JP2021181400A - Method for producing calcium phosphate sintered compact particle - Google Patents

Abstract

To provide a method for producing a calcium phosphate sintered compact particle group having a smaller particle size without causing bubble generation regardless of a use mode.SOLUTION: A ceramic particle group comprises substantially spherical ceramic particles, in which the particle diameter of the ceramic particles falls within the range of 10 nm to 700 nm, the coefficient of variation of the particle diameter of the ceramic particle group is 20% or less, the ceramic particles are calcium phosphate sintered compact particles, and the ceramic particle group substantially does not contain calcium carbonate.SELECTED DRAWING: None

Description

The present invention relates to novel calcium phosphate sintered body particles, a method for producing the same, 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 HAp is used as a biomaterial, it has been proposed to bake it at a high temperature to produce hydroxyapatite particles (ceramic particles) having a high crystallinity in order to reduce the solubility and decomposability in the living body. There is. However, during this sintering, bonding occurs due to fusion between hydroxyapatite (HAp) particles (primary particles), and the primary particles become amorphous secondary particles bonded to each other, resulting in a decrease in dispersibility and specific surface area. There was a problem.

Therefore, in Prior Patent Document 1, the primary particles made of the ceramic raw material before sintering are mixed so as to intervene between the particles of the primary particles to form mixed particles, and the mixed particles are sintered and after the firing. A manufacturing method for washing away the anti-fusing agent has been proposed. According to this production method, it is possible to obtain a ceramic particle group having a high crystallinity and a small particle size.

Japanese Patent No. 5043436

However, the present inventors have obtained the finding that the ceramic particle group obtained by the production method contains a crystal phase of calcium carbonate. When calcium phosphate is used for applications, especially for medical devices introduced into a living body, unfavorable events may occur from the viewpoint of expressing biocompatibility and changing solubility. Furthermore, calcium phosphate has the property of actively adsorbing endotoxin, and it is unavoidable to adsorb endotoxin slightly contained in water, containers, etc. used for washing in the manufacturing process. On the other hand, endotoxin is known as a pyrogen, and when the calcium phosphate is used as a medical material for introduction into a living body (for example, DDS), it is necessary to remove the adsorbed endotoxin. Therefore, heat treatment is performed at about 300 ° C. to decompose the adsorbed endotoxin. However, at this time, the present inventors have obtained the finding that the original particle size is more than doubled when the heat treatment is performed. In particular, when a calcined calcium phosphate body is used for an application in which a finer particle size is required, such an increase in particle size is an unfavorable event. Therefore, it is an object of the present invention to provide a calcium phosphate sintered body particle group having a smaller particle size while suppressing a decrease in biocompatibility and a change in solubility caused by calcium carbonate as much as possible regardless of the mode of use. do.

By the way, in Patent Document 1, a polymer compound having any one of a carboxyl group, a sulfate group, a sulfonic acid group, a phosphoric acid group, a phosphonic acid group or an amino group can be used as a fusion inhibitor. As specific compounds, polyacrylic acid, polymethacrylic acid, polyglutamic acid, ethylene sulfonic acid, polymethacrylic acid alkyl sulfonic acid ester, polyacryloylaminomethylphosphonic acid, and polypeptides are mentioned. Based on this, the present inventors presume that the cause of calcium carbonate production is carbonic acid, which is a decomposition product of the polymer compound used as the anti-fusing agent. Therefore, the present inventor has studied a method for obtaining a calcium phosphate sintered body particle group having a high crystallinity and a small particle size without using an anti-fusion agent, and has completed the present invention.

The present invention is a group of ceramic particles composed of substantially spherical ceramic particles.
The particle size of the ceramic particles is in the range of 10 nm to 700 nm, and the coefficient of variation of the particle size of the ceramic particle group is 20% or less.
The ceramic particles are calcium phosphate sintered body particles, and the ceramic particles are
The ceramic particle group is characterized in that it does not substantially contain calcium carbonate. Here, the scope of the present patent claim and "substantially containing no calcium carbonate" in the present specification mean that calcium carbonate is below the detection limit when X-ray diffraction is performed {specifically, calcium carbonate (formula). Amount: 100.09) / hydroxyapatite (formula: 1004.62) = 0.1 / 99.9 (formula conversion ratio) or less}, and according to the pharmaceutical non-medicinal product raw material standard 2006 (hydroxyapatite) It means that the amount of bubbles generated is 0.25 mL or less when tested in accordance with the above.
The present invention is a group of ceramic particles composed of substantially spherical ceramic particles.
When a single crystal primary particle or a particle mass obtained by assembling the single crystal primary particles by ionic interaction is defined as a single crystal primary particle.
The ratio of single crystal primary particles contained in the ceramic particle group occupies the majority,
The ceramic particles are calcium phosphate sintered body particles, and the ceramic particles are
The ceramic particle group is characterized in that it does not substantially contain calcium carbonate.
Here, the particle size of the ceramic particles may be in the range of 10 nm to 700 nm.
Further, the coefficient of variation of the particle size of the ceramic particle group may be 20% or less.
The present invention is a group of ceramic particles composed of rod-shaped ceramic particles.
The ceramic particles have a maximum diameter of 50 nm to 5 μm on the minor axis and 75 nm to 10 μm on the major axis, grow in the c-axis direction, and have a crystal aspect ratio (c-axis length / a-axis length) of 1. It is a ceramic particle having a vertical columnar structure having a tip angle of about 30 and having an oblique surface.
The ceramic particles are calcium phosphate sintered body particles, and the ceramic particles are
The ceramic particle group is characterized in that it does not substantially contain calcium carbonate.
Here, the ceramic particles may be hydroxyapatite sintered body particles.
In addition, the ceramic particles were washed with water.
When the particle size of the ceramic particles after washing with water is used as a reference, the rate of change in the particle size when heated at 300 ° C. under normal pressure in air after washing with water may be ± 20%.
The present invention is a medical material for introduction into a living body, which is obtained by using the ceramic particle group.
The present invention is a medical device obtained by using the medical material for introduction into a living body as one material.
The present invention relates to a method for producing a group of ceramic particles composed of particulate ceramic particles.
A pre-process in which an aqueous medium containing primary particles, which is a ceramic raw material before sintering, is frozen to obtain a frozen body, and then the frozen body is thawed to obtain a thawed body.
A firing step of firing the primary particles obtained by removing the aqueous medium from the thawed body, and
Including a crushing step of crushing the fired body obtained by the firing step to obtain the ceramic particle group.
A method for producing a group of ceramic particles, wherein the ceramic particles are calcium phosphate sintered body particles.
Here, the particle shape may be a substantially spherical shape or a substantially rod shape.
Further, the ceramic particles may be hydroxyapatite sintered body particles.
Further, the ceramic particle group may be a medical material for introduction into a living body.
Further, the ceramic particle group may be used for medical devices.

According to the present invention, it is possible to provide a ceramic particle group having high crystallinity and a small particle size without mixing the crystal phase of calcium carbonate. Further, for unknown reasons, the calcined calcium phosphate according to the present invention has almost no change in particle size even when heated at 300 ° C. for removing endotoxin. Therefore, according to the present invention, it is possible to obtain a group of calcium phosphate sintered body particles having a smaller particle size.

FIG. 1 is a chart showing the results of X-ray diffraction of hydroxyapatite (HAp) sintered body particles obtained in Example 1. FIG. 2 is a chart showing the results of X-ray diffraction of hydroxyapatite (HAp) sintered body particles obtained in Comparative Example. FIG. 3 is an SEM photograph of the hydroxyapatite (HAp) sintered body particles obtained in Example 1. FIG. 4 is an SEM photograph of the hydroxyapatite (HAp) sintered body particles obtained in Example 1. FIG. 5 is an SEM photograph of the hydroxyapatite (HAp) sintered body particles obtained in Example 2. FIG. 6 is an SEM photograph of the hydroxyapatite (HAp) sintered body particles obtained in Example 2.

Hereinafter, the method for producing the calcium phosphate particle group according to the present invention will be described, then the ceramic particle group obtained by the production method will be described, and then the use of the ceramic particle group will be described.

≪1. Manufacturing method of ceramic particles ≫
<1-1. Raw materials>
Specific examples of calcium phosphate (CaP) as 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 can be mentioned. 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, a hydrothermal method, or the like, and bones and teeth. It may be of natural origin obtained from the above.

<1-2. Process>
(1-1. Primary particle generation step)

-Primary particle generation step 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 particle group. It means particles. That is, it means the particles formed for the first time in the process of manufacturing ceramic particles. In a narrow sense, it means single crystal particles. In the claims and the specification, the "primary particles" include those in an amorphous state, those in a low crystallinity state, and those in a sintered body state obtained by sintering thereafter. It means. On the other hand, the "secondary particle" means that a plurality of "primary particles" are bonded to each other by a physical bond such as fusion, a Van der Waals force, an electrostatic interaction, or a chemical bond such as a covalent bond. It means the particles in the state formed by the above. In particular, the number of bonds between the primary particles, the shape after the bonds, and the like are not limited, and mean all the particles in which two or more primary particles are bonded. Further, in particular, the "single crystal primary particle" means a primary particle made of a single crystal of a ceramic raw material or a particle mass in which the primary particles made of the single crystal are aggregated by ionic interaction. The "particle mass aggregated by ionic interaction" is a particle mass that self-assembles by ionic interaction when dispersed in a medium containing water or an organic solvent, and is obtained by sintering. It does not contain secondary particles that are polycrystallized by melting between the particles.

The primary particle generation step is known in itself and is not particularly limited as long as it is a step capable of producing the primary particles, and may be appropriately selected and adopted depending on the raw material of the ceramic to be produced. For example, if phosphoric acid is dropped onto a calcium hydroxide slurry at room temperature, particles of calcium phosphate (CaP) precipitate.

The method for producing a ceramic particle group according to the present invention is to produce a ceramic particle group by sintering a primary particle group composed of primary particles generated by the above primary particle generation step while preventing fusion and the like. .. Therefore, the state of the primary particles (particle size, particle size distribution) generated by the primary particle generation step is directly reflected in the state of the ceramic particles (particle size, particle size distribution) which is 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 the particle size is uniform (the particle size distribution is narrow), it is necessary to generate a primary particle group.

In such a case, the particle size (average particle size and particle size distribution) of the primary particles is preferably 10 nm to 500 nm, more preferably 15 nm to 450 nm, and most preferably 20 nm to 400 nm. Further, the coefficient of variation of the particle size 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 size and coefficient of variation of the primary particles may be calculated by measuring the particle size of at least 100 or more primary particles using a dynamic light scattering method or an electron microscope.

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

The method for generating a primary particle group having a fine particle size (nanometer size) and a uniform particle size (narrow particle size distribution) as described above is not particularly limited, and is, for example, Japanese Patent Application Laid-Open No. 2002-137910. , Patent No. 5043436, Journal of Nanoscience and Nanotechnology Vol. 7, 848-851, 2007.

Further, this step may include a step of washing the generated primary particles with water or the like, a step of recovering the primary particles by centrifugation, filtration or the like.

-Primary particle generation process of substantially rod-shaped ceramic particles Approximately rod-shaped ceramic particles {The particle diameter of the particles is 30 nm to 5 μm on the minor axis and 75 nm to 10 μm on the major axis, and grows in the c-axis direction and crystallizes. The primary particle generation step of the ceramic particles having a head-shaped columnar structure in which the aspect ratio (c-axis length / a-axis length) is 1 to 30 and the tip angle has an oblique surface} is known per se. For example, the methods described in JP-A-2002-137910, Journal of Nanoparticle Research (2007) 9: 807-815 can be mentioned.

Further, this step may include a step of washing the generated primary particles with water or the like, a step of recovering the primary particles by centrifugation, filtration or the like.

(Freezing process)
The freezing step is a step of freezing an aqueous medium containing calcium phosphate (CaP) before sintering. Here, the aqueous medium is a liquid medium containing water as a main component (preferably 90% by mass or more based on the total mass of the liquid medium). Preferably, only water is used, and a liquid (alcohol or the like) miscible with water may be added as appropriate. Further, the liquid obtained by dissolving calcium phosphate (CaP) as the primary particles, that is, the liquid obtained by dissolving the phosphoric acid source and the calcium source in water may be frozen as it is. Here, the freezing temperature is preferably −1 to -269 ° C. More preferably, it is −5 to -196 ° C. The freezing time is preferably 1 minute to 24 hours.

(Thawing process)
The thawing step is a step of arranging the frozen body obtained in the freezing step at a temperature exceeding the melting point of the water-based medium of the frozen body to thaw the water-based medium.

(Separation process)
The separation step is a step of separating calcium phosphate from the aqueous medium containing calcium phosphate thawed in the thawing step. As the separation method, a method of collecting the precipitate after thawing may be used, or a method of centrifuging and collecting the precipitate may be used.

(Baking process)
The sintering step is a step of exposing the calcium phosphate primary particle composition obtained by the separation step to the sintering temperature to turn the primary particles contained in the composition into ceramic particles (sintered body particles). Although the reason is not clear, even if the anti-fusing agent as in Patent Document 1 is not used, the above-mentioned freezing / thawing step is obtained and fired, and the case is exposed to high temperature conditions in the sintering step. Also, it is possible to prevent fusion of primary particles. Here, the sintering temperature in the sintering step may be appropriately set so that the crystallinity of the ceramic particles has a desired hardness, and is preferably 300 to 1000 ° C., for example. The rate of temperature rise in the sintering step is preferably 1 to 20 ° C./min, for example. Further, the sintering time in the sintering step may be appropriately set based on the hardness of the ceramic particles and the like, and is preferably 0.5 to 3 hours, for example. The apparatus or the like used in the sintering step is not particularly limited, and a commercially available firing furnace may be appropriately selected and adopted according to the production scale, production conditions, and the like.

(Crushing process)
The pulverization step is a step of pulverizing the agglomerates after the sintering step to obtain a group of calcined calcium phosphate particles having a desired size. Here, usually, it is almost impossible to reduce the size of the fired body made into secondary particles to the size of the primary particles even if a considerable degree of pulverization step is carried out. 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 step. Here, the crushing method is not particularly limited, and is, for example, an ultrasonic treatment or a crushing treatment using a crushing ball. After the crushing treatment, particles having a smaller diameter may be collected by removing unground particles or the like.

(Washing process)
The cleaning step involves components other than the calcined calcium phosphate particles, such as impurities derived from the raw materials used in producing the primary particles of calcium phosphate (eg, impurities derived from calcium and phosphoric acid that were not involved in calcium phosphate formation, nitrates and ammonium. It is a process of cleaning the impurities). It is preferable to wash with water. In the case of hydroxyapatite (HAp) sintered body particles, since the hydroxyapatite (HAp) sintered body particles are dissolved under the condition of pH 4.0 or less, the removal step may be performed at pH 4.0 to pH 12.0. Suitable. Further, the order is not limited, such as performing the crushing process and the cleaning process alternately.

(Drying process)
The drying step is a step of removing the solvent by heating or the like after the crushing step or the washing step to obtain a calcium phosphate particle group. The drying method is not particularly limited.

(Endotoxin removal process)
The endotoxin removal step is a step performed by heating at 300 ° C. under normal pressure under air. After firing, the calcium phosphate calcined body is preferably subjected to water washing in the above-mentioned washing step. At this time, the calcined calcium phosphate body adsorbs endotoxin that is slightly present in the environment such as water, a storage container, and a handling atmosphere. Here, this endotoxin is a harmful substance, and the fact that it remains in the calcined calcium phosphate body is unsuitable especially when the calcined calcium phosphate body is used as a biomaterial. Therefore, the process is carried out. The endotoxin removal step may be performed in combination with the above-mentioned drying step.

≪2. Calcium Phosphate Sintered Particle Group Obtained by This Manufacturing Method ≫
<2-1. Approximately spherical calcium phosphate sintered body particle group>
The group of substantially spherical calcium phosphate sintered body particles obtained by this production method is a group of ceramic particles composed of substantially spherical ceramic particles, and the particle size of the ceramic particles is within the range of 10 nm to 700 nm, and the ceramic particles. The variation coefficient of the particle size of the group is 20% or less, the ceramic particles are calcium phosphate sintered body particles, and the ceramic particle group does not substantially contain calcium carbonate. It is a group. The ceramic particle group is fine particles and has a uniform particle size (particle size distribution is narrow). Therefore, it has the effect of being able to be more uniformly adsorbed on the medical polymer material without performing additional operations such as particularly advanced classification. Moreover, since it does not substantially contain calcium carbonate, it is possible to prevent a situation in which the biocompatibility and solubility of the material change when used as a biomaterial.

From another aspect, the substantially spherical calcium phosphate sintered body particle group obtained by the present production method is a ceramic particle group composed of substantially spherical ceramic particles, and is composed of primary particles composed of a single crystal or the single crystal. When the particle mass in which the primary particles are aggregated by ionic interaction is regarded as a single crystal primary particle, the ratio of the single crystal primary particle contained in the ceramic particle group occupies the majority, and the ceramic particle is a calcium phosphate sintered body. It is a group of ceramic particles which is a particle and is characterized in that the group of ceramic particles does not substantially contain calcium carbonate. The majority of the ceramic particle group is a primary particle composed of a single crystal having excellent dispersibility in a solvent, or a particle mass (single crystal primary particle) in which the primary particles composed of the single crystal are aggregated by ionic interaction. It exists as. Therefore, it has the effect of facilitating adsorption to the above-mentioned medical polymer base material. In addition, the specific surface area is high because there is no bond between the primary particles. Further, since it is highly stable in the living body and has excellent dispersibility, it has an effect that it can be used as a medical material capable of carrying and sustained release of a drug. Moreover, since it does not substantially contain calcium carbonate, the biocompatibility of the material and the original solubility of calcium phosphate are maintained when used as a biomaterial.

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 adopting such a configuration, there is an effect that the adsorption to the medical polymer base material becomes easy.

Further, in the ceramic particle group, the particle size of the ceramic particles may be in the range of 10 nm to 700 nm. According to this configuration, it has the effect of being able to be more uniformly adsorbed on the medical polymer material.

Further, in the ceramic particle group, the coefficient of variation of the particle size of the ceramic particle group may be 20% or less. By adopting this configuration, there is an effect that it can be more uniformly adsorbed on the medical polymer material without performing additional operations such as particularly advanced classification.

Further, the ceramic particles may be hydroxyapatite sintered body particles. The particles are made of a hydroxyapatite sintered body that is more biocompatible and can be used in a wide range of applications. Therefore, it is particularly preferable as a medical material.

Further, the ceramic particle group was washed with water, and when the particle size of the ceramic particle group after the water washing was used as a reference, the ceramic particle group was heated at 300 ° C. under normal pressure in the air after the water washing. The rate of change in particle size may be ± 20%.

<2-2. Approximately rod-shaped calcium phosphate sintered body particle group>
The substantially rod-shaped calcium phosphate sintered body particle group obtained by this production method is a ceramic particle group composed of rod-shaped ceramic particles, and the particle diameter of the ceramic particles is long, with a maximum diameter of 50 nm to 5 μm on the minor axis. A cylindrical columnar structure having an axis of 75 nm to 10 μm, growing in the c-axis direction, a crystal aspect ratio (c-axis length / a-axis length) of 1 to 30, and a tip angle having an oblique surface. It is a ceramic particle group, wherein the ceramic particle is a calcium phosphate sintered body particle, and the ceramic particle group does not substantially contain calcium carbonate. Since the rod-shaped calcined calcium phosphate particle group has a much larger area to be adhered than the conventional fine particles, the adhesiveness to the polymer base material can be improved. Suitable for modifying. Moreover, since it does not substantially contain calcium carbonate, it is possible to prevent a situation in which carbon dioxide gas is generated from the material when it is used as a biomaterial. As a method for modifying the surface of the polymer, a silicone rubber obtained by graft-polymerizing an active group of calcium phosphate (for example, hydroxyapatite nanoparticles) and a polymer substrate, for example, a vinyl-based polymerizable monomer having a carboxyl group on the surface. A method of chemically reacting with the active group of, to form a composite, a method of using a curable adhesive, a method of heating a polymer base material to near the melting point and burying it in the base material, etc. can be used. The same applies to the above-mentioned group of substantially spherical calcium phosphate sintered body particles).

Further, the ceramic particles may be hydroxyapatite sintered body particles. The particles are made of a hydroxyapatite sintered body that is more biocompatible and can be used in a wide range of applications. Therefore, it is particularly preferable as a medical material.

Further, the ceramic particle group was washed with water, and when the particle size of the ceramic particle group after the water washing was used as a reference, the ceramic particle group was heated at 300 ° C. under normal pressure in the air after the water washing. The rate of change in particle size may be ± 20%.

≪Use≫
Since the calcium phosphate calcined body particle group according to the present invention has extremely high biocompatibility and bioactivity, in the medical field, for example, a dental material such as a bone filler, a dental filler, a drug sustained-release agent, or a medical use. It can be widely used as a material.

≪Manufacturing example≫
(Example 1: Spherical hydroxyapatite calcined particle group)
Calcium nitrate tetrahydrate, diammonium hydrogen phosphate aqueous solution and aqueous ammonia were added to the reaction vessel containing deionized water while stirring {calcium: phosphoric acid (molar ratio) = 5: 3}, hydroxy. Primary particles of apatite were obtained. Then, after transferring the supernatant in the reaction vessel to the wastewater vessel, deionized water was added, the mixture was stirred with a stirrer, and the supernatant was transferred to the waste vessel, and the operation was repeated twice. Then, the whole reaction vessel containing the precipitate was frozen overnight at −10 ° C. to −15 ° C. Then, it was thawed at room temperature, and the precipitate after thawing was collected by filtration. Then, about 400 g of the precipitate was placed in a baking dish, placed in a baking furnace, heated to 600 ° C. over 1 hour, kept at 600 ° C. for 1 hour, and then cooled over 1 hour to carry out firing. Then, deionized water was added to the fired body, and ultrasonic waves were irradiated for 30 minutes or more. Then, it was transferred to a pod mill, a crushed ball was put in, and the crushed ball was crushed for 1 hour. After completion of crushing, the mixture was transferred to a beaker with a handle, and an uncrushed calcined body was removed using a 150 μm sieve with an opening. After that, deionized water washing was repeated 6 times. Then, it was dried at 60 to 80 degreeC, and the hydroxyapatite fired body which concerns on Example 1 was obtained.

(Example 2: Rod-shaped hydroxyapatite calcined particle group)
While stirring the calcium nitrate tetrahydrate aqueous solution in the reaction vessel containing the deionized water, the diammonium hydrogen phosphate aqueous solution and the ammonia water were dropped onto the calcium nitrate tetrahydrate aqueous solution {calcium: phosphoric acid (mol). Ratio) = 5: 3}, primary particles of hydroxyapatite were obtained. Then, after transferring the supernatant in the reaction vessel to the wastewater vessel, deionized water was added, the mixture was stirred with a stirrer, and the supernatant was transferred to the waste vessel, and the operation was repeated 5 times. Then, the whole reaction vessel containing the precipitate was frozen overnight at −10 ° C. to −15 ° C. Then, it was thawed at room temperature, and the precipitate after thawing was collected by filtration. Then, about 400 g of the precipitate was placed in a baking dish, placed in a baking furnace, heated to 600 ° C. over 1 hour, kept at 600 ° C. for 1 hour, and then cooled over 1 hour to carry out firing. Then, deionized water was added to the fired body, and ultrasonic waves were irradiated for 30 minutes or more. Then, it was transferred to a pod mill, a crushed ball was put in, and the crushed ball was crushed for 1 hour. After completion of crushing, the mixture was transferred to a beaker with a handle, and an uncrushed calcined body was removed using a 150 μm sieve with an opening. After that, deionized water washing was repeated 7 times. Then, it was dried at 60 to 80 degreeC, and the hydroxyapatite fired body which concerns on Example 2 was obtained. The ceramic particles have an average maximum diameter of 47 on the minor axis and 146 on the major axis, and grow in the c-axis direction, and the aspect ratio of the crystal (c-axis length / a-axis length) is 3. It was 1 and was a ceramic particle having a head-shaped columnar structure having an oblique surface at the tip angle.

(Comparative example)
According to Example 1 of Japanese Patent No. 5043336, a hydroxyapatite fired body according to a comparative example was obtained.

≪X-ray diffraction test≫
1 and 2 are the results of X-ray diffraction of the hydroxyapatite fired body according to Example 1 and Comparative Example, respectively. As can be seen from the figure, no peak of calcium carbonate was observed in FIG. 1, whereas a clear peak of calcium carbonate was observed in FIG. 2. More specifically, in FIG. 1, only the pattern corresponding to hydroxyapatite (PDF 74-0565) can be confirmed, while in FIG. 2, a peak not present in hydroxyapatite is observed at 29.4 ° and calcium carbonate (calcium carbonate (PDF 74-0565). It matched with calcite: PDF 72-1937). The X-ray diffractometer and measurement conditions are as follows. Crystal structure analysis was performed using a powder X-ray diffractometer {MiniFlex, manufactured by Rigaku Denki Co., Ltd.}. CuKα radiation source {λ = 1.541841Å (Angstrom)} was used as the X-ray source used in the XRD, the output was 30 kV / 15 mA, the scan speed was 1.0 ° / min, the sampling width was 0.01 °, and the measurement was performed. The mode was a continuous condition.

≪Appearance observation test≫
3 and 4 are SEM photographs of the hydroxyapatite calcined particle group according to Example 1 (different scales). From these photographs, the hydroxyapatite calcined particle group according to Example 1 is a hydroxyapatite calcined particle group composed of substantially spherical hydroxyapatite calcined particles, and is composed of primary particles composed of a single crystal or the single crystal. It can be seen that, assuming that the particle mass in which the primary particles are aggregated by ionic interaction is a single crystal primary particle, the proportion of the single crystal primary particle contained in the hydroxyapatite calcined body particle group occupies the majority. Further, FIGS. 5 and 6 are SEM photographs of the hydroxyapatite calcined particle group according to Example 2 (different scales).

<< Particle size measurement test >>
Average particle size and standard deviation of the hydroxyapatite calcined product (endotoxin inactivated) according to Example 1 and Comparative Example (confirm the particle size of 100 particles by SEM and calculate the average value and standard deviation). bottom. In addition, with respect to the inactivated hydroxyapatite fired product (endotoxin inactivated) according to Example 1 and Comparative Example, the average particle size and standard deviation (particle size of 100 particles were confirmed by SEM). Then, the average value and standard deviation were calculated). The inactivation procedure is as follows: (1) Weigh the HAp powder into an ampoule that has been dry-heat sterilized (300 ° C for 2 hours) in advance, and (2) put the ampoule containing HAp into a dry-heat sterilizer in the opened state. Then, dry heat sterilize (300 ° C, 2 hours), (3) melt the ampoule cooled to room temperature (sealed), and (4) dry heat sterilize the sealed ampoule again in a dry heat sterilizer (300). ° C., 2 hours). Table 1 shows the hydroxyapatite fired body according to Example 1, and Table 2 shows the hydroxyapatite fired body according to Comparative Example.

≪Effervescence confirmation test≫
The hydroxyapatite calcined product according to Examples 1 and 2 and Comparative Example was subjected to a test according to the procedure shown in (4) Carbonate in the purity test listed in the quasi-drug raw material standard 2006 “Hydroxyapatite”. Specifically, 1.0 g of the sample was weighed at room temperature (20 ° C.), 5 mL of water was added, the mixture was shaken, and the pressure was reduced for 1 hour using an aspirator to degas. After degassing, 2 mL of concentrated hydrochloric acid (35.0% by mass) was added, and the presence or absence of effervescence was confirmed. As a result, in the HAp obtained by the example, foaming could not be confirmed (gas generation amount was less than 0.25 ml). On the other hand, in the HAp obtained by the comparative example, the generated foam foamed to the extent that the supernatant became cloudy.

Claims (1)

A method for producing a group of ceramic particles, which is substantially described herein and described with reference to Examples.

Images