JP-2026076376-A - Medical-grade calcium carbonate composition, related medical compositions, and methods for producing the same.

JP2026076376AJP 2026076376 AJP2026076376 AJP 2026076376AJP-2026076376-A

Abstract

[Problem] To provide a medical calcium carbonate composition, a medical calcium phosphate composition related to the medical calcium carbonate composition, and a method for producing the same, which highly satisfy the following requirements for medical materials implanted in the body: 1) tissue affinity, 2) bioavailability, 3) reactivity, and 4) mechanical strength. [Solution] By controlling the polymorphism and structure of calcium carbonate, medical compositions such as calcium carbonate and related medical compositions that highly satisfy the above elements can be manufactured. [Selection Diagram] Figure 7

Inventors

石川邦夫
都留寛治
戸井田力
中島康晴

Assignees

石川邦夫

Dates

Publication Date: 20260511
Application Date: 20260221
Priority Date: 20190827

Claims (10)

A medical-grade calcium carbonate composition or a medical-grade calcium phosphate composition characterized by satisfying all of the following conditions (A) to (C) and (F). (A) The volume is 10⁻¹² m³ or more. (B) When the composition is dissolved in 1 molar concentration hydrochloric acid in a volume equivalent to 20 molars, the acid-dissolved residue, which is a mass percentage of the mass of the calcium carbonate composition or calcium phosphate composition, is 1% by mass or less. (C) Primarily consisting of vaterite or calcite, with a purity of 99% by mass or more as calcium carbonate, or having a composition selected from the group consisting of carbonate apatite, apatite containing 4 HPO groups, tricalcium phosphate, witrochite, and calcium hydrogen phosphate, with a purity of 99% by mass or more as calcium phosphate. (F) A granular porous body having multiple through holes extending in multiple directions, formed by the bonding of multiple granules having a maximum diameter and length of 50 μm or more and 500 μm or less, wherein the pore volume of the granular porous body with a diameter of 10 μm or less is 0.05 cm³ /g or more, as measured by mercury intrusion method.
The calcium carbonate composition is formed by the bonding of calcium carbonate powders that satisfy any of the following conditions (AJ1) to (AJ4). Alternatively, it is a medical calcium phosphate composition that satisfies any of the following conditions (W4), (W5), (W6), or (W7): A medical calcium carbonate composition or a medical calcium phosphate composition according to feature 1. (AJ1) The average particle size is between 2 μm and 8 μm. (AJ2) The degree of sphericity is 0.9 or higher. (AJ3) The Mg content is 5 × 10⁻⁴ % by mass or more and 3 × 10⁻³ % by mass or less. (AJ4) The Sr content is 3 × 10⁻³ mass% or more and 1.5 × 10⁻² mass% or less. (W4) This is an aggregate of calcium phosphate with an average particle size of 2 μm or more and 8 μm or less. (W5) An aggregate of calcium phosphate with a sphericity of 0.9 or higher. (W6) The Mg content is 5 × 10⁻⁴ % by mass or more and 3 × 10⁻³ % by mass or less. (W7) The Sr content is 3 × 10⁻³ % by mass or more and 1.5 × 10⁻² % by mass or less.
A method for producing a medical calcium carbonate composition according to claim 1 that satisfies the above condition (F), using calcium oxide granules as a raw material, A method for producing a medical calcium carbonate composition, comprising the steps of (F1) and (F2) below, and at least one of the steps of (F3) and (F4). (F1) Introduction and Closure Process: A process in which calcium oxide granules are placed in a reaction vessel and the opening of the reaction vessel is closed to prevent discharge from the reaction vessel. (F2) Porous Body Formation Process: A process in which water or acetic acid is added to the calcium oxide granules inside the reaction vessel to form calcium hydroxide or calcium acetate, and the granules are expanded to produce a porous body. (F3) Carbonation Process: A carbonation process in which carbon dioxide is added to the calcium hydroxide porous body simultaneously with or after the porous body formation process to produce a calcium carbonate porous body, or a carbonation process in which calcium acetate is heat-treated to produce a calcium carbonate porous body after the porous body formation process. (F4) Calcium Oxide Carbonation Process: A carbonation process from a calcium oxide porous body in which at least one porous body selected from the group consisting of calcium hydroxide porous body, calcium carbonate porous body, and calcium acetate porous body is heat-treated to produce a calcium oxide porous body, and the calcium oxide porous body is exposed to carbon dioxide to produce a calcium carbonate porous body.
A method for producing a medical calcium carbonate composition according to claim 1 that satisfies the above condition (F), using calcium sulfate granules as a raw material, A method for producing a medical calcium carbonate composition, characterized by including the steps (F5) and (F6) below, or including the steps (F5), (F7), and (F9) below, with step (F8) being an optional step. (F5) Introduction process: A process in which calcium sulfate granules are placed in a reaction vessel. (F6) Porous material formation carbonation process: A process in which the calcium sulfate granules and carbonate ions inside the reaction vessel are reacted to convert the composition to calcium carbonate and harden the granules together to form a porous material. (F7) Porous material formation process: A process in which water is added to calcium sulfate hemihydrate granules or calcium sulfate anhydrous granules to produce a porous calcium sulfate dihydrate material. (F8) Heat treatment process: A process in which the porous calcium sulfate dihydrate material is heat-treated to produce a porous calcium sulfate anhydrous material. (F9) Carbonation process: A process in which the porous calcium sulfate dihydrate material or porous calcium sulfate anhydrous material is exposed to water containing carbonate ions to convert the composition to calcium carbonate.
A method for producing the medical calcium carbonate composition according to claim 1 that satisfies the conditions of (F) above, A method for producing a medical calcium carbonate composition, characterized in that (F10) and (F11) below, and one selected from the group (F12) to (F16) are required steps, and (F17) is an optional step. (F10) Introduction process: A process of placing polymer material-containing raw material calcium composition granules with a volume of 10⁻¹² m³ or more into a reaction vessel. (F11) Porous body formation process: A process of producing a granule-bonded porous body having a volume of 3 × 10⁻¹¹ m³ or more and having multiple through holes extending in multiple directions, formed by bonding multiple granules with a maximum diameter length of 50 μm or more and a maximum diameter length of 500 μm or less. (F12) Degreasing calcium carbonate sintering process: A degreasing and sintering process in which polymer material-containing calcium carbonate is degreasing by heating so that the acid-dissolved residue is 1% by mass or less, and the calcium carbonate is sintered. (F13) Degreasing carbonation process (F14) Degreasing and Carbonation Process via Calcium Oxide A process in which a porous calcium hydroxide material containing a polymer material is degreased by heating at an oxygen concentration of less than 30% so that the acid-dissolved residue is 1% by mass or less, and at the same time carbonated. A process in which a porous calcium hydroxide material containing a polymer material or a porous calcium carbonate material containing a polymer material is degreased by heating so that the acid-dissolved residue is 1% by mass or less, and is converted into a porous calcium oxide material, and thereafter the porous calcium oxide material is exposed to carbon dioxide to convert it into a porous calcium carbonate material. (F15) Degreasing and Carbonation Process via Calcium Carbonate and Calcium Oxide A process in which a porous calcium carbonate material containing a polymer material is heat-treated in the presence of carbon dioxide to convert it into a porous calcium carbonate material containing a polymer material, and thereafter the acid-dissolved residue is degreased by heating at an oxygen concentration of less than 30%, and is converted into a porous calcium oxide material, and thereafter the porous calcium oxide material is exposed to carbon dioxide to convert it into a porous calcium carbonate material. (F16) Degreasing and Carbonation Process via Calcium Sulfate A degreasing and carbonation process (F17) in which calcium sulfate containing polymer material is heated and degreased so that the acid -dissolved residue is 1% by mass or less, and then carbon dioxide or carbonate ions are applied to the resulting porous calcium sulfate to produce calcium carbonate. A shaping and finishing process performed after the degreasing and carbonation process.
A method for producing a medical calcium carbonate composition according to any one of 3 to 5, characterized by comprising at least one step selected from the group (L) to (Q) below. (L) A step of degreasing with an oxygen partial pressure of 30 kPa or higher. (M) A step of degreasing or carbonation with a carbon dioxide partial pressure of 30 kPa or higher. (N) A step of degreasing or carbonation with a gas containing oxygen or carbon dioxide at 150 kPa or higher. (O) A step of increasing the carbon dioxide concentration in the reaction vessel by replacing some or all of the air in the reaction vessel with carbon dioxide and then introducing carbon dioxide into the reaction vessel. (P) A carbonation step of supplying carbon dioxide so that the pressure in the closed reaction vessel becomes a constant value. (Q) A carbonation step of stirring or circulating the carbon dioxide in the reaction vessel.
A medical-grade calcium sulfate curable composition characterized by satisfying all of the following conditions (T1) to (T5). (T1) The acid-dissolved residue is 1% by mass or less. (T2) The volume is 5 × 10⁻¹³ m³ or more. (T3) The purity of calcium sulfate is 99% by mass or higher. (T4) The calcium sulfate hemihydrate content is 50% by mass or more. (T5) When the compositions are brought into contact with each other and immersed in water, they harden and form a porous body with a compressive strength of 0.3 MPa or more.
A method for producing a medical calcium sulfate hemihydrate granule, according to claim 7, characterized in that it includes (U2) and (U3) below as essential steps and (U1) and (U4) as optional steps. (U1) Polymer material degreasing process: A process of degreasing the polymer material-containing calcium sulfate granules or blocks by heat treatment to reduce the acid-dissolved residue to 1% by mass or less. (U2) Calcium sulfate dihydrate manufacturing process: A process of manufacturing calcium sulfate dihydrate granules or blocks by adding water to the calcium sulfate anhydrous or semihydrate granules or blocks formed in the polymer material degreasing process, or by adding water to calcium sulfate semihydrate powder and hardening it. (U3) Calcium sulfate semihydrate manufacturing process: A process of manufacturing calcium sulfate semihydrate granules or blocks by dehydrating the calcium sulfate dihydrate granules or blocks in the gas phase. (U4) Granule size adjustment process: A process of adjusting the size so that the granules have a volume of 5 × 10⁻¹³ m³ or more.
A medical calcium phosphate composition characterized by satisfying the following (AG6) and (AG1) or (AG2), and selecting the following (AG3) or (AG4). (AG1) The composition is one selected from the group consisting of carbonate apatite, apatite containing four HPO groups, vitrokite, and calcium hydrogen phosphate, and is in the form of granules or blocks with a volume of 10⁻¹² m³ or more, and contains 0.01% to 3% by mass of silver or a silver compound. (AG2) The composition is one selected from the group consisting of hydroxyapatite sintered body, tricalcium phosphate sintered body, carbonate apatite, apatite containing HPO4 groups, vitrokite, and calcium hydrogen phosphate, and the granules or blocks have a volume of 10⁻¹² m³ or more and contain silver phosphate crystals bonded to the surface of calcium phosphate, and the silver phosphate content is 0.01% by mass or more and 3% by mass or less. (AG3) The silver compound is silver phosphate. (AG4) The calcium phosphate composition contains silver or a silver compound in both the surface and interior, and the ratio of the silver concentration in the surface to the silver concentration at a distance of at least 50 μm from the surface toward the center is 1.2 or more. (AG6) A granular porous body formed by the bonding of multiple granules with a maximum diameter and length of 50 μm or more and 500 μm or less, having multiple through-holes extending in multiple directions.
A method for producing a medical calcium phosphate composition according to claim 1, 2, or 9, The medical calcium carbonate composition is immersed in an aqueous solution of (X3) or (X5) to impart a phosphoric acid component to the medical calcium carbonate composition. Alternatively, a method for producing a medical calcium phosphate composition by adding a phosphate component to a medical calcium carbonate composition produced by the manufacturing method described in any one of claims 3 to 6, characterized in that it includes a step that satisfies at least one condition selected from the group (Y1) to (Y6), A method for producing a medical-grade calcium phosphate composition. (X3) An aqueous solution containing both a phosphoric acid component and a carbonate component at a concentration of 0.5 molars or less. (X5) An aqueous solution containing both a phosphoric acid component and a magnesium component. (Y1) A step of replacing some or all of the gas in the pores of a medical calcium carbonate composition immersed in an aqueous solution containing a phosphoric acid component with an aqueous solution containing a phosphoric acid component. (Y2) A step of vibrating a medical calcium carbonate composition immersed in an aqueous solution containing a phosphate component, thereby replacing some or all of the gas in the pores of the medical calcium carbonate composition with the aqueous solution containing a phosphate component. (Y3) A step of flowing an aqueous solution containing a phosphate component around the medical calcium carbonate composition to replace some or all of the gas in the internal pores of the medical calcium carbonate composition with the aqueous solution containing a phosphate component. (Y4) A step of replacing some or all of the gas in the pores of the medical calcium carbonate composition with the aqueous solution containing the phosphoric acid component by degassing a container containing an aqueous solution containing a phosphoric acid component under reduced pressure. (Y5) A step of replacing some or all of the gas in the pores of a medical calcium carbonate composition with a gas that has a higher solubility in an aqueous solution containing a phosphoric acid component than air. (Y6) A step of replacing some or all of the gas in the pores of a medical calcium carbonate composition with a solvent that has a smaller contact angle than water and a lower boiling point than water.

Description

The present invention relates to medical compositions and methods for producing the same. Specifically, it relates to medical calcium carbonate compositions for implantation in vivo, cell culture scaffolds for use outside the body, and related medical calcium sulfate curable compositions, medical calcium phosphate compositions, medical calcium hydroxide compositions, bone defect reconstruction treatment kits, and methods for producing the same. More specifically, this invention relates to a medical calcium carbonate composition that highly satisfies the following criteria: 1) tissue affinity, 2) bioavailability, 3) reactivity, and 4) mechanical strength, as well as related medical compositions and methods for producing them. The skeletal composition of invertebrates is calcium carbonate, while the skeletal composition of vertebrates is carbonate apatite, a type of calcium phosphate in which a phosphate component is added to calcium carbonate. Calcium carbonate is being studied as a bone graft material, and calcium phosphate and calcium sulfate, which contain carbonate apatite, are being used clinically as bone graft materials. (tissue affinity) Medical compositions, such as bone graft materials, differ from industrial compositions in their required properties, with in vivo reactions being paramount. Implanting powders into the body can trigger inflammatory responses. Therefore, medical compositions implanted in the body are required to have a certain volume or more from the perspective of tissue compatibility. Antibacterial properties may also be required from the perspective of infection prevention. As medical compositions, being substantially pure is also an essential requirement. (Bioabsorption) As bone graft materials, medical-grade calcium carbonate compounds and related medical compositions are sometimes expected to be absorbed in the body and replaced by the desired tissue. Tissue replacement requires both material absorption and tissue regeneration. Calcium carbonate and some calcium phosphates are absorbed by osteoclasts, but for absorption to occur, they must not contain materials that are not absorbed in the body. (Responsiveness) Medical calcium carbonate compositions are sometimes required to exhibit excellent tissue reactivity, such as tissue replacement, within the body, or to exhibit chemical reactivity. For the former, the penetration and dissolution of tissues, cells, and tissue fluid are key factors, and pore control, polymorphism, and crystallite size are important. For the latter, the penetration and dissolution of aqueous solutions are key factors, and pore control, polymorphism, and crystallite size are important. Regarding the latter, medical-grade calcium carbonate compositions are not only expected to be used as bone graft materials, but are also useful as precursors in the production of medical-grade calcium phosphate compositions such as medical-grade carbonate apatite compositions. For example, when a calcium carbonate block is immersed in an aqueous phosphate solution, the composition changes to carbonate apatite while maintaining its macroscopic shape through a dissolution and extraction reaction, and carbonate apatite blocks can be produced (Patent Document 1). However, since the dissolution and extraction reaction proceeds from the surface of the calcium carbonate block, if the calcium carbonate block is large or has low reactivity, the composition may not be completely converted to carbonate apatite, and a core may remain. Therefore, there is a need for highly reactive medical-grade calcium carbonate compositions and manufacturing methods that accelerate the addition of phosphate components. The reactivity of calcium carbonate compositions is greatly influenced not only by their composition and polymorphism, but also by their structure. Interconnected porous structures, in particular, are desirable because they allow cells and tissues to migrate into them. While macropores of a certain size or larger are necessary for cell and tissue migration, smaller micropores are also important when tissue replacement is desired. (mechanical strength) Generally, a high number of macropores and micropores is desirable, but as porosity increases, mechanical strength decreases. Therefore, a balance between porosity and mechanical strength is important. Furthermore, medical-grade calcium phosphate compositions manufactured from medical-grade calcium carbonate compositions, as well as medical-grade calcium hydroxide compositions, medical-grade calcium sulfate compositions, and bone defect reconstruction treatment kits necessary for the manufacture of medical-grade calcium carbonate compositions, are also important as related medical compositions. (Reactivity of calcium carbonate: polymorphism, stomata, and density) The reactivity of calcium carbonate is influenced by various factors such as polymorphism, porosity, and density. Vaterite is metastable at room temperature and pressure, does not