JP2018002579A - Method for producing calcium phosphate sintered compact particle - Google Patents

Abstract

Provided is a calcium phosphate sintered body particle group suitable as a material for medical use, particularly a medical device introduced into a living body. A ceramic particle group composed of ceramic particles, wherein the particle diameter of the ceramic particle is in a range of 10 nm to 700 nm, and the coefficient of variation of the particle diameter of the ceramic particle group is 20% or less, A group of ceramic particles in which the ceramic particles are calcium phosphate sintered particles, the ceramic particles substantially do not contain calcium carbonate, and the ceramic particles include carbonate apatite at least on the surface thereof. A group of ceramic particles, wherein the ceramic particles are substantially spherical. Ceramic particles having a maximum minor axis diameter of 30 nm to 5 μm, a major axis having a particle diameter of 75 nm to 10 μm, growing in the c-axis direction, and a crystal aspect ratio of 1 to 30. group. [Selection figure] None

Description

  The present invention relates to a novel calcium phosphate sintered body particle, a production method thereof, and an application thereof.

  Hydroxyapatite (HAp) is known to exhibit high biocompatibility and is used in various fields including biomaterials.

  By the way, when the hydroxyapatite (HAp) is used as a biomaterial, the solubility and degradability in the living body can be reduced by producing high crystallinity hydroxyapatite particles (ceramic particles) fired at a high temperature. I can do it. However, during this sintering, bonding occurs due to fusion between hydroxyapatite (HAp) particles (primary particles), resulting in irregular secondary particles in which the primary particles are bonded, resulting in a decrease in dispersibility and specific surface area. There was a problem.

  Therefore, in prior patent document 1, mixed particles are mixed so that the anti-fusing agent is interposed between the primary particles made of the ceramic raw material before sintering, and the mixed particles are sintered, and after the firing A method for washing away the anti-fusing agent has been proposed. According to the production method, it is possible to obtain a group of ceramic particles having a high crystallinity and a small particle size.

Japanese Patent No. 5043436

  However, the present inventors have obtained knowledge that the ceramic particle group obtained by the production method of Patent Document 1 contains a crystal phase of calcium carbonate. When calcium phosphate is used in medical applications, particularly in medical devices introduced into the living body, undesirable events may occur from the viewpoint of biocompatibility and changes in solubility. Therefore, this invention makes it the 1st subject to provide the calcium-phosphate sintered compact particle group by which the biocompatibility fall and solubility change resulting from calcium carbonate were suppressed as much as possible.

  Next, the present inventors have found that the ceramic particle group obtained by the production method of Patent Document 1 may not have sufficient dispersibility. When the dispersibility is low, aggregation or the like is caused, and as a result, an immune reaction can be caused in vivo, which is not preferable. Therefore, this invention makes it the 2nd subject to provide the calcium-phosphate sintered compact particle group which shows high dispersibility.

  As a result of intensive studies, the present inventors have found that the above-mentioned problems can be solved by making the ceramic particles substantially free of calcium carbonate and containing at least the surface of carbonate apatite. It came to complete.

  That is, the present invention is as follows.

The present invention (1)
A group of ceramic particles composed of ceramic particles,
The particle diameter of the ceramic particles is within a range of 10 nm to 700 nm, and the coefficient of variation of the particle diameter of the ceramic particle group is 20% or less,
The ceramic particles are calcium phosphate sintered particles,
The ceramic particles are substantially free of calcium carbonate, and
The ceramic particles are a group of ceramic particles characterized by containing carbonate apatite at least on the surface thereof.
The present invention (2)
It is the ceramic particle group of the present invention (1), wherein the ceramic particles are substantially spherical.
The present invention (3)
A group of ceramic particles composed of ceramic particles,
The ceramic particles have a minor axis maximum diameter of 30 nm to 5 μm and a major axis of 75 nm to 10 μm, grow in the c-axis direction, and have an aspect ratio (c-axis length / a-axis length) of 1 ˜30, and the ceramic particles having a truncated columnar structure having a beveled front end angle,
The ceramic particles are calcium phosphate sintered particles,
The ceramic particles are substantially free of calcium carbonate, and
The ceramic particles are a group of ceramic particles characterized by containing carbonate apatite at least on the surface thereof.
The present invention (4)
A group of ceramic particles composed of ceramic particles,
The particle diameter of the ceramic particles is within a range of 10 nm to 700 nm, and the coefficient of variation of the particle diameter of the ceramic particle group is 20% or less,
The ceramic particles are calcium phosphate sintered particles,
The ceramic particles have the following general formula Ca _x (PO ₄ ) _6-y (CO ₃ ) _y (OH) ₂
(In the formula, x is a number from 8 to 12, and y is a number greater than 0 and 3 or less.)
It is a ceramic particle group characterized by these.
The present invention (5)
A group of ceramic particles composed of ceramic particles,
The ceramic particles have a minor axis maximum diameter of 30 nm to 5 μm and a major axis of 75 nm to 10 μm, grow in the c-axis direction, and have an aspect ratio (c-axis length / a-axis length) of 1 ˜30, and the ceramic particles having a truncated columnar structure having a beveled front end angle,
The ceramic particles are calcium phosphate sintered particles,
The ceramic particles have the following general formula Ca _x (PO ₄ ) _6-y (CO ₃ ) _y (OH) ₂
(In the formula, x is a number from 8 to 12, and y is a number greater than 0 and 3 or less.)
It is a ceramic particle group characterized by these.
The present invention (6)
It is a ceramic particle group of the present invention (1) to (5) which does not substantially contain an alkali metal.
The present invention (7)
In the ceramic particle group of the present invention (1) to (6), the ceramic particles are hydroxyapatite sintered particles.
The present invention (8)
A medical material for introduction into a living body, which is obtained using the ceramic particle group of the present invention (1) to (7).
The present invention (9)
This is a medical device obtained using the medical material for introduction into a living body of the present invention (8) as one material.
The present invention (10)
In the method for producing a ceramic particle group consisting of ceramic particles,
The ceramic particle group is the ceramic particle group of the present invention (1) to (7), and
A mixing step of mixing calcium phosphate and an anti-fusing agent to obtain mixed particles;
Exposing the mixed particles to a sintering temperature to form calcium phosphate sintered particles, and a sintering step;
Washing the calcium phosphate sintered particles with an acid, a pickling step;
It is a manufacturing method of the ceramic particle group containing this.
The present invention (11)
It is a manufacturing method of this invention (10) in which the said ceramic particle does not contain an alkali metal substantially.
The present invention (12)
It is a manufacturing method of this invention (10)-(11) whose said ceramic particle is a hydroxyapatite sintered compact particle.
The present invention (13)
It is a manufacturing method of this invention (10)-(12) whose said ceramic particle group is a medical material for in-vivo introduction | transduction.
The present invention (14)
It is a manufacturing method of this invention (13) whose said ceramic particle group is an object for medical devices.

  According to the present invention, since the calcium carbonate crystal phase is not mixed, it is possible to suppress a decrease in biocompatibility and a change in solubility due to calcium carbonate. Moreover, according to this invention, the calcium-phosphate sintered compact particle group which shows high dispersibility can be provided.

1 shows the results of thermogravimetric differential thermal analysis (TG-DTA) measurement of the hydroxyapatite (HAp) fired particle group according to Example 1. FIG. FIG. 2 shows the results of thermogravimetric differential thermal analysis (TG-DTA) measurement of the hydroxyapatite (HAp) fired particles according to Comparative Example 1. FIG. 3 is a chart showing the absorbance obtained by calculating the spectrum obtained in the FT-IR measurement by the Kubelka-Munk (KM) equation. In producing the hydroxyapatite (HAp) particles of Example 1, it was examined how the amount of calcium carbonate was changed by the pickling process. The left chart in FIG. 3 shows hydroxyapatite (HAp) particles that have not been pickled, and the right chart in FIG. 3 shows hydroxyapatite particles that have been pickled. 4 is a chart showing an FT-IR spectrum of hydroxyapatite (HAp) sintered body particles obtained in Example 1. FIG. FIG. 5 is a chart showing an FT-IR spectrum of hydroxyapatite (HAp) sintered particles obtained in Example 2. 6 is an SEM photograph of the hydroxyapatite (HAp) sintered body particle group obtained in Example 1. FIG. FIG. 7 is an SEM photograph of the hydroxyapatite (HAp) sintered body particle group obtained in Example 1. FIG. 8 is an SEM photograph of the hydroxyapatite (HAp) sintered body particle group obtained in Example 2. FIG. 9 is an SEM photograph of the hydroxyapatite (HAp) sintered body particle group obtained in Example 2. FIG. 10 is a SEM photograph of a test material manufactured using the hydroxyapatite (HAp) sintered body particle group according to Example 1. Cell adhesion was evaluated. FIG. 11 is an SEM photograph of a test material manufactured using the hydroxyapatite (HAp) sintered particles according to Example 2. Cell adhesion was evaluated. FIG. 12 is an SEM photograph of a test material manufactured using the hydroxyapatite (HAp) sintered particles according to Comparative Example 1. Cell adhesion was evaluated.

  Hereinafter, the manufacturing method of the calcium phosphate particle group according to the present invention will be described, then the ceramic particle group obtained by the manufacturing method will be described, and then the application of the ceramic particle group will be described.

<< 1. Manufacturing method of ceramic particles >>
<1-1. Raw material>
Specific examples of calcium phosphate (CaP) that is a ceramic raw material before firing include hydroxyapatite (Ca ₁₀ (PO ₄ ) ₆ (OH) ₂ ), tricalcium phosphate (Ca ₃ (PO ₄ ) ₂ ), and calcium metaphosphate. (Ca (PO ₃ ) ₂ ), Ca ₁₀ (PO ₄ ) ₆ F ₂ , Ca ₁₀ (PO ₄ ) ₆ Cl _{2 and the} like. Here, the calcium phosphate (CaP) may be artificially produced by a known production method such as a wet method, a dry method, a hydrolysis method, or a hydrothermal method. Naturally derived ones obtained from the above may be used.

<1-2. Process>
The method for producing a ceramic particle group according to the present invention may include at least a “mixing step”, a “sintering step”, and a “pickling step”, but other steps (for example, “primary particle generation step”). ”,“ Removal step ”,“ pulverization step ”,“ drying step ”and the like.

  For example, the method for producing a ceramic particle group according to the present invention is performed in the order of “1. primary particle generation process” → “2. Mixing process” → “3. Sintering process” → “4. Pickling process”. .

(Primary particle generation process)
Hereinafter, in the method for producing a calcium phosphate particle group according to the present invention, the case where the primary particles are substantially spherical and substantially rod-shaped will be exemplified, but the production method of the present invention is not limited thereto, and the primary particles are produced as the primary particles. It can be any shape possible.

-Primary particle generation process of substantially spherical ceramic particles First, "primary particles" were formed of ceramic raw materials {calcium phosphate (CaP), hydroxyapatite (HAp), etc.} before sintering in the manufacturing process of the ceramic particles. Means particles. That is, it means a particle formed for the first time in the production process of ceramic particles. In a narrow sense, it means single crystal particles. In the claims and specification, “primary particles” include those in an amorphous state, a low crystalline state, and those in a sintered body state after sintering. Meaning. On the other hand, “secondary particles” are a combination of multiple “primary particles” by physical bonds such as fusion, chemical bonds such as Van der Waals force, electrostatic interaction, or covalent bonds. It means a particle in a state of being formed. In particular, the number of bonds between primary particles, the shape after bonding, and the like are not limited, and mean all bonded two or more primary particles. In particular, the “single crystal primary particle” means a primary particle made of a single crystal of a ceramic raw material or a particle lump in which the primary particles made of the single crystal are assembled by ionic interaction. The “particle aggregate assembled by ionic interaction” is a particle aggregate that self-assembles by ionic interaction when dispersed in a medium containing water or an organic solvent. It does not contain secondary particles that are melted and polycrystallized.

  The primary particle generation step is known per se and is not particularly limited as long as it is a step capable of generating the primary particles, and may be appropriately selected depending on the ceramic raw material to be manufactured. For example, if phosphoric acid is dropped into a calcium hydroxide slurry at room temperature, calcium phosphate (CaP) particles are precipitated.

  The method for producing a ceramic particle group according to the present invention is a method for producing a ceramic particle group by sintering the primary particle group composed of the primary particles produced by the primary particle production step while preventing fusion or the like. . Therefore, the state (particle size, particle size distribution) of the primary particles generated by the primary particle generation step is directly reflected in the state (particle size, particle size distribution) of the ceramic particles as the final product. Therefore, in the case of producing a ceramic particle group having a fine particle size (nanometer size) and a uniform particle size (narrow particle size distribution), the particle size is fine (nanometer size) in the primary particle generation step. ) And a uniform particle size (narrow particle size distribution) must be generated.

  In this case, the primary particle size (average particle size and particle size distribution) is preferably 10 nm to 700 nm, more preferably 15 nm to 450 nm, and most preferably 20 nm to 400 nm. Further, the coefficient of variation of the particle diameter of the primary particle group composed of primary particles is preferably 20% or less, more preferably 18% or less, and most preferably 15% or less. The particle diameter and variation coefficient of the primary particles may be calculated by measuring the particle diameter of at least 100 primary particles using dynamic light scattering or an electron microscope.

  The “variation coefficient” is a value indicating the variation in particle diameter between particles that can be calculated by standard deviation ÷ average particle diameter × 100 (%).

  There is no particular limitation on the method of generating the primary particle group that is fine (nanometer size) and has a uniform particle size (narrow particle size distribution) as described above. For example, JP 2002-137910 A And the method described in Japanese Patent No. 5044336, Journal of Nanoscience and Nanotechnology 7, 848-851, 2007.

  In addition, this step may include a step of washing the generated primary particles with water or the like, and a step of collecting the primary particles by centrifugation, filtration, or the like.

Primary rod generation process of substantially rod-shaped ceramic particles {Roughly rod-shaped ceramic particles {particles having a maximum minor axis diameter of 30 nm to 5 μm, a major axis of 75 nm to 10 μm, and growing in the c-axis direction to form crystals The primary particle production process of the aspect ratio (c-axis length / a-axis length) of 1 to 30 and the tip angle of the ceramic particles having a truncated columnar structure having an oblique surface is known per se, For example, the method described in Unexamined-Japanese-Patent No. 2002-137910, Journal of Nanoparticle Research 9, 807-815, 2007 can be mentioned.

  In addition, this step may include a step of washing the generated primary particles with water or the like, and a step of collecting the primary particles by centrifugation, filtration, or the like.

(Mixing process)
The mixing step is a step of mixing the primary particles and the anti-fusing agent. By interposing an anti-fusing agent between the particles of the primary particle group obtained by the primary particle generation step, it is possible to prevent the fusion of primary particles in the subsequent sintering step. It is. The mixture of primary particles and anti-fusing agent obtained by the mixing step is referred to as “mixed particles”.

  Here, the “fusion preventive agent” is not particularly limited as long as it can prevent fusion between primary particles, but may be non-volatile at a sintering temperature in a subsequent sintering step. preferable. Because it is non-volatile under the sintering temperature condition, it does not disappear from the primary particles during the sintering process, and the fusion of the primary particles can be reliably prevented. However, it is not necessary to have 100% non-volatility at the sintering temperature, as long as it is non-volatile so that 10% or more remains between the primary particles after the sintering process is completed. The anti-fusing agent may be chemically decomposed by heat after completion of the sintering process. That is, if it remains after the end of the sintering process, it is not necessary to be the same substance (compound) before and after the start of the sintering process.

  The anti-fusing agent is preferably a substance that dissolves in a solvent, particularly an aqueous solvent. As described above, by using an anti-fusing agent that dissolves in a solvent as an anti-fusing agent, the ceramic particles containing the anti-fusing agent can be fused only by suspending them in an aqueous solvent such as pure water. Inhibitors (such as calcium carbonate) can be removed. In particular, if the anti-fusing agent is soluble in an aqueous solvent, it is not necessary to use an organic solvent to remove the anti-fusing agent. It becomes. Therefore, it can be said that the anti-fusing agent can be removed from the ceramic particle group more easily. Although it does not specifically limit as said solvent, For example, water, ethanol, methanol etc. are mentioned as an aqueous solvent, Acetone, toluene etc. are mentioned as an organic solvent.

  The aqueous solvent may contain a chelate compound such as oxalate, ethylenediamine, bipyridine, and ethylenediaminetetraacetate in order to increase the solubility of the anti-fusing agent in water. Further, the aqueous solvent may contain electrolyte ions such as sodium chloride, ammonium nitrate and potassium carbonate in order to increase the solubility of the anti-fusing agent in water.

  Here, it can be said that the higher the solubility of the anti-fusing agent in the solvent is, the higher the removal efficiency becomes. The preferable solubility is preferably 0.01 g or more, more preferably 1 g or more, and most preferably 10 g or more, when the amount of solute (g) with respect to 100 g of solvent is the solubility.

  Specific examples of the anti-fusing agent include calcium chloride, calcium oxide, calcium sulfate, calcium nitrate, calcium carbonate, calcium hydroxide, calcium acetate, calcium citrate, and other calcium salts (or complexes), potassium chloride, potassium oxide. Potassium salts such as potassium sulfate, potassium nitrate, potassium carbonate, potassium hydroxide and potassium phosphate, sodium salts such as sodium chloride, sodium oxide, sodium sulfate, sodium nitrate, sodium carbonate, sodium hydroxide and sodium phosphate It is done.

  The method of mixing the primary particles and the anti-fusing agent in the mixing step is not particularly limited, and after mixing the solid anti-fusing agent with the solid primary particles, the mixture is mixed using a blender. Or a method of dispersing primary particles in a solution of an anti-fusing agent. However, since it is difficult to uniformly mix the solid and the solid, it can be said that the latter is a preferable method for interposing the anti-fusing agent uniformly and reliably between the primary particles. When the latter method is adopted, it is preferable to dry the anti-fusing agent solution in which primary particles are dispersed. This is because the state where the primary particles and the anti-fusing agent are uniformly mixed can be maintained over a long period of time. Also in the Example mentioned later, the hydroxyapatite (HAp) primary particle 0.5g is disperse | distributed to calcium carbonate saturated aqueous solution, It is made to dry at 80 degreeC, and the mixed particle is acquired.

  In the mixing step, a solution containing a polymer compound having any of a carboxyl group, a sulfate group, a sulfonic acid group, a phosphoric acid group, a phosphonic acid group or an amino group in the side chain is mixed with the primary particles, It may be a step of further adding a metal salt (alkali metal salt and / or alkaline earth metal salt and / or transition metal salt). By adopting the above steps, the polymer compound adsorbs on the surface of hydroxyapatite (HAp), so that contact between hydroxyapatite (HAp) in the anti-fusing agent mixing process can be surely prevented, and then calcium By adding the salt, the anti-fusing agent can be reliably deposited on the surface of hydroxyapatite (HAp). In the following description, a polymer compound having any of a carboxyl group, a sulfate group, a sulfonic acid group, a phosphoric acid group, a phosphonic acid group or an amino group in the side chain is simply referred to as “polymer compound”. .

  The polymer compound is not particularly limited as long as it is a compound having any of a carboxyl group, a sulfate group, a sulfonic acid group, a phosphoric acid group, a phosphonic acid group, or an amino group in the side chain. For example, examples of the polymer compound having a carboxyl group in the side chain include polyacrylic acid, polymethacrylic acid, carboxymethyl cellulose, styrene-maleic anhydride copolymer, and the like, as a polymer compound having a sulfate group in the side chain. And polyacrylic acid alkyl sulfate, polymethacrylic acid alkyl sulfate, polystyrene sulfuric acid and the like. Examples of the polymer compound having a sulfonic acid group in the side chain include polyacrylic acid alkyl sulfonic acid ester, polymethacrylic acid alkyl sulfone. Examples of the polymer compound having a phosphate group in the side chain include polyacrylic acid alkyl phosphate ester, polymethacrylic acid alkyl phosphate ester, polystyrene phosphoric acid, polyacryloylaminomethylphosphonic acid. Etc. Examples of the polymer compound having a phosphonic acid group in the side chain include polyacrylic acid alkylphosphonic acid ester, polymethacrylic acid alkylphosphonic acid ester, polystyrene phosphonic acid, polyacryloylaminomethylphosphonic acid, and polyvinylalkylphosphonic acid. Examples of the polymer compound having an amino group in the side chain include polyacrylamide, polyvinylamine, polymethacrylic acid aminoalkyl ester, polyaminostyrene, polypeptide, protein and the like. In the mixing step, any one of the above polymer compounds may be used, but a plurality of types of polymer compounds may be mixed and used.

  The molecular weight of the polymer compound is not particularly limited, but is preferably 100 g / mol or more and 1,000,000 g / mol or less, more preferably 500 g / mol or more and 500,000 g / mol or less, and 1,000 g / mol or less. Most preferably, it is at least mol but not more than 300,000 g / mol. If the ratio is less than the above preferable range, the ratio of entering between the primary particles decreases, and the ratio of preventing contact between the primary particles decreases. On the other hand, when the above preferred range is exceeded, the solubility of the polymer compound becomes low, and the operability such as increase in the viscosity of the solution containing the polymer compound becomes unfavorable.

  The solution containing the polymer compound is preferably an aqueous solution. This is because the hydroxyapatite (HAp) sintered body particles are dissolved under strong acidic conditions. The pH of the aqueous solution containing the polymer compound is not particularly limited as long as the pH is 5 or more and 14 or less and the HAp particles are insoluble. The aqueous solution containing the polymer compound may be prepared by dissolving the polymer compound in distilled water, ion-exchanged water or the like, and adjusting the pH with an aqueous solution of ammonia, sodium hydroxide, potassium hydroxide or the like.

  The concentration of the polymer compound contained in the aqueous solution is preferably 0.001% w / v or more and 50% w / v or less, more preferably 0.005% w / v or more and 30% w / v or less. Most preferred is 01% w / v or more and 10% w / v or less. When the amount is less than the above preferable range, the amount of entering between the primary particles is small, and the ratio of preventing contact between the primary particles is low. On the other hand, when the above preferred range is exceeded, it is not preferable because dissolution of the polymer compound becomes difficult and operability such as increase in the viscosity of the solution containing the polymer compound becomes worse.

  In the mixing step in the present invention, the solution containing the polymer compound and primary particles are mixed. Such mixing may be performed by, for example, adding primary particles into the solution and dispersing the primary particles by a stirring operation or the like. By such an operation, in the method for producing a ceramic particle group according to the present invention, the polymer compound is adsorbed on the surface of the primary particle, and a carboxyl group, a sulfate group, a sulfonic acid group, a phosphoric acid group, a phosphonic acid group, or an amino group. Either can be added to the surface of the primary particles. At this time, the carboxyl group, sulfuric acid group, sulfonic acid group, phosphoric acid group, phosphonic acid group or amino group is present in an ionic state in the solution.

Next, if a metal salt (alkali metal salt and / or alkaline earth metal salt and / or transition metal salt) is further added to the solution in which the polymer compound-containing solution and the primary particles are mixed, the surface of the primary particles is added. The existing carboxylate ion, sulfate ion, sulfonate ion, phosphate ion, phosphonate ion, amino ion and metal ion (alkali metal ion and / or alkaline earth metal ion and / or transition metal ion) are combined. Then, carboxylate, sulfate, sulfonate, phosphate, phosphonate, and amino acid salt are formed on the surface of the primary particles. Carboxylic acid salts, sulfates, sulfonates, phosphates, phosphonates, and amino acid salts of such metals (alkali metals and / or alkaline earth metals and / or transition metals) function as the anti-fusing agent. . Therefore, primary particles with metal (alkali metal and / or alkaline earth metal and / or transition metal) carboxylate, sulfate, sulfonate, phosphate, phosphonate, amino acid salt formed on the surface are These are so-called “mixed particles”. In addition, since the carboxylate, sulfate, sulfonate, phosphate, phosphonate, and amino acid salt of such metal (alkali metal and / or alkaline earth metal and / or transition metal) are precipitated, the precipitate After being recovered, it may be dried and subjected to a sintering step described later. The drying is performed under reduced pressure conditions (for example, preferably 1 × 10 ⁵ Pa or more and 1 × 10 ⁻⁵ Pa or less, more preferably 1 × 10 ³ Pa or more and 1 × 10 ⁻³ Pa or less, and more preferably 1 × 10 ² Pa or more and 1 × 10 ⁻² Pa or less is most preferable) and heating (0 ° C. or more and 200 ° C. or less is preferable, 20 ° C. or more and 150 ° C. or less is more preferable, and 40 ° C. or more and 120 ° C. or less is most preferable). It is done. The drying is preferably performed under reduced pressure because the drying temperature can be lowered, but may be performed under atmospheric pressure.

  The alkali metal salt is not particularly limited. For example, sodium chloride, sodium hypochlorite, sodium chlorite, sodium bromide, sodium iodide, sodium iodide, sodium oxide, sodium peroxide, Sodium sulfate, sodium thiosulfate, sodium selenate, sodium nitrite, sodium nitrate, sodium phosphide, sodium carbonate, sodium hydroxide, potassium chloride, potassium hypochlorite, potassium chlorite, potassium bromide, potassium iodide Potassium iodide, potassium oxide, potassium peroxide, potassium sulfate, potassium thiosulfate, potassium selenate, potassium nitrite, potassium nitrate, potassium phosphide, potassium carbonate, potassium hydroxide and the like can be used.

  Examples of the alkaline earth metal salt include magnesium chloride, magnesium hypochlorite, magnesium chlorite, magnesium bromide, magnesium iodide, magnesium iodide, magnesium oxide, magnesium peroxide, magnesium sulfate, and magnesium thiosulfate. , Magnesium selenate, magnesium nitrite, magnesium nitrate, magnesium phosphide, magnesium carbonate, magnesium hydroxide, calcium chloride, calcium hypochlorite, calcium chlorite, calcium bromide, calcium iodide, calcium iodate, oxidation Calcium, calcium peroxide, calcium sulfate, calcium thiosulfate, calcium selenate, calcium nitrite, calcium nitrate, calcium phosphide, calcium carbonate, calcium hydroxide and the like can be used.

  Examples of the transition metal salt include zinc chloride, zinc hypochlorite, zinc chlorite, zinc bromide, zinc iodide, zinc iodide, zinc oxide, zinc peroxide, zinc sulfate, zinc thiosulfate, and selenium. Zinc oxide, zinc nitrite, zinc nitrate, zinc phosphide, zinc carbonate, zinc hydroxide, iron chloride, iron hypochlorite, iron chlorite, iron bromide, iron iodide, iron iodide, iron oxide, Iron peroxide, iron sulfate, iron thiosulfate, iron selenate, iron nitrite, iron nitrate, iron phosphide, iron carbonate, iron hydroxide and the like can be used. Moreover, a nickel compound may be sufficient.

  Note that the metal salt (alkali metal salt, alkaline earth metal salt, transition metal salt) added to the solution in which the solution containing the polymer compound and the primary particles are mixed may be one kind or a mixture of two or more kinds. There may be. In addition, the metal salt (alkali metal salt, alkaline earth metal salt, transition metal) may be in a solid state, but for the reason that it can be added uniformly and the concentration to be added can be controlled. It is preferable to add it as an aqueous solution. In addition, the amount (concentration) of the metal salt (alkali metal salt and / or alkaline earth metal salt and / or transition metal salt) to be added depends on the carboxylate ion, sulfate ion, sulfonate ion, phosphoric acid present on the primary particle surface. Combined with ions, phosphonate ions, amino ions, metal (alkali metal and / or alkaline earth metal and / or transition metal) carboxylate, sulfate, sulfonate, phosphate, phosphonate, The conditions are not particularly limited as long as the amino acid salt is generated, and may be determined after appropriate examination.

  Since sodium polyacrylate is soluble in water, it can be used as an anti-fusing agent in this mixing step. However, since calcium polyacrylate is insoluble in water, only polyacrylic acid is temporarily removed from the primary particle surface. It is preferable that calcium acrylate is precipitated on the primary particle surface by adding a calcium salt or the like after adsorbing to the primary particle surface. In addition, since the polymer compound decomposes when the primary particles are calcined at a high temperature (about 300 ° C. or higher), the metal salt of the polymer compound is added to the primary particles so that it functions as an anti-fusing agent even after calcining. It can be said that it is preferable to deposit on the surface. However, when the primary particles are calcined (heat treatment) at a temperature at which the polymer compound is not decomposed (not softened), it is not particularly necessary to deposit the metal salt of the polymer compound on the surface of the primary particles.

(Sintering process)
The sintering step is a step in which the mixed particles obtained in the mixing step are exposed to a sintering temperature, and primary particles contained in the mixed particles are made into ceramic particles (sintered particles). Since the anti-fusing agent is interposed between the primary particles, it is possible to prevent the primary particles from fusing even when exposed to high temperature conditions in the sintering process.

  What is necessary is just to set suitably the sintering temperature in the said sintering process so that the hardness of a ceramic particle may become desired hardness, for example, the inside of the range of 100 to 1800 degreeC is more preferable, and 150 to 1500 degreeC is further more preferable. 200 ° C. to 1200 ° C. is most preferable. The sintering time may be appropriately set based on the desired ceramic particle hardness and the like. In the examples described later, sintering is performed at 800 ° C. for 1 hour.

  In addition, the apparatus etc. which are used for the said sintering process are not specifically limited, What is necessary is just to employ | adopt after selecting a commercially available baking furnace suitably according to a manufacturing scale, manufacturing conditions, etc.

(Removal process)
The said removal process is a process of removing the anti-fusing agent mixed between the particles of the ceramic particle group obtained by the sintering process.

  The removal means and method may be appropriately employed according to the anti-fusing agent employed in the mixing step. For example, when an anti-fusing agent having solvent solubility is used, it is possible to prevent fusion by using a solvent that does not dissolve ceramic particles (non-soluble) and a solvent that dissolves anti-fusing agent (soluble). Only the agent can be dissolved and removed. The solvent to be used is not particularly limited as long as it satisfies the above requirements, and may be an aqueous solvent or an organic solvent. For example, water, ethanol, methanol, etc. are mentioned as an aqueous solvent, and acetone, toluene, etc. are mentioned as an organic solvent.

  The aqueous solvent may contain a chelate compound such as oxalate, ethylenediamine, bipyridine, and ethylenediaminetetraacetate in order to increase the solubility of the anti-fusing agent in water. Further, the aqueous solvent may contain electrolyte ions such as sodium chloride, ammonium nitrate and potassium carbonate in order to increase the solubility of the anti-fusing agent in water.

  However, for the reasons such as that the equipment corresponding to the use of the organic solvent in the removal step becomes unnecessary, the organic solvent waste liquid treatment becomes unnecessary, the safety of the manufacturing work is high, and the risk to the environment is low. The solvent used is preferably an aqueous solvent.

  In the case of hydroxyapatite (HAp) sintered particles, since the hydroxyapatite (HAp) sintered particles dissolve under the condition of pH 4.0 or lower, the removal step can be performed at pH 4.0 to pH 12.0. preferable.

  By the way, when removing the anti-fusing agent using a solvent, after suspending the ceramic particle group containing the anti-fusing agent obtained by the sintering process in the solvent, only the ceramic particles are removed by filtration or centrifugation. Collect it. In the method for producing a ceramic particle group according to the present invention, the above operation is not limited to once, and may be performed twice or more. It can be said that the removal rate of the anti-fusing agent between the ceramic particles is further improved by performing the above operation a plurality of times. However, it is not preferable to perform the above operation more than necessary because the manufacturing process becomes complicated, the manufacturing cost increases, the recovery rate of ceramic particles decreases, and the like. Therefore, the number of operations may be appropriately determined based on the target anti-fusing agent removal rate.

  This step may further include a step of classifying to make the particle diameter uniform.

  In addition to the method of removing the anti-fusing agent using the solvent, the anti-fusing agent can be removed using a magnet by using a magnetic substance as the anti-fusing agent. More specifically, after suspending and dispersing the ceramic particles (coarse ceramic particles) group containing the anti-fusing agent obtained by the sintering process in an appropriate solvent (water, etc.), the magnetic force is applied to the suspension. , Only the anti-fusing agent is adsorbed to the magnet, and only the ceramic particles that have not been adsorbed are recovered. In addition, a method of separating the anti-fusing agent with a magnet may be performed after the coarse ceramic particles are ground into a powder without being suspended in a solvent. However, it can be said that the removal rate of the anti-fusing agent is higher because the ceramic particles and the anti-fusing agent are more easily separated from the suspension. In addition, it is preferable that the ceramic particle which can apply this method is a nonmagnetic material or a weak magnetic material.

(Pickling process)
The pickling step is a step of washing the ceramic particles (sintered particles) obtained by the sintering step with an acid. The purpose of the cleaning process is to remove calcium carbonate and the like contained in the sintered particles.

  As the acid, a weak acid that does not damage the ceramic particles is used. Examples thereof include hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, or ammonium salts thereof.

  The pickling process is performed by suspending the calcium phosphate sintered body in an acid solution. For example, an operation of suspending a calcium phosphate sintered body in an acid solution, centrifuging, and then discarding the supernatant is performed by adjusting the pH of the supernatant to 6.0 to 9 (preferably 6.5 to 8.5, The pickling step is preferably carried out by repeating until 7.0 to 7.5). More specifically, for example, HAp is suspended in a 0.2 wt% ammonium nitrate aqueous solution, subjected to ultrasonic irradiation for 5 minutes, subjected to solid-liquid separation by centrifugation, and the supernatant is discarded. After repeating this operation until the pH of the supernatant is 8, the pickling step may be performed by suspending in deionized water, centrifuging, and discarding the supernatant three times or more. .

(Crushing process)
The pulverization step is a step of pulverizing the aggregate after the sintering step to obtain a calcined calcium phosphate particle group having a desired size. Here, normally, the fired body that has been made into secondary particles can hardly be reduced to the size of the primary particles even if a considerable pulverization step is performed. On the other hand, according to the method of the present invention, it is possible to easily pulverize to the primary particle size level even with a simple pulverization process. Here, the pulverization method is not particularly limited, and examples thereof include ultrasonic treatment and pulverization using a pulverized sphere. After the pulverization treatment, particles having a smaller diameter may be collected by removing unpulverized ones.

(Drying process)
A drying process is a process of removing a solvent by heating etc. after the said grinding | pulverization process or the said washing | cleaning process, and obtaining a calcium-phosphate particle group. The drying method is not particularly limited.

≪2. Calcium phosphate sintered particles obtained by this production method >>
<2-1. Spherical Calcium Phosphate Sintered Particle Group>
The spherical calcium phosphate sintered body particle group obtained by this production method is a ceramic particle group made of ceramic particles, and the particle diameter of the ceramic particles is in the range of 10 nm to 700 nm, and the particle diameter of the ceramic particle group The coefficient of variation is 20% or less, the ceramic particles are sintered calcium phosphate particles, the ceramic particles are substantially free of calcium carbonate, and the ceramic particles are at least carbonated on the surface thereof. It is a ceramic particle group characterized by containing apatite.

  The ceramic particle group is a fine particle and a uniform particle size (narrow particle size distribution). Therefore, there is an effect that it can be more uniformly adsorbed to the medical polymer material without performing an additional operation such as a particularly advanced classification. Moreover, since calcium carbonate is not substantially contained, it is possible to prevent a situation in which the biocompatibility and solubility of the material change when used as a biomaterial. The ceramic particle group exhibits high dispersibility.

  Further, from another aspect, the spherical calcium phosphate sintered body particle group obtained by this production method is a ceramic particle group composed of spherical ceramic particles, which is a primary particle composed of a single crystal or a primary particle composed of the single crystal. When a particle lump in which particles are aggregated by ionic interaction is a single crystal primary particle, the ratio of the single crystal primary particles contained in the ceramic particle group occupies a majority, and the ceramic particles are sintered calcium phosphate particles. The ceramic particle group is characterized by being substantially free of calcium carbonate. The ceramic particle group is a primary particle composed of a single crystal having a superior dispersibility in a solvent, or a particle lump in which the primary particles composed of the single crystal are assembled by ionic interaction (single crystal primary particles). Exist as. Therefore, there is an effect that the adsorption to the medical polymer base material described above is facilitated. Moreover, since there is no coupling | bonding of primary particles, a specific surface area is high. Furthermore, since it is highly stable in vivo and excellent in dispersibility, it has an effect that it can be used as a medical material capable of carrying and sustained release of a drug. And since it does not contain calcium carbonate substantially, when it uses as a biomaterial, the biocompatibility of material and the original solubility of calcium phosphate are maintained. In addition, it is good also considering the particle lump which the primary particle which consists of the said single crystal assembled by the ionic interaction in this way as a ceramic particle.

  Further, in the ceramic particle group, the ratio of the single crystal primary particles contained in the ceramic particle group may be 70% or more. By taking such a structure, there exists an effect that it becomes easy to adsorb | suck to a medical polymeric base material.

  Moreover, the ceramic particle group may have a particle diameter of the ceramic particles in a range of 10 nm to 700 nm. According to the said structure, there exists an effect that it can adsorb | suck more uniformly with respect to medical polymeric material.

  The ceramic particle group may have a coefficient of variation of the particle diameter of the ceramic particle group of 20% or less. By adopting such a configuration, there is an effect that it can be more uniformly adsorbed to the medical polymer material without performing an additional operation such as particularly high classification.

  The ceramic particles may be hydroxyapatite (HAp) sintered particles. The particles are composed of a hydroxyapatite (HAp) sintered body that has higher biocompatibility and can be used for a wide range of applications. Therefore, it is particularly preferable as a medical material.

<2-2. Rod-like Calcium Phosphate Sintered Particle Group>
The rod-shaped calcium phosphate sintered body particle group obtained by this production method is a ceramic particle group composed of ceramic particles, and the particle diameter of the ceramic particles is such that the maximum diameter of the minor axis is 30 nm to 5 μm, and the major axis is 75 nm to It is 10 μm, grows in the c-axis direction, has a crystal aspect ratio (c-axis length / a-axis length) of 1 to 30, and has a truncated columnar structure having a beveled columnar structure. The ceramic particles are substantially free of calcium carbonate, and the ceramic particles contain at least a carbonate apatite on the surface thereof.

  Since the rod-shaped calcium phosphate baked particle group has a much wider area for adhesion than conventional fine particles, it can improve the adhesion to the polymer substrate, so it can be applied to the polymer surface such as biocompatible medical materials such as catheters. Suitable for modification. And since it does not contain calcium carbonate substantially, when using as a biomaterial, it becomes possible to prevent the situation where carbon dioxide gas is generated from a material. In addition, as a method for modifying the polymer surface, graft polymerization may be carried out by grafting an active group of calcium phosphate (for example, hydroxyapatite (HAp) nanoparticles) and a polymer substrate, for example, a vinyl polymerizable monomer having a carboxyl group on the surface. It is possible to use a method of chemically reacting with an active group of silicone rubber, a method of using a curable adhesive, a method of using a curable adhesive, a method of heating a polymer substrate to the vicinity of the melting point, and embedding it in the substrate. (This also applies to the spherical calcium phosphate sintered body particles described above).

  The ceramic particles may be hydroxyapatite sintered particles. The particles are composed of a hydroxyapatite sintered body that has higher biocompatibility and can be used for a wide range of applications. Therefore, it is particularly preferable as a medical material.

<2-3. Calcium phosphate sintered particles represented by general formula>
The calcium phosphate sintered particles of the above-mentioned 2-1 and 2-2 obtained by the present production method have the following general formula Ca _x (PO ₄ ) _6-y (CO ₃ ) _y (OH) ₂
(Wherein x is a number of 8 or more and 12 or less (preferably a number of 9 or more and 11 or less, more preferably a number of 9.5 or more and 10.5 or less), and y is greater than 0 and 3 or less. A number (preferably a number greater than 0 and less than or equal to 2, more preferably a number greater than 0 and less than or equal to 1)
It may be represented by

The measuring method of Ca, (PO ₄ ) and CO ₃ is as follows. For Ca and PO ₄ , the measurement solution is dissolved in 1N nitric acid, the measurement solution is adjusted to 100 ppm in terms of formula weight, and the above measurement solution is measured using ICP emission analysis (manufactured by Thermo Fisher Scientific, iCAP7600Duo). Was measured. In addition, CO ₃ was measured at 10 ° C./min. Under a nitrogen stream using a thermogravimetric differential thermal analyzer (TG-DTA) (manufactured by Seiko Instruments Inc., EXSTAR6000). The amount of decarboxylation was evaluated from the weight decreased in the temperature range of 700 ° C to 950 ° C.

<2-3. Structure>
Next, the structure of the calcium phosphate sintered body particle group obtained by the production method according to the present invention will be described.

  The present invention is a calcium phosphate sintered body particle group that is substantially free of calcium carbonate and includes at least the surface thereof including carbonate carbonate apatite.

  The inventors have found that when the invention of Patent Document 1 is implemented, calcium carbonate is generated on the surface of the calcium phosphate sintered particles. Surprisingly, the calcium phosphate sintered body is not only used when using an anti-fusing agent containing carbonic acid such as calcium carbonate, but also when using an anti-fusing agent containing no carbonic acid such as calcium nitrate and sodium nitrate. Calcium carbonate was formed on the surface of the particles (see Comparative Examples 2 and 3 below). The reason is that calcium nitrate and sodium nitrate change to calcium oxide and sodium oxide when heated. These substances are strong bases and react with carbon dioxide present in the electric furnace to produce calcium carbonate. In addition, since hydroxyapatite (HAp) easily causes ion exchange, ions constituting the salt used as the anti-fusing agent and ions constituting hydroxyapatite (HAp) are exchanged to change the crystal structure. In that case, it is estimated that the hydroxyapatite surface becomes excessive in calcium ions and reacts with carbon dioxide in the electric furnace to generate calcium carbonate. The inventors of the present invention have found that carbonate apatite is generated on the surface of the calcium phosphate sintered body particles (particle group) by removing the calcium carbonate by a pickling process or the like.

  In the present invention, it is substantially free of calcium carbonate, and at least the surface of the calcium phosphate sintered body particles (particle group) contains carbonate apatite, thereby suppressing a decrease in biocompatibility and a change in solubility. It becomes possible to make calcium phosphate sintered body particles exhibiting dispersibility.

  Furthermore, in the present invention, by containing substantially no alkali metal element, it becomes possible to obtain calcium phosphate sintered body particles that are further improved in crystallinity, are hardly dissolved, and are excellent in cell adhesion.

Here, “substantially does not contain calcium carbonate” means that calcium carbonate is substantially absent as a result of measurement according to a known calcium carbonate measurement method. For example, (1) in thermogravimetric differential thermal analysis (TG-DTA) measurement, no weight loss of 2% or more with a clear endotherm is observed at 650 ° C. to 800 ° C., or (2) obtained in FT-IR measurement. in spectrum Kubelka-Munk (KM) chart showing the calculated absorbance by the formula is, wave number separates the peaks appearing between ^{860cm -1 ~890cm} -1, ^877cm -1 peak near observed attributed to calcium carbonate Say that not. The peak separation can be performed by using, for example, software called fityk 0.9.4 under the conditions of Function Type: Gaussian and Fitting Method: Levenberg-Marquardt.

“Containing carbonate apatite” means that carbonate apatite is present as a result of measurement according to a known method for measuring carbonate apatite. For example, the FT-IR ^spectrum, means that the absorption is observed 1350cm ^-1 ~1500cm -1.

The FT-IR analyzer and measurement conditions are as follows. A hydroxyapatite (HAp) calcined particle group was taken so as to be 10% by weight with respect to potassium bromide [KBr], and a measurement sample sufficiently ground in an agate mortar was diffusely reflected using FT-IR Spectrum 100 manufactured by PerkinElmer. by measuring the range of ^{450cm -1 ~4000cm} -1 at 8 cumulative.

  The thermogravimetric differential thermal analysis (TG-DTA) measurement conditions are as follows. Thermogravimetric differential thermal analyzer (TG-DTA) (manufactured by Seiko Instruments Inc., EXSTAR 6000) under a nitrogen stream at 10 ° C./min. The amount of decarboxylation is evaluated from the weight decreased in the temperature range of 700 ° C to 950 ° C.

  Further, “substantially free of alkali metal elements” means that the weight of alkali metal elements with respect to the total weight of the calcium phosphate sintered particles is 10 ppm or less (preferably 1 ppm or less). Indicates. In addition, a conventionally well-known method can be applied as an analysis method, for example, it may analyze by ICP-MS.

  Furthermore, as described above, according to the present invention, it is also possible to obtain a calcium phosphate sintered body particle group that does not substantially contain an alkaline earth metal element other than calcium or a transition metal element.

  Thus, by containing substantially no alkaline earth metal elements other than calcium and transition metal elements, the crystallinity is further enhanced, the dissolution is difficult, and the calcium phosphate sintered body particles are excellent in cell adhesion. It becomes possible to do. Moreover, it becomes possible to improve the safety | security to a biological body substantially by not containing a transition metal element.

  As used above, “substantially free of alkaline earth metal elements other than calcium” (“substantially free of transition metal elements”) means each alkaline earth metal element (each transition metal element) as described above. , The weight of the alkaline earth metal element (transition metal element) other than calcium is 10 ppm or less (preferably 1 ppm or less) with respect to the total weight of the calcium phosphate sintered body particles. In addition, a conventionally well-known method can be applied as an analysis method, for example, it may analyze by ICP-MS.

≪Usage≫
Since the calcium phosphate calcined particles according to the present invention have extremely high biocompatibility and bioactivity, in the medical field, for example, medical materials such as bone fillers, dental fillers, sustained drug release agents, and external preparations. Alternatively, it can be widely used as a dental material, and can be applied to all other uses such as food additives. In addition, since the calcium phosphate calcined particle group according to the present invention is excellent in cell adhesion, it is suitable for use as a medical material for introduction into a living body (for example, in-vivo indwelling material) and a medical device using the material as one material. Is available. In addition, as a more specific use of the calcium phosphate calcined particle group according to the present invention, for example, cosmetics (breast augmentation promoters, basic cosmetics, cosmetics, dentifrices, etc.), injecting agents (dermal fillers, etc.), medical equipment, etc. {Wound dressings (especially hernia mesh), etc.}, surgical implantable medical devices {artificial bones, artificial joints (orthopedic implants), dental implants, etc.}, cardiovascular medical devices {catheter (cuff support) / Inner surface treatment), artificial blood vessel, stent, coil for cerebral embolism} and the like.

≪Production example≫
(Example 1: Spherical hydroxyapatite (HAp) sintered body particle group containing carbonate apatite)
(Primary particle generation process)
In a reaction vessel containing deionized water, calcium nitrate tetrahydrate, aqueous diammonium hydrogen phosphate solution and aqueous ammonia were added with stirring {calcium: phosphoric acid (molar ratio) = 5: 3}, 24 The reaction was allowed to stir at room temperature for an hour. Hydroxyapatite (HAp) primary particles were obtained.
(Mixing process)
By dispersing 1.0 g of hydroxyapatite (HAp) primary particle group in 100 ml of an aqueous solution having a pH of 12.0 containing 1.0 g of sodium polyacrylate (manufactured by ALDRICH, weight average molecular weight: 15,000 g / mol), Sodium polyacrylate was adsorbed on the surface of the particles. The pH of this aqueous solution was measured using a CyberScan pH 1100 manufactured by EUTECH and a CyberScan pH 1100 manufactured by EUTECH.
Next, 100 ml of a 0.12 mol / l calcium nitrate [Ca (NO ₃ ) ₂ ] aqueous solution was added to the dispersion prepared above to precipitate calcium polyacrylate on the surface of the primary particles. Such calcium polyacrylate is an anti-fusing agent. The resulting precipitate was collected and dried at 80 ° C. under reduced pressure (about 0.1 Pa) to obtain mixed particles.
(Sintering process)
The mixed particles were put in a crucible, heated to a sintering temperature of 600 ° C. at a heating rate of 200 ° C./hour, and held for 1 hour for sintering. At this time, the calcium polyacrylate was thermally decomposed to become calcium oxide [CaO], and a part thereof became calcium carbonate [CaCO ₃ ].
(Pickling process)
In order to increase the solubility of the anti-fusing agent and calcium carbonate in water, an aqueous solution of 50 mmol / l ammonium nitrate [NH ₄ NO ₃ ] was prepared. Next, the sintered body obtained in the above step is suspended in 500 ml of the aqueous solution prepared above, subjected to ultrasonic irradiation for 5 minutes and subjected to solid-liquid separation by centrifugation, and the resulting precipitate is again made into an ammonium nitrate aqueous solution. The suspension was subjected to ultrasonic irradiation, centrifugation, and the above steps were repeated until the supernatant had a pH of 7.5 or less. The suspension was further suspended in distilled water, and similarly separated and washed by centrifugation to remove the anti-fusing agent and ammonium nitrate, and to recover highly crystalline hydroxyapatite (HAp) fine particles.

(Example 2: Rod-like hydroxyapatite (HAp) fired particle group containing carbonate apatite)
(Primary particle generation process)
In a reaction vessel containing deionized water, calcium nitrate tetrahydrate, aqueous diammonium hydrogen phosphate solution and aqueous ammonia were added with stirring {calcium: phosphoric acid (molar ratio) = 5: 3}, 24 The reaction was allowed to proceed with stirring at 80 ° C. for an hour. Hydroxyapatite (HAp) primary particles were obtained.
(Mixing process) ・ (Sintering process) ・ (Pickling process)
The same operation as in Example 1 was performed.

(Comparative Example 1: Hydroxyapatite baked (HAp) adult particle group produced based on Japanese Patent No. 5044336 using a fusion inhibitor as calcium acrylate)
(Primary particle generation process)
In a reaction vessel containing deionized water, calcium nitrate tetrahydrate, aqueous diammonium hydrogen phosphate solution and aqueous ammonia were added with stirring {calcium: phosphoric acid (molar ratio) = 5: 3}, 24 The reaction was allowed to stir at room temperature for an hour. Hydroxyapatite (HAp) primary particles were obtained.
(Mixing process)
By dispersing 1.0 g of hydroxyapatite (HAp) primary particle group in 100 ml of an aqueous solution having a pH of 12.0 containing 1.0 g of sodium polyacrylate (manufactured by ALDRICH, weight average molecular weight: 15,000 g / mol), Sodium polyacrylate was adsorbed on the surface of the particles. The pH of this aqueous solution was measured using a CyberScan pH 1100 manufactured by EUTECH and a CyberScan pH 1100 manufactured by EUTECH.
Next, 100 ml of a 0.12 mol / l calcium nitrate [Ca (NO ₃ ) ₂ ] aqueous solution was added to the dispersion prepared above to precipitate calcium polyacrylate on the surface of the primary particles. Such calcium polyacrylate is an anti-fusing agent. The resulting precipitate was collected and dried at 80 ° C. under reduced pressure (about 0.1 Pa) to obtain mixed particles.
(Sintering process)
The mixed particles were put in a crucible, heated to a sintering temperature of 600 ° C. at a heating rate of 200 ° C./hour, and sintered for 1 hour. At this time, the calcium polyacrylate was thermally decomposed to become calcium oxide [CaO], and a part thereof became calcium carbonate [CaCO ₃ ].
(Removal process)
In order to increase the solubility of the anti-fusing agent in water, a 50 mmol / l ammonium nitrate [NH ₄ NO ₃ ] aqueous solution was prepared. Next, the sintered body obtained in the above step is suspended in 500 ml of the aqueous solution prepared above, separated and washed by centrifugation, suspended in distilled water, and similarly separated and washed by centrifugation. The anti-fusing agent and ammonium nitrate were removed, and highly crystalline hydroxyapatite (HAp) fine particles were recovered.

(Comparative example 2: hydroxyapatite fired body particle group manufactured based on Japanese Patent No. 5044336 using the fusion inhibitor as calcium nitrate)
(Primary particle generation process)
Similar to Comparative Example 1.
(Mixing process)
1.0 g of hydroxyapatite (HAp) primary particles were suspended in 100 ml of a 0.12 mol / l calcium nitrate aqueous solution. The resulting precipitate was collected and dried at 80 ° C. under reduced pressure (about 0.1 Pa) to obtain mixed particles.
(Sintering process) ・ (Removal process)
Similar to Comparative Example 1.

(Comparative example 3: hydroxyapatite fired body particle group manufactured based on Japanese Patent No. 5044336 using the fusion inhibitor as sodium nitrate)
(Primary particle generation process)
Similar to Comparative Example 1.
(Mixing process)
1.0 g of hydroxyapatite (HAp) primary particle group was suspended in 100 ml of 0.12 mol / l sodium nitrate aqueous solution. The resulting precipitate was collected and dried at 80 ° C. under reduced pressure (about 0.1 Pa) to obtain mixed particles.
(Sintering process) ・ (Removal process)
Similar to Comparative Example 1.

  In Examples 1 and 2, the weight of the alkali metal element or the like was 10 ppm or less.

≪Thermogravimetric differential thermal analysis≫
1 and 2 show the results of thermogravimetric differential thermal analysis (TG-DTA) measurement of the hydroxyapatite fired body particles according to Example 1 and Comparative Example 1. FIG. As can be seen from the figure, in Example 1 (FIG. 1), a weight loss of 2% or more with a clear endotherm at 650 ° C. to 800 ° C. was not observed. On the other hand, in Comparative Example 1 (FIG. 2), a weight loss of 2% or more with a clear endotherm was observed at 650 ° C. to 800 ° C. Therefore, it was confirmed that Example 1 contains substantially no calcium carbonate, whereas Comparative Example 1 contains calcium carbonate.

  Similarly, it was confirmed that Example 2 contains substantially no calcium carbonate, whereas Comparative Examples 2 to 3 contain calcium carbonate.

≪FT-IR analysis≫
(About calcium carbonate)
The present inventors examined how the amount of calcium carbonate changed by the pickling process when producing the hydroxyapatite (HAp) particles of Example 1. This is shown in FIG. The left chart in FIG. 3 shows hydroxyapatite particles that have not been pickled, and the right chart in FIG. 3 shows hydroxyapatite (HAp) particles that have been pickled. In particular, in chart showing the absorbance of calculating the spectrum obtained in the FT-IR measurement in Kubelka-Munk (KM) equation, to separate the peak wavenumber appears between ^{860cm -1 ~890cm} -1, it was evaluated. As a result, it was confirmed that in the hydroxyapatite particles subjected to the pickling step (the right diagram in FIG. 3), a peak near 877 cm ⁻¹ attributed to calcium carbonate is not observed. On the other hand, in the hydroxyapatite particles not subjected to the pickling step (the left diagram in FIG. 3), a peak around 877 cm ⁻¹ attributed to calcium carbonate was observed.
(About carbonate apatite)
4 to 5 are FT-IR spectra of hydroxyapatite (HAp) fired particles according to Example 1 and Example 2. FIG. As can be seen from the figure, in Example 1 and Example 2, absorption was observed at 1350 cm ^{−1 to} 1500 cm ⁻¹ . Therefore, it was confirmed that Example 1 and Example 2 contain carbonate apatite.

≪Consideration based on the results of thermogravimetric differential thermal analysis and FT-IR analysis≫
From the results of thermogravimetric differential thermal analysis and FT-IR analysis, Example 1 and Example 2 were substantially free of calcium carbonate and contained carbonate apatite.
On the other hand, Comparative Examples 1-3 contained calcium carbonate from the result of the thermogravimetric differential thermal analysis.
When producing hydroxyapatite particles, it is considered that calcium carbonate was removed by a pickling process or the like.

The FT-IR analyzer and measurement conditions are as follows. A hydroxyapatite (HAp) calcined particle group was taken so as to be 10% by weight with respect to potassium bromide [KBr], and a measurement sample sufficiently ground in an agate mortar was diffusely reflected using FT-IR Spectrum 100 manufactured by PerkinElmer. the range of ^{450cm -1 ~4000cm} -1 at was measured at 8 cumulative. In addition, peak separation was performed by using software called fityk 0.9.4 under the conditions of Function Type: Gaussian and Fitting Method: Levenberg-Marquardt.

  The thermogravimetric differential thermal analysis (TG-DTA) measurement conditions are as follows. Thermogravimetric differential thermal analyzer (TG-DTA) (manufactured by Seiko Instruments Inc., EXSTAR 6000) under a nitrogen stream at 10 ° C./min. The amount of decarboxylation was evaluated from the weight decreased in the temperature range of 700 ° C to 950 ° C.

≪Appearance observation test≫
6 and 7 are SEM photographs of the hydroxyapatite (HAp) fired particles according to Example 1 (difference in scale). From these photographs, it can be seen that the hydroxyapatite (HAp) fired body particle group according to Example 1 is a hydroxyapatite fired body particle group composed of substantially spherical hydroxyapatite (HAp) fired body particles. 8 and 9 are SEM photographs of the hydroxyapatite fired particles according to Example 2 (difference in scale). From these photographs, it can be seen that the hydroxyapatite (HAp) fired body particle group according to Example 1 is a hydroxyapatite (HAp) fired body particle group composed of substantially rod-like hydroxyapatite fired body particles.

≪Composition analysis≫
As a result of composition analysis of the ceramic particles according to Examples 1 and 2,
Ca _x (PO ₄ ) _6-y (CO ₃ ) _y (OH) ₂
(Wherein, x is a number of 8 or more and 12 or less, and y is a number greater than 0 and 3 or less).
The measuring method is as described above.

≪Dispersibility test≫
60 mg of sintered hydroxyapatite (HAp) (sintered hydroxyapatite (HAp) according to Example 1 and Comparative Example 1) and 3 ml of ethanol were mixed and ultrasonically irradiated for 30 minutes to prepare a sintered hydroxyapatite dispersion. . 200 ml of water was added to a water circulation flow cell of a laser scattering particle size distribution meter (manufactured by Shimadzu Corporation, SALD-7500 nano), and a sintered hydroxyapatite dispersion was dropped so that the intensity of the laser scattered light became the measurement region of the apparatus. The circulation tank was irradiated with ultrasonic waves for 5 minutes, and the particle size distribution was measured. Dispersibility was evaluated by examining the abundance (%) of 500 nm or less in terms of volume from the obtained particle size distribution. The higher the abundance (%) of 500 nm or less, the higher the dispersibility. The results are shown in Table 1 below.

  From the above table, it is clear that Example 1 exhibits significantly higher dispersibility than Comparative Example 1.

  In addition, the variation coefficient of the particle diameter of Example 1 was 17%. Further, the particle diameter of Example 2 is that the maximum diameter of the short axis is 51 nm, the long axis is 170 nm, the crystal grows in the c-axis direction, and the crystal aspect ratio (c-axis length / a-axis length) is 3.33. there were.

≪Cell adhesion test≫
<Manufacture of test materials>
(Cleaning process)
A circular polyethylene terephthalate (PET) sheet (diameter 9 mm, thickness 0.1 mm) was subjected to alcohol treatment (ultrasonic irradiation for 5 minutes in alcohol (ethanol, 2-propanol, etc.)).

(Linker introduction process)
Corona discharge treatment (100 V, 15 seconds on one side) was applied to both surfaces of the PET sheet that had been subjected to the cleaning treatment. A PET sheet after corona discharge treatment and 10 ml of acrylic acid (manufactured by Wako Pure Chemical Industries, Ltd.) were placed in a 20 ml test tube, and the inside of the test tube was depressurized with a vacuum pump to perform a deaeration operation. The test tube was sealed under reduced pressure, and graft polymerization was performed in a water bath at a temperature of 60 ° C. for 60 minutes. After the treatment, in order to remove the acrylic acid homopolymer adhering to the substrate surface, the mixture was stirred in water at room temperature for 60 minutes, and then the substrate surface was washed with water and then with ethanol.

(Sintered hydroxyapatite (HAp) fine particle immobilization treatment)
After the above treatment, the base material is dispersed in 1% sintered hydroxyapatite (HAp) fine particles (sintered hydroxyapatite (HAp) fine particles according to Example 1, Example 2 and Comparative Example 1) (dispersion medium: Ethanol) and left at 20 ° C. for 30 minutes. Then, ultrasonic irradiation was performed for 5 minutes, the base material was taken out and dried at 20 ° C. and normal pressure to obtain a test material.

<Evaluation of cell adhesion and cell morphology>
Cell adhesion and cell morphology evaluation tests were performed using the prepared test materials. Prior to the test, the test material was washed with ethanol, washed with phosphate buffered saline (PBS) and medium (MEM α (serum-free)) (3 times), then immersed in the medium and incubated until use. (37 ° C., 5% CO ₂ ). And cell culture was implemented in the following procedures. First, a culture medium (200 μL / hole) and a test material (test sheet) were placed in a 48-well plate. Thereafter, a suspension of osteoblast-like cells (MC3T3-E1 (subclone 14)) was added (about 1 × 10 ⁵ cells / 200 μL / well) and cultured for 3 hours.

(Cell observation)
10 to 12 are SEM photographs of specimens manufactured using the hydroxyapatite (HAp) sintered particles according to Example 1, Example 2, and Comparative Example 1, respectively. Based on the photograph, the state of cell aggregation, cell morphology, and cell density were determined. The results are shown in Table 2. As for the cell density, the greater the number of “+”, the higher the cell density. Moreover, the average coverage of each test material is calculated from SEM photographs.

As can be seen from FIGS. 10 to 12 and Table 2, when the hydroxyapatite sintered particles according to Example 1 and Example 2 were used, it was confirmed that excellent cell adhesiveness was exhibited, and most cells Was also confirmed to show a greatly elongated cell morphology. On the other hand, when the hydroxyapatite sintered body particle group according to Comparative Example 1 was used, it was confirmed that the cell adhesion was inferior.

Claims (14)

A group of ceramic particles composed of ceramic particles,
The particle diameter of the ceramic particles is within a range of 10 nm to 700 nm, and the coefficient of variation of the particle diameter of the ceramic particle group is 20% or less,
The ceramic particles are calcium phosphate sintered particles,
The ceramic particles are substantially free of calcium carbonate, and
A group of ceramic particles, wherein the ceramic particles include carbonate apatite at least on the surface thereof.   The ceramic particle group according to claim 1, wherein the ceramic particles are substantially spherical. A group of ceramic particles composed of ceramic particles,
The ceramic particles have a minor axis maximum diameter of 30 nm to 5 μm and a major axis of 75 nm to 10 μm, grow in the c-axis direction, and have an aspect ratio (c-axis length / a-axis length) of 1 ˜30, and the ceramic particles having a truncated columnar structure having a beveled front end angle,
The ceramic particles are calcium phosphate sintered particles,
The ceramic particles are substantially free of calcium carbonate, and
A group of ceramic particles, wherein the ceramic particles include carbonate apatite at least on the surface thereof. A group of ceramic particles composed of ceramic particles,
The particle diameter of the ceramic particles is within a range of 10 nm to 700 nm, and the coefficient of variation of the particle diameter of the ceramic particle group is 20% or less,
The ceramic particles are calcium phosphate sintered particles,
The ceramic particles have the following general formula Ca _x (PO ₄ ) _6-y (CO ₃ ) _y (OH) ₂
(In the formula, x is a number from 8 to 12, and y is a number greater than 0 and 3 or less.)
The ceramic particle group characterized by these. A group of ceramic particles composed of ceramic particles,
The ceramic particles have a minor axis maximum diameter of 30 nm to 5 μm and a major axis of 75 nm to 10 μm, grow in the c-axis direction, and have an aspect ratio (c-axis length / a-axis length) of 1 ˜30, and the ceramic particles having a truncated columnar structure having a beveled front end angle,
The ceramic particles are calcium phosphate sintered particles,
The ceramic particles have the following general formula Ca _x (PO ₄ ) _6-y (CO ₃ ) _y (OH) ₂
(In the formula, x is a number from 8 to 12, and y is a number greater than 0 and 3 or less.)
The ceramic particle group characterized by these.   The ceramic particle group according to any one of claims 1 to 5, which is substantially free of alkali metal.   The ceramic particle group according to any one of claims 1 to 6, wherein the ceramic particles are hydroxyapatite sintered particles.   A medical material for introduction into a living body, wherein the medical material is obtained using the ceramic particle group according to any one of claims 1 to 7.   A medical device obtained using the medical material for introduction into a living body according to claim 8 as one material. In the method for producing a ceramic particle group consisting of ceramic particles,
The ceramic particle group is the ceramic particle group according to any one of claims 1 to 7, and
A mixing step of mixing calcium phosphate and an anti-fusing agent to obtain mixed particles;
Exposing the mixed particles to a sintering temperature to form calcium phosphate sintered particles, and a sintering step;
Washing the calcium phosphate sintered particles with an acid, a pickling step;
The manufacturing method of the ceramic particle group containing this.   The manufacturing method of Claim 10 with which the said ceramic particle does not contain an alkali metal substantially.   The manufacturing method according to claim 10, wherein the ceramic particles are hydroxyapatite sintered particles.   The manufacturing method according to claim 10, wherein the ceramic particle group is a medical material for introduction into a living body.   The manufacturing method according to claim 13, wherein the ceramic particle group is for a medical device.