JP2012236854A - Method for producing calcium phosphate composition - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for producing a calcium phosphate composition excellent in X-ray radiopacity, whose cured object has high mechanical strength when being used in a clinical field or the like.SOLUTION: In this method for producing calcium phosphate composition, a calcium phosphate composition is produced, which comprises tetracalcium phosphate particles (A), calcium hydrogenphosphate particles (B) and X-ray contrast agent particles (C) with the blending ratio (A/B) between (A) and (B) of 40/60-60/40 in terms of the molar ratio, and which has following properties, after mixing and crushing (B) and (C) and then mixing (A) therewith, namely, the average particle size of (A) is 5-30 μm, the average particle size of (B) is 0.1-5 μm, the average particle size of (A) is larger than the average particle size of (B), the average particle size of (C) is ≤3 μm, and 1-50 pts.wt. (C) is contained with respect to a 100 pts.wt total of (A) and (B), wherein the mean value of X-ray impermeability of a cured object having a thickness of 1 mm obtained by curing the composition at the powder/liquid mixing weight ratio of 2.5 is 3-9 mm in terms of the thickness of an aluminum plate.

Description

  The present invention relates to a method for producing a calcium phosphate composition. In particular, it relates to a method for producing a calcium phosphate composition comprising tetracalcium phosphate particles, calcium hydrogen phosphate particles and X-ray contrast agent particles.

Hydroxyapatite (Ca ₁₀ (PO ₄ ) ₆ (OH) ₂ ) obtained by sintering a calcium phosphate composition has a composition close to that of inorganic components such as bones and teeth, and has a property of directly binding to bone Since it has activity, it has been reported to be used as a material for repairing bone defects and bone voids. However, such a material composed of hydroxyapatite has excellent biocompatibility, but it may be difficult in terms of moldability to be applied to a part having a complicated form.

  On the other hand, among the calcium phosphate compositions, the cement type, that is, the curable calcium phosphate composition, is gradually converted into bioabsorbable hydroxyapatite in the living body and in the oral cavity and further integrated with the living hard tissue while maintaining the form. It is known to get. Such a calcium phosphate composition is not only excellent in biocompatibility, but also has moldability, so that it can be easily applied to a part having a complicated form.

  For example, Japanese Patent No. 3017536 (Patent Document 1) describes that a mixture of tetracalcium phosphate and anhydrous calcium hydrogen phosphate reacts in the presence of water to produce hydroxyapatite. In addition, it is known that adding an X-ray contrast agent to these calcium phosphate compositions has contrast properties, and monitoring of the filling operation of the calcium phosphate composition paste and the change after filling are known. The mechanical strength of the hardened | cured material of the contained calcium phosphate composition may not necessarily be high, and various problems generate | occur | produced in the clinical field.

Japanese Patent No. 3017536

  The present invention has been made to solve the above problems, and provides a method for producing a calcium phosphate composition having high mechanical strength of a cured product and good X-ray contrast properties when used in a clinical field. It is for the purpose.

The subject is a method for producing a calcium phosphate composition comprising tetracalcium phosphate particles (A), calcium hydrogen phosphate particles (B) and X-ray contrast agent particles (C),
From mixing calcium hydrogen phosphate particles (B) and X-ray contrast agent particles (C) and pulverizing them, and then mixing with tetracalcium phosphate particles (A),
The mixing ratio (A / B) of the tetracalcium phosphate particles (A) and the calcium hydrogen phosphate particles (B) is 40/60 to 60/40 in terms of molar ratio, and the average particles of the tetracalcium phosphate particles (A) The diameter is 5 to 30 μm, the average particle diameter of the calcium hydrogen phosphate particles (B) is 0.1 to 5 μm, and the tetracalcium phosphate particles ( The average particle diameter of A) is large, the average particle diameter of the X-ray contrast agent particles (C) is 3 μm or less, and the total of 100 parts by weight of the tetracalcium phosphate particles (A) and the calcium hydrogen phosphate particles (B) In contrast, a calcium phosphate composition containing 1 to 50 parts by weight of X-ray contrast agent particles (C) is produced,
X-ray opaqueness defined by ISO6876 (issued in 2001) of a 1 mm thick cured product obtained by curing the calcium phosphate composition at a powder / liquid mixture weight ratio (calcium phosphate composition / solution) 2.5. It is solved by providing the manufacturing method of the calcium-phosphate composition characterized by the average value of being 3-9 mm by the thickness of an aluminum plate. At this time, the average value was obtained by averaging the remaining 10 X-ray opacity values, excluding the upper 5 points and the lower 5 points from the larger value when 20 points of X-ray opacity were measured. Indicates the value.

  At this time, the X-ray contrast agent particles (C) are at least one selected from the group consisting of iodine-containing organic compounds, zirconium compounds, ytterbium compounds, barium compounds, gadolinium compounds, and bismuth compounds. Is preferred. Moreover, the value of the radiopacity prescribed | regulated by ISO6876 (issued in 2001) of the hardened | cured material obtained by hardening | curing the said calcium-phosphate composition is {(maximum value)-(average value)} / (average value). It is preferable to satisfy the relational expression of ≦ 0.5 (I). At this time, the maximum value indicates the maximum value of X-ray opacity when 20 points of X-ray opacity are measured, and the average value is large when 20 points of X-ray opacity are measured. A value obtained by averaging the X-ray opacity values of the remaining 10 points excluding the upper 5 points and the lower 5 points from the direction is shown.

  In addition, the tetracalcium phosphate particles (A) and / or calcium hydrogen phosphate particles (B) and the X-ray contrast agent particles (C) are supplied from a reika machine, a high-speed rotating mill, a ball mill, a planetary mill, and a jet mill. It is also preferable to grind using at least one selected from the group consisting of:

  The calcium phosphate composition obtained by the present invention has a high mechanical strength of a cured product and a good X-ray contrast when used in a clinical field.

  The calcium phosphate composition of the present invention comprises tetracalcium phosphate particles (A), calcium hydrogen phosphate particles (B), and X-ray contrast agent particles (C).

  When the calcium phosphate composition containing the tetracalcium phosphate particles (A) and the calcium hydrogen phosphate particles (B) is kneaded in the presence of water, a thermodynamically stable hydroxyapatite is generated and cured. At this time, in addition to the tetracalcium phosphate particles (A) and the calcium hydrogen phosphate particles (B), the X-ray contrast agent particles (C) are further contained, so that X-ray contrast can be performed, and the calcium phosphate composition It is known that monitoring of paste filling operations and changes after filling can be tracked.

The manufacturing method of the tetracalcium phosphate [Ca ₄ (PO ₄ ) ₂ O] particles (A) used in the present invention is not particularly limited. Commercially available tetracalcium phosphate particles may be used as they are, or may be used by appropriately pulverizing and adjusting the particle diameter. As the pulverization method, a method similar to the pulverization method of the calcium hydrogen phosphate particles (B) described later can be employed.

  The average particle diameter of the tetracalcium phosphate particles (A) is preferably 5 to 30 μm. When the average particle size is less than 5 μm, the pH of the aqueous solution increases due to excessive dissolution of the tetracalcium phosphate particles (A). As a result, the precipitation of hydroxyapatite is not smooth, and the mechanical strength of the cured product may be reduced. The average particle size is more preferably 8 μm or more. On the other hand, when the average particle size exceeds 30 μm, the paste properties obtained by mixing with the liquid agent may not be sufficiently viscous, or the paste properties may be unfavorable, for example, the feeling of roughness may be increased. In addition, when used as a dental root canal filler or the like, the tip of the nozzle may be clogged when injecting into a narrow transplantation site using a syringe. The average particle size is more preferably 20 μm or less. Here, the average particle diameter of the tetracalcium phosphate particles (A) used in the present invention is measured and calculated using a laser diffraction particle size distribution measuring device.

The calcium hydrogen phosphate particles (B) used in the present invention may be anhydrous [CaHPO ₄ ] or dihydrate [CaHPO ₄ .2H ₂ O]. From the viewpoint of the storage stability of the composition, an anhydride is preferably used. The average particle size of the calcium hydrogen phosphate particles (B) is preferably 0.1 to 5 μm. When the average particle size is less than 0.1 μm, the viscosity of the paste obtained by mixing with the liquid may be too high, and more preferably 0.5 μm or more. On the other hand, when the average particle diameter exceeds 5 μm, the calcium hydrogen phosphate particles (B) are difficult to dissolve in the liquid agent, so that the precipitation of hydroxyapatite is not smooth and the mechanical strength of the cured product may be reduced. More preferably, it is 2 μm or less. The average particle diameter of the calcium hydrogen phosphate particles (B) is calculated in the same manner as the average particle diameter of the tetracalcium phosphate particles (A).

  The production method of the calcium hydrogen phosphate particles (B) having such an average particle diameter is not particularly limited, and if a commercially available product can be obtained, it may be used, but the commercially available product may be further pulverized. Often preferred. In that case, pulverization apparatuses such as a likai machine, a high-speed rotary mill, a ball mill, a planetary mill, and a jet mill can be used. Further, calcium hydrogen phosphate particles (B) are prepared by pulverizing calcium hydrogen phosphate raw material powder together with a liquid medium such as alcohol using a lykai machine, a ball mill or the like, and drying the obtained slurry. You can also get A ball mill is preferably used as the pulverizer at this time, and alumina or zirconia is preferably used as the material of the pot and ball.

  As described above, by increasing the average particle diameter of the tetracalcium phosphate particles (A) compared to the average particle diameter of the calcium hydrogen phosphate particles (B), the solubility of both is balanced, and the pH of the aqueous solution is increased. Can be maintained at 8.5-9. As a result, it is possible to smoothly produce hydroxyapatite crystals and improve the mechanical strength of the cured product. Specifically, the average particle size of (A) is more preferably 2 times or more than the average particle size of (B), more preferably 4 times or more, and particularly preferably 7 times or more. . On the other hand, the average particle size of (A) is more preferably 35 times or less of the average particle size of (B), more preferably 30 times or less, and particularly preferably 25 times or less.

  The X-ray contrast agent particles (C) used in the present invention are particles added to the tetracalcium phosphate particles (A) and the calcium hydrogen phosphate particles (B), and the type thereof is not particularly limited. Examples thereof include iodine-containing organic compounds, zirconium-based compounds, ytterbium-based compounds, barium-based compounds, gadolinium-based compounds, and bismuth-based compounds. Specific examples of the iodine-containing organic compound include iodoform, amidotrizoic acid, ioxagric acid, ioxirane, iotaramic acid, iopodate sodium, iodamide and the like. Specific examples of the zirconium-based compound include zirconium oxide and zircon. Specific examples of ytterbium compounds include ytterbium fluoride and xenotime. Specific examples of the barium compound include barium sulfate. Specific examples of the gadolinium compound include gadolinium powder. Specific examples of the bismuth compound include bismuth oxide, bismuth carbonate and bismuth nitrate. Suitable as the X-ray contrast agent particles (C) are bismuth compounds, particularly bismuth oxide or bismuth subcarbonate. The reason why such a bismuth compound is suitable is that X-ray opacity can be efficiently imparted with a small amount of addition.

  The average particle diameter of the X-ray contrast agent particles (C) is preferably 5 μm or less. If the average particle size exceeds 5 μm, the paste properties may be adversely affected, such as the paste becoming crushed, and the mechanical strength and radiopacity of the cured calcium phosphate may be reduced. The average particle diameter of the X-ray contrast agent particles (C) is more preferably 3 μm or less, and even more preferably 1 μm or less. The average particle diameter of the X-ray contrast agent particles (C) is calculated by dispersing the X-ray contrast agent particles (C) in an epoxy resin and observing the primary particles using a transmission electron microscope.

  The calcium phosphate composition of the present invention contains 1 to 50 parts by weight of X-ray contrast agent particles (C) with respect to a total of 100 parts by weight of tetracalcium phosphate particles (A) and calcium hydrogen phosphate particles (B). Is preferred. When the content of the X-ray contrast agent particles (C) is less than 1 part by weight, the radiopacity may be lowered. The content of the X-ray contrast agent particles (C) is more preferably 4 parts by weight or more, and even more preferably 7 parts by weight or more. In addition, when the calcium phosphate composition of the present invention is used for dental applications, particularly for applications that require extremely high radiopacity such as root canal filler, the content of the X-ray contrast agent particles (C) is 10 wt. More preferably, it is more preferably 12 parts by weight or more, and particularly preferably 15 parts by weight or more. On the other hand, when the content of the X-ray contrast agent particles (C) exceeds 50 parts by weight, the X-ray opacity is high, but the mechanical strength of the cured product may be reduced. Further, the calcium phosphate composition of the present invention is preferably used as a medical composition, but when the damaged part in the living body is filled with the composition, the content of the X-ray contrast agent particles (C) is 50 parts by weight. If it exceeds, the sealing property becomes insufficient, and body fluid such as blood may easily infiltrate the filling site. The content of the X-ray contrast agent particles (C) is more preferably 47 parts by weight or less, and even more preferably 45 parts by weight or less.

  The blending ratio (A / B) of the tetracalcium phosphate particles (A) and the calcium hydrogen phosphate particles (B) is not particularly limited, but the blending ratio is such that the molar ratio is in the range of 40/60 to 60/40. Are preferably used. Thereby, a calcium phosphate composition having high mechanical strength of the cured product can be obtained. The blending ratio (A / B) is more preferably 45/55 to 55/45, and most preferably 50/50.

  The calcium phosphate composition of the present invention contains components other than tetracalcium phosphate particles (A), calcium hydrogen phosphate particles (B), and X-ray contrast agent particles (C) as long as the effects of the present invention are not impaired. It doesn't matter. For example, a thickener can be mix | blended as needed. This is for improving the moldability or uniform filling property of the calcium phosphate composition paste. Examples of the thickener include carboxymethylcellulose, sodium carboxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinyl alcohol, polyethylene glycol, polyacrylic acid, polyglutamic acid, polyglutamate, polyaspartic acid, polyaspartate, and cellulose. Selected from starch, alginic acid, hyaluronic acid, polysaccharides such as pectin, chitin, chitosan, acidic polysaccharide esters such as propylene glycol alginate, and polymers such as proteins such as collagen, gelatin and derivatives thereof One or two or more may be mentioned, but from the viewpoint of solubility in water and viscosity, sodium carboxymethylcellulose, hydroxypropylcellulose, Mud carboxymethyl cellulose, alginate, chitosan, polyglutamic acid, at least one selected from polyglutamic acid salts. A thickener can be mix | blended with a calcium-phosphate composition, can mix | blend with a liquid agent, or can be mix | blended with the paste in kneading | mixing.

  In addition, any pharmacologically acceptable drug or the like can be added, such as a disinfectant, an anticancer agent, an antibiotic, an antibacterial agent, a blood circulation improving agent such as actosine or PEG1, a growth factor such as bFGF, PDGF, or BMP, Cells that promote the formation of hard tissue such as cells, odontoblasts, and undifferentiated bone marrow-derived stem cells can be added.

  The calcium phosphate composition of the present invention is produced by mixing tetracalcium phosphate particles (A), calcium hydrogen phosphate particles (B), and X-ray contrast agent particles (C). At this time, it is preferable to have a step of mixing and pulverizing the tetracalcium phosphate particles (A) and / or the calcium hydrogen phosphate particles (B) and the X-ray contrast agent particles (C). At this time, as described above, it is preferable to use X-ray contrast agent particles (C) having an average particle size of 5 μm or less as the X-ray contrast agent particles (C). By adopting the above process, a composition in which the X-ray contrast agent particles (C) are uniformly dispersed is obtained, and the composition contains a relatively small amount of X-ray contrast agent particles (C) and exhibits good contrast properties and is cured. The mechanical strength of things is also high. Specifically, (i) tetracalcium phosphate particles (A), calcium hydrogen phosphate particles (B), and X-ray contrast agent particles (C) are mixed and pulverized in a lump. A method of obtaining a composition comprising particles (A), calcium hydrogen phosphate particles (B) and X-ray contrast agent particles (C); (ii) tetracalcium phosphate particles (A) and X-ray contrast agent particles (C) In which the calcium hydrogen phosphate particles (B) are further added to and mixed with the obtained mixture of (A) and (C); and (iii) calcium hydrogen phosphate particles ( A method in which B) and X-ray contrast agent particles (C) are mixed in advance and pulverized, and then the tetracalcium phosphate particles (A) are further added to and mixed with the obtained mixture of (B) and (C). , Etc. Among these methods, method (ii) and method (iii) are preferable, and method (iii) is more preferable. As described above, when obtaining the calcium phosphate composition of the present invention, it is preferable to increase the average particle size of the tetracalcium phosphate particles (A) as compared with the average particle size of the calcium hydrogen phosphate particles (B). According to the study by the present inventors, it is more preferable to mix the particles (A) having a larger particle diameter and the X-ray contrast agent particles (C) and pulverize them, and then mix the calcium hydrogen phosphate particles (B). The dispersibility of (C) in the composition is improved by mixing and pulverizing (B) having a small diameter and X-ray contrast agent particles (C) and then mixing (A) having a large particle diameter. , Mechanical strength and radiopacity tend to be improved.

  Moreover, the method of mixing and pulverizing the tetracalcium phosphate particles (A) and / or calcium hydrogen phosphate particles (B) and the X-ray contrast agent particles (C) is not particularly limited. For example, a pulverization method using a container-driven mill such as a raikai machine or a ball mill, or a high-speed rotating mill having a rotating blade at the bottom, a planetary mill, or a jet mill can be used. Moreover, it is more preferable from the viewpoint of dispersibility of the X-ray contrast agent particles (C) to perform wet pulverization using a liquid medium during the pulverization. In the wet pulverization, it is preferable to use a container-driven mill such as a ball mill, and as the material of the pot and balls, alumina or zirconia is preferably employed. Moreover, any liquid medium is used for the wet pulverization. When tetracalcium phosphate comes into contact with water, hydroxyapatite is formed on the surface of the particles, which may adversely affect the curability of the calcium phosphate composition. Therefore, in the case where the tetracalcium phosphate raw material powder and the X-ray contrast agent particles (C) are mixed and wet pulverized, it is preferable to use a hydrophobic liquid as the liquid medium. Specifically, an alkane or cycloalkane solvent is preferably used, and hexane or cyclohexane is preferably used. On the other hand, when the calcium hydrogen phosphate raw material powder and the X-ray contrast agent particles (C) are mixed and wet pulverized, such a problem does not occur. As a liquid medium, alcohols such as ethanol are used. Preferably used. Further, from the viewpoint of safety and consideration of the surrounding environment, it is preferable to use a mixed solvent of water and alcohol, or water as the liquid medium, and it is particularly preferable to use water.

  Moreover, the method of mixing the tetracalcium phosphate particles (A) with the composition comprising the calcium hydrogen phosphate particles (B) and the X-ray contrast agent particles (C) obtained by the above method is not particularly limited. . The method of mixing calcium hydrogen phosphate particles (B) with a composition comprising tetracalcium phosphate particles (A) and X-ray contrast agent particles (C) is not limited in the same manner. When the production scale is not so large, it is preferable to mix using a high-speed rotating mill having rotating blades at the bottom. In the case of such a mixing method, there is an advantage that the change in the particle size of the particles contained in the composition can be extremely reduced before and after the mixing operation. On the other hand, when the production scale is large, it is preferable to perform mixing using a ball mill from the viewpoint of workability and the like.

  The calcium phosphate composition of the present invention is sold as a powder composition. When used in a medical field, the calcium phosphate composition is kneaded with a liquid agent to form a calcium phosphate powder composition paste, which can be used by being filled or applied to a desired site. it can. The liquid agent used at this time may be an aqueous solution in which components other than water are dissolved, or an aqueous dispersion in which other components are dispersed. Examples of the ingredients blended with water include phosphoric acid, disodium phosphate, sodium phosphate such as monosodium phosphate, and mixtures thereof, potassium phosphates, ammonium phosphates, N, N-bis ( PH buffer such as 2-hydroxyethyl) -2-aminoethanesulfonic acid, N-tris (hydroxymethyl) methyl-2-aminoethanesulfonic acid, fluoride salts such as sodium fluoride, potassium fluoride, ammonium fluoride And water-soluble polyhydric alcohols such as glycerin and propylene glycol. Especially, it is preferable to mix | blend sodium phosphate salts, such as a disodium phosphate, a monosodium phosphate, and these mixtures from the surface of safety | security.

  The mass ratio of the calcium phosphate composition to the liquid agent (calcium phosphate composition / liquid agent) in preparing the calcium phosphate composition paste is not particularly limited, but is preferably 10/10 to 60/10, more preferably 25. / 10 to 45/10. After sufficiently kneading so that the calcium phosphate composition and the liquid agent are uniformly mixed, the bone tissue can be quickly filled or applied. In addition, the calcium phosphate composition of the present invention can be injected and filled with only the composition as a powder in bone tissue and cured by moisture in the living body. A method of applying the liquid agent to the filling site later is also used as a preferred embodiment.

The X-ray opaqueness defined by ISO6876 (issued in 2001) of a 1 mm thick cured product obtained by curing the calcium phosphate composition of the present invention is in the range of 3 to 9 mm in terms of the thickness of the aluminum plate. Here, the radiopacity defined by ISO6876 (issued in 2001) is expressed by the thickness of the aluminum plate, and the cured product having a thickness of 1 mm arranged on the film for X-ray photography, and similarly X-ray opacity corresponding to each thickness of the aluminum plate can be obtained by irradiating the aluminum step wedges arranged in an overlapping manner with X-rays and comparing the image density of the developed film thereafter. Hereinafter, “equivalent to an aluminum plate having a thickness of 3 mm” may be expressed as “3 mm Al”. When the radiopacity is less than 3 mm in terms of the thickness of the aluminum plate, ISO 6876 (issued in 2001) states that it has no radiopacity. The radiopacity is preferably 3.5 mm or more, and more preferably 4 mm or more. In addition, when the calcium phosphate composition of the present invention is used for dental applications, particularly for applications requiring extremely high radiopacity such as root canal fillers, the radiopacity may be 4.5 mm or more. More preferably, it is 5 mm or more. On the other hand, when the radiopacity exceeds 9 mm in the thickness of the aluminum plate, the X-ray contrast property of the calcium phosphate cured product is improved, but the mechanical strength may be lowered, and is preferably 8 mm or less. More preferably, it is 7.5 mm or less. At this time, the hardened material having a thickness of 1 mm used for the evaluation of the radiopacity is added with a 0.2 M (mol / l) Na ₂ HPO ₄ aqueous solution having a weight 0.4 times that of the calcium phosphate composition. And kneading.

It is preferable that the radiopaque value defined by ISO6876 (issued in 2001) of a cured product obtained by curing the calcium phosphate composition of the present invention satisfies the following relational expression (I).
{(Maximum value)-(average value)} / (average value) ≦ 0.5 (I)
At this time, the maximum value indicates the maximum value of X-ray opacity when 20 points of X-ray opacity are measured, and the average value is large when 20 points of X-ray opacity are measured. A value obtained by averaging the X-ray opacity values of the remaining 10 points excluding the upper 5 points and the lower 5 points from the direction is shown. If the value representing the variation in radiopacity exceeds 0.5, the radiographic unevenness tends to increase when an X-ray photograph is taken, and there is a risk of hindering accurate diagnosis. Is 0.4 or less, more preferably 0.3 or less.

  The calcium phosphate composition of the present invention is suitably used for various medical uses. For example, suitable as a material to make up bones lost due to accidents, a material to fill bone gaps caused by surgical operations such as incision and cutting of bone, or a dental root canal filler, root canal restoration material, cement material Used for. When the calcium phosphate composition of the present invention is used for the above-mentioned applications, it has excellent paste filling properties and can be filled up to every corner of a complex shape. And since the contrast is good, it is possible to confirm the transplantation status of the calcium phosphate composition under X-ray photography, and it is possible to easily diagnose the prognosis by observing the status of the transplanted cured product even after surgery. is there. In addition, since the cured product generated in the body has high mechanical strength, there is no fear of cracking or loss.

Hereinafter, the present invention will be described more specifically with reference to examples. In this example, the average particle size of the tetracalcium phosphate particles (A) and the calcium hydrogen phosphate particles (B) was measured using a laser diffraction particle size distribution analyzer (“SALD-2100 type” manufactured by Shimadzu Corporation). The median diameter calculated from the measurement results was taken as the average particle diameter. The average particle size of the X-ray contrast agent particles (C) was calculated by dispersing the X-ray contrast agent particles (C) in an epoxy resin and observing the primary particles using a transmission electron microscope. That is, the average particle diameter of the X-ray contrast agent particles (C) was measured as follows. Luft method (Luft JH: Improvements in epoxy resin embedding methods, J Biophys
Biochem Cytol, 9: 409-414, 1961.) To 1 g of the epoxy resin before curing prepared by adding 1 g of X-ray contrast agent particles (C) and stirring with a magnetic stirrer until uniform, And deaerated. Thereafter, it was added into a curing beam capsule (inner diameter 8 mm, height 15 mm) and cured by incubating at 60 ° C. for 2 days. An ultra-thin section (about 90 nm) obtained by using an ultramicrotome ("Super Nova" manufactured by Reichert-Jung Co., Ltd.) was obtained by trimming the upper part of the cured product by about 5 mm. The particle size of the X-ray contrast agent particles (C) was measured.

Example 1
(1) Preparation of calcium phosphate composition As tetracalcium phosphate particles (A) used in this example, commercially available tetracalcium phosphate particles (produced by Taihei Chemical Industrial Co., Ltd., average particle size: 8.75 μm) are used. As anhydrous calcium hydrogen phosphate particles (B), commercially available anhydrous calcium hydrogen phosphate particles (manufactured by Taihei Chemical Industrial Co., Ltd., average particle size 10.1 μm) were used. Further, as the X-ray contrast agent particles (C), bismuth carbonate particles (Iwaki Pharmaceutical Co., Ltd., average particle size 0.12 μm) were used.

  27 g of the anhydrous calcium hydrogen phosphate particles and 25 g of the above-mentioned bismuth carbonate particles were added into a 400 ml alumina grinding pot (“Type A-3 HD Pot Mill” manufactured by Nikkato Corporation). Further, 120 g of 95% ethanol (“Ethanol (95)” manufactured by Wako Pure Chemical Industries, Ltd.) and 240 g of zirconia balls having a diameter of 10 mm are added into the pot, and wet grinding is performed at a rotational speed of 120 rpm for 24 hours to obtain a slurry. Got. Ethanol was distilled off from the obtained slurry using a rotary evaporator, dried at 60 ° C. for 6 hours, and further vacuum-dried at 60 ° C. for 24 hours to obtain anhydrous calcium hydrogen phosphate particles (B) and X-ray contrast A powder composition comprising agent particles (C) was obtained.

  A high-speed rotating mill (ASONE Corporation) was prepared by using 26 g of the powder composition comprising the anhydrous calcium hydrogen phosphate particles (B) and the X-ray contrast agent particles (C) prepared above and 36.5 g of the tetracalcium phosphate particles (A). In addition, the calcium phosphate composition of the present invention was obtained by mixing for 3 minutes at a rotating blade speed of 3000 rpm. At this time, the average particle diameters of the tetracalcium phosphate particles (A), the anhydrous calcium hydrogen phosphate particles (B), and the X-ray contrast agent particles (C) before and after mixing were not substantially changed. . The obtained calcium phosphate composition is a composition containing 25 parts by weight of X-ray contrast agent particles (C) with respect to a total of 100 parts by weight of tetracalcium phosphate particles (A) and anhydrous calcium hydrogen phosphate particles (B). there were. Using the prepared calcium phosphate composition, the radiopaqueness, radiopaque variation, visual dispersibility, and compressive strength were evaluated according to the following methods.

(2) X-ray opacity measurement 1.5 g of the calcium phosphate composition prepared above is precisely weighed, and 0.6 g of a 0.2 M Na ₂ HPO ₄ aqueous solution is added thereto and kneaded to obtain a calcium phosphate composition paste. (The powder / liquid mixing weight ratio at this time is 2.5). Using the calcium phosphate composition paste thus obtained, a sample (thickness 1 mm) for measuring radiopacity was prepared according to ISO6876 (issued in 2001). The sample is placed next to an aluminum step wedge in the center of an X-ray film (manufactured by Kodak Co., Ltd., bite type “Ultra Speed DF-50”), and a digital X-ray imaging apparatus (Morita Manufacturing Co., Ltd., “Max DC70”). ) Was used for X-ray irradiation under conditions of a target-film distance of 300 mm and a tube voltage of 70 kV. After developing, fixing, and drying the film after irradiation, the image density of the sample was set to 20 points using an optical densitometer (DENSITOMETER, “PDA-85”, measurement area (3 mmφ), manufactured by Kodak Co., Ltd.). The X-ray opacity corresponding to the thickness of the aluminum plate was determined by measuring and comparing the image density of the sample with the image density of each thickness of the aluminum step wedge.

(3) Evaluation of X-ray opacity variation In the X-ray opacity measured based on the above method, the value represented by the following formula was defined as "X-ray opacity variation".
(X-ray opacity variation) = {(maximum value) − (average value)} / (average value)
However,
Maximum value: The maximum value of radiopacity when the radiopacity of the sample was measured at 20 points.
Average value: A value obtained by averaging the X-ray opacity values of the remaining 10 points excluding the upper 5 points and the lower 5 points from the larger value when the X-ray opacity of the sample was measured at 20 points. .
Respectively.

(4) Evaluation of dispersibility by visual observation Obtained by visual observation of the X-ray film after X-ray irradiation obtained in the above-described measurement operation of X-ray opacity, and obtained by curing the calcium phosphate composition. The dispersion state of the X-ray contrast medium in the cured product was evaluated according to the following criteria.
A: X-ray contrast medium is uniformly dispersed, and aggregation of the X-ray contrast medium cannot be confirmed by visual observation.
○: An extremely fine aggregate of the X-ray contrast medium is visually observed.
Δ: Aggregation of X-ray contrast agent is clearly seen, but the difference in image density between the agglomerated portion and its surroundings is small.
X: Aggregation of the X-ray contrast agent is clearly seen, and the difference in image density between the agglomerated portion and its surroundings is large.

(5) Measurement of compressive strength 1.5 g of the calcium phosphate composition obtained above is precisely weighed, and 0.43 g of a 0.2 M Na ₂ HPO ₄ aqueous solution is added thereto and kneaded to obtain a calcium phosphate powder composition paste. (The powder / liquid mixing weight ratio at this time is 3.5). Place a severable stainless steel mold with a diameter of 6 mm and a depth of 3 mm on a smooth glass plate, fill the paste with care not to contain gas, and compress with a smooth glass plate from the top. Then, a calcium phosphate composition paste was molded (n = 9). Then, after incubating for 4 hours in an environment of 37 ° C. and 100% relative humidity, the columnar cured product of the calcium phosphate composition was taken out of the mold, immersed in 150 ml of distilled water at 37 ° C., and held for another 20 hours. Thereafter, the compressive strength of the cured product of the calcium phosphate composition was determined by Chow et al. (LC Chow, S. Hirayama, S. Takagi, E.
Parry, J. Biomed. Mater. Res. (Appl. Biomater.) 53: 511-517, 2000.) A mechanical strength measuring device (“AG-I 100 kN” manufactured by Shimadzu Corporation) was used. The compressive strength was measured by applying a load at a speed of 1 mm / min in the axial direction of the cylindrical cured product (n = 9).

  The X-ray opacity of the calcium phosphate composition in this example was 5.5 mmAl, the X-ray opacity variation was 0.2, and the visual evaluation of dispersibility was ◎. The compressive strength was 51 MPa.

Comparative Example 6
50 g of commercially available anhydrous calcium hydrogen phosphate particles (manufactured by Taihei Chemical Industrial Co., Ltd., average particle size 10.1 μm) were added to an alumina grinding pot having an internal volume of 400 ml (“Type A-3 HD pot mill” manufactured by Nikkato Co., Ltd.). . Further, 120 g of 95% ethanol (“Ethanol (95)” manufactured by Wako Pure Chemical Industries, Ltd.) and 240 g of zirconia balls having a diameter of 10 mm are added into the pot, and wet grinding is performed for 24 hours at a rotation speed of 120 rpm, Obtained. Ethanol was distilled off from the obtained slurry using a rotary evaporator, then, dried at 60 ° C. for 6 hours, and further vacuum dried at 60 ° C. for 24 hours to obtain anhydrous calcium hydrogen phosphate particles (B). The average particle diameter of the obtained anhydrous calcium hydrogen phosphate particles (B) was 1.2 μm.

  As the tetracalcium phosphate particles (A), commercially available tetracalcium phosphate particles (produced by Taihei Chemical Sangyo Co., Ltd., average particle size: 8.75 μm) are used. (Iwagi Pharmaceutical Co., Ltd., average particle size 0.12 μm) was used.

  The above-mentioned tetracalcium phosphate particles 73 g and the above-mentioned bismuth carbonate particles 25 g were added to a 400 ml alumina grinding pot (“Type A-3 HD Pot Mill” manufactured by Nikkato Corporation). Furthermore, 120 g of 95% ethanol (“Ethanol (95)” manufactured by Wako Pure Chemical Industries, Ltd.) and 240 g of zirconia balls having a diameter of 10 mm are added into the pot, and wet grinding is performed at a rotational speed of 120 rpm for 24 hours. A slurry was obtained. After distilling off ethanol from the obtained slurry using a rotary evaporator, it was dried at 60 ° C. for 6 hours, and further vacuum dried at 60 ° C. for 24 hours, whereby tetracalcium phosphate particles (A) and X-ray contrast agent A powder composition comprising particles (C) was obtained.

  13.5 g of the pulverized anhydrous calcium hydrogen phosphate particles (B) produced above and 49 g of the powder composition comprising the tetracalcium phosphate particles (A) and the X-ray contrast agent particles (C) were mixed with a high-speed rotating mill ( In addition, the calcium phosphate composition of the present invention was obtained by mixing for 3 minutes at a rotating blade speed of 3000 rpm. At this time, the average particle diameters of the tetracalcium phosphate particles (A), the anhydrous calcium hydrogen phosphate particles (B), and the X-ray contrast agent particles (C) before and after mixing were not substantially changed. . The obtained calcium phosphate composition is a composition containing 25 parts by weight of X-ray contrast agent particles (C) with respect to a total of 100 parts by weight of tetracalcium phosphate particles (A) and anhydrous calcium hydrogen phosphate particles (B). there were. Using the prepared calcium phosphate composition, evaluation was made in the same manner as in Example 1 with respect to radiopacity, variation in radiopacity, visual dispersibility, and compressive strength. The obtained results are summarized in Table 1.

Example 2
In Example 1, a calcium phosphate composition was prepared in the same manner as in Example 1, except that dibismuth trioxide particles (Iwagi Pharmaceutical Co., Ltd., average particle size 0.15 μm) were used as the X-ray contrast agent particles (C). Prepared and evaluated. The obtained results are summarized in Table 1.

Example 3
In Example 1, a calcium phosphate composition was prepared in the same manner as in Example 1 except that barium sulfate particles (manufactured by Wako Pure Chemical Industries, Ltd., average particle size 0.88 μm) were used as the X-ray contrast agent particles (C). Prepared and evaluated. The obtained results are summarized in Table 1.

Comparative Example 7
In Comparative Example 6, a calcium phosphate composition was prepared in the same manner as in Comparative Example 6 except that zirconium oxide particles (manufactured by Kyowa Material Co., Ltd., average particle size 0.05 μm) were used as the X-ray contrast agent particles (C). And evaluated. The obtained results are summarized in Table 1.

Example 4
In Example 1, the blending amount when preparing the composition powder composed of anhydrous calcium hydrogen phosphate particles (B) and X-ray contrast agent particles (C) is based on 27 g of anhydrous calcium hydrogen phosphate particles (B). A composition powder comprising anhydrous calcium hydrogen phosphate particles (B) and X-ray contrast agent particles (C) was prepared in the same manner as in Example 1 except that 40 g of the X-ray contrast agent particles (C) was used. 33.5 g of the obtained composition powder and 36.5 g of commercially available tetracalcium phosphate particles (manufactured by Taihei Chemical Industrial Co., Ltd., average particle size 8.75 μm) are mixed in the same manner as in Example 1. Thus, a calcium phosphate composition was prepared. The calcium phosphate composition was a composition containing 40 parts by weight of X-ray contrast agent particles (C) with respect to a total of 100 parts by weight of tetracalcium phosphate particles (A) and anhydrous calcium hydrogen phosphate particles (B). . Evaluation was performed in the same manner as in Example 1 using the prepared calcium phosphate composition. The obtained results are summarized in Table 1.

Example 5
In Example 1, the compounding quantity at the time of preparing the composition powder which consists of anhydrous calcium hydrogenphosphate particles (B) and X-ray contrast agent particles (C) is set to 35 g of anhydrous calcium hydrogenphosphate particles (B). A composition powder comprising anhydrous calcium hydrogen phosphate particles (B) and X-ray contrast agent particles (C) was prepared in the same manner as in Example 1 except that 25 g of the X-ray contrast agent particles (C) was used. By mixing 30 g of the obtained composition powder and 32.5 g of commercially available tetracalcium phosphate particles (produced by Taihei Chemical Sangyo Co., Ltd., average particle size: 8.75 μm) in the same manner as in Example 1. A calcium phosphate composition was prepared. The calcium phosphate composition contains 25 parts by weight of X-ray contrast agent particles (C) with respect to a total of 100 parts by weight of tetracalcium phosphate particles (A) and anhydrous calcium hydrogen phosphate particles (B), and tetraphosphate 4 The composition (A / B) of the calcium particles (A) and the anhydrous calcium hydrogen phosphate particles (B) was a composition having a molar ratio of 0.7. Evaluation was performed in the same manner as in Example 1 using the prepared calcium phosphate composition. The obtained results are summarized in Table 1.

Comparative Example 1
In Comparative Example 6, X-ray contrast agent particles (C) were not used, and instead of 49 g of the composition powder consisting of tetracalcium phosphate particles (A) and X-ray contrast agent particles (C), commercially available phosphoric acid was used. Tetracalcium phosphate particles (A) and anhydrous calcium hydrogen phosphate particles (as in Comparative Example 6) except that 36.5 g of tetracalcium particles (produced by Taihei Chemical Sangyo Co., Ltd., average particle size 8.75 μm) were used. A calcium phosphate composition consisting of B) was prepared. Evaluation was performed in the same manner as in Example 1 using the prepared calcium phosphate composition. The obtained results are summarized in Table 1.

Comparative Example 2
In Example 1, the blending amount when preparing the composition powder composed of anhydrous calcium hydrogen phosphate particles (B) and X-ray contrast agent particles (C) is based on 27 g of anhydrous calcium hydrogen phosphate particles (B). A composition powder comprising anhydrous calcium hydrogen phosphate particles (B) and X-ray contrast agent particles (C) was prepared in the same manner as in Example 1 except that the amount was 55 g of X-ray contrast agent particles (C). By mixing 41 g of the obtained composition powder and 36.5 g of commercially available tetracalcium phosphate particles (manufactured by Taihei Chemical Industrial Co., Ltd., average particle size of 8.75 μm) in the same manner as in Example 1, A calcium phosphate composition was prepared. The calcium phosphate composition was a composition containing 55 parts by weight of the X-ray contrast agent particles (C) with respect to a total of 100 parts by weight of the tetracalcium phosphate particles (A) and the anhydrous calcium hydrogen phosphate particles (B). . Evaluation was performed in the same manner as in Example 1 using the prepared calcium phosphate composition. The obtained results are summarized in Table 1.

Comparative Example 3
In Example 1, the blending amount when preparing the composition powder composed of anhydrous calcium hydrogen phosphate particles (B) and X-ray contrast agent particles (C) is based on 27 g of anhydrous calcium hydrogen phosphate particles (B). A composition powder comprising anhydrous calcium hydrogen phosphate particles (B) and X-ray contrast agent particles (C) was prepared in the same manner as in Example 1 except that 0.8 g of X-ray contrast agent particles (C) was used. did. 13.9 g of the obtained composition powder and 36.5 g of commercially available tetracalcium phosphate particles (manufactured by Taihei Chemical Industry Co., Ltd., average particle size 8.75 μm) are mixed in the same manner as in Example 1. Thus, a calcium phosphate composition was prepared. The calcium phosphate composition is a composition containing 0.8 parts by weight of X-ray contrast agent particles (C) with respect to a total of 100 parts by weight of tetracalcium phosphate particles (A) and anhydrous calcium hydrogen phosphate particles (B). there were. Evaluation was performed in the same manner as in Example 1 using the prepared calcium phosphate composition. The obtained results are summarized in Table 1.

Comparative Example 4
As the tetracalcium phosphate particles (A), commercially available tetracalcium phosphate particles (produced by Taihei Chemical Sangyo Co., Ltd., average particle size: 8.75 μm) are used. As X-ray contrast agent particles (C), bismuth carbonate particles are used. (Iwagi Pharmaceutical Co., Ltd., average particle size 0.12 μm) was used. Moreover, as anhydrous calcium hydrogen phosphate particles (B), anhydrous calcium hydrogen phosphate particles (B) having an average particle diameter of 1.2 μm prepared by the method described in Comparative Example 6 were used. 36.5 g of the tetracalcium phosphate particles (A), 13.5 g of the anhydrous calcium hydrogen phosphate particles (B), and 12.5 g of the X-ray contrast agent particles (C) were mixed with an alumina grinding pot (manufactured by Nikkato Corporation, “ In addition to “Type A-3 HD pot mill”), a calcium phosphate composition was prepared by mixing for 24 hours at a rotational speed of 120 rpm without adding 95% ethanol and zirconia balls. The calcium phosphate composition was a composition containing 25 parts by weight of X-ray contrast agent particles (C) with respect to a total of 100 parts by weight of tetracalcium phosphate particles (A) and anhydrous calcium hydrogen phosphate particles (B). . Evaluation was performed in the same manner as in Example 1 using the prepared calcium phosphate composition. The obtained results are summarized in Table 1.

Comparative Example 5
As the tetracalcium phosphate particles (A), commercially available tetracalcium phosphate particles (produced by Taihei Chemical Sangyo Co., Ltd., average particle size: 8.75 μm) are used. As X-ray contrast agent particles (C), bismuth carbonate particles are used. (Iwagi Pharmaceutical Co., Ltd., average particle size 0.12 μm) was used. Moreover, as anhydrous calcium hydrogen phosphate particles (B), anhydrous calcium hydrogen phosphate particles (B) having an average particle diameter of 1.2 μm prepared by the method described in Comparative Example 6 were used. 27 g of the anhydrous calcium hydrogen phosphate particles (B) and 25 g of the X-ray contrast agent particles (C) were added to a 400 ml alumina grinding pot (“Type A-3 HD Pot Mill” manufactured by Nikkato Co., Ltd.), and 95% Wet grinding was performed for 24 hours at a rotational speed of 120 rpm without adding ethanol and zirconia balls to obtain a powder composition comprising anhydrous calcium hydrogen phosphate particles (B) and X-ray contrast agent particles (C).

  A high-speed rotating mill (ASONE Corporation) was prepared by using 26 g of the powder composition comprising the anhydrous calcium hydrogen phosphate particles (B) and the X-ray contrast agent particles (C) prepared above and 36.5 g of the tetracalcium phosphate particles (A). In addition to “SM-1”), a calcium phosphate composition was obtained by mixing for 3 minutes at a rotating blade speed of 3000 rpm. At this time, the average particle diameters of the tetracalcium phosphate particles (A), the anhydrous calcium hydrogen phosphate particles (B), and the X-ray contrast agent particles (C) before and after mixing were not substantially changed. . The obtained calcium phosphate composition is a composition containing 25 parts by weight of X-ray contrast agent particles (C) with respect to a total of 100 parts by weight of tetracalcium phosphate particles (A) and anhydrous calcium hydrogen phosphate particles (B). there were. Evaluation was performed in the same manner as in Example 1 using the prepared calcium phosphate composition. The obtained results are summarized in Table 1.

  As can be seen from Table 1, 1 to 50 parts by weight of the X-ray contrast agent particles (C) is contained for 100 parts by weight of the total of the tetracalcium phosphate particles (A) and the calcium hydrogen phosphate particles (B). In Examples 1 to 5 having a step of mixing and pulverizing acid tetracalcium particles (A) and / or calcium hydrogen phosphate particles (B) and X-ray contrast agent particles (C), the compressive strength of the cured product , High radiopacity, and good uniformity. On the other hand, in Comparative Example 1 containing no X-ray contrast agent particles (C), the cured product had high compressive strength, but almost no radiopacity was observed. Further, in Comparative Example 2 in which the blending amount of the X-ray contrast agent particles (C) exceeds 50 parts by weight, the X-ray opacity was good, but the compression strength of the cured product was greatly reduced. In Comparative Example 3 in which the blending amount of the X-ray contrast agent particles (C) was less than 1 part by weight, the cured product had a high compressive strength, but a decrease in radiopacity was observed. Comparative Example 4 in which only the mixing operation of tetracalcium phosphate particles (A), calcium hydrogen phosphate particles (B) and X-ray contrast agent particles (C) was performed without adding 95% ethanol and zirconia balls. In Comparative Example 5, the radiopacity was low, the variation was large, and the compressive strength of the cured product was greatly reduced.

  In Comparative Example 6 having the step of mixing and pulverizing the tetracalcium phosphate particles (A) and the X-ray contrast agent particles (C), and then mixing with the calcium hydrogen phosphate particles (B), the calcium hydrogen phosphate particles (B) and X-ray contrast agent particles (C) are mixed and pulverized and then mixed with tetracalcium phosphate particles (A) (Example 1). Also, the visual dispersibility evaluation of the calcium phosphate composition was slightly inferior. On the other hand, in Example 2 using dibismuth trioxide particles having an average particle diameter of 0.15 μm as the X-ray contrast agent particles (C), when the particles are bismuth carbonate particles having an average particle diameter of 0.12 μm ( Compared with Example 1), the compression strength of the cured product was slightly inferior. Further, in Example 3 using barium sulfate particles having an average particle diameter of 0.88 μm, radiopacity is lower than that in the case of bismuth carbonate particles having an average particle diameter of 0.12 μm (Example 1). A little inferior. Further, in Comparative Example 7 using zirconium oxide particles having an average particle diameter of 0.05 μm, radiopacity is lower than that in the case of bismuth carbonate particles having an average particle diameter of 0.12 μm (Comparative Example 6). A little inferior. Further, in Example 4 in which the blending amount of the X-ray contrast agent particles (C) was 40 parts by weight, the radiopacity was higher than that in the case of 25 parts by weight (Example 1). The compression strength was slightly inferior. Moreover, the dispersibility by visual observation of the calcium phosphate composition was slightly inferior. In Example 5 in which the molar ratio (A / B) of the tetracalcium phosphate particles (A) to the calcium hydrogen phosphate particles (B) was 0.7, the molar ratio (A / B) was 1.0. Although the dispersibility by visual observation of the calcium phosphate composition was better than that of Example 1, the compressive strength of the cured product was slightly inferior.

Claims (4)

A method for producing a calcium phosphate composition comprising tetracalcium phosphate particles (A), calcium hydrogen phosphate particles (B) and X-ray contrast agent particles (C),
From mixing calcium hydrogen phosphate particles (B) and X-ray contrast agent particles (C) and pulverizing them, and then mixing with tetracalcium phosphate particles (A),
The mixing ratio (A / B) of the tetracalcium phosphate particles (A) and the calcium hydrogen phosphate particles (B) is 40/60 to 60/40 in terms of molar ratio, and the average particles of the tetracalcium phosphate particles (A) The diameter is 5 to 30 μm, the average particle diameter of the calcium hydrogen phosphate particles (B) is 0.1 to 5 μm, and the tetracalcium phosphate particles ( The average particle diameter of A) is large, the average particle diameter of the X-ray contrast agent particles (C) is 3 μm or less, and the total of 100 parts by weight of the tetracalcium phosphate particles (A) and the calcium hydrogen phosphate particles (B) In contrast, a calcium phosphate composition containing 1 to 50 parts by weight of X-ray contrast agent particles (C) is produced,
X-ray opaqueness defined by ISO6876 (issued in 2001) of a 1 mm thick cured product obtained by curing the calcium phosphate composition at a powder / liquid mixture weight ratio (calcium phosphate composition / solution) 2.5. The method of producing a calcium phosphate composition is characterized in that the average value of is a thickness of the aluminum plate is 3 to 9 mm.
However, the average value is the value obtained by averaging the X-ray opacity values of the remaining 10 points excluding the upper 5 points and the lower 5 points from the larger value when 20 points of X-ray opacity were measured. Indicates.   The X-ray contrast agent particle (C) is at least one selected from the group consisting of iodine-containing organic compounds, zirconium-based compounds, ytterbium-based compounds, barium-based compounds, gadolinium-based compounds, and bismuth-based compounds. A method for producing a calcium phosphate composition. The calcium phosphate according to claim 1 or 2, wherein the X-ray opacity value defined by ISO6876 (issued in 2001) of the cured product obtained by curing the calcium phosphate composition satisfies the following relational expression (I): A method for producing the composition.
{(Maximum value)-(average value)} / (average value) ≦ 0.5 (I)
However,
Maximum value: The maximum value of radiopacity when 20 points of radiopacity are measured.
Average value: A value obtained by averaging the X-ray opacity values of the remaining 10 points excluding the upper 5 points and the lower 5 points from the larger value when 20 points of X-ray opacity were measured.
Respectively.   The above-mentioned tetracalcium phosphate particles (A) and / or calcium hydrogen phosphate particles (B) and X-ray contrast agent particles (C) are composed of a Leica machine, a high-speed rotating mill, a ball mill, a planetary mill and a jet mill. The manufacturing method of the calcium-phosphate composition in any one of Claims 1-3 grind | pulverized using at least 1 sort (s) selected from.