

[0525] That is, the step of "(D3) exposing a raw calcium composition containing at least one of the group consisting of organic solvents, water-soluble organics, ammonia, and ammonium salts to carbon dioxide or carbonate ions, and at least one of the group consisting of organic solvents, water-soluble organics, ammonia, and ammonium salts" is sometimes preferred as a method for manufacturing a medical calcium carbonate composition that satisfies condition (D). Raw calcium compositions containing organic solvents can be treated as pastes, and therefore, are sometimes useful from an operational point of view.

[0526] Methanol, ethanol, and ammonium carbonate are evaporable substances and are easily removed from the manufactured medical-grade aragonite composition. Additionally, glycerol and ethylene glycols are highly water-soluble substances and are also easily removed from the manufactured medical-grade aragonite composition. Here, ethylene glycols refer to ethylene glycol and polyethylene glycol.

[0527] These are preferred materials from the viewpoint of simplicity of manufacturing process and balance of aragonite inhibition effect. That is, the step of "(D4) exposing the raw calcium composition to carbon dioxide or carbonate ions and at least one selected from the group consisting of methanol, ethanol, glycerol, ethylene glycol and ammonium carbonate" as a method of manufacturing medical calcium carbonate composition that satisfies condition (D) is more preferred, and "(D5) exposing the raw calcium composition containing at least one selected from the group consisting of methanol, ethanol, glycerol, ethylene glycol and ammonium carbonate to carbon dioxide or carbonate ions and at least one selected from the group consisting of methanol, ethanol and ammonium carbonate" is even more preferred.

[0528] As described above, the metastable aragonite transforms into the stable calcite phase. Therefore, "(D6) the process of suppressing the transformation from aragonite to calcite" is useful for a medical calcium carbonate composition that satisfies condition (D). As described above, the transformation from aragonite to calcite is promoted by water. In the case of manufacturing a medical aragonite composition by reacting a raw calcium composition with carbon dioxide, water equal in molar amount to calcium carbonate is generated as a byproduct within the raw calcium composition. Therefore, "(D7) the process of removing water from the raw calcium composition" is useful for a medical calcium carbonate composition that satisfies condition (D).

[0529] To remove water generated as a byproduct within the raw calcium composition, it is necessary to diffuse the water through evaporation or the like, discharging it from the interior to the exterior of the raw calcium composition. While a depressurization process can be performed during the carbonation of the raw calcium composition to remove water, the step of "(D8) causing carbon dioxide or carbonate ions containing organic solvent to flow around the raw calcium composition" is useful because the water inside the raw calcium composition is easily evaporated and can be carried out continuously. Examples of methods for causing carbon dioxide or carbonate ions containing organic solvent to flow around the raw calcium composition include: blowing carbon dioxide or carbonate ions containing organic solvent into the raw calcium composition using a fan or the like, or circulating carbon dioxide or carbonate ions containing organic solvent around the raw calcium composition.

[0530] Medical-grade aragonite compositions can be manufactured by imparting carbon dioxide to a raw calcium composition under specific conditions, with calcium hydroxide being the preferred raw calcium composition. This is because it does not generate compositions other than water as byproducts. Calcium hydroxide powder is typically used, but if the powder is immersed in a liquid phase such as an organic solvent, it collapses and cannot maintain its shape. Therefore, it is necessary to impart carbon dioxide in the gas phase. On the other hand, in the gas phase, a uniform reaction is less likely to occur compared to the liquid phase. Therefore, it is useful to employ a process of manufacturing a medical-grade aragonite composition under at least one condition selected from the group consisting of (D1) to (D8), and "(D9) exposing the raw calcium composition to carbon dioxide or carbonate ions in the gas phase to partially carbonize it, and then exposing the raw calcium composition to carbon dioxide or carbonate ions in the liquid phase."

[0531] When calcium hydroxide powder is immersed in a liquid phase such as 90% ethanol, it will disintegrate. However, if calcium hydroxide paste is placed in a mold and immersed in the liquid phase, it will not disintegrate. Therefore, it is useful to employ a process of manufacturing a medical aragonite composition under at least one condition selected from the group consisting of (D1) to (D8), and "(D10) a process of exposing the raw calcium composition contained in the mold to carbon dioxide or carbonate ions". The shape of the mold is not particularly limited, but since it is necessary to react with carbon dioxide or carbonate ions, a mold that is at least partially open and capable of reacting with external carbon dioxide or carbonate ions is required. For the reaction to occur from the entire surface, a mold made of a breathable material is preferred. It is useful from the viewpoint that the raw calcium composition contained in the mold does not need to be immersed in the liquid phase, and that the desired form of the medical aragonite composition can be produced even when the reaction is carried out in the gas phase.

[0532] If a raw calcium composition containing calcium hydroxide powder, calcium hydroxide paste, or other similar materials is exposed to carbon dioxide or carbonate ions, a medical-grade aragonite composition can be manufactured. Even if the raw calcium composition contains pore-forming materials such as sodium chloride, sodium dihydrogen phosphate, polymer beads, or fibers, the pore-forming materials and fibers will not react. Pore-forming materials are useful for manufacturing porous bodies, and fibers are useful for manufacturing compositions with excellent operability. For example, if a process for manufacturing a medical-grade aragonite composition is employed under at least one condition selected from the group consisting of (D1) to (D8), and "(D11) the raw calcium composition containing the pore-forming material is exposed to carbon dioxide or carbonate ions," a medical-grade calcium carbonate composition containing the pore-forming material and satisfying condition (D) can be manufactured. By removing this pore-forming material, medical-grade porous calcium carbonate, medical-grade porous calcium phosphate, etc., can be manufactured. The pore-forming material can be mixed into the raw calcium carbonate.

[0533] Furthermore, if a process for manufacturing a medical aragonite composition is employed under at least one condition selected from the group consisting of (D1) to (D8), and "(D12) the fiber-linked raw material calcium composition is exposed to carbon dioxide or carbonate ions," then a medical calcium carbonate composition consisting of fiber-linked particles, etc., satisfying condition (D), can be manufactured. As described above, the medical calcium carbonate composition and the medical calcium phosphate composition with fiber-linked components exhibit excellent operability.

[0534] (Preferred raw material calcium composition)

[0535] In the manufacturing process of a medical calcium carbonate composition that satisfies condition (D), the raw calcium composition is not particularly limited as long as it contains calcium, but calcium hydroxide and calcium oxide are particularly preferred. This is because, as described above, when calcium carbonate is formed in the process of exposing both to carbonic acid or carbonate ions, compositions other than water are not generated as byproducts.

[0536] (Organic solvents)

[0537] In this invention, the term "organic solvent" refers to a solvent for organic substances, including aqueous organic solvents. Examples of organic solvents include alcohols, ketones, and hexane.

[0538] From the viewpoints of ability to suppress calcite formation, cost, water content, and ease of removal, alcohols or ketones are preferred, lower alcohols or lower alkyl ketones are more preferred, and aliphatic alcohols with 1 to 4 carbon atoms or di-lower alkyl ketones with 3 to 6 total carbon atoms are even more preferred.

[0539] Examples of lower alcohols include methanol, ethanol, and propanol. Methanol, ethanol, and propanol are preferred, with methanol and ethanol being more preferred.

[0540] Examples of lower alkyl ketones include acetone, methyl ethyl ketone, diethyl ketone, and methyl isobutyl ketone, with acetone and methyl ethyl ketone being the most suitable.

[0541] (Water-soluble organic matter)

[0542] In this invention, the term "water-soluble organic matter" refers to organic matter that dissolves in water, including salts of organic matter. Examples include nonionic surfactants, lignin sulfonates, sugars such as sucrose, alkylamine salt surfactants, glycerol, ethylene glycol, polyethylene glycol, propylene glycol, polypropylene glycol, etc.

[0543] Water-soluble organic matter needs to be completely removed after manufacturing medical calcium carbonate compositions. Compared with evaporated organic solvents, ammonia, and ammonium chloride, it is often less useful. However, glycerol, ethylene glycol, and polyethylene glycol have high viscosity and high solubility in water, so they are sometimes useful in extrusion molding and removal from the manufactured product.

[0544] (ammonia, ammonium salts)

[0545] In this invention, ammonia refers to NH3, including ammonia water (NH4OH). Furthermore, ammonium salts in this invention refer to salts of ammonia, such as ammonium carbonate, ammonium chloride, and ammonium nitrate.

[0546] Ammonium carbonate is particularly useful as it can also be used in the carbonation process.

[0547] [II. Method for manufacturing medical-grade calcium carbonate compositions: (D) Sintered aragonite body]

[0548] Next, we will explain [6].

[0549] As described above, aragonite is a metastable phase and is known as a low-temperature stable phase, therefore it is not considered capable of sintering. However, it has been found that a sintered body containing aragonite for medical use, containing 20% ​​or more by mass, can be manufactured by pressing calcium carbonate powder containing 20% ​​or more by mass into powder and then firing it. The pressing and firing conditions are not particularly limited, as long as the powder agglomerates to produce a sintered body. The pressing pressure is preferably 100 MPa or more, more preferably 130 MPa or more, and even more preferably 160 MPa or more. The firing temperature is preferably 200°C or more, more preferably 220°C or more, and even more preferably 240°C or more. When the calcium carbonate powder containing 20% ​​or more by mass is fired, sintering occurs, but above a certain temperature, the aragonite decomposes into calcite. This temperature is also environmentally dependent and therefore not particularly limited. However, in the case of atmospheric firing, the firing temperature is preferably below 600°C, more preferably below 550°C, and even more preferably below 500°C. It should be noted that, as mentioned above, the phase transformation from the metastable aragonite to the stable calcite phase is promoted by moisture. Therefore, moisture-free firing conditions are preferred, and a carbon dioxide atmosphere is even more preferred from the viewpoint of inhibiting decomposition. Therefore, a moisture-free carbon dioxide atmosphere is further preferred.

[0550] [II. Method for manufacturing medical-grade calcium carbonate compositions: (E) Carbonate apatite honeycomb structure]

[0551] Next, we will explain [7].

[0552] For medical calcium carbonate honeycomb structures, the “(E1) extrusion process” and one of the “degreasing and carbonation process” selected from the group of (E5) to (E9) are required processes, and the processes selected from the group of (E2) to (E4) and (E10) are performed as needed to manufacture the structure.

[0553] <(E1) Extrusion Process>

[0554] In the extrusion process, a raw material calcium composition containing polymer materials is extruded through a die used to form a honeycomb structure, producing a volume of 3×10⁻⁶. -11 m 3 The above describes a raw material honeycomb structure that has multiple through holes extending in one direction.

[0555] As a polymer material, known polymer materials are used. It should be noted that, based on the meaning of binding powders, polymer materials are sometimes also referred to as polymeric binders or organic binders, but in this invention, they have the same meaning.

[0556] As a polymer material, it is preferred to use a polymer material that serves as an organic binder for wax-acrylic resin systems (also simply referred to as wax-based systems). This is because, unlike other molding methods, in the molding of honeycomb structures, both flowability during extrusion and curing properties after extrusion are necessary.

[0557] <(E2) Molding process after extrusion>

[0558] Sometimes it is useful to perform the molding process after (E1), which is a necessary process.

[0559] In this process, the honeycomb structure, composed of a calcium-based raw material containing polymer materials, is softened by heat treatment and then subjected to pressure to be molded into the desired shape. The softening temperature is adjusted according to the type of polymer material, but is typically between 50°C and 200°C.

[0560] By molding to the desired shape, the "(E3) outer peripheral sidewall removal process" becomes easier. It should be noted that the term "after the extrusion process" refers to the situation where the raw calcium composition containing polymer material passes through the mold used to form the honeycomb structure, and molding is performed while the raw calcium composition containing polymer material has just passed through the mold used to form the honeycomb structure.

[0561] In addition, when manufacturing a honeycomb structure in which the diameter of the circle passing through the two ends of the through hole and the center of the through hole is 1 cm or more and 50 cm or less, it is preferable to form it into this shape during this stage.

[0562] In the “(E3) peripheral sidewall removal process”, the peripheral sidewall is removed after (E1) or (E2) and before one of the “degreasing and carbonation processes” selected from (E5) to (E9).

[0563] In the “(E4) Molding process after removing the outer peripheral sidewall”, the honeycomb structure, composed of a calcium-based raw material containing polymer materials, is softened by heat treatment and then subjected to pressure to be molded into the desired shape. The softening temperature is adjusted according to the type of polymer material, but is usually between 50°C and 200°C.

[0564] The "degreasing and carbonation process" is performed after the essential process (E1) and the optional processes (E2) to (E4). The "degreasing and carbonation process" here refers to the process of degreasing and forming or maintaining calcium carbonate. When the raw material calcium composition is calcium carbonate, carbon dioxide is not required; however, in this invention, even when calcium carbonate is used as the raw material, it is defined as a degreasing and carbonation process. Furthermore, the case where a sintering process is performed simultaneously is also included in the "degreasing and carbonation process."

[0565] Degreasing, in this context, refers to the process of removing polymeric materials, typically through heat treatment. In the preparation of alumina and cordierite honeycomb structures, these ceramics do not undergo thermal decomposition, making degreasing relatively easy. However, in the manufacture of the highly reactive medical calcium carbonate composition of this invention, degreasing is extremely difficult. This is because calcium carbonate or the raw materials used to manufacture calcium carbonate undergo thermal decomposition at high temperatures, or transform into poorly reactive calcium carbonate. Therefore, degreasing must be performed under specific conditions to reduce the residual amount of polymeric material or its thermal decomposition product (acid dissolution product) to less than 1% by mass. Reducing the residual amount of acid dissolution to less than 1% by mass after the degreasing process is essential, preferably to less than 0.5% by mass, more preferably to less than 0.3% by mass, even more preferably to less than 0.1% by mass, and ideally to be substantially 0% by mass.

[0566] Various factors, including composition, porosity, particle size, atmosphere, temperature, degreasing time, and heating rate, affect degreasing. The indicator of degreasing is the acid-soluble residue of the degreased calcium carbonate composition, which cannot be evaluated by factors such as color.

[0567] It should be noted that, as mentioned above, carbonation may sometimes need to be carried out simultaneously with or after defatting.

[0568] The degreasing and carbonation process is a process that includes at least one process selected from the group consisting of (E5) to (E9) below. It should be noted that, in the pore distribution measurement based on mercury intrusion porosimetry, the pore volume with a pore diameter of 10 μm or less relative to the mass of the honeycomb structure becomes greater than 0.02 cm³. 3 Degreasing and carbonation are carried out in a / g manner. The pore volume decreases at higher degreasing temperatures; therefore, a pore volume of 0.02 cm⁻² is required. 3 When the volume is below / g, the pore volume can be increased by lowering the degreasing temperature.

[0569] Regarding the <(E5) degreased calcium carbonate sintering process>

[0570] As described in Patent Document 11, regarding the manufacture of calcium carbonate honeycomb structures, calcium carbonate is considered unsuitable as a raw material due to its lack of sinterability and thermal decomposition at high temperatures, and the method using calcium hydroxide is deemed useful. That is, in the manufacture of honeycomb structures requiring large quantities of polymer materials, when manufacturing medical-grade calcium carbonate honeycomb structures from calcium composite honeycomb structures containing polymer materials, it is impossible to apply pressure between the powder particles; therefore, it is considered that high temperatures are required compared to the sintering of ceramic pressed powders. However, calcium carbonate thermally decomposes at high temperatures. Furthermore, due to the lack of sinterability of calcium carbonate, it is considered impossible to sinter calcium carbonate honeycomb structures containing polymer materials manufactured using calcium carbonate powder containing polymer materials.

[0571] Surprisingly, it was discovered that under specific conditions, calcium carbonate containing polymeric materials can be degreased by heating in a manner that dissolves the residue in acid to less than 1% by mass, and the calcium carbonate is then sintered to produce porous calcium carbonate for medical use with high mechanical strength.

[0572] The necessary condition for manufacturing medical calcium carbonate honeycomb structures with excellent mechanical strength from calcium carbonate honeycomb structures containing polymer materials is to perform heating degreasing under the specific conditions described below, so that the acid-dissolving residue is less than 1% by mass, but the detailed reasons for this have not been fully explained at present.

[0573] Calcium carbonate is difficult to thermally decompose up to approximately 500°C. Therefore, heating can be performed in the atmosphere without controlling the atmosphere up to approximately 500°C. In the atmosphere, it begins to thermally decompose at temperatures above approximately 500°C, eventually becoming calcium oxide, but it remains stable up to 920°C in a carbon dioxide atmosphere. Therefore, when performing debinding at temperatures above approximately 500°C, it is necessary to increase the partial pressure of carbon dioxide and perform debinding under conditions where calcium carbonate does not thermally decompose. The sintering temperature of calcium carbonate varies depending on the powder size, as described below. Furthermore, in the case of manufacturing highly reactive calcium carbonate honeycomb, the pore volume must be greater than 0.02 cm³, with a pore diameter of less than 10 μm relative to the mass of the honeycomb structure, as determined by mercury intrusion porosimetry. 3 Degreasing and carbonation are carried out in a / g manner. It should be noted that, due to cost and other considerations, atmospheric heating degreasing is generally preferred, but from the viewpoint of suppressing the decomposition of calcium carbonate, heating degreasing at a carbon dioxide concentration higher than that in the air is preferred.

[0574] As described above, in this invention, the presence or absence of sintering is determined by whether the sintered material can maintain its shape without collapsing under conditions of immersion in water and ultrasonic irradiation.

[0575] Regarding the <(E6) degreasing and carbonation process>

[0576] In a process where porous calcium hydroxide containing polymeric materials is degreased by heating and carbonation simultaneously under conditions of oxygen concentration less than 30%, the calcium hydroxide containing polymeric materials is degreased and carbonated at the same time by acid dissolution of the residue to less than 1% by mass. Here, "simultaneously" means within a single process; in practice, degreasing is performed first by heating. When carbonation is performed simultaneously with degreasing of the polymeric materials, controlling the heating and degreasing temperature, atmosphere, and time is crucial. This is because, under low carbon dioxide partial pressure conditions, calcium hydroxide begins to thermally decompose into calcium oxide from approximately 345°C. While it is not necessary to increase the carbon dioxide partial pressure up to this temperature, varying the carbon dioxide partial pressure during the process is cumbersome; therefore, it is preferable to increase the carbon dioxide partial pressure from the beginning.

[0577] As described in Patent Document 12, regarding degreasing, it was thought that the polymer material needed to be incinerated. However, in-depth research revealed that incineration is one method of degreasing, and degreasing can be achieved through depolymerization, evaporation, etc., even without incineration. Furthermore, it was found that if the polymer material is incinerated, incomplete combustion sometimes occurs, leaving carbon residues as acid-dissolved remnants.

[0578] Therefore, it has been surprisingly found that degreasing is sometimes preferred under conditions where the polymer material is not incinerated. In order to degrease the polymer material by methods other than incineration, such as depolymerization or evaporation, the oxygen concentration must be less than 30% by volume. Preferably, the oxygen concentration is less than 15%, more preferably less than 10%, and the absence of oxygen, i.e., a substantially 0% oxygen concentration, is further preferred.

[0579] It should be noted that the degreasing behavior of calcium hydroxide containing polymers differs from that of calcium carbonate containing polymers. When calcium carbonate containing polymers is heated for degreasing, even in the presence of oxygen, acid-dissolving residues are not easily retained. On the other hand, for calcium hydroxide containing polymers, acid-dissolving residues are easily retained in the presence of oxygen. The reason for this is not fully elucidated, but it is believed to be due to the reactivity of calcium hydroxide with polymers. That is, the reactivity of calcium carbonate with polymers is limited, therefore the polymers are easily degreased through depolymerization, evaporation, etc. On the other hand, it is believed that the reactivity of calcium hydroxide with polymers is relatively high, therefore calcium hydroxide interacts or reacts with the polymers. Polymers that have interacted or reacted with calcium hydroxide are believed to be easily degreased through depolymerization, evaporation, etc.

[0580] To prevent the thermal decomposition of calcium hydroxide and to carry out degreasing and carbonation, it is preferable to carry out degreasing and carbonation at a temperature of 600°C to 800°C under conditions of carbon dioxide of 50% or more and oxygen of less than 30% by volume.

[0581] One of the essential conditions for this invention is the complete degreasing of the polymer material. If complete degreasing and carbonation cannot be achieved even under conditions of 50% or more carbon dioxide and less than 30% oxygen at temperatures between 600°C and 800°C, then the manufacturing method is not included in this invention. Furthermore, in the case of a honeycomb structure, the pore volume must be greater than 0.02 cm³, with a pore diameter of 10 μm or less relative to the mass of the honeycomb structure, as determined by mercury intrusion porosimetry. 3 Degreasing and carbonation are carried out in a / g manner. The heat treatment temperature, atmosphere, and time are appropriately studied to ensure complete degreasing of the polymer material during heat treatment.

[0582] <Regarding (E7) the degreasing and carbonation process via calcium oxide>

[0583] In the aforementioned "(E6) degreasing and carbonation process," calcite porous bodies can be manufactured relatively easily from calcium hydroxide porous bodies containing polymeric materials. However, because calcite is formed at temperatures above 600°C and below 800°C, the reactivity of the manufactured calcite porous bodies is often insufficient. The reason for this is not fully elucidated, but it is believed that heat treatment at temperatures above 600°C and below 800°C is usually required, which results in the formation of calcite with low reactivity.

[0584] From this perspective, a degreasing process can be performed at high temperatures, and then the temperature can be lowered to form calcite or aragonite.

[0585] If degreasing is performed by heating without forming calcite from the porous calcium hydroxide containing polymeric materials, the calcium hydroxide undergoes thermal decomposition to become calcium oxide. Because it is a high-temperature process, it has the advantage of complete degreasing. However, if the heat treatment temperature is too high, the porous calcium oxide becomes denser or more crystalline, making it impossible to produce calcium carbonate with low crystallinity. Therefore, the heat treatment temperature for producing calcium oxide is preferably 700°C to 1000°C, more preferably 750°C to 950°C, and even more preferably 800°C to 900°C.

[0586] Similarly, for porous calcium carbonate containing polymeric materials, if degreasing is performed by heating, the calcium carbonate undergoes thermal decomposition to become calcium oxide. Calcium carbonate is less reactive than calcium hydroxide, therefore degreasing can be performed at low temperatures. The heat treatment temperature for producing calcium oxide from porous calcium carbonate containing polymeric materials is preferably 500°C to 1000°C, more preferably 530°C to 800°C, and even more preferably 550°C to 650°C.

[0587] After degreasing, carbon dioxide is introduced into the calcium oxide porous body at a lower temperature to produce calcite porous bodies or aragonite porous bodies. The lower the temperature at which carbon dioxide is introduced into the calcium oxide porous body, the more reactive the calcite porous body can be produced, but the introduction of carbon dioxide takes longer. Considering a balance between the two, the preferred temperature for introducing carbon dioxide into the calcium oxide porous body is 300°C to 500°C, more preferably 310°C to 400°C, and even more preferably 320°C to 380°C. When producing aragonite porous bodies from calcium oxide porous bodies, carbon dioxide is introduced into the calcium oxide porous body using the methods described above (D1) to (D12).

[0588] <Regarding (E8) the degreasing and carbonation process via calcium carbonate and calcium oxide>

[0589] Through the aforementioned "(E7) degreasing and carbonation process via calcium oxide," highly reactive calcite porous bodies or extremely reactive aragonite porous bodies can be manufactured. However, compared to the case where calcium hydroxide porous bodies containing polymeric materials are directly formed into calcium oxide porous bodies, if calcium hydroxide containing polymeric materials is heat-treated in the presence of carbon dioxide to produce calcium carbonate porous bodies containing polymeric materials, and then degreased by heating to produce calcium oxide porous bodies, and then carbon dioxide is introduced into the calcium oxide porous bodies after cooling to produce calcite porous bodies or aragonite porous bodies, then calcium carbonate porous bodies with greater mechanical strength or those less prone to cracking can be manufactured. The reason for this is not fully explained, but it is believed that by introducing carbon dioxide into the calcium hydroxide, the heating time required for calcium hydroxide porous bodies with poor mechanical strength can be reduced. It should be noted that, similar to "(E7) Degreasing and Carbonation Process via Calcium Oxide", the temperature at which carbon dioxide is imparted to the porous calcium oxide body is preferably 300°C to 500°C, more preferably 310°C to 400°C, and even more preferably 320°C to 380°C.

[0590] <Regarding the (E9) calcium sulfate defatting and carbonation process>

[0591] Compared to the aforementioned cases using calcium carbonate or calcium hydroxide, the use of calcium sulfate allows for the creation of porous calcite bodies with numerous micropores. The reasons for this are not fully elucidated, but it is speculated that one contributing factor is the coarse crystal structure of calcium sulfate.

[0592] In the degreasing and carbonation process for producing calcium carbonate, calcium sulfate is used as the raw material calcium composition in a process where calcium sulfate containing polymeric materials is degreased by heating to reduce the residue to less than 1% by mass through acid dissolution, and then carbon dioxide or carbonate ions are introduced into the manufactured porous calcium sulfate body. First, the following process is performed: the porous calcium sulfate containing polymeric materials is degreased by heat treatment at 700°C or above to reduce the residue to less than 1% by mass through acid dissolution. Next, carbonate ions are introduced into the manufactured porous calcium sulfate body to produce a porous calcium carbonate body for medical use.

[0593] Calcium sulfate is stable even at relatively high temperatures. Degreasing at temperatures above 700°C is necessary, but the final heat treatment temperature is preferably 750°C to 1100°C, more preferably 800°C to 1000°C, and even more preferably 850°C to 950°C.

[0594] <(E10) Shaping process performed after degreasing and carbonation>

[0595] After any of the degreasing and carbonation processes described in (E5) to (E9), a "shape finishing process (E10) performed after the degreasing and carbonation process" is carried out. In the shape finishing process, shape finishing processes such as removal of the outer peripheral sidewalls are performed.

[0596] [II. Method for manufacturing medical-grade calcium carbonate compositions: (E) Specific calcium carbonate honeycomb structures]

[0597] Next, we will explain [8].

[0598] The following method for manufacturing a medical calcium carbonate composition is useful: it is a method for manufacturing a medical calcium carbonate composition that satisfies the aforementioned (E), characterized in that it satisfies at least one condition selected from the group consisting of (E11) to (E14) below.

[0599] (E11) is the following process: In the aforementioned "(E1) extrusion process", the thickness of the outer peripheral sidewall of the honeycomb structure is greater than the thickness of the partition wall, and the cross-sectional area of ​​the surface perpendicular to the through hole is 1 cm². 2 Extrusion is performed using the methods described above.

[0600] This is because if the cross-sectional area of ​​the surface perpendicular to the through hole is 1 cm² 2 From the perspective of shape retention during extrusion, it is easier to maintain the shape when extruding by making the thickness of the outer peripheral sidewall thicker than that of the honeycomb structure.

[0601] On the other hand, the thickness of the outer peripheral sidewall is greater than that of the honeycomb structure, and the cross-sectional area of ​​the surface perpendicular to the through hole is 1 cm². 2In the above-mentioned degreasing and carbonation process of the honeycomb structure of the raw material calcium composition containing polymer materials, cracks are easily formed between the outer peripheral sidewalls and the partitions, and inside the honeycomb structure, due to the difference in shrinkage between the outer peripheral sidewalls and the partitions. Therefore, it is preferable to perform the "(E3) outer peripheral sidewall removal process" before the degreasing and carbonation process selected from the group of (E5) to (E9) mentioned above.

[0602] The cross-sectional area of ​​the surface perpendicular to the through hole is less than 1 cm². 2 In such cases, the morphology retention during extrusion is limited. When the thickness of the outer peripheral sidewall is the same as or less than the thickness of the septum in the honeycomb structure, the shrinkage rate is the same or less; therefore, the necessity of the "(E3) outer peripheral sidewall removal process" is limited. Furthermore, the cross-sectional area of ​​the surface perpendicular to the through-hole is less than 1 cm². 2 In such cases, even if the shrinkage rates are different, the difference in shrinkage is limited, so cracks are not likely to occur. Therefore, the necessity of the "(E3) peripheral sidewall removal process" is limited.

[0603] (E12) is a manufacturing method in which, in at least one step selected from the group consisting of "(E1) extrusion process", "(E2) molding process after extrusion process", "(E4) molding process after outer peripheral sidewall removal process", and "(E10) shape finishing process after degreasing and carbonation process", a heat-softened honeycomb structure composed of a raw material calcium composition containing polymer material is subjected to pressure and bent in such a way that the diameter of the circle passing through the two ends of the through hole and the center of the through hole is 1 cm or more and 50 cm or less.

[0604] The softening temperature is adjusted according to the type of polymer material, but it is usually between 50°C and 200°C.

[0605] (E13) is a manufacturing method in which the aforementioned “(E3) peripheral sidewall removal process” is performed by grinding and the aforementioned “(E10) shape finishing process performed after degreasing and carbonation process” is performed by polishing. It is useful as a manufacturing method for medical calcium carbonate honeycomb with excellent shape.

[0606] Although this phenomenon is believed to be unique to the removal of the outer peripheral sidewalls of a raw material honeycomb structure formed from a raw material calcium composition containing polymer materials, if the outer peripheral sidewalls of this raw material honeycomb structure are attempted to be removed by grinding using a diamond point or similar tool, the outer peripheral sidewalls are removed, but new outer peripheral sidewalls are formed. This is believed to be due to the softening of the outer peripheral sidewalls caused by the heat generated during the grinding process. On the other hand, the heat generated by the grinding process is limited compared to that of the grinding process. Therefore, the outer peripheral sidewall removal process is preferably performed by grinding using a planer or similar tool.

[0607] If the outer peripheral sidewall is removed by grinding the calcium carbonate honeycomb structure manufactured by degreasing and carbonating the raw material honeycomb structure, chipping occurs. Therefore, the outer peripheral sidewall removal finishing process is not performed by grinding, but preferably by grinding with diamond or the like.

[0608] (E14) is a method for manufacturing anhydrous calcium sulfate as the raw material calcium composition in the aforementioned "(E1) extrusion process".

[0609] To date, no calcium sulfate honeycomb structure has been manufactured. In the extrusion process of forming the raw material honeycomb structure, the mixture of the raw calcium composition and the polymer material is heated. Calcium sulfate exists in anhydrous, hemihydrate, and dihydrate forms; however, when hydrated calcium sulfate is used as the raw material calcium composition, the water evaporates, causing the raw material honeycomb structure formed from calcium sulfate containing the polymer material to expand and deform. Therefore, anhydrous calcium sulfate must be used as the calcium sulfate.

[0610] [II. Method for manufacturing medical-grade calcium carbonate composition: (F) Expansion of calcium oxide particles]

[0611] Next, the process of manufacturing a medical calcium carbonate composition that satisfies the aforementioned (F) using calcium oxide particles as raw material will be described [9].

[0612] To enable particles to bond in a manner that leaves gaps, it is necessary to impart a certain bonding ability to the particles. Methods for imparting this bonding ability can be categorized into those using polymer materials and those not using polymer materials. First, the manufacturing method without polymer materials will be explained. In the case of not using polymer materials, the bonding of the raw material calcium composition is utilized; expansion due to calcium oxide hydration and the curing reaction of calcium sulfate are useful. First, the manufacturing method using calcium oxide particles as the raw material will be explained.

[0613] Calcium oxide swells upon contact with water, acetic acid, etc., to become calcium hydroxide and calcium acetate. This reaction is used to bind the particles together and carbonate them. In this manufacturing method, at least one of (F1) and (F2) described below, and (F3) and (F4) are necessary conditions.

[0614] Regarding <(F1) Introduction of Closed Process>

[0615] In this process, calcium oxide particles are loaded into a reaction vessel, and the opening of the reaction vessel is sealed so that the particles do not exit the vessel. This process is performed to ensure that the particles within the reaction vessel are uniformly bonded together or to apply compressive stress between the particles. If the sealing process is not performed, the particles will not bond together uniformly, therefore, it is not preferable as a porous material for medical use. To form a uniform porous structure, the opening of the reaction vessel must be sealed; the introduction process without sealing the opening is not included in this invention. It should be noted that whether or not particles exit the reaction vessel is the criterion for determining whether a seal is present or not; an opening in which particles do not exit the reaction vessel is defined as substantially sealed. Furthermore, even for a mesh-like reaction vessel, if it is sealed in a way that prevents particles from exiting the reaction vessel, it is defined as having undergone an introduction sealing process.

[0616] Regarding the <(F2) porous body formation process>

[0617] This process involves introducing water or acetic acid into the calcium oxide particles inside the reaction vessel after the sealing process. The calcium oxide particles react with water or acetic acid to become calcium hydroxide or calcium acetate, and then expand. By sealing the reaction vessel, the opening is closed, thus increasing the contact between the particles and forming a porous body of calcium hydroxide or calcium acetate with a uniform pore structure. Furthermore, due to the expansion of the calcium oxide particles, the pore volume of the particle-bonded porous body (below 10 μm), as determined by mercury porosimetry, is 0.05 cm³. 3 / g or more.

[0618] Regarding the <(F3) Carbonation Process>

[0619] In the case of producing a calcium hydroxide porous body, carbon dioxide is then introduced into the calcium hydroxide porous body either simultaneously with or after the calcium hydroxide porous body formation process. The calcium hydroxide porous body is then carbonated, becoming a calcium carbonate porous body.

[0620] On the other hand, after producing a calcium acetate porous body, the formed calcium acetate porous body is subjected to heat treatment. Calcium acetate is thermally decomposed into calcium carbonate porous body. The heat treatment is carried out at the decomposition temperature of calcium acetate, i.e., above 400°C.

[0621] Regarding the <(F4) calcium oxide carbonation process>

[0622] Medical-grade porous calcium carbonate can also be manufactured by including all of the manufacturing processes described in (F1) to (F3) above. However, sometimes the compressive strength of the porous body is low. To increase the compressive strength, the following processes are useful: heat-treating a porous calcium hydroxide, porous calcium carbonate, or porous calcium acetate to produce a porous calcium oxide, or exposing the calcium oxide to carbon dioxide to produce a porous calcium carbonate.

[0623] [II. Method for manufacturing medical-grade calcium carbonate composition: (F) Curing reaction of calcium sulfate particles]

[0624] Next, we will explain

[10] .

[0625] A medical calcium carbonate composition that satisfies the foregoing (F) can also be manufactured by solidifying calcium sulfate particles of appropriate size together.

[0626] That is, porous bodies can be manufactured by a solidification reaction of calcium sulfate particles with water containing carbonate ions, or by a solidification reaction of calcium sulfate hemihydrate particles or calcium sulfate anhydrous particles with water. In the former case, a porous calcium carbonate body is directly manufactured. In the latter case, a porous calcium sulfate dihydrate body is manufactured, and thus, the porous body is converted from a calcium sulfate dihydrate composition to calcium carbonate through a carbonation process. That is, the former is a manufacturing method including the steps (F5) and (F6) described below, and the latter is a manufacturing method including the steps (F5), (F7) and (F9) described below, with step (F8) as an optional step. Through these methods, a method for manufacturing a medical calcium carbonate composition that satisfies the aforementioned (F) can be provided.

[0627] Regarding the <(F5) Import Process>

[0628] In this process, calcium sulfate granules are loaded into the reaction vessel.

[0629] Regarding the <(F6) porous body formation carbonation process>

[0630] It is a process in which calcium sulfate particles in a reaction vessel react with carbonate ions.

[0631] For example, calcium sulfate particles placed in a reaction vessel can be immersed in an aqueous sodium carbonate solution. In this process, the calcium sulfate particles are converted into calcium carbonate while maintaining their macroscopic morphology. Simultaneously, through the bridging of the formed calcium carbonate crystals, the particles solidify together, forming a particle-bonded porous body.

[0632] Regarding the <(F7) Porous Body Forming Process>

[0633] When calcium sulfate particles are composed of calcium sulfate hemihydrate or calcium sulfate anhydrous, water is introduced into the particles in the reaction vessel, and the particles are transformed into calcium carbonate while maintaining their macroscopic morphology. Simultaneously, through the bridging of the formed calcium carbonate crystals, the particles solidify together, forming a porous, particle-bonded structure.

[0634] Regarding the <(F8) heat treatment process>

[0635] This process involves heat-treating and dehydrating the calcium sulfate dihydrate porous body manufactured through the "(F7) Porous Body Forming Process" to produce anhydrous calcium sulfate porous bodies. The heat treatment process enables the manufacture of medical-grade calcium carbonate porous bodies with high compressive strength.

[0636] Regarding <(F9) Carbonation Process>

[0637] In this process, porous calcium sulfate dihydrate or porous calcium sulfate anhydrous polyhydrate is exposed to water containing carbonate ions. While maintaining its macroscopic morphology, the composition of the porous calcium sulfate dihydrate or porous calcium sulfate anhydrous polyhydrate is converted to calcium carbonate, thus producing a medical-grade porous calcium carbonate polyhydrate.

[0638] Through process (F5) or (F9), the pore volume of the particle-bonded porous body below 10 μm, as determined by mercury porosimetry, is 0.05 cm³. 3 / g or more.

[0639] [II. Method for manufacturing medical-grade calcium carbonate compositions: (F) Process using polymers]

[0640] Next, the method for manufacturing

[11] , namely, a medical calcium carbonate composition that uses polymer materials and satisfies the aforementioned (F), will be described.

[0641] If a raw calcium composition containing polymeric material is used as a mixture of a raw calcium composition and a polymeric material, the polymeric material can be used to bind the particles of the mixture. On the other hand, since a polymeric material is used, as mentioned above, in order to manufacture the medical calcium carbonate composition of the present invention, the polymeric material must be removed by degreasing. The requirement to perform degreasing under specific conditions and to reduce the polymeric material or acid-dissolved residue as a thermal decomposition product to less than 1% by mass is also the same as in the case of medical calcium carbonate honeycomb structures.

[0642] By making (F10) and (F11) below, and one of the group selected from (E5) to (E9) above, a method for manufacturing a medical calcium carbonate composition that satisfies (F) above can be provided.

[0643] Regarding the <(F10) Introduction Process>

[0644] It is a volume of 10 -12 m 3 The above steps involve loading the raw material calcium composition particles containing polymer materials into the reaction vessel.

[0645] Regarding the <(F11) porous body formation process>

[0646] In this process, any one of the following steps—heat-treating the particles inside the reaction vessel to soften and fuse their surfaces together, dissolving the surface of the particles to bond their surfaces together, or using a plasticizer to fuse the surfaces of the particles together—will produce a volume of 3 × 10⁻⁶. -11 m 3 A particle-bonded porous body is formed by combining multiple particles with a maximum diameter of 50 μm to 500 μm, possessing multiple through-pores extending in multiple directions. Furthermore, the fine pore volume of the particle-bonded porous body with a diameter of 10 μm or less, as determined by mercury porosimetry, is 0.05 cm³. 3 / g or more.

[0647] In a process where heat treatment is performed to soften and fuse the surfaces together, the particles are heated. In the case of thermoplastic polymers, the particles soften, and the softened particles fuse together using their own weight or compressive stress from the reaction vessel.

[0648] In the process of dissolving the surface of particles to bond the particles together, solvents such as acetone and dimethyl sulfoxide are used to dissolve the surface of the particles and bond them together.

[0649] In the process of fusing the surfaces of the particles together using a plasticizer, the following methods can be exemplified: a method of pre-adding a plasticizer to the interior of the raw material calcium composition particles containing a polymer material, thereby fusing the particles together by bringing the particles into contact with each other; and a method of applying a plasticizer to the surface of the particles, thereby softening the particle surface and fusing the particles together.

[0650] [II. Method for manufacturing medical-grade calcium carbonate composition: (G) Porous aggregate with pores]

[0651] Next, the method for manufacturing

[12] , namely, the medical calcium carbonate composition that satisfies the aforementioned (G), will be described.

[0652] This manufacturing method is a method of manufacturing in which one of the following (G1) and one selected from (D1) to (D10) and (E5) to (E9) is a required step, and the following (G2) and (G3) and the aforementioned (E10) are optional steps.

[0653] Regarding <(G1) Mixing Process>

[0654] "(G1) Mixing Step" is the step of mixing the raw calcium composition powder or raw calcium composition paste with the pore-forming material. When the raw calcium is calcium hydroxide, calcium carbonate, calcium sulfate, etc., and its solubility in water is limited, calcium carbonate paste is preferred as it better ensures flowability. On the other hand, in the case of water-soluble calcium compounds such as calcium acetate, it is preferable to mix them while they are still in powder form. There are no particular limitations on the raw calcium composition, but calcium oxide, calcium hydroxide, and calcium carbonate are preferred, with calcium hydroxide and calcium carbonate being particularly preferred.

[0655] As mentioned above, there are no particular limitations on the pore-forming material, and examples include sodium chloride, sodium dihydrogen phosphate, and polymer beads. Since the pore-forming material is used to control the pore diameter, it is necessary to avoid pore-forming materials with a maximum diameter length of 800 μm or more. Furthermore, pore-forming materials with a maximum diameter length of 50 μm to 400 μm are preferred.

[0656] Regarding the <(G2) pressing process>

[0657] "(G2) Pressing Process" is a process of pressing the raw calcium composition powder or a mixture of raw calcium composition paste and pore-forming material into powder. Known pressing methods, including uniaxial pressing by hand and hydrostatic pressing, can be used without limitation. If a raw calcium composition paste is used, drying is performed after this process as needed. Since a certain pressure is applied during the process of mixing the raw calcium composition paste with the pore-forming material, the pressing process is sometimes unnecessary; therefore, this process is optional.

[0658] Regarding the <(G3) Pore-forming material removal process>

[0659] "(G3) Pore Material Removal Process" is a process in which the pore material is removed by dissolving it in a solvent. When manufacturing porous calcium phosphate bodies for medical use using a medical calcium carbonate composition as a raw material, the pore material is removed by impregnating the medical calcium carbonate composition with disodium hydrogen phosphate, etc. Therefore, it is not necessary to remove the pore material during the manufacturing stage of the medical calcium carbonate composition. Therefore, (G3) is an optional process.

[0660] In this manufacturing method, polymer materials are sometimes used as pore-forming materials. In such cases, the "(E10) shape finishing process performed after the degreasing and carbonation process" in the carbonate apatite honeycomb structure using polymer materials sometimes becomes useful. Therefore, (E10) is also an optional process.

[0661] It should be noted that, in order to meet condition (G), the pore volume below 10 μm of this aggregated porous body, as determined by mercury porosimetry, must be 0.05 cm³. 3 / g or more. The pore volume is adjusted by the mixing ratio of the raw material calcium composition powder and the solvent in the mixing process of (G1) and the pressing pressure in the pressing process of (G2).

[0662] [II. Method for manufacturing medical-grade calcium carbonate composition: Degreasing conditions]

[0663] Next, we will explain

[13] .

[0664] In the manufacturing method of medical calcium carbonate compositions using polymeric materials, the polymeric materials used must be removed. This process is called degreasing, and specifically, the polymeric materials are removed through processes such as depolymerization and evaporation. In the present invention, when manufacturing medical calcium carbonate honeycomb structures, the distance between calcium composition powders in the calcium composition containing polymeric materials increases due to the degreasing of the polymeric materials. Therefore, it is preferable to adjust the degreasing speed of the polymeric materials in a way that keeps the distance between the calcium composition powders constant. It should be noted that when the degreasing temperature is below 200°C, a larger amount of polymeric material remains, resulting in higher fluidity; therefore, the distance between the calcium composition powders remains relatively constant.

[0665] Therefore, in the degreasing process at 200°C or above, it is preferable to reduce the mass of the calcium composition containing polymeric materials by less than 1% by mass per minute. However, the temperature at which the mass of the calcium composition containing polymeric materials is reduced by less than 1% by mass per minute is preferably set to 150°C or above, more preferably 100°C or above, and even more preferably 50°C or above.

[0666] The reduction of the polymer material is more preferably less than 0.9% by mass per minute, and even more preferably less than 0.8% by mass per minute.

[0667] It should be noted that the rate of mass reduction in polymer materials is not constant with respect to temperature rise; it occurs abruptly at specific temperatures. For example, the depolymerization of acrylic resins occurs abruptly at 250°C. Therefore, these degreasing conditions can be optimized using thermogravimetric analysis (TGA). Essentially, the heating rate is adjusted based on the differential value of the mass reduction in TGA, but it is also possible to maintain a temperature approximately 20°C lower than the temperature at which the abrupt mass reduction begins for a certain period.

[0668] [II. Method for manufacturing medical-grade calcium carbonate compositions: Specific manufacturing method]

[0669] Next, we will explain

[14] .

[0670] In the manufacturing process of medical calcium carbonate compositions, the control of carbon dioxide and oxygen is sometimes preferred.

[0671] "(L) A degreasing process with an oxygen partial pressure of 30 kPa or higher" is sometimes preferred in degreasing processes. Polymer materials are degreased through heat treatment via depolymerization, evaporation, thermal decomposition, or incineration. Sometimes, degreasing is easier at high oxygen partial pressures, and it is sometimes preferred because it reduces the amount of residue dissolved by acid. The oxygen partial pressure in air is about 20 kPa, but preferably 30 kPa or higher, more preferably 60 kPa or higher, and even more preferably 90 kPa or higher.

[0672] The step of "(M) performing degreasing or carbonation at a carbon dioxide partial pressure of 30 kPa or higher" is sometimes preferred in the degreasing or carbonation process. This is because carbonation of the raw calcium composition requires carbon dioxide, and sometimes degreasing does not require the combustion of polymer materials; the acid decomposition residue can be reduced to less than 1% by mass simply through the depolymerization, evaporation, and thermal decomposition of the polymer materials. Furthermore, calcium carbonate begins to thermally decompose into calcium oxide at around 340°C when the carbon dioxide partial pressure is 0 kPa. Therefore, it is sometimes preferred to perform the degreasing or degreasing carbonation process at a certain or higher carbon dioxide partial pressure. Since the amount of carbon dioxide in the atmosphere is limited, a carbon dioxide partial pressure of 30 kPa or higher is preferred in the carbonation process for efficient carbonation, more preferably 60 kPa or higher, and even more preferably 90 kPa or higher. Additionally, it is sometimes preferred to perform degreasing in an environment equivalent to a pure carbon dioxide environment, i.e., a carbon dioxide partial pressure of 101.3 kPa.

[0673] "(N) The process of degreasing or carbonation in a gas containing oxygen or carbon dioxide at a pressure of 150 kPa or higher" is sometimes preferred in degreasing and carbonation processes.

[0674] In the manufacturing process of medical-grade calcium carbonate compositions, degreasing or carbonation is sometimes performed. For example, if carbon dioxide is allowed to flow or otherwise expose the raw calcium composition to carbon dioxide, the raw calcium composition is carbonated to produce a medical-grade calcium carbonate composition. However, in the case of carbon dioxide flow, most of the carbon dioxide is not used in the manufacturing process and is discarded. In addition, when carbonating porous or pressed powder forms of the raw calcium composition, there is a problem that it is difficult to introduce carbon dioxide into the interior of the porous or pressed powder form.

[0675] In such a case, it is preferable to establish a substantially closed system and pressurize the interior of the closed system. Theoretically, if pressurization is applied, oxygen or carbon dioxide will permeate into the interior of the porous body or compressed powder, exposing the raw calcium composition to oxygen or carbon dioxide. However, from an efficiency point of view, it is preferable to carry out the degreasing or carbon dioxide process in a gas containing oxygen or carbon dioxide at a pressure of 150 kPa or higher. The gas pressure is preferably 150 kPa or higher, more preferably 200 kPa or higher, and even more preferably 300 kPa or higher. Theoretically, there is no upper limit to the gas pressure, but since a pressurized closed reaction apparatus is required, the gas pressure is preferably 2 MPa or lower, more preferably 1 MPa or lower, and even more preferably 500 kPa or lower.

[0676] It should be noted that in order to maintain the pressurized state, the reaction device needs to be set as a closed system in principle. However, for purposes such as to discharge the degreased polymer material components from the reaction device, it can also be set as an open system temporarily or continuously under pressurized conditions.

[0677] "(O) The process of replacing part or all of the air in the reaction vessel with carbon dioxide and then introducing carbon dioxide into the reaction vessel, thereby increasing the carbon dioxide concentration in the reaction vessel" is sometimes useful in the carbonation process. This is to increase the partial pressure of carbon dioxide, thereby accelerating the carbonation rate.

[0678] The method of replacing the air in the reaction vessel with carbon dioxide by introducing carbon dioxide from one side and expelling the atmosphere from the other side is simple and effective.

[0679] Furthermore, by reducing the gas content in the raw calcium composition through a decompression process, carbon dioxide is introduced into the reaction vessel, thereby increasing the displacement from air to carbon dioxide. In other words, to manufacture medical calcium carbonate blocks or other medical-grade calcium carbonate compositions that do not contain the raw calcium composition from raw calcium compositions such as calcium hydroxide powder, it is necessary to introduce carbon dioxide into the interior of the powder, etc. However, diffusion alone is time-consuming or may not allow carbonation to proceed to the interior. By reducing the air content inside the calcium hydroxide powder through a decompression process, and then introducing a gas with a higher carbon dioxide concentration than air into the reaction vessel, carbon dioxide can be introduced into the interior of the calcium hydroxide powder.

[0680] To depressurize the reaction vessel, the pressure can be less than atmospheric pressure, i.e., 101.3 kPa, but preferably 90 kPa or less, more preferably 60 kPa or less, and even more preferably 30 kPa or less. The depressurization process reduces the amount of air inside the calcium hydroxide powder, and then a gas with a carbon dioxide concentration higher than that of air is introduced into the reaction vessel. In principle, a carbon dioxide concentration higher than that of air is sufficient, but the carbon dioxide concentration of the introduced gas is preferably 10% by volume or more, more preferably 50% by volume or more, more preferably 90% by volume or more, and ideally, substantially pure carbon dioxide. The pressure of the reaction vessel when introducing carbon dioxide is not particularly limited. However, from the viewpoint of increasing the reaction rate of the raw material calcium composition, it is preferable to introduce carbon dioxide at a reaction vessel pressure of atmospheric pressure, i.e., 101.3 kPa or more, more preferably 150 kPa or more, and even more preferably 200 kPa or more.

[0681] The carbonation process of supplying carbon dioxide in a manner where the pressure in a closed reaction vessel is kept constant (P) is useful for the process of imparting carbon dioxide to a medical calcium composition in a closed reaction vessel. It should be noted that, as described above, the "closed reaction vessel" in this invention refers to a non-open reaction vessel. Generally, carbonation using a closed reaction vessel is costly, but since the medical calcium carbonate composition of this invention is a medical material, manufacturing in a closed system is sometimes preferred from the viewpoint of preventing foreign matter contamination.

[0682] Apart from the case of manufacturing medical-grade calcium carbonate compositions from raw calcium carbonate, carbon dioxide or carbonate ions are required to impart a carbonate group to the raw calcium composition. For example, to produce 1 mole of calcium carbonate by imparting carbon dioxide to 1 mole of calcium hydroxide, 1 mole of carbon dioxide is required, and 1 mole of carbon dioxide is approximately 22.4 L under standard conditions.

[0683] Therefore, to manufacture 1 mole of a medical-grade calcium carbonate composition, a large reaction vessel is required capable of containing at least 22.4 L of carbon dioxide under standard conditions. On the other hand, by supplying carbon dioxide in a closed system at a constant pressure within the reaction vessel, a smaller reaction vessel can be used. There are no particular limitations on the pressure value, but the process of supplying carbon dioxide from a carbon dioxide storage cylinder to the reaction vessel using a pressure-reducing valve at a constant pressure within the reaction vessel is simple; therefore, it is preferable that the pressure within the reaction vessel is greater than atmospheric pressure. Furthermore, since the goal is to supply carbon dioxide into the reaction vessel, increasing the pressure within the reaction vessel beyond what is necessary would only make the reaction vessel expensive and the operation cumbersome. Therefore, the pressure of carbon dioxide in the reaction vessel is preferably 0.5 MPa or less above atmospheric pressure, more preferably 0.3 MPa or less above atmospheric pressure, and even more preferably 0.2 MPa or less above atmospheric pressure.

[0684] This process is useful not only in gas-phase carbonation but also in liquid-phase carbonation as described in (D9) above. Furthermore, since no gases other than carbon dioxide are consumed in a closed system, the carbon dioxide concentration in the reaction vessel is low if only this process is performed. Therefore, a process that includes both this process and the "O" process is preferred.

[0685] "(Q) Carbonation process of stirring or circulating carbon dioxide in a reaction vessel" is sometimes useful for the process of imparting carbon dioxide to a medical calcium composition in a reaction vessel, especially when using a closed system reaction vessel.

[0686] This process is also useful in "(D8)", which is one of the methods for manufacturing a medical calcium carbonate composition characterized by the aforementioned "(D)", but it is not limited to the method for manufacturing a medical calcium carbonate composition characterized by the aforementioned "(D)". Sometimes it is useful as a method for manufacturing the medical calcium carbonate composition of the present invention.

[0687] [II. Method for manufacturing medical-grade calcium carbonate compositions: specific raw material calcium compositions]

[0688] Next,

[15] will be explained. As a raw material calcium composition, compositions containing calcium are widely used, but it is preferred that the composition of the raw material calcium composition is selected from the group consisting of calcium oxide, calcium hydroxide, and calcium carbonate. This is because, in the process of adding carbonic acid components to the raw material calcium composition to manufacture a medical calcium carbonate composition, no composition other than water is generated as a byproduct.

[0689] [II. Method for manufacturing medical-grade calcium carbonate compositions: specific raw material calcium compositions]

[0690] Next,

[16] will be explained.

[16] is particularly related to the method of manufacturing the calcium carbonate composition of [3], and is a manufacturing method that satisfies at least one of the following conditions.

[0691] (R1) Use calcium carbonate powder with an average particle size of 2 μm to 8 μm.

[0692] (R2) Use calcium carbonate powder with a sphericity of 0.9 or higher.

[0693] (R3) Uses a Mg content of 5×10 -4 3×10 of the above % by mass -3 Calcium carbonate powder with a mass percentage of less than 5%.

[0694] (R4) Uses an Sr content of 3×10 -3 1.5 × 10⁻⁶ (by weight) or more -2 Calcium carbonate powder with a mass percentage of less than 5%.

[0695] These are all conditions used to improve the reactivity of the manufactured medical calcium carbonate composition by controlling micropores. Preferred micropores can be formed by using specific raw material calcium powder.

[0696] (R1) is related to the specific average particle size of the calcium carbonate powder used as a raw material in the calcium composition. The average particle size is preferably 2 μm or more and 8 μm or less, more preferably 3 μm or more and 7 μm or less, and even more preferably 4 μm or more and 6 μm or less.

[0697] The sphericity of (R2) is preferably 0.9 or more, and more preferably 0.95 or more.

[0698] The preferred Mg content of (R3) is 5 × 10⁻⁶. -4 3×10 of the above % by mass -3 Less than 1% by mass, more preferably 1×10 -3 2.5 × 10⁻⁶ (by weight) or more -3 Less than 1% by mass, more preferably 1.5 × 10⁻⁶. -3 2.5 × 10⁻⁶ (by weight) or more -3 Less than % of the mass.

[0699] The preferred Sr content of (R4) is 3 × 10⁻⁶. -3 1.5 × 10⁻⁶ (by weight) or more -2 Less than 10% by mass, more preferably 4×10 -3 1.3 × 10⁻⁶ (by weight) or more -2 Less than 5% by mass, more preferably 5×10 -3 1×10 of mass% or more -2 Less than % of the mass.

[0700] It is preferable to satisfy any one of the conditions (R1) to (R4), more preferably to satisfy multiple conditions, and even more preferably to satisfy all conditions.

[0701] [III. Medical Grade Calcium Sulfate Curing Composition]

[0702] Next, we will describe

[17] a medical calcium sulfate curing composition that can also be used as a raw material for a medical calcium carbonate composition.

[0703] Medical calcium sulfate curing compositions that meet all of the conditions in (T1) to (T5) below exhibit curing properties and are therefore useful medical materials.

[0704] (T1) The acid-dissolved residue is less than 1% by mass.

[0705] (T2) has a volume of 5×10 -13 m 3 above.

[0706] (T3) is a medical composition that is essentially pure calcium sulfate.

[0707] (T4) The content of calcium sulfate hemihydrate is 50% or more by mass.

[0708] (T5) If multiple compositions in contact are immersed in water, solidification occurs to form a porous body with a compressive strength of 0.3 MPa or more.

[0709] Previously, it was known that calcium sulfate hemihydrate powder could be cured, but it was not known that calcium sulfate with an acid-dissolving residue of less than 1% by mass and substantially pure for medical use, and a volume of 5 × 10⁻⁶, was available. -13 m 3 The calcium sulfate particles solidify to form a porous body with a compressive strength of 0.3 MPa or higher.

[0710] If the particles contain more than 50% by mass of calcium sulfate hemihydrate, and are kneaded in water, some or all of them will become calcium sulfate dihydrate. Through the bridging of the precipitated calcium sulfate dihydrate crystals, the particles combine with each other to form a porous body.

[0711] Even in volumes smaller than 5×10 -13 m 3 In certain conditions, solidification can occur to form porous bodies, thus gaining usefulness, but its usefulness is limited. Therefore, a volume of 5 × 10⁻⁶ is required. -13 m 3 The above. From the viewpoint of the formation of porous bodies useful for tissue invasion and compressive strength, the volume is preferably 5 × 10⁻⁶. -13 m 3 Above 1×10 -9m 3 The following is more preferably 4×10 -12 m 3 Above 5×10 -10 m 3 The volume is further preferably 1.4 × 10⁻⁶. -11 m 3 Above 1.1×10 -10 m 3 the following.

[0712] From the viewpoint of curability, the calcium sulfate hemihydrate content must be 50% by mass or more. Curability increases with increasing calcium sulfate hemihydrate content; therefore, the calcium sulfate hemihydrate content is preferably 70% by mass or more, more preferably 80% by mass or more, and even more preferably 90% by mass or more.

[0713] The formation of a porous calcium sulfate body is useful in itself, but its usefulness is limited when the mechanical strength of the porous body is low. In this invention, a necessary condition is that if multiple components in contact are immersed in water, curing occurs to form a porous body with a compressive strength of 0.3 MPa or higher. The compressive strength of the cured body is preferably 0.5 MPa or higher, more preferably 1.0 MPa or higher. The compressive strength varies depending on the degree of contact; therefore, when different compressive strengths are obtained, the highest compressive strength is taken as the compressive strength of the composition.

[0714] [IV. Method for manufacturing a medical-grade calcium sulfate composition]

[0715] Next,

[18] will be described. A method for manufacturing medical calcium sulfate hemihydrate particles as a medical calcium sulfate curable composition is useful, characterized in that it is the manufacturing method of the aforementioned “III Medical Calcium Sulfate Curable Composition”, and the manufacturing method includes (U2) and (U3) as necessary steps and (U1) and (U4) as optional steps.

[0716] "(U1) Degreasing process of polymer materials" is a process of degreasing calcium sulfate particles or blocks containing polymer materials by heat treatment so that the acid-dissolved residue is less than 1% by mass.

[0717] This process is used when calcium sulfate blocks or granules containing polymeric materials are used as raw materials. It involves degreasing the raw material through heat treatment to reduce the acid-dissolving residue to less than 1% by mass. A residue of less than 1% by mass is essential, preferably less than 0.5% by mass, more preferably less than 0.3% by mass, even more preferably less than 0.1% by mass, and ideally 0% by mass. The heat treatment is typically carried out at 700°C or higher. Calcium sulfate becomes anhydrous at 700°C or higher; therefore, anhydrous calcium sulfate blocks or granules can be produced through this process.

[0718] The “(U2) Calcium sulfate dihydrate manufacturing process” is as follows: water is added to anhydrous calcium sulfate or calcium sulfate hemihydrate particles or blocks formed by a polymer material degreasing process, or water is added to calcium sulfate hemihydrate powder to solidify it, thereby manufacturing calcium sulfate dihydrate particles or blocks.

[0719] When using calcium sulfate containing polymer materials, anhydrous calcium sulfate granules or blocks can be manufactured through a polymer degreasing process. Therefore, water is added to produce calcium sulfate dihydrate granules or blocks.

[0720] Without the need to use calcium sulfate containing polymer materials, calcium sulfate hemihydrate powder is mixed with water and solidified to produce calcium sulfate dihydrate granules or blocks.

[0721] "(U3) Calcium sulfate hemihydrate manufacturing process" is a process of dehydrating calcium sulfate dihydrate particles or blocks to produce calcium sulfate hemihydrate particles or blocks.

[0722] This process involves dehydrating calcium sulfate dihydrate particles or lumps in the gas phase to produce calcium sulfate hemihydrate particles or lumps with a content of 50% by mass or more. Typically, dehydration in the atmospheric gas phase is carried out using known heat treatment methods, and the calcium sulfate hemihydrate content can be easily controlled by optimizing the heat treatment time and temperature.

[0723] "(U4) Particle size adjustment process" is based on forming a volume of 5×10 -13 m 3 The above describes the process of adjusting the size of particles.

[0724] This process involves forming a volume of 5×10. -13 m 3 The above process involves adjusting the size of the particles. This process can be performed at any point in the overall process. For example, calcium sulfate powder can be mixed with polymers such as polyvinyl alcohol and then spray-dried to form a particle size of 5 × 10⁻⁶. -13 m 3 The above are spherical particles.

[0725] In addition, calcium sulfate blocks can be crushed and sieved.

[0726] As mentioned above, the volume needs to be adjusted to be 5×10. -13 m 3 The above. From the viewpoint of the formation of porous bodies useful for tissue invasion and compressive strength, it is preferable to adjust the volume to 5 × 10. -13 m 3 Above 1×10 -9 m 3 The following is a preferred adjustment to 4×10 -12 m 3 Above 5×10 -10 m 3 The following is a further optimization and adjustment to 1.4×10 -11 m 3 Above 1.1×10 -10 m 3 the following.

[0727] [V Medical Grade Calcium Phosphate Composition]

[0728] Next, we will describe

[19] , namely, the medical calcium phosphate composition made from the medical calcium carbonate composition.

[0729] The following medical calcium phosphate composition is highly useful, characterized in that it satisfies all of the conditions (V1) to (V3) below, and at least one condition selected from the group of (V4) to (V10), with (V11) or (V12) as an optional condition.

[0730] It should be noted that (V1), (V2), (V5), (V6), (V9), and (V10) are each as necessary as (A), (B), (F), (G), (J), and (K) mentioned above.

[0731] The condition "(V3) As a medical composition, it is substantially pure calcium phosphate, and its composition is selected from the group consisting of carbonate apatite, apatite containing HPO4 groups, tricalcium phosphate, leucite, and dicalcium phosphate." is a condition shared with the medical calcium composition of the present invention. In the case of a composition selected from the group consisting of carbonate apatite, apatite containing HPO4 groups, tricalcium phosphate, leucite, and dicalcium phosphate, the reactivity is excellent, and therefore it is particularly preferred. These calcium phosphates, except for tricalcium phosphate, cannot be manufactured by sintering, but can be manufactured by a compositional transformation reaction of dissolution and exudation using calcium carbonate or the like as a precursor in an aqueous solution. Regarding carbonate apatite, as described in Patent Document 1. Highly reactive apatite containing HPO4 groups, leucite, and dicalcium phosphate can also be manufactured in an aqueous solution, but the HPO4 groups turn into pyrophosphate upon heating, and therefore cannot be manufactured by sintering.

[0732] Additionally, “(V4) A honeycomb structure having multiple through-holes extending in one direction (excluding honeycomb structures that do not meet any of the following conditions: composed of tricalcium phosphate, and having a pore volume of 0.01 cm³ relative to the mass of the honeycomb structure as determined by mercury porosimetry). 3 / g or more; the diameter of the circle passing through the two ends and the center of any one through hole is 1 cm or more and 50 cm or less; the arithmetic mean roughness (Ra) of the partition surface in the direction of the through hole in the honeycomb structure is 0.7 μm or more. ) ” is the same as the aforementioned “(E) is a honeycomb structure having multiple through holes extending in one direction, and in the fine pore distribution measurement based on mercury intrusion porosimetry, the fine pore volume with a pore diameter of 10 μm or less relative to the mass of the honeycomb structure is greater than 0.02 cm 3 / g. Similar conditions apply, but when the composition is not tricalcium phosphate, there are no conditions related to pore volume. However, considering bone replacement and tissue affinity of medical calcium phosphate compositions, in pore distribution determination based on mercury intrusion porosimetry, pore volumes with pore diameters of 10 μm or less relative to the mass of the honeycomb structure are greater than 0.02 cm³. 3 / g is preferred, and the volume is more preferably 0.04cm³. 3 / g or more, further preferably 0.08cm 3 / g or more.

[0733] "(V7) In the mercury porosimetry determination, the pore volume with a pore size of 1 μm or more and 6 μm or less relative to the pore volume with a pore size of 6 μm or less is 5% or more." This is a condition similar to the aforementioned "(H)". When manufacturing a medical calcium phosphate composition using a medical calcium carbonate composition as a raw material, phosphoric acid is imparted, thus reducing the number of pores with small pore volumes. Therefore, the pore volume with a pore size of 1 μm or more and 6 μm or less relative to the pore volume with a pore size of 6 μm or less is set to 5% or more, more preferably 7% or more, and even more preferably 10% or more.

[0734] "(V8) The maximum compressive strength obtained in any direction is greater than or equal to the reference compressive strength [S] calculated by the following formula (wherein, it does not include honeycomb structures having multiple through holes extending in one direction, and in the mercury porosimetry determination, the pore volume with a pore diameter of less than 10 μm relative to the mass of the honeycomb structure is 0.02 cm³). 3 The following are examples of / g.

[0735] S = S0 × C × exp(-b × P)

[0736] (Where, S0 and b are constants, S0 is 500, b is 0.068, C is a constant determined according to the composition, which is 1 in the case of carbonate apatite or apatite containing HPO4 groups or tricalcium phosphate, 0.5 in the case of leucobrycete, and 0.1 in the case of dicalcium phosphate, and P is the percentage of porosity of the composition.)” is a condition similar to that described above (I), but the constant C is a constant determined according to the composition rather than the polymorphism of calcium carbonate.

[0737] "(V11) Composed of apatite with a carbonate content of 10% by mass or more." is an optional condition. Furthermore, since the carbonate content is 10% by mass or more, it is carbonate apatite. Carbonate apatite is a component of vertebrate bone, therefore it has high utility.

[0738] "(V12) Composition with apatite containing less than 10% by mass of carbonate groups" is also an optional condition. Since the apatite contains less than 10% by mass of carbonate groups, it becomes carbonate apatite and hydroxyapatite with low carbonate group content. Depending on the condition, slow bone replacement is sometimes desired. In such conditions, a medical calcium phosphate composition containing apatite containing less than 10% by mass of carbonate groups is preferred. Since the rate of bone replacement is controlled by the amount of carbonate groups in the apatite structure, the carbonate group content is more preferably 6% by mass or less, and sometimes further preferably 3% by mass or less. Additionally, hydroxyapatite without carbonate groups is sometimes preferred.

[0739] [V Medical Calcium Phosphate Composition: Specific Trace Components]

[0740] Next,

[20] will be explained. Calcium phosphate compositions, especially apatite, have high adsorption capacity. In addition, calcium phosphate produced in aqueous solution has a high specific surface area. In cases where these calcium phosphate compositions are already infected, tissue affinity cannot be expected. Therefore, it is sometimes preferable to have calcium phosphate compositions containing trace components to prevent infection. As trace components, silver or silver compounds are useful.

[0741] From the viewpoint of preventing infection, a medical calcium phosphate composition that satisfies either (AG1) or (AG2) is a useful medical calcium phosphate composition. A medical calcium phosphate composition that satisfies either (AG1) or (AG2) and also satisfies one of the optional conditions (AG3) to (AG10) below is sometimes a more preferred medical calcium phosphate composition.

[0742] The necessity of the volume requirement in (AG1) and (AG2) is the same as that in (A).

[0743] In (AG1), it is essential that the calcium phosphate compound contains 0.01% to 3% by mass of silver or a silver compound. In (AG2), it is essential that the calcium phosphate compound contains 0.01% to 3% by mass of silver phosphate. Sometimes silver is introduced into the calcium phosphate crystal structure, but silver primarily exerts its antibacterial properties in the form of silver ions. Therefore, to prevent postoperative infection, silver or a silver compound not contained in the calcium phosphate crystal structure is effective. Furthermore, the content of silver or a silver compound is extremely important; low content results in no antibacterial effect, while high content adversely affects tissue affinity. Therefore, the amount of silver or a silver compound contained in the medical calcium phosphate composition must be 0.01% to 3% by mass. This content is preferably 0.02% to 2% by mass, more preferably 0.03% to 1% by mass, and even more preferably 0.05% to 1% by mass. Moreover, these contents are preferably ensured by excluding silver contained in the calcium phosphate crystal structure.

[0744] The condition for (AG1), "selected from the group consisting of carbonate apatite, apatite containing an HPO4 group, leucobrycite, and dicalcium phosphate," cannot be manufactured by sintering and is a condition related to calcium phosphate manufactured in aqueous solution. It is unknown whether a calcium phosphate composition obtained by containing silver or silver compounds in a calcium phosphate compound that could not previously be manufactured by sintering is available.

[0745] Regarding (AG2), the calcium phosphate composition also includes sintered hydroxyapatite and tricalcium phosphate bodies that can be manufactured by sintering, but the bonding of silver phosphate crystals to the surface of the calcium phosphate composition is essential. If silver phosphate crystals are bonded to the surface of the calcium phosphate composition, the silver phosphate dissolves from the composition surface, resulting in a high antibacterial effect. Furthermore, the dissolution of silver phosphate begins at surfaces that have never been bonded to the calcium phosphate composition, thus resulting in a calcium phosphate composition exhibiting a longer-lasting antibacterial function. The area ratio of silver phosphate crystals bonded to the surface of the calcium phosphate composition is preferably 20% or more of the surface area of ​​the silver phosphate crystals, more preferably 30% or more, and even more preferably 40% or more. Additionally, the area of ​​silver phosphate bonded to calcium phosphate is preferably 2 × 10⁻⁶. -12 m 2 The above is preferred, specifically 6×10 -12 m 2 The above is further preferred to be 1×10 -11 m 2 above.

[0746] (AG3) to (AG10) are optional conditions, not mandatory. (AG3) is an optional condition related to (AG1). Silver phosphate, with its low solubility, is expected to have a long-term antibacterial effect and is therefore sometimes preferred over other silver compounds.

[0747] "(AG4) The calcium phosphate composition contains silver or silver compounds in its surface and interior portions, and the ratio of the silver concentration in the surface portion to the silver concentration in a portion at least 50 μm from the surface toward the center is 1.2 or higher." This is an optional condition associated with specific calcium phosphate compositions having different silver concentrations within the composition. Postoperative infections include early infections occurring shortly after surgery and delayed infections, such as infections occurring more than 2 months after surgery, and prevention of both is desirable. In the early postoperative period, infection prevention is prioritized over tissue affinity, therefore a higher silver concentration is preferred. Therefore, when tissue reconstruction is performed using a calcium phosphate composition, it is desirable to have a greater number of free silver ions around the composition. This can be achieved by having a high concentration of silver or silver phosphate in the surface portion of the composition.

[0748] In the case of bioabsorbable calcium phosphates such as carbonate apatite and tricalcium phosphate, if the surface portion is absorbed, the silver or silver compound in the surface portion also disappears. After a certain period post-surgery, the risk of infection decreases, thus tissue affinity becomes more important, but prevention of delayed infection is still necessary. Therefore, it is preferable that silver or silver compounds are contained in both the surface and interior portions of the calcium phosphate composition, and the ratio of the silver concentration in the surface portion to the silver concentration in the portion at least 50 μm from the surface towards the center is preferably 1.2 or more. This ratio is more preferably 2 or more, and even more preferably 3 or more.

[0749] The surface portion and the interior portion of this composition are essentially the surface portion absorbed by osteoclasts and the interior portion excluding the surface portion. In the case of a porous body having interconnecting pores of 30 μm or more that osteoclasts can penetrate, the portion other than the surface portion (not the apparent surface) excluding the portion without interconnecting pores of 30 μm or more is considered the interior portion. The ratio of the concentration of silver or silver compounds in the surface portion to the interior portion is quantified by performing surface analysis and interior analysis using an energy-dispersive X-ray analyzer, an X-ray photoelectron spectroscopy analyzer, or the like. It should be noted that the term "surface portion" is defined as the portion located within 50 μm of the surface, and the term "interior portion" is defined as the portion located at least 50 μm of the surface. In cases where it is difficult to determine the silver concentration in the surface and interior using the above-described method, a dissolution rate test as specified in JIS-T0330-3, 9.3, is performed on the calcium phosphate composition using an aqueous solution at pH 5.5. The ratio between the silver concentration in the surface layer (calculated from the amount of silver dissolved until the weight decreases to the same level as when 50 μm of the surface layer is dissolved) and the silver concentration in the sample is calculated.

[0750] (AG5) to (AG10) are optional conditions associated with specific porous calcium phosphate structures. Porous structures are more likely to become foci of infection than dense structures, and since these porous structures are useful as medical calcium phosphate compositions, they are intended to prevent infection in medical calcium phosphate compositions.

[0751] [V Medical Calcium Phosphate Composition: Specific Cellular Structure and Specific Microstructure and Composition]

[0752] Next, we will describe the compositions that are particularly useful in

[21] medical calcium phosphate compositions.

[0753] Similar to medical calcium carbonate compositions, medical calcium phosphate compositions require high reactivity and disease-specific properties. Therefore, it is preferable to satisfy at least one of the following conditions (W1) to (W7).

[0754] "(W1) is a honeycomb structure with multiple through-holes extending in one direction, and in mercury porosimetry, the pore volume with a pore diameter of less than 10 μm relative to the mass of the honeycomb structure is 0.01 cm³." 3 / g or more. This relates to the micropores in the trabecular bone. Composition is a factor related to osteoconduction and bone replacement, and both large and micropores significantly affect the usefulness of the medical composition. The presence of specific micropores in a certain quantity or more influences useful properties such as promoting osteoclast-based reabsorption. The pore volume, preferably 0.01 cm³, has a pore diameter of 10 μm or less relative to the mass of the honeycomb structure. 3 / g or more, more preferably 0.03cm 3 / g or more, further preferably 0.05cm 3 / g or more.

[0755] "(W2) is a honeycomb structure having multiple through holes extending in one direction, and the diameter of the circle passing through the two ends and the center of any one through hole is 1 cm to 50 cm." This is a honeycomb structure useful for specific conditions. As mentioned above, bones also include curved columnar bones that are not straight columns. In bone reconstruction procedures, medical calcium phosphate honeycomb structures with curved columnar shapes are useful. Furthermore, in cases of bone reconstruction in a direction perpendicular to the bone surface, it is desirable for the through holes of the honeycomb structure to not open relative to the surrounding binding tissue, but only relative to the bone surface.

[0756] In a honeycomb structure, it is preferred that the diameter of the circle passing through the two ends and the center of any through hole is 1 cm or more and 50 cm or less. More preferably, the diameter of the circle is 2 cm or more and 20 cm or less, and even more preferably, the diameter of the circle is 3 cm or more and 10 cm or less.

[0757] "(W3) In a honeycomb structure, the arithmetic mean roughness (Ra) of the septum wall surface in the through-hole direction is 0.7 μm or more." This is an effective honeycomb structure for cell adhesion, etc. The arithmetic mean roughness (Ra) of the septum wall surface in the through-hole direction referred to here is the arithmetic mean roughness of the honeycomb surface independent of the septum walls. In medical carbonate apatite honeycomb structures, when the arithmetic mean roughness (Ra) increases, cell adhesion and other properties improve, resulting in increased osteoconductivity. The arithmetic mean roughness (Ra) is more preferably 1.0 μm or more, and even more preferably 1.5 μm or more.

[0758] (W4)~(W7) correspond to (AJ1)~(AJ4) in [3], and are medical calcium phosphate compositions with excellent tissue affinity and bone replacement properties.

[0759] The average particle size of (W4) is preferably 2 μm or more and 8 μm or less, more preferably 3 μm or more and 7 μm or less, and even more preferably 4 μm or more and 6 μm or less.

[0760] The sphericity of (W5) is preferably 0.9 or more, and more preferably 0.95 or more.

[0761] The preferred Mg content of (W6) is 5 × 10⁻⁶. -4 3×10 of the above % by mass -3 Less than 1% by mass, more preferably 1×10 -3 2.5 × 10⁻⁶ (by weight) or more -3Less than 1% by mass, more preferably 1.5 × 10⁻⁶. -3 2.5 × 10⁻⁶ (by weight) or more -3 Less than % of the mass.

[0762] The preferred Sr content of (W7) is 3×10⁻⁶. -3 1.5 × 10⁻⁶ (by weight) or more -2 Less than 10% by mass, more preferably 4×10 -3 1.3 × 10⁻⁶ (by weight) or more -2 Less than 5% by mass, more preferably 5×10 -3 1×10 of mass% or more -2 Less than % of the mass.

[0763] It should be noted that, for the average particle size and sphericity, the particles are distinguished and measured and calculated according to the grain boundaries of the calcium phosphate composition.

[0764] It is preferable to satisfy any one of the conditions (W1) to (W7), more preferably to satisfy multiple conditions, and even more preferably to satisfy all conditions.

[0765] [VI. Method for manufacturing medical-grade calcium phosphate compositions: specific trace components]

[0766] Next, the method for manufacturing the medical-grade calcium phosphate composition will be described.

[0767] First,

[22] will be explained. Calcium phosphate compositions containing silver or silver phosphate, such as

[20] and

[21] , can be manufactured under conditions of (AH1) or (AH2). If necessary, more preferred compositions can be manufactured under specific conditions where (AH3) to (AH9) are optional.

[0768] The term "volume is 10" is used in both (AH1) and (AH2). -12 m 3 The condition of "the above-mentioned particles or lumps" is a necessary condition for manufacturing calcium phosphate compositions with excellent tissue affinity.

[0769] (AH1) relates to a method for manufacturing calcium phosphate compositions that cannot be produced by sintering, "using silver or a silver compound comprising 0.01% to 3% by mass, and having a composition selected from the group consisting of calcium carbonate, calcium hydroxide, calcium oxide, calcium sulfate, and calcium hydrogen phosphate, and having a volume of 10 -12 m 3 In the above-mentioned granular or block-shaped raw material calcium composition, a process is performed to "attribute a carbonate group to the composition when the raw material calcium composition is other than calcium carbonate," thereby converting the composition of the calcium composition into calcium carbonate. For example, in the case of calcium hydroxide, the calcium hydroxide is exposed to carbon dioxide.

[0770] Furthermore, the process includes "a step of exposing the sample to an aqueous solution of phosphate or a mixed aqueous solution of phosphate and magnesium salt, thereby transforming its composition to include silver or silver compounds, selected from the group consisting of carbonate apatite, apatite containing HPO4 groups, leucobite, and dicalcium phosphate." To expose the sample to the aqueous solution of phosphate or the mixed aqueous solution of phosphate and magnesium salt, it can be done by simply immersing it in the aqueous solution, or by spraying the aqueous solution onto the raw calcium composition. Through this exposure step, a calcium phosphate composition can be manufactured. The carbonation step, the step of exposing the sample to the aqueous solution of phosphate or the mixed aqueous solution of phosphate and magnesium salt, and the carbonation step can be performed simultaneously.

[0771] (AH2) includes the following steps: exposing a raw calcium composition selected from the group consisting of apatite, tricalcium phosphate, leucobalite, octacalcium phosphate, and calcium hydrogen phosphate, as a calcium phosphate composition, to an aqueous solution containing silver ions, thereby forming silver phosphate in the raw calcium composition. For example, if tricalcium phosphate is immersed in an aqueous solution of silver nitrate, a portion of the tricalcium phosphate dissolves, releasing phosphate ions and calcium ions. The solubility of silver phosphate formed from silver ions and phosphate ions is lower than that of tricalcium phosphate; therefore, silver phosphate precipitates on the surface of the tricalcium phosphate composition. It should be noted that when the tricalcium phosphate is porous and the aqueous solution of silver nitrate permeates into the porous body, silver phosphate precipitates on the surface of the tricalcium phosphate in contact with the aqueous solution of silver nitrate. The type, concentration, and immersion time of the aqueous solution containing silver ions are not particularly limited, but silver nitrate or silver carbonate are preferred due to their solubility.

[0772] Satisfying (AG1) or (AG2) is a necessary condition, but by further satisfying (AG3) to (AG10), it is sometimes possible to manufacture a more preferred medical calcium phosphate composition.

[0773] (AH3) is a manufacturing method related to (AG4) in

[20] . By adjusting the silver ion concentration and immersion time of the aqueous solution, it is also possible to manufacture calcium phosphate compositions with different silver concentrations in the interior and the surface, but the manufacturing time is shorter when using aqueous solutions with different silver ion concentrations. In many cases, the raw calcium phosphate composition is immersed in a first aqueous solution to precipitate a lower concentration of silver phosphate in the interior, and then immersed in a second aqueous solution to precipitate a higher concentration of silver phosphate on the surface. Therefore, the silver ion concentration of the second aqueous solution must be higher than that of the first aqueous solution.

[0774] (AH4) to (AH9) are conditions related to the raw material calcium composition necessary for manufacturing (AG5) to (AG10) of

[20] .

[0775] [VI. Method for manufacturing medical-grade calcium phosphate compositions: specific raw materials]

[0776] Next,

[23] will be explained.

[23] relates to any of the medical calcium phosphate compositions described in

[19] to

[21] , and particularly to (W4) to (W7) of

[21] . A medical calcium phosphate composition satisfying the conditions of (W4) to (W7) can be achieved by using calcium carbonate powder satisfying the conditions of (AI1) to (AI4) as a calcium source.

[0777] The average particle size of (AI1) is preferably 2 μm or more and 8 μm or less, more preferably 3 μm or more and 7 μm or less, and even more preferably 4 μm or more and 6 μm or less.

[0778] The sphericity of (AI2) is preferably 0.9 or more, and more preferably 0.95 or more.

[0779] The preferred Mg content of (AI3) is 5 × 10⁻⁶. -4 3×10 of the above % by mass -3 Less than 1% by mass, more preferably 1×10 -3 2.5 × 10⁻⁶ (by weight) or more -3 Less than 1% by mass, more preferably 1.5 × 10⁻⁶. -3 2.5 × 10⁻⁶ (by weight) or more -3 Less than % of the mass.

[0780] The preferred Sr content of (AI4) is 3 × 10⁻⁶. -3 1.5 × 10⁻⁶ (by weight) or more -2 Less than 10% by mass, more preferably 4×10 -3 1.3 × 10⁻⁶ (by weight) or more -2 Less than 5% by mass, more preferably 5×10 -3 1×10 of mass% or more -2 Less than % of the mass.

[0781] It is preferable to satisfy any one of the conditions (AI1) to (AI4), more preferably to satisfy multiple conditions, and even more preferably to satisfy all conditions.

[0782] Next,

[24] will be described. A method for manufacturing a medical calcium carbonate composition of the present invention, or a medical calcium phosphate composition of the present invention, which imparts a phosphoric acid component to the medical calcium carbonate composition of the present invention under specific conditions, is useful.

[0783] As a method of imparting this material, it is preferable to impregnate a medical calcium carbonate composition in an aqueous solution containing phosphoric acid, such as a phosphate aqueous solution.

[0784] The type of calcium phosphate formed by imparting phosphoric acid to a calcium carbonate composition can be controlled by factors such as the pH of the solution and coexisting ions. This allows for the manufacture of medical-grade calcium phosphate compositions containing compounds such as carbonate apatite, hydroxyapatite, tricalcium phosphate, leucite, octacalcium phosphate, calcium hydrogen phosphate, and calcium dihydrogen phosphate. In manufacturing these medical-grade calcium phosphate compositions, the medical-grade calcium carbonate contains carbonate groups in its composition; therefore, medical-grade carbonate apatite compositions containing carbonate groups are particularly useful.

[0785] The amount of carbonate groups in a medical-grade apatite composition can be controlled using pH. Previously, a 1-molar concentration of Na₂HPO₄ at pH 8.9 or Na₃PO₄ at pH 13.1 was used. However, it was found that by setting the pH below 8.9, the amount of carbonate groups in the medical-grade apatite composition could be controlled. By setting the pH below 8.9, a medical-grade apatite composition with a lower carbonate group content than previously manufactured apatite can be produced, but the effect is limited at pH 8.8. Therefore, in this invention, aqueous solutions containing phosphoric acid with a pH of 8.5 or higher and aqueous solutions containing phosphoric acid with a pH below 8.5 are distinguished.

[0786] Even more surprisingly, it was found that lowering the pH of the phosphate aqueous solution accelerated the dissolution reaction from calcium carbonate to calcium phosphate, thus shortening the calcium phosphate production time. The reason is presumably that the dissolution reaction is accelerated at lower pH levels, but the details remain unclear.

[0787] In addition, by setting the pH below 5.5, the composition of calcium carbonate can be converted into calcium hydrogen phosphate, and by preparing an aqueous solution containing both phosphoric acid and magnesium, tricalcium phosphate such as leucobrycete can be manufactured.

[0788] Lowering the pH of the phosphate solution shortens the production time of calcium phosphate, but also reduces the amount of carbonate groups in the production of carbonate apatite. To shorten the production time of carbonate apatite without reducing the amount of carbonate groups, the phosphate solution with a low pH should contain carbonate components. However, it was found that carbonate apatite cannot be produced if the carbonate concentration exceeds 1.0 mol. Furthermore, it was found that even at a carbonate concentration of 0.6 mol, carbonate apatite production is time-consuming. While the details are not fully elucidated, it is believed that this is because the presence of carbonate ions in the aqueous solution reduces the difference in supersaturation between calcium carbonate and carbonate apatite, making it difficult to form carbonate apatite.

[0789] That is, in order to achieve this purpose, an aqueous solution containing both phosphoric acid and carbonic acid at a concentration of less than 0.5 moles with a pH of less than 8.5 is useful.

[0790] Furthermore, it was found that when a medical calcium carbonate composition was given a phosphoric acid component using an aqueous solution containing both phosphoric acid and a carbonate component at a concentration of less than 0.5 moles, the arithmetic mean roughness (Ra) increased. The mechanism is unclear, but the presence of carbonate groups in the solution reduces the difference in supersaturation relative to calcium carbonate and apatite, resulting in limited nucleus formation. This is believed to promote the growth of the formed apatite, leading to an increase in the arithmetic mean roughness (Ra) of the honeycomb structure surface.

[0791] As an aqueous solution imparting phosphoric acid to a medical calcium carbonate composition from these combinations, at least one aqueous solution selected from the group consisting of the following aqueous solutions is useful.

[0792] (X1) An aqueous solution containing phosphoric acid with a pH of 8.5 or higher.

[0793] (X2) An aqueous solution containing phosphoric acid with a pH less than 8.5.

[0794] (X3) An aqueous solution containing both phosphoric acid and carbonic acid at a concentration of less than 0.5 moles, with a pH of 8.5 or higher.

[0795] (X4) An aqueous solution containing both phosphoric acid and carbonic acid at a concentration of less than 0.5 moles, with a pH less than 8.5.

[0796] (X5) An aqueous solution containing both phosphoric acid and magnesium.

[0797] [VI. Method for manufacturing medical-grade calcium phosphate compositions: Method for gas replacement within the composition]

[0798] Next,

[25] will be explained. As described above, a medical calcium carbonate composition is manufactured by exposing a medical calcium carbonate composition to an aqueous phosphate solution, etc., by means of impregnation, etc. However, as described above, the method for manufacturing a medical calcium phosphate composition from a medical calcium carbonate composition uses a dissolution-extraction reaction. Therefore, it is necessary to dissolve the medical calcium carbonate composition from the surface. Basically, it is sufficient to impregnate the medical calcium carbonate composition in an aqueous phosphate solution, etc., but the medical calcium carbonate composition basically has internal pores that are large or micropores. Therefore, sometimes the dissolution reaction is hindered by gases such as air in the internal pores. In this case, the composition becomes a calcium phosphate composition with unreacted calcium carbonate residue, which is sometimes not preferred as a medical calcium phosphate composition. In order to prevent the hindrance to the reaction, the gas in the internal pores of the medical calcium carbonate composition can be replaced with an aqueous solution containing phosphoric acid.

[0799] That is, the process of "(Y1) replacing part or all of the gas in the pores of the medical calcium carbonate composition that has been impregnated in an aqueous solution containing phosphoric acid with an aqueous solution containing phosphoric acid" can be performed.

[0800] There are several useful steps to replace part or all of the gas in the pores of a medical calcium carbonate composition impregnated in an aqueous solution containing phosphoric acid with the aqueous solution containing phosphoric acid. However, since the medical calcium carbonate composition is essentially a material wetted in an aqueous solution containing phosphoric acid, the step of "(Y2) applying vibration to the medical calcium carbonate composition impregnated in an aqueous solution containing phosphoric acid to replace part or all of the gas in the pores of the medical calcium carbonate composition with the aqueous solution containing phosphoric acid" is also effective. For example, an ultrasonic vibrator is effective for applying vibration.

[0801] As a process similar to the vibration application process, (Y3) is also useful in that it involves flowing an aqueous solution containing phosphoric acid around the medical calcium carbonate composition and replacing part or all of the gas in the pores of the medical calcium carbonate composition with an aqueous solution containing phosphoric acid. By flowing an aqueous solution containing phosphoric acid around the medical calcium carbonate composition, it is possible to promote the wetting of the surface of the pores inside the medical calcium phosphate composition by the aqueous solution containing phosphoric acid.

[0802] "(Y4) The process of degassing a container containing an aqueous solution of phosphoric acid impregnated with a medical-grade calcium carbonate composition under reduced pressure, thereby replacing part or all of the gas in the pores of the medical-grade calcium carbonate composition with the aqueous solution containing phosphoric acid," is related to the so-called degassing under reduced pressure. By reducing pressure, the gas in the internal pores of the medical-grade calcium carbonate composition is reduced, and by releasing the pressure, the surrounding aqueous solution containing phosphoric acid is introduced into the internal pores of the medical-grade calcium carbonate composition. From the viewpoint of maximizing the degree of replacement, it is preferable to repeatedly perform depressurization and depressurization.

[0803] "(Y5) The step of replacing part or all of the gas in the internal pores of a medical calcium carbonate composition with a gas that has a higher solubility in an aqueous solution containing phosphoric acid than air" is also useful. For example, carbon dioxide has a higher solubility in an aqueous solution containing phosphoric acid than air. If a medical calcium carbonate composition whose internal pores have been replaced with carbon dioxide is impregnated in an aqueous solution containing phosphoric acid, the carbon dioxide dissolves in the aqueous solution containing phosphoric acid, and therefore, the air in the internal pores of the medical calcium carbonate composition is replaced with the aqueous solution containing phosphoric acid.

[0804] "(Y6) The process of replacing part or all of the gas in the internal pores of the medical calcium carbonate composition with a solvent having a contact angle smaller than that of water and being compatible with water" is also effective. For example, ethanol has a contact angle smaller than that of water. Therefore, ethanol can easily penetrate into the internal pores of the medical calcium carbonate composition. If a medical calcium carbonate composition whose internal pores have been partially or completely filled with ethanol is impregnated in an aqueous solution containing phosphoric acid, the ethanol is compatible with the aqueous solution, and through diffusion, the ethanol in the internal pores is replaced with an aqueous solution containing phosphoric acid. The solvent, having a contact angle smaller than that of water and being compatible with water, reduces the contact angle of the aqueous solution containing phosphoric acid relative to the medical calcium carbonate composition like a surfactant. Therefore, it is not necessary to replace all the gas in the internal pores of the medical calcium carbonate composition; a very small portion is sufficient to function effectively.

[0805] [VI. Method for manufacturing medical-grade calcium phosphate composition: reaction vessel]

[0806] Next,

[26] will be explained. The medical calcium phosphate composition is manufactured by imparting a phosphoric acid component to the medical calcium carbonate composition of the present invention (which is manufactured by imparting a carbonic acid component to a raw calcium composition). Generally, medical materials need to be protected from foreign matter contamination, and from the viewpoint of simplifying the manufacturing process, it is preferable not to remove the material and to carry out the manufacturing process using the same reaction vessel.

[0807] The "reaction vessel" is not particularly limited, and any ordinary vessel can be used, but a vessel with an inlet and an outlet is preferred. This is because it is necessary to introduce carbonic acid and phosphoric acid into the reaction vessel. For the introduction of carbonic acid, an inlet for introducing carbon dioxide or the like into the reaction vessel is necessary. In addition, an outlet is necessary to expel air from the reaction vessel. Alternatively, pressure can be applied to the reaction vessel from the inlet to force solvents or the like out through the outlet.

[0808] From the viewpoint of ensuring a uniform reaction, a column-shaped container used in chromatography or a mesh container capable of holding a raw material calcium composition or a medical-grade calcium carbonate composition is preferred as the container. In the case of a column-shaped container, uniform reaction of the composition in the container can be ensured by circulating gas or solution within the column-shaped container. In the case of a reaction container capable of holding a mesh container, uniform reaction of the composition in the mesh container can be ensured by allowing gas or liquid to flow through the mesh.

[0809] This process prevents contamination and allows for the manufacture of medical-grade calcium phosphate compositions through simple operation. Therefore, "the manufacturing process of medical-grade calcium phosphate compositions, characterized by continuously carrying out the manufacturing process of medical-grade calcium phosphate compositions, and the manufacturing process is characterized by not removing the material, and continuously carrying out the following (Z1) to (Z4), or (Z1), (Z3), (Z4), or (Z1), (Z3) in the same reaction vessel in the order described," is a useful method for manufacturing medical-grade calcium phosphate compositions.

[0810] The step of "(Z1) imparting a carbonic acid component to the raw calcium composition to manufacture a medical calcium carbonate composition" is a necessary step, which involves exposing the raw calcium composition to carbon dioxide or carbonate ions to impart a carbonic acid component. It should be noted that, as described in (D9) above, there are also steps where the raw calcium composition is partially carbonated by exposing it to carbon dioxide or carbonate ions in the gas phase, and then exposed to carbon dioxide or carbonate ions in the liquid phase. In such cases, in principle, the steps after (D9) and (Z2) or (Z3) must be performed consecutively. It should be noted that it is preferable to perform all of the steps described in (D9) above.

[0811] "(Z2) Cleaning process of medical calcium carbonate composition" is an optional process. For example, it is a useful process when cleaning and removing the pore-forming material after carbonating the raw calcium composition containing the pore-forming material to manufacture the medical calcium carbonate composition.

[0812] This process involves imparting carbonic acid to a raw calcium composition to manufacture a medical-grade calcium carbonate composition. It does not require partial carbonation and subsequent carbonation to be performed without removing the material and using the same reaction vessel. However, it is preferable to perform partial carbonation and subsequent carbonation without removing the material and using the same reaction vessel.

[0813] "(Z3) The process of imparting phosphoric acid to the medical calcium carbonate composition" is a necessary process. For example, if the medical calcium carbonate composition is impregnated in an aqueous phosphate solution, the phosphoric acid is imparted to the medical calcium carbonate composition, and a medical calcium phosphate composition can be manufactured.

[0814] "(Z4) Cleaning process of medical calcium carbonate composition" is an optional process. Medical calcium phosphate composition is manufactured using the aforementioned (Z3), but this composition contains phosphates, etc., and this process removes substances other than those in the composition. A cleaning process is required in the manufacture of medical calcium phosphate composition, but sometimes other containers such as sieves are used to perform cleaning and dimensional adjustment simultaneously, therefore this is an optional process.

[0815] [VII. Medical Grade Calcium Hydroxide Composition]

[0816] Next, we will describe

[27] , namely, the medical calcium hydroxide composition.

[0817] A medical calcium hydroxide composition characterized by satisfying all of (AB1) to (AB3) and at least one of (AB4) to (AB8) is useful.

[0818] It should be noted that (AB1), (AB2), (AB4), (AB5), (AB6), (AB7), and (AB8) are the same as (A), (B), (V4), (F), (G), (J), and (K) mentioned above.

[0819] "(AB3) is a substantially pure calcium hydroxide as a medical composition." This is a common feature of the medical calcium composition of the present invention, but the essential feature of (AB3) is that it is composed of calcium hydroxide.

[0820] [XIII Method for manufacturing medical-grade calcium hydroxide composition: honeycomb structure]

[0821] Next, the process of manufacturing a medical calcium hydroxide composition that satisfies the aforementioned conditions (AB4) will be described.

[28]

[0822] Medical calcium hydroxide honeycomb structures are manufactured by using (AD1) and one of the groups (AD2) to (AD5) as a required process and (AD6) to (AD8) as optional processes.

[0823] It should be noted that (AD1), (AD6), (AD7), and (AD8) are the same as (E1), (E2), (E3), and (E4), respectively.

[0824] "(AD2) Degreasing process" is a process of degreasing the porous calcium hydroxide containing polymer materials by dissolving the residue with acid to less than 1% by mass. Degreasing must be carried out under conditions where calcium hydroxide will not decompose into calcium oxide or carbonate into carbonate apatite. For example, reduced pressure can be applied at a temperature where calcium hydroxide will not decompose to remove polymer materials that have become monomers through depolymerization, etc.

[0825] "(AD3) Hydration process via calcium oxide" is the following process: calcium hydroxide porous body containing polymer material is degreased by dissolving the residue with acid to less than 1% by mass, and calcium oxide porous body is prepared. Then, the calcium oxide porous body is hydrated to prepare calcium hydroxide porous body.

[0826] "(AD4) Hydration process via calcium carbonate and calcium oxide" is the following process: calcium hydroxide containing polymeric material is heat-treated in the presence of carbon dioxide to produce a porous calcium carbonate containing polymeric material. Then, the residue is degreased by dissolving it with acid to a mass of less than 1%, and a porous calcium oxide is produced. Then, the porous calcium oxide is hydrated to produce a porous calcium hydroxide.

[0827] "(AD5) Manufacturing process starting from calcium carbonate porous body" is as follows: calcium carbonate porous body containing polymer material is degreased by dissolving the residue with acid to less than 1% by mass, and calcium oxide porous body is prepared. Then, the calcium oxide porous body is hydrated to prepare calcium hydroxide porous body.

[0828] [Method for manufacturing XIII medical-grade calcium hydroxide composition: particulate-bound porous body]

[0829] Next, the process of manufacturing a medical calcium hydroxide composition that satisfies the aforementioned conditions (AB5) will be described.

[29]

[0830] The medical calcium hydroxide particle-bonded porous body that satisfies the aforementioned condition (AB5) is manufactured by using at least one of the following (AE1) and (AE2) and selected from the group consisting of (AD2) to (AD5) as a necessary process.

[0831] The "(AE1) Introducing Process" involves a volume of 10 -12 m 3 The above steps describe the process of loading calcium hydroxide granules containing polymer materials into the reaction vessel.

[0832] "(AE2) Particle bonding process" refers to any one of the following processes: a process of heat-treating the particles inside the reaction vessel to soften and fuse their surfaces together; a process of dissolving the surface of the particles to bond their surfaces together; and a process of fusing the surfaces of the particles together using a plasticizer, producing a volume of 3 × 10 -11 m 3 A particle-bonded porous body formed by combining multiple particles with a maximum diameter of 50 μm to 500 μm, and having multiple through-holes extending in multiple directions.

[0833] Through heat treatment, the polymer material softens and the particles bond together.

[0834] To dissolve the surface of the particle, it is necessary to expose the particle to a solvent that dissolves the polymer contained within it. For example, if the polymer is acrylic resin, it can be brought into contact with acetone or similar substances.

[0835] Plasticizers soften polymer materials. Known plasticizers can be used without restriction.

[0836] [XIII Method for manufacturing medical-grade calcium hydroxide composition: Method for manufacturing porous calcium oxide bodies]

[0837] Next, the process of manufacturing medical calcium hydroxide porous bodies using calcium hydroxide porous bodies or calcium carbonate porous bodies as raw materials will be described

[30] .

[0838] Medical-grade porous calcium hydroxide can be manufactured by thermally decomposing porous calcium hydroxide or porous calcium carbonate to produce porous calcium oxide, and then hydrating the porous calcium oxide.

[0839] [Manufacturing method of IX medical calcium composition: introduction sealing process or introduction process]

[0840] Next,

[31] will be explained. In the introduction and sealing process or the introduction process of combining multiple particles to create a particle-bonded porous body, there are no particular restrictions on the shape of the particles, and spheres, shapes with concave and convex shapes, broken objects, etc. can be used. In addition, dense bodies, porous bodies, hollow bodies, etc. can also be used without restriction.

[0841] However, from the viewpoint of improving the permeability and compressive strength of the manufactured medical calcium carbonate porous bodies, it is sometimes preferable to use particles that meet the requirements of "(AF1) the sphericity of the particles is 0.9 or higher" or "(AF2) the particles are hollow" for the sealing or introducing process.

[0842] "(AF1) The sphericity of the particles is 0.9 or higher." This is because by using spherical or near-spherical particles, the continuity of the pores formed between the particles is improved. Since spherical particles can easily contact each other, a porous body with high compressive strength can be manufactured.

[0843] The sphericity is preferably 0.9 or higher, more preferably 0.92 or higher, and even more preferably 0.95 or higher.

[0844] Furthermore, when particles satisfy the condition that "(AF2) particles are hollow," the hollow particles combine to form a particle-bonded porous body, thus possessing a double-layered pore shape. Such a porous body with a specific shape is sometimes considered particularly superior from the viewpoint of cell and tissue mobility and conduction, as well as bone replacement.

[0845] In addition, when loading the particles into the reaction vessel, it is sometimes preferred that "(AF3) the loose volume of the particles is more than 105% of the volume of the reaction vessel."

[0846] In the manufacture of a particle-bonded porous body with multiple through-holes extending in multiple directions, formed by the bonding of multiple particles, a sealing or introducing process is performed by loading the particles into a reaction vessel and sealing the opening of the reaction vessel in a manner that prevents the particles from discharging. After the sealing or introducing process, the particles are expanded or their composition is transformed, thereby bonding the particles together. For the formation of the porous body, it is necessary to use some method to bring the particles into contact or bond with each other, and increasing the contact area between the particles is effective in improving the compressive strength of the porous body. In addition, applying compressive stress between the particles is effective in increasing the contact area. As a method for applying compressive stress between the particles, the following method is effective: in the sealing or introducing process, the particles with a loose volume of more than the volume of the reaction vessel are loaded into the reaction vessel, and the opening of the reaction vessel is sealed as needed in a manner that prevents the particles from discharging.

[0847] In principle, by loading the particles with a loose volume greater than 100% of the volume of the reaction vessel into the reaction vessel, compressive stress can be added between the particles. However, from the viewpoint of increasing the compressive stress added between the particles, the loose volume of the particles loaded into the reaction vessel is preferably 105% or more, more preferably 110% or more, and even more preferably 120% or more, relative to the volume of the reaction vessel.

[0848] [Reagent Kit for X-Bone Defect Regeneration Therapy]

[0849] Next, we will describe

[32] , namely, "a kit for bone defect reconstruction therapy, which is composed of a solid part containing aragonite and tricalcium α-phosphate and a solution part containing phosphate, wherein when the solid part and the solution part are mixed, carbonate apatite is formed and solidified."

[0850] Medical aragonite compositions and medical carbonate apatite block compositions are useful for bone defect reconstruction, but in the case of block form, shaping into the bone defect shape is sometimes cumbersome, and in the case of granular form, it sometimes migrates from the bone defect. Therefore, a treatment kit for bone defect reconstruction that solidifies to form carbonate apatite is useful.

[0851] On the other hand, if α-tricalcium phosphate (αTCP) is mixed with a solution such as water, it dissolves, forming calcium and phosphate ions in the solution. This solution becomes supersaturated relative to calcium-deficient hydroxyapatite, causing calcium-deficient hydroxyapatite crystals to precipitate from the solution. The crystals then entangle, forming a solidified calcium-deficient hydroxyapatite body. However, calcium-deficient hydroxyapatite is not a bone component; for example, it exhibits poor osteoclast absorption compared to carbonate apatite, which is a bone component. If the calcium and phosphate ions formed in the solution from the dissolution of αTCP coexist with carbonate ions, carbonate apatite crystals (not calcium-deficient hydroxyapatite crystals) are formed, and the crystals entangle, forming a solidified carbonate apatite body. Calcium carbonate is useful as a carbonate ion source, but in calcium carbonate, the stable calcite dissolves slowly and cannot supply sufficient carbonate ions to the solution. Therefore, when a mixture of calcite and αTCP is mixed in solution, although some carbonate apatite crystals precipitate, the precipitation of calcium-deficient hydroxyapatite crystals is dominant.

[0852] On the other hand, compared to calcite, the metastable aragonite dissolves more rapidly and can supply a greater amount of carbonate ions into the solution. Therefore, when a mixture of aragonite and αTCP is mixed in solution, less calcium-deficient hydroxyapatite crystals precipitate, while carbonate apatite crystals precipitate predominate. Therefore, the solid component must contain both aragonite and αTCP.

[0853] Furthermore, phosphates must be included in the solution portion in which the solids are mixed. This is because calcium ions, carbonate ions, and phosphate ions are dissolved from aragonite and α-TCP into the solution containing phosphate ions, thereby making the solution supersaturated relative to the carbonate apatite, forming carbonate apatite in a shorter time, and thus ensuring a suitable curing time.

[0854] There are no particular limitations on the phosphate as long as it can dissolve and supply phosphate ions to the solution. From the viewpoint of solubility, NaH₂PO₄, Na₂HPO₄, Na₃PO₄, KH₂PO₄, K₂HPO₄, K₃PO₄, (NH₄)H₂PO₄, (NH₄)₂HPO₄, (NH₄)₃PO₄, and their mixed salts are further preferred. Furthermore, the phosphate concentration in the solution is preferably 0.1 mol or higher, more preferably 0.2 mol or higher, and even more preferably 0.4 mol or higher. This is because a higher phosphate concentration results in a higher supersaturation of the solution relative to the carbonate apatite.

[0855] In addition, there are no particular restrictions on the pH of the solution. However, from the point of view of tissue affinity, the pH of the solution is preferably above 6.0 and below 9.0.

[0856] [Reagent Kit for X-Bone Defect Regeneration Therapy: Aragonite Content]

[0857] Next,

[33] will be explained. The essential component of the solid part of the above-mentioned defect reconstruction treatment kit is aragonite and tricalcium α-phosphate. Therefore, if kneading is performed in the above-mentioned solution part, solidification occurs to form carbonate apatite. From the viewpoints of the amount of carbonate apatite formed, the amount of carbonate groups in the carbonate apatite structure, and the mechanical strength of the solidified body, the content of aragonite contained in the solid part is preferably 10% by mass or more and 60% by mass or less, more preferably 15% by mass or more and 50% by mass or less, and even more preferably 20% by mass or more and 40% by mass or less.

[0858] [Reagent Kit for X-Bone Defect Regeneration Therapy: Solution Section]

[0859] Next,

[34] will be explained. The solution portion must contain a phosphate, preferably an acid having multiple carboxyl groups, a bisulfite, a cellulose derivative, a dextran sulfate, a chondroitin sulfate, an alginate, or a glucomannan. It should be noted that a phosphate is essential for the solution portion; therefore, an acid having multiple carboxyl groups is substantially the same as a salt of an acid having multiple carboxyl groups.

[0860] Acids with multiple carboxyl groups can be exemplified by dicarboxylic acids and tricarboxylic acids. Examples of dicarboxylic acids include oxalic acid, malonic acid, succinic acid, malic acid, itaconic acid, phthalic acid, glutaric acid, and maleic acid. Examples of tricarboxylic acids include aconitic acid.

[0861] If an acid with multiple carboxyl groups is added to the solution, the curing time becomes shorter. This is believed to be because the acid with multiple carboxyl groups chelates with α-TCP or aragonite; therefore, if the solid portion is kneaded in the solution, curing based on a chelation reaction occurs.

[0862] Examples of bisulfites include sodium bisulfite and potassium bisulfite. While the mechanism of action of bisulfites is not fully understood, the curing time is shortened when bisulfite is included in the solution.

[0863] When cellulose derivatives, dextran sulfate, chondroitin sulfate, alginate, and glucomannan are added to the solution portion, viscosity is achieved. This improves operability when kneading the solid and solution portions together.

[0864] Cellulose derivatives are chemically modified cellulose compounds that impart solubility in solvents. Examples include carboxymethyl cellulose, methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, and their salts. Adding a cellulose derivative to the solution increases its viscosity, resulting in improved workability when kneading with the solid portion. The concentration of the cellulose derivative varies depending on the degree of polymerization, but is generally preferred to be 2% by mass or less.

[0865] For pastes obtained by kneading solid parts in a solution containing these additives, it is sometimes possible to suppress the property of the paste collapsing upon contact with bodily fluids. This is believed to be because the penetration of water into the paste before curing is the cause of collapse. That is, it is believed that by increasing the viscosity of the paste to inhibit the penetration of water into the paste or by promoting curing, water-induced disintegration can be suppressed.

[0866] [Reagent Kit for X-Bone Defect Regeneration Therapy: Volume of Aragonite]

[0867] Next,

[35] will be explained. The volume of the aragonite contained in the solid portion is not particularly limited, but the solid portion contains a volume of 10... -12 m 3 The above-mentioned kit for bone defect reconstruction treatment using aragonite is preferred because its solidified form sometimes exhibits high mechanical strength. Although the mechanism of increased mechanical strength is not fully elucidated, it is speculated to be 10... -12 m 3 The above-mentioned spherical aragonite performs the same function as the filler in the composite material. Additionally, the volume is 10... -12 m 3 The above-mentioned aragonite is not completely consumed in the reaction with αTCP. That is, calcite coated with carbonate apatite is formed within the solidified body. The calcium carbonate coating on the carbonate apatite surface is sometimes useful for improving osteoconductivity by releasing calcium ions. (Volume 10) -12 m 3 The above-mentioned aragonite is preferably contained in an amount of 10% by mass or more of the aragonite contained in the solid portion, and more preferably in an amount of 20% by mass or more.

[0868] [Reagent Kit for X-Bone Defect Regeneration Therapy: Volume of Aragonite]

[0869] Next,

[36] will be explained. On the other hand, when it is desirable to increase the purity or content of the carbonate apatite formed by imparting porosity to the solidified body, the average particle size of the aragonite contained in the solid part is preferably 6 μm or less. This particle size is more preferably 4 μm or less, and even more preferably 2 μm or less. It is believed that this is because if the particle size is small, the specific surface area is large, the dissolution rate of carbonate ions and calcium ions into the solution increases, and the formation of carbonate apatite can be promoted. On the other hand, if the particle size becomes smaller, the consistency of the kit for bone defect reconstruction treatment sometimes becomes worse when kneading. Therefore, this particle size is sometimes preferably 0.5 μm or more, or 1 μm or more.

[0870] The present invention will be described in more detail below using examples, but the scope of the present invention is not limited to the examples.

[0871] The general conditions are as described below. It should be noted that conditions different from these are described in individual embodiments or comparative examples.

[0872] <Raw Materials>

[0873] In this embodiment and comparative example, unless otherwise specified, the calcium hydroxide used was ultra-high purity (CSH) manufactured by Ube Material Co., Ltd., the calcium carbonate used was Calmaru manufactured by Sakai Chemical Industry Co., Ltd. with an average particle size of 5 μm, the tricalcium phosphate (α-type) used was α-TCP-B manufactured by Taihei Chemical Industry Co., Ltd., and the super-hard gypsum used was a specially selected product obtained by removing components other than calcium sulfate from NEW FUJI ROCK WHITE manufactured by GC Co., Ltd. Calcined gypsum is calcium sulfate hemihydrate. All conditions are satisfied (B).

[0874] All substances other than those mentioned above were prepared using premium reagents. Therefore, all materials manufactured in this embodiment and comparative example are artificial materials.

[0875] Calcium hydroxide spheres are manufactured as follows: Calcium hydroxide spheres with 0.5% by mass of KURARAY POVAL PVA-205C (manufactured by KURARAY Corporation) added as a binder are spherically shaped using a spray drying method. The spheres are then sieved to produce spheres that pass through a 200 μm sieve but not a 100 μm sieve. Surface tension is utilized during spray drying to create the spheres. Additionally, hollow spheres are produced, possibly due to drying from the periphery during the drying process. The manufactured calcium hydroxide spheres are heated to 1000°C at a rate of 5°C per minute using an electric furnace, and then heated at 1000°C for 6 hours, followed by furnace cooling.

[0876] In the manufacture of the honeycomb structure, a raw material calcium composition is mixed with a wax-based binder manufactured by Nagamine Manufacturing Co., Ltd. at a mass ratio of 75:25. Then, a mold for forming the honeycomb structure is installed on a LABO PLASTOMILL manufactured by Toyo Seiki Co., Ltd., and extrusion molding is performed. The honeycomb structure, which is essentially a cylindrical raw material calcium composition containing a polymer material and having outer peripheral sidewalls, is manufactured by extrusion molding. Degreasing is performed, and carbonation and removal of the outer peripheral sidewalls are carried out as needed.

[0877] <Reaction Vessel>

[0878] Unless otherwise specified, a split mold with a diameter of 6 mm and a height of 3 mm is used as the reaction vessel. The lower surface of the reaction vessel is sealed with a glass plate, while the upper surface is open. The raw materials are introduced into the reaction vessel through the upper surface of the opening. The glass plate seal prevents the raw materials from escaping from the reaction vessel, but water and water vapor can permeate into the interior of the reaction vessel through the gaps. Hereinafter, for simplicity, this reaction vessel will be referred to as a split mold reaction vessel with a diameter of 6 mm and a height of 3 mm.

[0879] It should be noted that the volumes of the calcium composition, calcium phosphate composition, and raw calcium composition in the examples are all 3 × 10⁻⁶. -11 m 3 Therefore, the description of volume is sometimes omitted in the embodiments and comparative examples.

[0880] 90% methanol is obtained by mixing methanol and water at 90% by volume and 10% by volume, 90% ethanol is obtained by mixing ethanol and water at 90% by volume and 10% by volume, and 90% acetone is obtained by mixing acetone and water at 90% by volume and 10% by volume.

[0881] "Carbonization using 90% methanol at 4°C" refers to the following process: Carbon dioxide containing 90% methanol at 4°C is introduced at a rate of 100 mL per minute into a 500 mL container at 4°C containing the raw calcium composition. The amount introduced is determined proportionally based on the container volume. This allows the 90% methanol at 4°C to flow around the raw calcium compound. Excess carbon dioxide is then discharged from the container's outlet, the reaction is carried out for 7 days, and then the mixture is dried.

[0882] <Powder X-ray Diffraction Analysis: XRD Analysis>

[0883] In this invention, a BRUKER D8 ADVANCE type powder X-ray diffractometer was used for compositional analysis. The output power was set to 40 kV and 40 mA, and the X-ray source was CuKα (λ = 0.15418 nm). The pattern obtained from the XRD analysis is referred to as the XRD pattern.

[0884] The content of aragonite and calcite in medical-grade calcium carbonate compositions is calculated based on the peak area ratio of the XRD pattern. The peaks representing aragonite are... Figure 3 The peak areas of the 110, 112, and 114 faces of the aragonite shown are used as the peaks of calcite. Figure 3 The peak area of ​​the 104 facets of the calcite shown.

[0885] In cases where substances other than aragonite and calcite are present in a medical calcium carbonate composition, the content of aragonite and calcite is calculated using the internal standard method.

[0886] <Average Particle Size>

[0887] Disperse the powder in 100 mL of distilled water and use an ultrasonic cleaner with a frequency of 45 kHz-100 W for 30 seconds. Then, use a laser diffraction particle size distribution measuring device (Shimadzu Corporation, SALD-300V) to determine the particle size distribution within 1 minute. The particle size at the 50% cumulative value of the particle size distribution is taken as the average particle size.

[0888] Arithmetic mean roughness (Ra)

[0889] The arithmetic mean roughness (Ra) of the material surface was measured using a Keyence VK-9710 color 3D laser microscope.

[0890] <Determination of Pore Distribution Based on Mercury Intrusion Porosimetry>

[0891] The pore size distribution was measured using an AUTOPORE 9420 manufactured by Shimadzu Corporation. The contact angle between mercury and the material used in the calculations is as described above.

[0892] <Acid-dissolved residue>

[0893] Acid-dissolved residue is the residue left when calcium carbonate or the like is dissolved in hydrochloric acid of 1 mole concentration in an amount equal to 20 moles of the calcium carbonate or the like. This dry mass is expressed as a percentage relative to the mass of the calcium carbonate or the like.

[0894] For example, in the case of a sample consisting of 0.2 g of calcium carbonate, it is dissolved in 40 mL of a 1 M hydrochloric acid aqueous solution, and the mixture is filtered and washed with water. The unfiltered acid-dissolved residue is dried and its mass is determined, expressed as a percentage relative to the sample mass.

[0895] Acid-dissolved residue is a value that is only meaningful when the raw calcium composition contains polymeric materials; therefore, it is sometimes omitted when using raw calcium compositions that do not contain polymeric materials.

[0896] <Compressive Strength>

[0897] As an indicator of mechanical strength, compressive strength is determined. The compressive strength of calcium hydroxide blocks was measured using a Shimadzu universal testing machine (AGS-J type). The specimen was broken at a crosshead speed of 10 mm per minute, and the compressive strength was determined by the maximum force exerted until failure.

[0898] <Volume>

[0899] The loose volume of the manufactured cylindrical composition is calculated by measuring the diameter and height. The same applies to other shapes. It should be noted that, except for Comparative Example 3, the volume of all materials manufactured in the examples and comparative examples is 10. -12 m 3 Therefore, descriptions are sometimes omitted in the embodiments and comparative examples.

[0900] <Antibacterial and Cytotoxicity Tests>

[0901] For antibacterial properties, the procedure was performed according to JIS Z2801. *Staphylococcus epidermidis* (NBRC12993) was used as the test strain. The bacterial count was adjusted to 4.35 × 10⁻⁶ using 1 / 500 ordinary broth medium. 4 The bacterial culture was inoculated onto the sample surface at a concentration of CFU / mL. One side of the sample was then covered with a polyethylene film, and the culture was carried out for 24 hours at 37°C and 90% relative humidity. After incubation, the bacterial culture was recovered, diluted as needed, and the bacterial count was determined using the agar plate method.

[0902] For cytotoxicity assays, the procedure shall be performed in accordance with ISO 10993-5:2009. That is, inoculate the sample surface with 1×10⁻⁶ spores. 4 MC3T3-E1 cells were cultured at 37°C in a 5 vol% CO2 incubator using a mixture of α-modified Eagle minimum essential medium, 10% fetal bovine serum, and 1% antibiotics. After 24 hours of culture, cells were fixed with 2% glutaraldehyde, stained with Hoechst stain, and counted. Cells with a viability of less than 70% were considered cytotoxic, while those with a viability of more than 70% were considered non-cytotoxic.

[0903] <Physical Property Evaluation of Reagent Kits for Bone Defect Reconstruction Therapy>

[0904] The curing properties of the bone defect reconstruction treatment kit were determined at 37°C and 100% relative humidity. Curing time was measured using the Vicat needle method, and indirect tensile strength was measured 24 hours after curing. The composition of the cured body was analyzed using XRD and FT-IR analysis.

[0905] (Example 1)

[0906] Wako Pure Pharmaceutical Reagent's premium calcium hydroxide powder is loaded into a mold and uniaxially pressurized at 20 MPa to produce calcium hydroxide compressed powder with a diameter of φ6 mm and a height of 9 mm.

[0907] Next, 100 mL of 90% methanol was added to a 500 mL reaction vessel, and calcium hydroxide powder was placed on a mesh set in a manner that prevented the sample from contacting the solvent. The temperature was set to 4 °C.

[0908] Carbon dioxide is introduced into the 90% methanol section of the reaction vessel at a rate of 100 mL per minute via a bubbler, and then discharged through a drain valve located at the top of the reaction vessel. As a result, the calcium hydroxide powder is exposed to carbon dioxide containing 90% methanol, which flows around the calcium hydroxide powder.

[0909] It should be noted that methanol inhibits the formation of calcite or the growth of calcite crystals, while relatively promoting the formation of calcium carbonate other than calcite.

[0910] Calcium hydroxide solidified, thus producing a volume of 2.5 × 10⁻⁶. -4 m 3 The powder is made from a block of calcium hydroxide. Furthermore, since it is manufactured by flowing carbon dioxide containing 90% methanol around the calcium hydroxide powder, water, which is generated as a byproduct in the reaction of calcium hydroxide and carbon dioxide, evaporates from the inside of the calcium hydroxide powder and is removed.

[0911] According to XRD analysis ( Figure 3 Unreacted calcium hydroxide was observed with an exposure period of 2 days, but pure calcium carbonate with a composition of 97% by mass of aragonite and 3% by mass of calcite was confirmed with an exposure period of 7 days. Acid-soluble residues were 0% by mass.

[0912] These results confirm that the medical aragonite composition of the present invention can be manufactured.

[0913] It should be noted that the porosity of this medical-grade aragonite composition is 45%, and since it contains more than 20% by mass of aragonite, the constant determined according to the polymorphism is 0.01. The baseline compressive strength was calculated to be 0.23 MPa, while the compressive strength of this composition is 24 MPa, confirming that it is above the baseline compressive strength.

[0914] Next, the medical aragonite composition was immersed in a 1-molar concentration Na2HPO4 aqueous solution at pH 8.9 for 3 days at 80°C, thereby imparting phosphate to the medical aragonite composition.

[0915] The volume of the manufactured composition is 2.5 × 10⁻⁶. -4 m 3 In XRD analysis ( Figure 4 Peaks of carbonate groups were detected in the infrared spectrophotometer and infrared spectrophotometer, confirming that the composition is pure carbonate apatite. Elemental analysis showed that the carbonate content was 10.8% by mass. Additionally, the acid-soluble residue was 0% by mass.

[0916] With a porosity of 42%, the baseline compressive strength was calculated to be 29 MPa, while the compressive strength of the composition was 32 MPa, confirming that it was above the baseline compressive strength.

[0917] These results confirm that medical-grade carbonate apatite compositions can be manufactured by imparting phosphates to the medical-grade aragonite compositions.

[0918] (Comparative Example 1)

[0919] Water was used instead of 90% methanol, and carbon dioxide was exposed to the calcium hydroxide powder using the same method as in Example 1.

[0920] When calcium hydroxide powder was exposed to carbon dioxide for 7 days, the calcium hydroxide solidified, producing a product with a volume of 2.5 × 10⁻⁶. -4 m 3 The block. Furthermore, XRD analysis revealed that the block consisted of 98% calcite by mass, 2% unreacted calcium hydroxide by mass, and 0% acid-dissolved residue by mass.

[0921] In mercury porosimetry, the ratio of the pore volume with a pore size of 1 μm to 6 μm to the pore volume with a pore size of 6 μm or less in this composition is 0%.

[0922] Furthermore, the porosity is 44%, and the reference compressive strength is calculated to be 25 MPa, while the compressive strength of the composition is 22 MPa, which is less than the reference compressive strength. In addition, since it does not meet any of (D) to (K) of [1], the manufactured calcite composition is not included in the present invention.

[0923] As can be seen from the comparison between Example 1 and this comparative example: by inhibiting the formation of calcite or the growth of calcite crystals and relatively promoting the formation of calcium carbonate other than calcite, it is possible to produce calcium carbonate containing more than 20% by mass of aragonite; methanol as an organic solvent is useful in this process; the formation of aragonite proceeds faster than the formation of calcite.

[0924] Next, the calcite block was impregnated in 2 molar concentration disodium hydrogen phosphate at 80°C for 3 days, thereby imparting phosphate to the medical aragonite composition.

[0925] The volume of the manufactured composition is 2.5 × 10⁻⁶. -4 m 3 The acid-dissolved residue was 0% by mass. However, XRD analysis confirmed that although apatite was formed, calcite, which was used as a raw material, remained.

[0926] The comparison between Example 1 and this comparative example confirms that the medical aragonite composition is more reactive than the calcite composition and is useful in the manufacture of apatite.

[0927] (Comparative Example 2)

[0928] The same manufacturing method as Example 11 of Patent Document 8 was implemented. Sifted 1-2 mm calcium sulfate interconnected porous anhydrous particles were immersed in 50 mL of a 2 mol concentration sodium carbonate aqueous solution at 4°C for 14 days. Compositional analysis by XRD yielded the same results as in Patent Document 8. Figure 3 b) The same XRD pattern shows that the polymorph of calcium carbonate is 83% by mass of calcite and 17% by mass of aragonite. The content of aragonite is less than 20% by mass. In addition, since it does not meet any of (D) to (K) of [1], the calcium carbonate composition produced is not included in the present invention.

[0929] Based on the comparison between Example 1 and this comparative example, the usefulness of the process, represented by the process using methanol, which inhibits the formation of calcite or the growth of calcite crystals and relatively promotes the formation of calcium carbonate other than calcite, is clear.

[0930] (Comparative Example 3)

[0931] The calcium hydroxide powder prepared in Example 1 was immersed in 50 mL of a 2 mol sodium carbonate aqueous solution at 4°C. Immediately after immersion, the powder disintegrated into a powder. The volume of the powder was less than 10... -12 m 3 Therefore, the calcite powder produced is not included in this invention.

[0932] As can be seen from the comparison of Examples 1, Comparative Examples 1 and 2 with this Comparative Example, when carbonation is carried out using a 2-molar concentration sodium carbonate aqueous solution at 4°C, not only is the content of aragonite formed limited, but it is also necessary to use calcium sulfate blocks that do not collapse even when immersed in the aqueous solution, and aragonite blocks cannot be manufactured by pressing calcium hydroxide powder. Therefore, it can be seen that the process of the present invention for manufacturing a medical aragonite composition by inhibiting the formation of calcite or the growth of calcite crystals and relatively promoting the formation of calcium carbonate other than calcite is excellent.

[0933] (Example 2)

[0934] <1. Preparation of the raw material calcium hydroxide composition>

[0935] Calcium hydroxide powder is loaded into a mold and uniaxially pressurized at 5 MPa to produce a product with a diameter of [missing information]. Calcium hydroxide powder with a height of 9mm.

[0936] In addition, the calcium hydroxide paste obtained by kneading the calcium hydroxide powder with ethanol at a mixing ratio of 1.0 under pressure of 5 MPa is pressed to produce calcium hydroxide paste powder.

[0937] In addition, the raw material calcium hydroxide paste is filled into an organosilicon tube with an inner diameter of 5 mm and a length of 5 mm, which serves as a mold, to manufacture a calcium paste composition contained in the mold.

[0938] In addition, the calcium hydroxide paste was mixed with sodium chloride particles (a porous material that passes through a 100μm sieve but not a 50μm sieve), and uniaxially pressurized at 5MPa to produce particles with a diameter of [missing information]. A powder of calcium hydroxide paste containing sodium chloride particles with a height of 9 mm, satisfying condition (AB6). All conditions (AB1) to (AB3) are satisfied.

[0939] Additionally, a portion of the pressed calcium hydroxide powder is used to manufacture pressed calcium hydroxide granules. Specifically, the pressed calcium hydroxide powder is pulverized using a scalpel-like method to produce pressed calcium hydroxide granules that pass through a 2mm mesh sieve but not through a 1.18mm mesh sieve. The minor diameter of these granules is 1mm or more and less than 5mm.

[0940] In addition, by clamping the fibers of the lactic acid-diol copolymer, the calcium hydroxide powder was uniaxially pressurized at a pressure of 5 MPa to manufacture a product with a diameter of [missing information]. Calcium hydroxide powder with a height of 2 mm is used to manufacture other calcium hydroxide powders by means of a 2 mm end portion. This process is repeated to produce fibers with a diameter satisfying (AB8). Furthermore, the central part of the 2mm high calcium hydroxide powder is bonded by bead-like fibers that bind the raw calcium hydroxide powder together at 2mm intervals.

[0941] All the calcium hydroxide compositions manufactured satisfy (AB1) to (AB3). Therefore, for the raw material calcium hydroxide compositions that satisfy (AB6) and (AB8) above, it has been confirmed that it is possible to manufacture a medical calcium hydroxide composition.

[0942] <2. Setup of the isotropic reaction vessel for the raw material calcium composition>

[0943] A stainless steel pressure vessel (TA125N) manufactured by AS ONE was used as the reaction vessel. This vessel has three threaded holes (hole A, hole B, and hole C) and a top cover. Pipe fittings manufactured by PISCO are used to connect pipes through hole A to the bottom of the reaction vessel; through hole B, a pipe extends 5 cm downwards from the top cover; and through hole C, a power cord for a blower is introduced into the reaction vessel from the outside. The inside of the pipe fittings is sealed with epoxy resin. Holes A and B function as inlet and outlet ports, respectively.

[0944] 90% ethanol and a stir bead are added to the reaction vessel. Next, a mesh container containing the raw material composition is placed in a manner that prevents it from contacting the 90% ethanol. A blower is installed on the mesh container. If the blower is plugged in, it supplies air to the mesh container side.

[0945] <3. Carbon Dioxide Replacement Process>

[0946] With the reaction vessel closed, carbon dioxide is introduced into the reaction vessel from the carbon dioxide storage cylinder through port A. Air in the reaction vessel is then expelled through port B, replacing it with carbon dioxide.

[0947] <4. Partial Carbonation Process>

[0948] Next, the orifice B is sealed, and the carbon dioxide pressure in the reaction vessel is increased to atmospheric pressure (100 kPa) using the pressure reducing valve of the carbon dioxide storage cylinder. The blower is then turned. This allows carbon dioxide containing 90% ethanol to flow around the calcium feedstock composition.

[0949] With orifice A closed, as carbonic acid is supplied to the raw material calcium composition, carbon dioxide in the reaction vessel is consumed and the pressure decreases. However, if the pressure reducing valve of the carbon dioxide storage cylinder is changed to below the set pressure, carbon dioxide is supplied, and the carbon dioxide pressure in the reaction vessel plus atmospheric pressure remains constant at 100 kPa.

[0950] The composition after 24 hours was analyzed using XRD, and the results showed that all samples contained aragonite and trace amounts of calcite in calcium hydroxide. Regarding the composition excluding sodium chloride (used as a pore-forming material) and fibers, the following results were obtained: for pressed calcium hydroxide powder, pressed calcium hydroxide granules, and pressed calcium hydroxide powder containing fibers, the aragonite content was 72% by mass, the calcite content was 3% by mass, and the calcium hydroxide content was 25% by mass. For pressed calcium hydroxide paste, calcium paste composition in a mold, and pressed calcium hydroxide paste containing sodium chloride particles, the aragonite content was 62% by mass, the calcite content was 4% by mass, and the calcium hydroxide content was 34% by mass.

[0951] Although unreacted calcium hydroxide remains, the raw calcium composition is partially carbonized to a state in which it can maintain its shape even when immersed in 90% ethanol without collapsing.

[0952] <5. Carbonation process>

[0953] Open the lid of the reaction vessel and remove the blower.

[0954] Next, 90% methanol is added so that the mesh container is completely immersed without contacting the pipe installed through hole B. After repeating the aforementioned <carbon dioxide replacement process>, hole B is sealed.

[0955] Next, the carbon dioxide storage cylinder is pressurized by adding atmospheric pressure to the carbon dioxide pressure in the reaction vessel to achieve a pressure of 100 kPa, and the stirrer is rotated with port A open.

[0956] Six days after the start of the carbonation process, disconnect the carbon dioxide storage cylinder connected to port A, open port B, and restore the pressure to atmospheric pressure. Then, introduce air into the reaction vessel through port B, discharging the solvent from port A. Next, seal port A and use a pump to depressurize the reaction vessel through threaded port B, thereby drying the medical-grade aragonite composition. After drying, stop the pump and introduce air into the reaction vessel through threaded port A to restore atmospheric pressure.

[0957] Further compositional analysis was performed using XRD. The results showed that, apart from sodium chloride and fibers used as pore-forming materials, the content of aragonite was 95% by mass and the content of calcite was 5% by mass in the cases of calcium hydroxide pressed powder, calcium hydroxide pressed powder particles, and calcium hydroxide pressed powder containing fiber. In the cases of calcium hydroxide paste pressed powder, calcium paste composition in a mold, and calcium hydroxide paste pressed powder containing sodium chloride particles, the content of aragonite was 93% by mass and the content of calcite was 7% by mass.

[0958] In a calcium carbonate composition manufactured from a powder of calcium hydroxide paste containing sodium chloride particles, an aggregation of multiple pores with diameters greater than 50 μm and less than 100 μm was identified, but no pores with a maximum diameter length greater than 100 μm were found. Furthermore, the volume of fine pores with diameters less than 10 μm, determined by mercury intrusion porosimetry, was 0.53 cm³. 3 / g.

[0959] Calcium hydroxide was not detected in any of the samples. Furthermore, acid-dissolved residues, excluding fibers, were 0% by mass.

[0960] Therefore, it was confirmed that a medical spherical aragonite block satisfying (D) was manufactured from calcium hydroxide powder, calcium hydroxide paste powder, and raw material calcium paste in a mold.

[0961] In addition, it was confirmed that medical-grade aragonite granules meeting conditions (D) and (G) were manufactured from calcium hydroxide paste containing sodium chloride particles as raw material.

[0962] In addition, it was confirmed that medical spherical aragonite particles satisfying (K) were manufactured from the bead-like fiber-bound raw material calcium hydroxide powder.

[0963] <6. Phosphoric acid infusion process>

[0964] A 1-molar concentration Na2HPO4 aqueous solution at pH 8.9, at 80°C, is introduced into the reaction vessel through hole A by immersion in a mesh container.

[0965] By sealing hole A and using a diaphragm pump, the air inside the reaction vessel is depressurized through threaded hole B, and then air is introduced through hole B. This operation degasses the air in the internal pores of the medical-grade calcium carbonate composition, filling these pores with the Na₂HPO₄ aqueous solution.

[0966] Next, the stir bead is rotated to maintain the temperature of the reaction vessel at 80°C.

[0967] <7. Cleaning and Drying Process>

[0968] Seven days after the phosphoric acid incorporation process, air is introduced through hole B, and the Na₂HPO₄ aqueous solution is discharged through hole A. Next, water at 80°C is introduced into the reaction vessel through hole A, and the water is discharged through hole B, thereby cleaning the product.

[0969] Next, air is introduced through hole B and water is discharged through hole A. Hole A is then sealed, and while maintaining the temperature of the reaction vessel at 80°C, air is discharged through hole B using a pump to dry the product under reduced pressure.

[0970] Peaks of carbonate groups were detected in XRD analysis and infrared spectroscopy, confirming that the composition was pure apatite carbonate. Elemental analysis showed a carbonate content of 10.8% by mass. Furthermore, acid-soluble residues were 0% by mass. Additionally, the volume of each component was 10... -12 m 3 above.

[0971] These analytical results confirm that medical carbonate apatite blocks satisfying all conditions in (V1) to (V3) were manufactured from raw calcium hydroxide powder, raw calcium hydroxide paste powder, and raw calcium paste in a mold.

[0972] The carbonate apatite composition manufactured using a calcium carbonate composition produced by pressing a calcium hydroxide paste containing sodium chloride particles into powder maintained its pore morphology, confirming the aggregation of multiple pores larger than 50 μm and smaller than 100 μm, but without any pores with a maximum diameter length exceeding 100 μm. Furthermore, the pore volume of fine pores smaller than 10 μm, determined by mercury intrusion porosimetry, was 0.80 cm³. 3 / g.

[0973] It was confirmed that sodium chloride particles, used as pore-forming materials, were dissolved to produce a porous medical carbonate apatite mass with (V6) pore aggregation.

[0974] It was also confirmed that bead-shaped fiber-bonded medical carbonate apatite blocks of the form of V10 were manufactured from the bead-shaped fiber-bonded raw material calcium hydroxide powder.

[0975] (Example 3)

[0976] Using the calcium hydroxide powder manufactured in <1. Manufacturing process of raw material calcium composition> in Example 2, after <2. Setting up the raw material calcium composition in the isotropic reaction vessel> and <3. Carbon dioxide replacement process> in Example 2, the reaction time in <4. Partial carbonation process> is extended to 7 days to carry out carbonation.

[0977] The composition of the manufactured product was analyzed by XRD after 7 days, and the results showed that it contained 95% by mass of aragonite, 4% by mass of calcite, and 1% by mass of calcium hydroxide.

[0978] As can be seen from the comparison between Example 2 and this Example, although a medical aragonite composition can be manufactured from raw calcium hydroxide powder by carbonation in the gas phase alone, 1% by mass of unreacted calcium hydroxide remains. Therefore, compared with the case of manufacturing a medical aragonite composition by carbonation in the gas phase alone, a medical aragonite composition with higher purity can be manufactured by performing partial carbonation in the gas phase followed by carbonation in the liquid phase.

[0979] (Comparative Example 4)

[0980] Perform the same procedures as in Example 3 without rotating the fan.

[0981] The composition of the manufactured product was analyzed by XRD after 7 days, and the result was a mixture of 71% by mass aragonite, 4% by mass calcite and 25% by mass calcium hydroxide.

[0982] In Example 3, where a blower was used to circulate carbon dioxide containing 90% ethanol around the feedstock calcium composition, after one day, it became 72% by mass aragonite, 3% by mass calcite, and 25% by mass calcium hydroxide. That is, it can be seen that in a closed reaction vessel, if carbon dioxide or carbonate ions containing organic solvents are not circulated around the feedstock calcium composition, the carbonation of the feedstock calcium compound is slow.

[0983] It is also known that because the water formed inside the raw material calcium hydroxide powder was not removed, a phase transformation from aragonite to calcite occurred, resulting in a decrease in the content of aragonite.

[0984] That is, it is known that in the manufacture of a medical aragonite composition starting from a raw calcium compound using a closed reaction vessel, the following method is useful: allowing substances such as ethanol, which inhibit calcite formation or calcite crystal growth and relatively promote aragonite formation, to flow around the raw calcium composition along with carbon dioxide, while removing water generated as a byproduct in the reaction between the raw calcium composition and carbon dioxide by means of evaporation.

[0985] (Example 4)

[0986] <1. Preparation of the raw material calcium hydroxide composition>

[0987] Calcium hydroxide and ammonium nitrate particles (a porous material that passes through a 100 μm sieve but not a 50 μm sieve) were mixed with an ammonium nitrate content of 20% by mass. The mixture was then subjected to uniaxial pressurization at 5 MPa to produce a particle with a diameter of [missing information]. Calcium hydroxide powder containing ammonium nitrate particles with a height of 9mm, meeting (AB7) standard.

[0988] <2. Setup of the isotropic reaction vessel for the raw material calcium composition>

[0989] The reaction vessel of Example 2 was used. However, instead of adding 90% ethanol and a stirring bead, approximately 10g of ammonium carbonate manufactured by Wako Pure Chemical Industries Co., Ltd. was added to the reaction vessel.

[0990] Next, a mesh container containing the compressed powder is set up so that it does not come into contact with ammonium carbonate. Additionally, a blower is installed on the mesh container.

[0991] <3. Carbon Dioxide Replacement Process>

[0992] Perform the same procedures as in Example 2.

[0993] <4. Carbonation process>

[0994] Next, seal hole B and heat the reaction vessel to 70°C. It should be noted that ammonium carbonate is known to decompose into carbon dioxide and ammonia at 58°C.

[0995] The carbon dioxide pressure in the reaction vessel is increased to 100 kPa by adding atmospheric pressure to the carbon dioxide pressure using a pressure reducing valve on a carbon dioxide storage cylinder, and then the blower is turned. This causes carbon dioxide containing ammonia to flow around the calcium feedstock composition.

[0996] Sev...

Claims

1. A kit for bone defect reconstruction therapy, comprising a solid portion containing aragonite and tricalcium alpha-phosphate, and a solution portion containing phosphate, wherein when the solid portion and the solution portion are mixed, carbonate apatite is formed and solidified.

2. The reagent kit for bone defect reconstruction therapy as described in claim 1, characterized in that, The content of aragonite in the solid part is more than 10% by mass and less than 60% by mass.

3. The kit for bone defect reconstruction therapy as described in claim 1 or 2, characterized in that, The solution contains at least one of an acid having multiple carboxyl groups, a bisulfite, a cellulose derivative, a dextran sulfate, a chondroitin sulfate, an alginate, and glucomannan, wherein the cellulose derivative is selected from carboxymethyl cellulose, methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, and their salts.

4. The kit for bone defect reconstruction therapy as described in claim 1 or 2, characterized in that, The solid portion has a volume of 10. -12 m 3 The above are garnets.

5. The kit for bone defect reconstruction therapy as described in claim 1 or 2, characterized in that, The average grain size of the aragonite is less than 6 μm.

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