JP2016193798A - Method for manufacturing method of calcium phosphate sintered body particle - Google Patents
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- 239000002245 particle Substances 0.000 title claims abstract description 264
- 239000001506 calcium phosphate Substances 0.000 title claims abstract description 60
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 title claims abstract description 60
- 229910000389 calcium phosphate Inorganic materials 0.000 title claims abstract description 59
- 235000011010 calcium phosphates Nutrition 0.000 title claims abstract description 59
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 30
- 238000000034 method Methods 0.000 title claims description 41
- 239000000919 ceramic Substances 0.000 claims abstract description 135
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 claims abstract description 46
- 229910000019 calcium carbonate Inorganic materials 0.000 claims abstract description 23
- 239000011164 primary particle Substances 0.000 claims description 66
- XYJRXVWERLGGKC-UHFFFAOYSA-D pentacalcium;hydroxide;triphosphate Chemical compound [OH-].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O XYJRXVWERLGGKC-UHFFFAOYSA-D 0.000 claims description 62
- 229910052588 hydroxylapatite Inorganic materials 0.000 claims description 61
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 32
- 239000013078 crystal Substances 0.000 claims description 30
- 230000008569 process Effects 0.000 claims description 21
- 238000005245 sintering Methods 0.000 claims description 18
- 239000012567 medical material Substances 0.000 claims description 12
- 239000002994 raw material Substances 0.000 claims description 11
- 238000010304 firing Methods 0.000 claims description 10
- 239000012736 aqueous medium Substances 0.000 claims description 9
- 239000000463 material Substances 0.000 claims description 9
- 230000008014 freezing Effects 0.000 claims description 8
- 238000007710 freezing Methods 0.000 claims description 8
- 230000003993 interaction Effects 0.000 claims description 8
- 230000008859 change Effects 0.000 claims description 7
- 238000010257 thawing Methods 0.000 claims description 6
- 238000004140 cleaning Methods 0.000 claims description 5
- 229960001714 calcium phosphate Drugs 0.000 description 46
- 238000005406 washing Methods 0.000 description 18
- 238000010298 pulverizing process Methods 0.000 description 11
- 239000002158 endotoxin Substances 0.000 description 10
- 230000000052 comparative effect Effects 0.000 description 9
- 239000011575 calcium Substances 0.000 description 8
- 239000008367 deionised water Substances 0.000 description 8
- 229910021641 deionized water Inorganic materials 0.000 description 8
- 239000000203 mixture Substances 0.000 description 8
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical group OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 7
- 238000006243 chemical reaction Methods 0.000 description 7
- 239000003795 chemical substances by application Substances 0.000 description 7
- 238000009826 distribution Methods 0.000 description 7
- 239000002244 precipitate Substances 0.000 description 7
- 239000012620 biological material Substances 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 229920000642 polymer Polymers 0.000 description 6
- 238000002441 X-ray diffraction Methods 0.000 description 5
- 238000010438 heat treatment Methods 0.000 description 5
- 239000006228 supernatant Substances 0.000 description 5
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 4
- 239000003708 ampul Substances 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 229960005069 calcium Drugs 0.000 description 4
- 229910052791 calcium Inorganic materials 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 230000004927 fusion Effects 0.000 description 4
- 239000011163 secondary particle Substances 0.000 description 4
- 238000000926 separation method Methods 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- ZHJGWYRLJUCMRT-UHFFFAOYSA-N 5-[6-[(4-methylpiperazin-1-yl)methyl]benzimidazol-1-yl]-3-[1-[2-(trifluoromethyl)phenyl]ethoxy]thiophene-2-carboxamide Chemical compound C=1C=CC=C(C(F)(F)F)C=1C(C)OC(=C(S1)C(N)=O)C=C1N(C1=C2)C=NC1=CC=C2CN1CCN(C)CC1 ZHJGWYRLJUCMRT-UHFFFAOYSA-N 0.000 description 3
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 3
- 238000005119 centrifugation Methods 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 238000011013 endotoxin removal Methods 0.000 description 3
- 239000010419 fine particle Substances 0.000 description 3
- 238000005187 foaming Methods 0.000 description 3
- 239000012535 impurity Substances 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- 239000002609 medium Substances 0.000 description 3
- 229920000307 polymer substrate Polymers 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 238000001179 sorption measurement Methods 0.000 description 3
- 230000001954 sterilising effect Effects 0.000 description 3
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
- 229920002845 Poly(methacrylic acid) Polymers 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- MNNHAPBLZZVQHP-UHFFFAOYSA-N diammonium hydrogen phosphate Chemical compound [NH4+].[NH4+].OP([O-])([O-])=O MNNHAPBLZZVQHP-UHFFFAOYSA-N 0.000 description 2
- 229910000388 diammonium phosphate Inorganic materials 0.000 description 2
- 235000019838 diammonium phosphate Nutrition 0.000 description 2
- 239000000945 filler Substances 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 238000000227 grinding Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 239000002105 nanoparticle Substances 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 2
- 239000010452 phosphate Substances 0.000 description 2
- 239000002861 polymer material Substances 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000004659 sterilization and disinfection Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 239000002699 waste material Substances 0.000 description 2
- 239000002351 wastewater Substances 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 229910014497 Ca10(PO4)6(OH)2 Inorganic materials 0.000 description 1
- 229910021532 Calcite Inorganic materials 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 108010020346 Polyglutamic Acid Proteins 0.000 description 1
- 229920002125 Sokalan® Polymers 0.000 description 1
- 238000005411 Van der Waals force Methods 0.000 description 1
- 239000000853 adhesive Substances 0.000 description 1
- 230000001070 adhesive effect Effects 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 1
- 239000000920 calcium hydroxide Substances 0.000 description 1
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 1
- ROPDWRCJTIRLTR-UHFFFAOYSA-L calcium metaphosphate Chemical compound [Ca+2].[O-]P(=O)=O.[O-]P(=O)=O ROPDWRCJTIRLTR-UHFFFAOYSA-L 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 239000005548 dental material Substances 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000002296 dynamic light scattering Methods 0.000 description 1
- 230000009881 electrostatic interaction Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- -1 for example Substances 0.000 description 1
- 238000010559 graft polymerization reaction Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 238000001027 hydrothermal synthesis Methods 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
- 230000001788 irregular Effects 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000000178 monomer Substances 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- ABLZXFCXXLZCGV-UHFFFAOYSA-N phosphonic acid group Chemical group P(O)(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 description 1
- 239000004584 polyacrylic acid Substances 0.000 description 1
- 229920002643 polyglutamic acid Polymers 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 238000000634 powder X-ray diffraction Methods 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 238000013094 purity test Methods 0.000 description 1
- 239000002510 pyrogen Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 229920002379 silicone rubber Polymers 0.000 description 1
- 239000004945 silicone rubber Substances 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L sulfate group Chemical group S(=O)(=O)([O-])[O-] QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 125000000542 sulfonic acid group Chemical group 0.000 description 1
- 238000013269 sustained drug release Methods 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 238000009210 therapy by ultrasound Methods 0.000 description 1
- 229910000391 tricalcium phosphate Inorganic materials 0.000 description 1
- 235000019731 tricalcium phosphate Nutrition 0.000 description 1
- 229940078499 tricalcium phosphate Drugs 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- NLVXSWCKKBEXTG-UHFFFAOYSA-N vinylsulfonic acid Chemical compound OS(=O)(=O)C=C NLVXSWCKKBEXTG-UHFFFAOYSA-N 0.000 description 1
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- Materials For Medical Uses (AREA)
- Dental Preparations (AREA)
- Medicinal Preparation (AREA)
Abstract
Description
本発明は、新規なリン酸カルシウム焼結体粒子、その製造方法及びその用途に関する。 The present invention relates to a novel calcium phosphate sintered body particle, a production method thereof, and an application thereof.
ハイドロキシアパタイト（ＨＡｐ）は、高い生体親和性を示すことが知られており、バイオマテリアルをはじめとする様々な分野で活用されている。 Hydroxyapatite (HAp) is known to exhibit high biocompatibility and is used in various fields including biomaterials.
ところで、当該ＨＡｐを生体材料に用いる場合、生体内での溶解性や分解性を低減させるため、高温で焼成させて高結晶化度のハイドロキシアパタイト粒子（セラミック粒子）を作成することが提案されている。但し、この焼結の際にハイドロキシアパタイト（ＨＡｐ）粒子（一次粒子）間の融着により結合が生じ、一次粒子が結合した不定形な二次粒子となり、分散性及び比表面積が低下してしまうという問題点があった。 By the way, when using the HAp as a biomaterial, it has been proposed to produce hydroxyapatite particles (ceramic particles) with high crystallinity by firing at a high temperature in order to reduce in vivo solubility and degradability. Yes. 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.
そこで、先行特許文献１には、焼結前のセラミック原料からなる一次粒子の粒子間に融着防止剤が介在するように混合して混合粒子とし、当該混合粒子を焼結し、当該焼成後に融着防止剤を洗い流す製法が提案されている。当該製法によれば、結晶化度が高く且つ粒子径が小さいセラミック粒子群を得ることが可能となる。 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.
しかしながら、本発明者らは、当該製法により得られたセラミック粒子群には、炭酸カルシウムの結晶相が含まれている知見を得た。用途、特に生体内に導入される医療機器にリン酸カルシウムを用いる際には、生体親和性発現、溶解性変化の観点より好ましくない事象が生じ得る。更には、リン酸カルシウムは、エンドトキシンを積極的に吸着する性質があり、製造過程において洗浄に使用する水、容器等にわずかに含まれるエンドトキシンの吸着は避けがたい。一方で、エンドトキシンは発熱物質として知られており、当該リン酸カルシウムを生体内導入用医療材料（例えばＤＤＳ）として用いる場合には、当該吸着されたエンドトキシンを除去する必要がある。そのため、３００℃程度で加熱処理を行い、当該吸着されたエンドトキシンを分解する。しかしながら、この際、本発明者らは、当該加熱処理を行うと、元々の粒径が倍以上となるという知見を得た。特に、より微小な粒径が求められる用途にリン酸カルシウム焼成体を用いる際には、このような粒径増大は好ましくない事象である。よって、本発明は、使用態様に拘わらず、炭酸カルシウムに起因する生体親和性低下や溶解性変化が極力抑制され、且つ、より小さい粒径のリン酸カルシウム焼結体粒子群を提供することを課題とする。 However, the present inventors have obtained knowledge that the ceramic particle group obtained by the production method contains a crystal phase of calcium carbonate. When calcium phosphate is used for an application, particularly a medical device introduced into a living body, an undesirable event may occur from the viewpoint of biocompatibility and change in solubility. Furthermore, calcium phosphate has a property of actively adsorbing endotoxin, and it is difficult to avoid adsorption of endotoxin contained in water, containers, and the like used for washing in the production process. On the other hand, endotoxin is known as a pyrogen, and when the calcium phosphate is used as a medical material for in vivo introduction (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 found that the original particle size is doubled or more when the heat treatment is performed. In particular, such an increase in particle size is an undesirable phenomenon when the calcium phosphate fired body is used for applications where a finer particle size is required. Therefore, it is an object of the present invention to provide a calcium phosphate sintered body particle group having a smaller particle diameter in which a decrease in biocompatibility and a change in solubility due to calcium carbonate are suppressed as much as possible regardless of the mode of use. To do.
ところで、特許文献１では、融着防止剤として、側鎖にカルボキシル基、硫酸基、スルホン酸基、リン酸基、ホスホン酸基又はアミノ基のいずれかを有する高分子化合物が使用可能であることが記載されており、具体的な化合物として、ポリアクリル酸、ポリメタクリル酸、ポリグルタミン酸、エチレンスルホン酸、ポリメタクリル酸アルキルスルホン酸エステル、ポリアクリロイルアミノメチルホスホン酸、ポリペプチドが挙げられている。これを踏まえ、本発明者らは、炭酸カルシウム生成の原因が、融着防止剤として用いた高分子化合物の分解物である炭酸であると推定した。よって、本発明者は、融着防止剤を使用することなく、結晶化度が高く且つ粒子径が小さいリン酸カルシウム焼結体粒子群を得る手法を検討し、本発明を完成するに至った。 By the way, in Patent Document 1, 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 can be used as an anti-fusing agent. Specific examples of the compound include polyacrylic acid, polymethacrylic acid, polyglutamic acid, ethylenesulfonic acid, polymethacrylic acid alkylsulfonic acid ester, polyacryloylaminomethylphosphonic acid, and polypeptide. Based on this, the present inventors estimated that the cause of calcium carbonate generation was carbonic acid, which is a decomposition product of the polymer compound used as an anti-fusing agent. Therefore, the present inventor has studied a technique for obtaining a calcium phosphate sintered body particle group having a high crystallinity and a small particle diameter without using an anti-fusing agent, and has completed the present invention.
本発明は、略球状のセラミック粒子からなるセラミック粒子群であって、
前記セラミック粒子の粒子径が、１０ｎｍ〜７００ｎｍの範囲内で、且つ前記セラミック粒子群の粒子径の変動係数が、２０％以下であり、
前記セラミック粒子が、リン酸カルシウム焼結体粒子であり、且つ、
前記セラミック粒子群が炭酸カルシウムを実質的に含有しないことを特徴とするセラミック粒子群である。ここで、本特許請求の範囲及び本明細書における「実質的に炭酸カルシウムを含有しない」とは、Ｘ線回折を行なった場合に炭酸カルシウムが検出限界以下｛具体的には、炭酸カルシウム（式量：１００．０９）／ハイドロキシアパタイト（式量：１００４．６２）＝０．１／９９．９（式量換算比）以下｝であり、且つ、医薬部外品原料規格２００６（ヒドロキシアパタイト）に準じて試験した際、気泡発生量が０．２５ｍＬ以下であることをいう。
本発明は、略球状のセラミック粒子からなるセラミック粒子群であって、
単結晶からなる一次粒子、もしくは前記単結晶からなる一次粒子がイオン的相互作用にて集合化した粒子塊を単結晶一次粒子とすると、
前記セラミック粒子群に含まれる単結晶一次粒子の割合が過半数を占め、
上記セラミック粒子が、リン酸カルシウム焼結体粒子であり、且つ、
前記セラミック粒子群が炭酸カルシウムを実質的に含有しないことを特徴とするセラミック粒子群である。
ここで、上記セラミック粒子の粒子径が、１０ｎｍ〜７００ｎｍの範囲内であってもよい。
また、上記セラミック粒子群の粒子径の変動係数が２０％以下であってもよい。
本発明は、ロッド状のセラミック粒子からなるセラミック粒子群であって、
前記セラミック粒子の粒子径が、短軸の最大直径が５０ｎｍ〜５μｍ、長軸が７５ｎｍ〜１０μｍであり、ｃ軸方向に成長し、結晶のアスペクト比（ｃ軸長／ａ軸長）が、１〜３０であり、先端角が斜角面を有する截頭形柱状構造のセラミック粒子であって、
前記セラミック粒子が、リン酸カルシウム焼結体粒子であり、且つ、
前記セラミック粒子群が炭酸カルシウムを実質的に含有しないことを特徴とするセラミック粒子群である。
ここで、上記セラミック粒子が、ハイドロキシアパタイト焼結体粒子であってもよい。
また、前記セラミック粒子群が水洗浄されたものであり、
前記水洗浄後の前記セラミック粒子群の粒子径を基準としたとき、前記水洗浄後に空気中常圧下にて３００℃で加熱した際の粒子径の変化率が±２０％であってもよい。
本発明は、前記セラミック粒子群を用いて得られたものであることを特徴とする生体内導入用医療材料である。
本発明は、前記生体内導入用医療材料を一材料として得られた医療機器である。
本発明は、粒子状のセラミック粒子からなるセラミック粒子群の製造方法において、
焼結前のセラミック原料である一次粒子を含有する水系媒体を凍結して凍結体を得た後に当該凍結体を解凍させて解凍体を得る前工程と、
前記解凍体から前記水系媒体を除去して得られた前記一次粒子を焼成する焼成工程と、
前記焼成工程により得られた焼成体を粉砕して前記セラミック粒子群を得る粉砕工程と
を含み、
前記セラミック粒子が、リン酸カルシウム焼結体粒子である
ことを特徴とするセラミック粒子群の製造方法である。
ここで、前記粒子状が、略球状又は略ロッド状であってもよい。
また、上記セラミック粒子が、ハイドロキシアパタイト焼結体粒子であってもよい。
また、前記セラミック粒子群が生体内導入用医療材料であってもよい。
また、前記セラミック粒子群が医療機器用であってもよい。
The present invention is a group of ceramic particles composed of substantially spherical 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 sintered calcium phosphate particles, and
The ceramic particle group is substantially free of calcium carbonate. Here, “substantially does not contain calcium carbonate” in the claims and the specification means that calcium carbonate is below the detection limit when X-ray diffraction is performed {specifically, calcium carbonate (formula Amount: 100.09) / hydroxyapatite (formula weight: 1004.62) = 0.1 / 99.9 (formula weight conversion ratio) or less} and quasi-drug raw material standard 2006 (hydroxyapatite) When tested in conformity, it means that the amount of bubbles generated is 0.25 mL or less.
The present invention is a group of ceramic particles composed of substantially spherical ceramic particles,
When a primary particle composed of a single crystal or a particle lump in which primary particles composed of the single crystal are aggregated by ionic interaction is defined as a single crystal primary particle,
The proportion of single crystal primary particles contained in the ceramic particle group accounts for the majority,
The ceramic particles are calcium phosphate sintered body particles, and
The ceramic particle group is substantially free of calcium carbonate.
Here, the particle diameter of the ceramic particles may be in the range of 10 nm to 700 nm.
Further, the coefficient of variation of the particle diameter 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 minor axis maximum diameter of 50 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 sintered calcium phosphate particles, and
The ceramic particle group is substantially free of calcium carbonate.
Here, the ceramic particles may be hydroxyapatite sintered particles.
Also, the ceramic particles are washed with water,
Based on the particle size of the ceramic particle group after the water washing, a change rate of the particle size when heated at 300 ° C. under atmospheric pressure after the water washing may be ± 20%.
The present invention is a medical material for introduction into a living body, which is obtained using the ceramic particle group.
The present invention is a medical device obtained using the medical material for introduction into a living body as one material.
The present invention is a method for producing a group of ceramic particles composed of particulate ceramic particles.
A pre-process for obtaining a thawed body by thawing the frozen body after freezing the aqueous medium containing the primary particles that are the ceramic raw material before sintering and obtaining the frozen body;
A firing step of firing the primary particles obtained by removing the aqueous medium from the thawed body,
And crushing the fired body obtained by the firing step to obtain the ceramic particles,
The method for producing a ceramic particle group, wherein the ceramic particles are calcium phosphate sintered particles.
Here, the particle shape may be a substantially spherical shape or a substantially rod shape.
The ceramic particles may be hydroxyapatite sintered particles.
The ceramic particle group may be a medical material for introduction into a living body.
Further, the ceramic particle group may be for medical equipment.
本発明によれば、炭酸カルシウムの結晶相が混入しない、結晶性が高く且つ粒子径が小さいセラミック粒子群を提供することが可能となる。更に、理由は定かでないが、本発明に係るリン酸カルシウム焼成体は、エンドトキシンを除去するために３００℃にて加熱しても、殆ど粒径が変化しない。よって、本発明によれば、より小さい粒径のリン酸カルシウム焼結体粒子群を得ることが可能となる。 ADVANTAGE OF THE INVENTION According to this invention, it becomes possible to provide the ceramic particle group with a high crystallinity and a small particle diameter which the calcium carbonate crystal phase does not mix. Further, although the reason is not clear, the calcined calcium phosphate according to the present invention hardly changes in particle size even when heated at 300 ° C. to remove endotoxin. Therefore, according to the present invention, it is possible to obtain a calcium phosphate sintered body particle group having a smaller particle diameter.
以下、本発明に係るリン酸カルシウム粒子群の製造方法を説明し、次いで、当該製造方法により得られたセラミック粒子群を説明し、次いで、当該セラミック粒子群の用途について説明する。 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．セラミック粒子群の製造方法≫
＜１−１．原料＞
焼成前のセラミック原料であるリン酸カルシウム（ＣａＰ）としては、具体例として、ハイドロキシアパタイト（Ｃａ１０（ＰＯ４）６（ＯＨ）２）、リン酸三カルシウム（Ｃａ３（ＰＯ４）２）、メタリン酸カルシウム（Ｃａ（ＰＯ３）２）、Ｃａ１０（ＰＯ４）６Ｆ２、Ｃａ１０（ＰＯ４）６Ｃｌ２等が挙げられる。ここで、当該リン酸カルシウム（ＣａＰ）は、湿式法や、乾式法、加水分解法、水熱法等の公知の製造方法によって、人工的に製造されたものであってもよく、また、骨、歯等から得られる天然由来のものであってもよい。
<< 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．プロセス＞
（１−１．一次粒子生成工程）
<1-2. Process>
(1-1. Primary particle generation step)
・略球状セラミック粒子の一次粒子生成工程
まず、「一次粒子」とは、セラミック粒子群の製造工程の焼結前に、セラミック原料｛リン酸カルシウム（ＣａＰ）、ハイドロキシアパタイト（ＨＡｐ）等｝によって形成された粒子のことを意味する。即ち、セラミック粒子の製造工程において、初めて形成された粒子のことを意味する。また狭義には単結晶粒子のことを意味する。尚、特許請求の範囲及び明細書において「一次粒子」とは、非晶質（アモルファス）、低結晶性の状態のもの、及びその後に焼結を行なった焼結体の状態のものをも含む意味である。これに対して「二次粒子」とは、複数の「一次粒子」同士が、融着等の物理的結合、Van der Waals力や静電的相互作用又は共有結合等の化学的結合によって、結合して形成された状態の粒子を意味する。特に一次粒子同士の結合の個数、結合後の形状等は限定されるものではなく、２つ以上の一次粒子が結合したもの全てを意味する。また、特に「単結晶一次粒子」とは、セラミック原料の単結晶からなる一次粒子、もしくは前記単結晶からなる一次粒子がイオン的相互作用にて集合化した粒子塊を意味する。尚、前記「イオン的相互作用にて集合化した粒子塊」とは、水もしくは有機溶媒を含む媒体にて分散させた場合にイオン的相互作用で自己集合する粒子塊であって、焼結により粒子間が溶融して多結晶化した二次粒子を含まないものである。
-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.
当該一次粒子生成工程は、それ自体公知であり、上記一次粒子を生成することができる工程であれば特に限定されるものではなく、製造するセラミックの原料により適宜選択の上、採用すればよい。例えば、常温下において水酸化カルシウムスラリーにリン酸を滴下すれば、リン酸カルシウム（ＣａＰ）の粒子が沈殿する。 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.
本発明に係るセラミック粒子群の製造方法は、上記の一次粒子生成工程によって生成した一次粒子からなる一次粒子群を、融着等を防止しながら焼結してセラミック粒子群を製造するものである。よって、当該一次粒子生成工程によって生成された一次粒子の状態（粒子径、粒度分布）が、最終生産物であるセラミック粒子の状態（粒子径、粒度分布）にそのまま反映される。したがって、粒子径が微細（ナノメートルサイズ）で且つ粒子径が均一な（粒度分布が狭い）セラミック粒子群を製造しようとする場合においては、当該一次粒子生成工程において粒子径が微細（ナノメートルサイズ）で且つ粒子径が均一な（粒度分布が狭い）一次粒子群を生成しておく必要がある。 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.
かかる場合の好ましい一次粒子の粒子径（平均粒子径及び粒度分布）としては、１０ｎｍ〜５００ｎｍが好ましく、１５ｎｍ〜４５０ｎｍが更に好ましく、２０ｎｍ〜４００ｎｍが最も好ましい。また、一次粒子からなる一次粒子群の粒子径の変動係数が、２０％以下であることが好ましく、１８％以下であることがさらに好ましく、１５％以下であることが最も好ましい。尚、一次粒子の粒子径及び変動係数は、動的光散乱法又は電子顕微鏡を用い、少なくとも１００個以上の一次粒子について粒子径を測定して計算すればよい。 In this case, the preferred primary particle size (average particle size and particle size distribution) 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 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 coefficient of variation of the primary particles may be calculated by measuring the particle diameter of at least 100 primary particles using a dynamic light scattering method or an electron microscope.
尚、「変動係数」は、標準偏差÷平均粒子径×１００（％）で計算することができる粒子間の粒子径のバラツキを示す値である。 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 (%).
上記のような微細（ナノメートルサイズ）で且つ粒子径が均一な（粒度分布が狭い）一次粒子群を生成する方法については、特に限定されるものではなく、例えば、特開２００２−１３７９１０号公報、特許第５０４３４３６号公報、Journal of Nanoscience and Nanotechnology Vol. 7, 848-851, 2007に記載された方法を挙げることができる。 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 No. 5044336, Journal of Nanoscience and Nanotechnology Vol. 7, 848-851, 2007.
また、本工程には、生成した一次粒子を水等で洗浄する工程、遠心分離、ろ過等で一次粒子を回収する工程が含まれていてもよい。 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.
・略ロッド状セラミック粒子の一次粒子生成工程
略ロッド状セラミック粒子｛粒子の粒子径が、短軸の最大直径が３０ｎｍ〜５μｍ、長軸が７５ｎｍ〜１０μｍであり、ｃ軸方向に成長し、結晶のアスペクト比（ｃ軸長／ａ軸長）が、１〜３０であり、先端角が斜角面を有する截頭形柱状構造のセラミック粒子｝の一次粒子生成工程は、それ自体公知であり、例えば、特開２００２−１３７９１０号公報、Journal of Nanoparticle Research (2007) 9:807-815に記載された方法を挙げることができる。
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 (2007) 9: 807-815 can be mentioned.
また、本工程には、生成した一次粒子を水等で洗浄する工程、遠心分離、ろ過等で一次粒子を回収する工程が含まれていてもよい。 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.
（凍結工程）
凍結工程は、焼結前のリン酸カルシウム（ＣａＰ）を含有する水系媒体を凍結する工程である。ここで、水系媒体は、水を主成分（好適には液体媒体の全質量を基準として９０質量％以上）をした液体媒体である。好適には、水のみであり、他に水と混和性のある液体（アルコール等）を適宜添加してもよい。また、一次粒子であるリン酸カルシウム（ＣａＰ）を製造した液、即ち、リン酸源とカルシウム源とを水に溶解させることにより得られた液をそのまま凍結させてもよい。ここで、凍結温度は、好適には、−１〜−２６９℃である。さらに好適には、−５〜−１９６℃である。また、凍結時間は、好適には、１分〜２４時間である。
(Freezing process)
The freezing step is a step of freezing the 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 miscible with water (alcohol or the like) may be appropriately added. In addition, a solution for producing calcium phosphate (CaP) as primary particles, that is, a solution obtained by dissolving a phosphate source and a 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.
（解凍工程）
解凍工程は、前記凍結工程にて得た凍結体を、凍結体の水系媒体の融点を超える温度下に配し、当該水系媒体を融解させる工程である。
(Thawing process)
The thawing step is a step in which the frozen body obtained in the freezing step is placed at a temperature exceeding the melting point of the aqueous medium of the frozen body to melt the aqueous medium.
（分離工程）
分離工程は、前記解凍工程にて融解した、リン酸カルシウムを含有する水系媒体から、リン酸カルシウムを分離する工程である。分離手法としては、解凍後の沈殿を濾取する手法であってもよく、遠心分離捕集する手法であってもよい。
(Separation process)
The separation step is a step of separating calcium phosphate from the aqueous medium containing calcium phosphate melted in the thawing step. The separation method may be a method of collecting the precipitate after thawing, or a method of collecting by centrifugation.
（焼成工程）
当該焼結工程は、上記分離工程によって得られた、リン酸カルシウム一次粒子組成物を焼結温度に曝して、当該組成物に含まれる一次粒子をセラミック粒子（焼結体粒子）にする工程である。理由は定かでないが、特許文献１のような融着防止剤を使用せずとも、前記の凍結・解凍工程を得て焼成させた場合、焼結工程における高温条件に曝された場合であっても一次粒子同士の融着を防止することができるというものである。ここで、当該焼結工程における焼結温度は、セラミック粒子の結晶性が所望の硬度となるように適宜設定すればよく、例えば、３００〜１０００℃が好適である。また、当該焼結工程における昇温速度は、例えば、１〜２０℃／ｍｉｎが好適である。更には、当該焼結工程における焼結時間は、セラミック粒子の硬度等を基準に適宜設定すればよく、例えば、０．５〜３時間が好適である。尚、当該焼結工程に用いる装置等は特に限定されるものではなく、製造規模、製造条件等に応じて市販の焼成炉を適宜選択の上、採用すればよい。
(Baking process)
The said sintering process is a process which exposes the calcium-phosphate primary particle composition obtained by the said isolation | separation process to sintering temperature, and makes the primary particle contained in the said composition a ceramic particle (sintered body particle). Although the reason is not clear, even when the anti-fusing agent as in Patent Document 1 is not used, when the above freeze / thaw process is obtained and fired, it is exposed to high temperature conditions in the sintering process. Also, it is possible to prevent fusion between 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 for example, 300 to 1000 ° C. is suitable. Moreover, 1-20 degrees C / min is suitable for the temperature increase rate in the said sintering process, for example. Furthermore, the sintering time in the sintering step may be appropriately set based on the hardness of the ceramic particles and the like, and for example, 0.5 to 3 hours is preferable. 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.
（粉砕工程）
粉砕工程は、前記焼結工程後の凝集体を粉砕し、所望サイズの焼成リン酸カルシウム粒子群を得る工程である。ここで、通常、二次粒子化した焼成体は、相当程度の粉砕工程を実施しても一次粒子サイズまで微小化することはほぼ不可能である。他方、本発明の手法によると、簡素な粉砕工程でも、容易に一次粒子サイズレベルまで粉砕することが可能となる。ここで、粉砕手法は、特に限定されず、例えば、超音波処理、粉砕球を用いての粉砕処理である。尚、粉砕処理後、未粉砕のものを除去する等して、より径の小さい粒子を収集してもよい。
(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.
（洗浄工程）
洗浄工程は、焼成リン酸カルシウム粒子以外の成分、例えば、リン酸カルシウムの一次粒子を製造する際に用いた原料由来の不純物（例えば、リン酸カルシウム形成に関与しなかったカルシウムやリン酸由来の不純物、硝酸やアンモニウム由来の不純物）を洗浄する工程である。好適には、水を用いて洗浄することが好適である。尚、ハイドロキシアパタイト（ＨＡｐ）焼結体粒子の場合は、ｐＨ４．０以下の条件においてハイドロキシアパタイト（ＨＡｐ）焼結体粒子が溶解するため、ｐＨ４．０〜ｐＨ１２．０で除去工程を行なうことが好適である。また、粉砕工程や洗浄工程を交互に行う等、この順番は問わない。
(Washing process)
The washing step is a component other than the calcined calcium phosphate particles, for example, impurities derived from raw materials used in producing the primary particles of calcium phosphate (for example, calcium or phosphate-derived impurities not involved in calcium phosphate formation, nitric acid or ammonium-derived This is a step 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 dissolve under conditions of pH 4.0 or lower, the removal step can be performed at pH 4.0 to pH 12.0. Is preferred. Moreover, this order does not ask | require, such as performing a grinding | pulverization process and a washing | cleaning process alternately.
（乾燥工程）
乾燥工程は、前記粉砕工程や前記洗浄工程後、加熱する等して、溶媒を除去し、リン酸カルシウム粒子群を得る工程である。乾燥手法は、特に限定されない。
(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.
（エンドトキシン除去工程）
エンドトキシン除去工程は、空気下、常圧にて３００℃加熱することにより行う工程である。リン酸カルシウム焼成体は、焼成後、上述した洗浄工程にて好適には水洗浄に付される。この際、リン酸カルシウム焼成体は、水中、保管容器や取り扱い雰囲気など環境中に僅かに存在するエンドトキシンを吸着する。ここで、このエンドトキシンは有害物質であり、リン酸カルシウム焼成体に残存していることは、特に生体材料として当該リン酸カルシウム焼成体を用いる場合には不適である。よって、当該処理を実施する。尚、当該エンドトキシン除去工程は、上述した乾燥工程を併せて行ってもよい。
(Endotoxin removal step)
The endotoxin removal step is a step performed by heating at 300 ° C. in air at normal pressure. The calcined calcium phosphate is preferably subjected to water washing in the washing step described above after firing. At this time, the calcined calcium phosphate adsorbs endotoxin that is slightly present in the environment such as in water, in a storage container or in a handling atmosphere. Here, this endotoxin is a harmful substance, and remaining in the calcined calcium phosphate is unsuitable particularly when the calcined calcium phosphate is used as a biomaterial. Therefore, this processing is performed. In addition, you may perform the said endotoxin removal process combining the drying process mentioned above.
≪２．本製造方法により得られるリン酸カルシウム焼結体粒子群≫
＜２−１．略球状リン酸カルシウム焼結体粒子群＞
本製造方法により得られる略球状リン酸カルシウム焼結体粒子群は、略球状のセラミック粒子からなるセラミック粒子群であって、前記セラミック粒子の粒子径が、１０ｎｍ〜７００ｎｍの範囲内で、且つ前記セラミック粒子群の粒子径の変動係数が、２０％以下であり、前記セラミック粒子が、リン酸カルシウム焼結体粒子であり、且つ、前記セラミック粒子群が炭酸カルシウムを実質的に含有しないことを特徴とするセラミック粒子群である。当該セラミック粒子群は、微粒子且つ粒子径の均一な（粒度分布が狭い）ものである。それゆえ、特に高度な分級等の付加的な操作を行なうことなく、医療用高分子材料に対してより均一に吸着させることができるという効果を奏する。しかも、炭酸カルシウムを実質的に含有しないので、生体材料として使用した際に、材料の生体親和性、溶解性が変化する事態を防止することが可能となる。
≪2. Calcium phosphate sintered particles obtained by this production method >>
<2-1. Spherical Calcium Phosphate Sintered Particle Group>
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 the ceramic particle has a particle diameter in the range of 10 nm to 700 nm. The particle diameter variation coefficient of the group is 20% or less, the ceramic particle is a calcium phosphate sintered body particle, and the ceramic particle group does not substantially contain calcium carbonate. A group. 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.
また、別の側面からは、本製造方法により得られる略球状リン酸カルシウム焼結体粒子群は、略球状のセラミック粒子からなるセラミック粒子群であって、単結晶からなる一次粒子、もしくは前記単結晶からなる一次粒子がイオン的相互作用にて集合化した粒子塊を単結晶一次粒子とすると、前記セラミック粒子群に含まれる単結晶一次粒子の割合が過半数を占め、上記セラミック粒子が、リン酸カルシウム焼結体粒子であり、且つ、前記セラミック粒子群が炭酸カルシウムを実質的に含有しないことを特徴とするセラミック粒子群である。当該セラミック粒子群は、その過半数が溶媒中で分散性の優れた単結晶からなる一次粒子、もしくは前記単結晶からなる一次粒子がイオン的相互作用にて集合化した粒子塊（単結晶一次粒子）として存在している。それゆえ、既述の医療用高分子基材への吸着がし易くなるという効果を奏する。また、一次粒子同士の結合が無いため、比表面積が高い。更には、生体内で安定性が高く、分散性に優れることから薬剤の担持及び徐放が可能な医療用材料として利用できるという効果を奏する。しかも、炭酸カルシウムを実質的に含有しないので、生体材料として使用した際に、材料の生体親和性やリン酸カルシウム本来の溶解性が維持される。 Further, 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 aggregate in which the primary 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 with calcium phosphate. The ceramic particle group is a particle group, and the ceramic particle group substantially does not contain 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.
また、当該セラミック粒子群は、上記セラミック粒子群に含まれる単結晶一次粒子の割合が、７０％以上であってもよい。このような構成を採ることで、医療用高分子基材への吸着がし易くなるという効果を奏する。 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 is facilitated.
また、当該セラミック粒子群は、上記セラミック粒子の粒子径が、１０ｎｍ〜７００ｎｍの範囲内であってもよい。当該構成によれば、医療用高分子材料に対してより均一に吸着させることができるという効果を奏する。 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.
また、当該セラミック粒子群は、上記セラミック粒子群の粒子径の変動係数が、２０％以下であってもよい。当該構成を採ることにより、特に高度な分級等の付加的な操作を行なうことなく、医療用高分子材料に対してより均一に吸着させることができるという効果を奏する。 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 this 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.
また、当該セラミック粒子が、ハイドロキシアパタイト焼結体粒子であってもよい。当該粒子は、更に生体適合性が高く、広範な用途に利用可能なハイドロキシアパタイト焼結体で構成されている。そのため、医療用材料として特に好ましい。 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.
また、当該セラミック粒子群は、水洗浄されたものであり、且つ、前記水洗浄後の前記セラミック粒子群の粒子径を基準としたとき、前記水洗浄後に空気中常圧下にて３００℃で加熱した際の粒子径の変化率が±２０％であってもよい。 Further, the ceramic particle group was washed with water, and heated at 300 ° C. under atmospheric pressure in the air after the water washing, based on the particle diameter of the ceramic particle group after the water washing. The change rate of the particle diameter at the time may be ± 20%.
＜２−２．略ロッド状リン酸カルシウム焼結体粒子群＞
本製造方法により得られる略ロッド状リン酸カルシウム焼結体粒子群は、ロッド状のセラミック粒子からなるセラミック粒子群であって、前記セラミック粒子の粒子径が、短軸の最大直径が５０ｎｍ〜５μｍ、長軸が７５ｎｍ〜１０μｍであり、ｃ軸方向に成長し、結晶のアスペクト比（ｃ軸長／ａ軸長）が、１〜３０であり、先端角が斜角面を有する截頭形柱状構造のセラミック粒子であって、前記セラミック粒子が、リン酸カルシウム焼結体粒子であり、且つ、前記セラミック粒子群が炭酸カルシウムを実質的に含有しないことを特徴とするセラミック粒子群である。当該ロッド状リン酸カルシウム焼成粒子群は、接着に供する面積が従来の微粒子より格段に広いため、高分子基材との接着性を向上できるので、カテーテル等の生体親和性医療材料など、高分子表面に修飾するのに適している。しかも、炭酸カルシウムを実質的に含有しないので、生体材料として使用した際に、材料から炭酸ガスが発生する事態を防止することが可能となる。尚、高分子表面に修飾する方法としては、リン酸カルシウム（例えばハイドロキシアパタイトナノ粒子）の活性基と高分子基体、例えば、表面にカルボキシル基を有するビニル系重合性単量体をグラフト重合させたシリコーンゴム、の活性基と化学反応させて複合体とする方法や、硬化性接着剤を用いる方法、高分子基材を融点近傍まで加熱して基材に埋設させる方法等を用いることができる（これは前記の略球状リン酸カルシウム焼結体粒子群も同様）。
<2-2. Substantially 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 ceramic particle has a short axis maximum diameter of 50 nm to 5 μm and a long length. It has a truncated columnar structure having an axis of 75 nm to 10 μm, grown 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. Ceramic particles, wherein the ceramic particles are calcium phosphate sintered particles, and the ceramic particles are substantially free of calcium carbonate. 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. As a method for modifying the polymer surface, an active group of calcium phosphate (for example, hydroxyapatite nanoparticles) and a polymer substrate, for example, a silicone rubber obtained by graft polymerization of a vinyl polymerizable monomer having a carboxyl group on the surface , A method of chemically reacting with an active group, a method of using a curable adhesive, a method of heating a polymer substrate to near the melting point and embedding it in the substrate, etc. The same applies to the substantially spherical calcium phosphate sintered body particle group).
また、当該セラミック粒子が、ハイドロキシアパタイト焼結体粒子であってもよい。当該粒子は、更に生体適合性が高く、広範な用途に利用可能なハイドロキシアパタイト焼結体で構成されている。そのため、医療用材料として特に好ましい。 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.
また、当該セラミック粒子群は、水洗浄されたものであり、且つ、前記水洗浄後の前記セラミック粒子群の粒子径を基準としたとき、前記水洗浄後に空気中常圧下にて３００℃で加熱した際の粒子径の変化率が±２０％であってもよい。 Further, the ceramic particle group was washed with water, and heated at 300 ° C. under atmospheric pressure in the air after the water washing, based on the particle diameter of the ceramic particle group after the water washing. The change rate of the particle diameter at the time may be ± 20%.
≪用途≫
本発明に係るリン酸カルシウム焼成体粒子群は、生体親和性、生体活性が非常に高いため、医療分野において、例えば、骨充填剤、歯科用充填剤、薬物徐放剤等の歯科用材料又は医療用材料として広く用いることができる。
≪Usage≫
Since the calcium phosphate calcined particles according to the present invention have extremely high biocompatibility and bioactivity, in the medical field, for example, dental materials such as bone fillers, dental fillers, sustained drug release agents, or medical use It can be widely used as a material.
≪製造例≫
（実施例１：球状ハイドロキシアパタイト焼成体粒子群）
脱イオン水が入った反応容器内に、撹拌しながら、硝酸カルシウム四水和物、リン酸水素二アンモニウム水溶液及びアンモニア水を添加し｛カルシウム：リン酸（モル比）＝５：３｝、ハイドロキシアパタイトの一次粒子を得た。その後、反応容器内の上澄みを廃水容器に移した後、脱イオン水を加え、攪拌器で撹拌し、上澄みを廃棄容器に移す、という作業を２回繰り返した。その後、当該沈殿物の入った反応容器ごと、−１０℃〜−１５℃にて一夜冷凍した。その後、室温で解凍し、解凍後の沈殿をろ取した。その後、焼成皿に約４００ｇの沈殿を入れ、焼成炉に入れ、１時間強かけて６００℃までにし、６００℃１時間保った後、１時間以上かけて冷却することで焼成を実施した。その後、焼成体へ脱イオン水を加え、３０分間以上超音波照射した。そして、ポッドミルへ移し、粉砕球を入れて１時間粉砕した。粉砕終了後、手付きビーカーへ移し、目開き１５０μm篩を用い、未粉砕焼成体を除去した。尚、この後、脱イオン水洗浄を6回繰り返した。その後、６０〜８０℃で乾燥し、実施例１に係るハイドロキシアパタイト焼成体を得た。
≪Production example≫
(Example 1: Spherical hydroxyapatite fired body particle group)
In a reaction vessel containing deionized water, calcium nitrate tetrahydrate, diammonium hydrogen phosphate aqueous solution and aqueous ammonia were added with stirring {calcium: phosphoric acid (molar ratio) = 5: 3}, and hydroxy Apatite primary particles were obtained. Thereafter, the operation of transferring the supernatant in the reaction vessel to a waste water vessel, adding deionized water, stirring with a stirrer, and transferring the supernatant to a waste vessel was repeated twice. Thereafter, the reaction vessel containing the precipitate was frozen overnight at −10 ° C. to −15 ° C. Thereafter, the mixture was thawed at room temperature and the thawed precipitate was collected by filtration. Thereafter, about 400 g of precipitate was put in a baking dish, put in a baking furnace, heated to 600 ° C. over 1 hour, kept at 600 ° C. for 1 hour, and then cooled for 1 hour or more to carry out baking. Then, deionized water was added to the fired body and irradiated with ultrasonic waves for 30 minutes or more. Then, the mixture was transferred to a pod mill, and pulverized balls were added and pulverized for 1 hour. After the pulverization was completed, the powder was transferred to a hand-held beaker, and an unground baked product was removed using a sieve having an opening of 150 μm. Thereafter, deionized water washing was repeated 6 times. Then, it dried at 60-80 degreeC and the hydroxyapatite baking body which concerns on Example 1 was obtained.
（実施例２：ロッド状ハイドロキシアパタイト焼成体粒子群）
脱イオン水が入った反応容器内に、硝酸カルシウム四水和物水溶液を撹拌しながら、リン酸水素二アンモニウム水溶液及びアンモニア水を硝酸カルシウム四水和物水溶液に滴下し｛カルシウム：リン酸（モル比）＝５：３｝、ハイドロキシアパタイトの一次粒子を得た。その後、反応容器内の上澄みを廃水容器に移した後、脱イオン水を加え、攪拌器で撹拌し、上澄みを廃棄容器に移す、という作業を５回繰り返した。その後、当該沈殿物の入った反応容器ごと、−１０℃〜−１５℃にて一夜冷凍した。その後、室温で解凍し、解凍後の沈殿をろ取した。その後、焼成皿に約４００ｇの沈殿を入れ、焼成炉に入れ、１時間強かけて６００℃までにし、６００℃１時間保った後、１時間以上かけて冷却することで焼成を実施した。その後、焼成体へ脱イオン水を加え、３０分間以上超音波照射した。そして、ポッドミルへ移し、粉砕球を入れて１時間粉砕した。粉砕終了後、手付きビーカーへ移し、目開き１５０μm篩を用い、未粉砕焼成体を除去した。尚、この後、脱イオン水洗浄を7回繰り返した。その後、６０〜８０℃で乾燥し、実施例２に係るハイドロキシアパタイト焼成体を得た。尚、当該セラミック粒子の粒子径は、短軸の平均最大直径が４７、長軸が１４６であり、ｃ軸方向に成長し、結晶のアスペクト比（ｃ軸長／ａ軸長）が、３．１であり、先端角が斜角面を有する截頭形柱状構造のセラミック粒子であった。
(Example 2: Rod-like hydroxyapatite fired particles)
In a reaction vessel containing deionized water, while stirring the calcium nitrate tetrahydrate aqueous solution, diammonium hydrogen phosphate aqueous solution and aqueous ammonia were dropped into the calcium nitrate tetrahydrate aqueous solution {calcium: phosphoric acid (mol). Ratio) = 5: 3} to obtain primary particles of hydroxyapatite. Thereafter, the operation of transferring the supernatant in the reaction vessel to a waste water vessel, adding deionized water, stirring with a stirrer, and transferring the supernatant to a waste vessel was repeated 5 times. Thereafter, the reaction vessel containing the precipitate was frozen overnight at −10 ° C. to −15 ° C. Thereafter, the mixture was thawed at room temperature and the thawed precipitate was collected by filtration. Thereafter, about 400 g of precipitate was put in a baking dish, put in a baking furnace, heated to 600 ° C. over 1 hour, kept at 600 ° C. for 1 hour, and then cooled for 1 hour or more to carry out baking. Then, deionized water was added to the fired body and irradiated with ultrasonic waves for 30 minutes or more. Then, the mixture was transferred to a pod mill, and pulverized balls were added and pulverized for 1 hour. After the pulverization was completed, the powder was transferred to a hand-held beaker, and an unground baked product was removed using a sieve having an opening of 150 μm. Thereafter, deionized water washing was repeated 7 times. Then, it dried at 60-80 degreeC and the hydroxyapatite baking body which concerns on Example 2 was obtained. The ceramic particles have a minor axis average maximum diameter of 47 and a major axis of 146, grow in the c-axis direction, and the crystal aspect ratio (c-axis length / a-axis length) is 3. The ceramic particles had a truncated columnar structure with a tip angle of 1 and a beveled surface.
（比較例）
特許第５０４３４３６号公報の実施例１に従い、比較例に係るハイドロキシアパタイト焼成体を得た。
(Comparative example)
According to Example 1 of Japanese Patent No. 5043436, a hydroxyapatite fired body according to a comparative example was obtained.
≪Ｘ線回折試験≫
図１及び図２は、それぞれ実施例１及び比較例に係るハイドロキシアパタイト焼成体のＸ線回折の結果である。当該図から分かるように、図１では炭酸カルシウムのピークが観察されなかったのに対し、図２では炭酸カルシウムの明確なピークが観察された。より具体的には、図１では、ハイドロキシアパタイト（PDF 74-0565）に一致するパターンのみ確認出来、一方、図２では、ハイドロキシアパタイトには存在しないピークが２９．４°に観察され炭酸カルシウム（calcite : PDF 72-1937）と一致した。尚、Ｘ線回折装置及び測定条件は下記の通りである。粉末Ｘ線回析装置｛理学電機（株）製、MiniFlex｝を用いて、結晶構造解析を行った。ＸＲＤで使用したＸ線源としてはＣｕＫα線源｛λ＝１．５４１８４１Å（オングストローム）｝を用い、出力は３０ｋＶ／１５ｍＡ、スキャンスピードは１．０°／ｍｉｎ、サンプリング幅は０．０１°、測定モードは連続の条件とした。
≪X-ray diffraction test≫
1 and 2 show the results of X-ray diffraction of the fired hydroxyapatite bodies according to Example 1 and Comparative Example, respectively. As can be seen from the figure, no calcium carbonate peak was observed in FIG. 1, whereas a clear peak of calcium carbonate was observed in FIG. More specifically, in FIG. 1, only a pattern corresponding to hydroxyapatite (PDF 74-0565) can be confirmed, while in FIG. 2, a peak that does not exist in hydroxyapatite is observed at 29.4 ° and calcium carbonate ( calcite: PDF 72-1937). The X-ray diffractometer and measurement conditions are as follows. Crystal structure analysis was performed using a powder X-ray diffraction device {MiniFlex} manufactured by Rigaku Corporation. The X-ray source used in XRD was a CuKα source {λ = 1.541841 Å (angstrom)}, output was 30 kV / 15 mA, scan speed was 1.0 ° / min, sampling width was 0.01 °, measurement The mode was a continuous condition.
≪外観観察試験≫
図３及び図４は、実施例１に係るハイドロキシアパタイト焼成体粒子群のＳＥＭ写真である（スケール違い）。これら写真から、実施例１に係るハイドロキシアパタイト焼成体粒子群は、略球状のハイドロキシアパタイト焼成体粒子からなるハイドロキシアパタイト焼成体粒子群であって、単結晶からなる一次粒子、もしくは前記単結晶からなる一次粒子がイオン的相互作用にて集合化した粒子塊を単結晶一次粒子とすると、前記ハイドロキシアパタイト焼成体粒子群に含まれる単結晶一次粒子の割合が過半数を占めることが分かる。また、図５及び図６は、実施例２に係るハイドロキシアパタイト焼成体粒子群のＳＥＭ写真である（スケール違い）。
≪Appearance observation test≫
3 and 4 are SEM photographs of the hydroxyapatite fired particles according to Example 1 (difference in scale). From these photographs, the hydroxyapatite fired body particle group according to Example 1 is a hydroxyapatite fired body particle group composed of substantially spherical hydroxyapatite fired body particles, and is composed of primary particles composed of a single crystal or the single crystal. When the particle lump in which the primary particles are aggregated by ionic interaction is defined as the single crystal primary particle, it can be seen that the majority of the single crystal primary particles contained in the hydroxyapatite fired body particle group occupy the majority. 5 and 6 are SEM photographs of the hydroxyapatite fired particles according to Example 2 (difference in scale).
≪粒径測定試験≫
実施例１及び比較例に係るハイドロキシアパタイト焼成体（エンドトキシン未不活性化）に関し、平均粒径及び標準偏差（ＳＥＭにて１００個の粒子の粒径を確認し、平均値及び標準偏差を算出）した。加えて、実施例１及び比較例に係るハイドロキシアパタイト焼成体（エンドトキシン未不活性化）を不活性化したものに関し、同じく平均粒径及び標準偏差（ＳＥＭにて１００個の粒子の粒径を確認し、平均値及び標準偏差を算出）した。尚、不活性化手順は、（１）あらかじめ乾熱滅菌（３００℃、２時間）アンプルにＨＡｐ粉体を計り入れる、（２）、ＨＡｐを入れたアンプルを開封状態のまま乾熱滅菌器にて、乾熱滅菌（３００℃、２時間）、（３）室温まで冷却したアンプルを溶封（封管）、（４）封管済みアンプルを再度乾熱滅菌器にて、乾熱滅菌（３００℃、２時間）、である。表１は、実施例１に係るハイドロキシアパタイト焼成体であり、表２は、比較例に係るハイドロキシアパタイト焼成体である。
≪Particle size measurement test≫
Regarding the hydroxyapatite fired bodies (endotoxin non-inactivated) according to Example 1 and Comparative Example, the average particle size and standard deviation (the particle size of 100 particles was confirmed by SEM, and the average value and standard deviation were calculated) did. In addition, regarding the inactivated hydroxyapatite fired bodies (endotoxin non-inactivated) according to Example 1 and Comparative Example, the average particle diameter and the standard deviation (the particle diameter of 100 particles were confirmed by SEM). Average value and standard deviation were calculated). The inactivation procedure is as follows: (1) dry heat sterilization (300 ° C., 2 hours), measure HAp powder into ampoule; (2) leave the ampoule with HAp open in a dry heat sterilizer. Dry heat sterilization (300 ° C., 2 hours), (3) sealing the ampule cooled to room temperature (sealed tube), and (4) sterilizing the sealed ampule again with 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 the comparative example.
≪発泡確認試験≫
実施例１及び２並びに比較例に係るハイドロキシアパタイト焼成体について、医薬部外品原料規格２００６「ヒドロキシアパタイト」に収載の純度試験（４）炭酸塩に示された手順に準じて試験実施した。具体的には、常温（２０℃）にてサンプル１．０ｇを秤量し、水５ｍＬを加え振り混ぜ、アスピレーターを用いて１時間減圧し脱気した。脱気後、濃塩酸（３５．０質量％）２ｍＬを加え、発泡の有無を確認した。その結果、実施例により得られたＨＡｐでは、発泡は確認できなかった（気体発生量が０．２５ｍｌ未満）。他方、比較例により得られたＨＡｐでは、生じた泡で上澄みが白濁するほど発泡した。
≪Foaming confirmation test≫
The hydroxyapatite fired bodies according to Examples 1 and 2 and Comparative Example were tested according to the procedure shown in Purity Test (4) Carbonate Listed in Quasi-drug Raw Material Standard 2006 “Hydroxyapatite”. Specifically, 1.0 g of a sample was weighed at room temperature (20 ° C.), 5 mL of water was added and shaken, and the mixture was deaerated by reducing pressure for 1 hour using an aspirator. After deaeration, 2 mL of concentrated hydrochloric acid (35.0% by mass) was added to check for foaming. As a result, foaming could not be confirmed in the HAp obtained in the example (gas generation amount was less than 0.25 ml). On the other hand, in the HAp obtained by the comparative example, the resulting foam was so foamed that the supernatant became cloudy.
Claims (14)
前記セラミック粒子の粒子径が、１０ｎｍ〜７００ｎｍの範囲内で、且つ前記セラミック粒子群の粒子径の変動係数が、２０％以下であり、
前記セラミック粒子が、リン酸カルシウム焼結体粒子であり、且つ、
前記セラミック粒子群が炭酸カルシウムを実質的に含有しないことを特徴とするセラミック粒子群。 A group of ceramic particles composed of substantially spherical 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 sintered calcium phosphate particles, and
The ceramic particle group, wherein the ceramic particle group does not substantially contain calcium carbonate.
単結晶からなる一次粒子、もしくは前記単結晶からなる一次粒子がイオン的相互作用にて集合化した粒子塊を単結晶一次粒子とすると、
前記セラミック粒子群に含まれる単結晶一次粒子の割合が過半数を占め、
上記セラミック粒子が、リン酸カルシウム焼結体粒子であり、且つ、
前記セラミック粒子群が炭酸カルシウムを実質的に含有しないことを特徴とするセラミック粒子群。 A group of ceramic particles composed of substantially spherical ceramic particles,
When a primary particle composed of a single crystal or a particle lump in which primary particles composed of the single crystal are aggregated by ionic interaction is defined as a single crystal primary particle,
The proportion of single crystal primary particles contained in the ceramic particle group accounts for the majority,
The ceramic particles are calcium phosphate sintered body particles, and
The ceramic particle group, wherein the ceramic particle group does not substantially contain calcium carbonate.
前記セラミック粒子の粒子径が、短軸の最大直径が３０ｎｍ〜５μｍ、長軸が７５ｎｍ〜１０μｍであり、ｃ軸方向に成長し、結晶のアスペクト比（ｃ軸長／ａ軸長）が、１〜３０であり、先端角が斜角面を有する截頭形柱状構造のセラミック粒子であって、
前記セラミック粒子が、リン酸カルシウム焼結体粒子であり、且つ、
前記セラミック粒子群が炭酸カルシウムを実質的に含有しないことを特徴とするセラミック粒子群。 A group of ceramic particles composed of rod-shaped 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 sintered calcium phosphate particles, and
The ceramic particle group, wherein the ceramic particle group does not substantially contain calcium carbonate.
前記水洗浄後の前記セラミック粒子群の粒子径を基準としたとき、前記水洗浄後に空気中常圧下にて３００℃で加熱した際の粒子径の変化率が±２０％である、請求項１〜６のいずれか一項記載のセラミック粒子群。 The ceramic particles are washed with water,
The change rate of the particle diameter when heated at 300 ° C. under atmospheric pressure after the water cleaning is ± 20%, based on the particle diameter of the ceramic particle group after the water cleaning. The ceramic particle group according to claim 6.
焼結前のセラミック原料である一次粒子を含有する水系媒体を凍結して凍結体を得た後に当該凍結体を解凍させて解凍体を得る前工程と、
前記解凍体から前記水系媒体を除去して得られた前記一次粒子を焼成する焼成工程と、
前記焼成工程により得られた焼成体を粉砕して前記セラミック粒子群を得る粉砕工程と
を含み、
前記セラミック粒子が、リン酸カルシウム焼結体粒子である
ことを特徴とするセラミック粒子群の製造方法。 In the method for producing a ceramic particle group composed of particulate ceramic particles,
A pre-process for obtaining a thawed body by thawing the frozen body after freezing the aqueous medium containing the primary particles that are the ceramic raw material before sintering and obtaining the frozen body;
A firing step of firing the primary particles obtained by removing the aqueous medium from the thawed body,
And crushing the fired body obtained by the firing step to obtain the ceramic particles,
The method for producing a group of ceramic particles, wherein the ceramic particles are calcium phosphate sintered body particles.
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