JP2015211810A - Self-curable calcium phosphate composition, and kit and method for producing the same - Google Patents
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- 239000000203 mixture Substances 0.000 title claims abstract description 74
- 239000001506 calcium phosphate Substances 0.000 title claims abstract description 33
- 229910000389 calcium phosphate Inorganic materials 0.000 title claims abstract description 33
- 235000011010 calcium phosphates Nutrition 0.000 title claims abstract description 33
- 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 33
- 238000004519 manufacturing process Methods 0.000 title claims description 9
- 239000002245 particle Substances 0.000 claims abstract description 96
- 229920001661 Chitosan Polymers 0.000 claims abstract description 54
- GBNXLQPMFAUCOI-UHFFFAOYSA-H tetracalcium;oxygen(2-);diphosphate Chemical compound [O-2].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O GBNXLQPMFAUCOI-UHFFFAOYSA-H 0.000 claims abstract description 54
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 claims abstract description 37
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 claims abstract description 37
- 239000001630 malic acid Substances 0.000 claims abstract description 37
- 235000011090 malic acid Nutrition 0.000 claims abstract description 37
- 238000002156 mixing Methods 0.000 claims abstract description 18
- 235000019700 dicalcium phosphate Nutrition 0.000 claims abstract description 14
- XAAHAAMILDNBPS-UHFFFAOYSA-L calcium hydrogenphosphate dihydrate Chemical compound O.O.[Ca+2].OP([O-])([O-])=O XAAHAAMILDNBPS-UHFFFAOYSA-L 0.000 claims abstract description 13
- 239000000843 powder Substances 0.000 claims description 49
- 239000007788 liquid Substances 0.000 claims description 41
- 239000000243 solution Substances 0.000 claims description 25
- 239000007864 aqueous solution Substances 0.000 claims description 11
- 210000000988 bone and bone Anatomy 0.000 abstract description 12
- 239000004568 cement Substances 0.000 description 26
- 239000000047 product Substances 0.000 description 22
- HECLRDQVFMWTQS-UHFFFAOYSA-N Dicyclopentadiene Chemical compound C1C2C3CC=CC3C1C=C2 HECLRDQVFMWTQS-UHFFFAOYSA-N 0.000 description 19
- 239000002504 physiological saline solution Substances 0.000 description 13
- 239000000463 material Substances 0.000 description 12
- 238000005259 measurement Methods 0.000 description 10
- 238000007654 immersion Methods 0.000 description 7
- 238000001727 in vivo Methods 0.000 description 7
- 239000000126 substance Substances 0.000 description 7
- 230000006835 compression Effects 0.000 description 5
- 238000007906 compression Methods 0.000 description 5
- 230000006196 deacetylation Effects 0.000 description 5
- 238000003381 deacetylation reaction Methods 0.000 description 5
- 238000006703 hydration reaction Methods 0.000 description 5
- 229920003229 poly(methyl methacrylate) Polymers 0.000 description 5
- 239000004926 polymethyl methacrylate Substances 0.000 description 5
- 239000011148 porous material Substances 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 4
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 description 4
- MCMNRKCIXSYSNV-UHFFFAOYSA-N Zirconium dioxide Chemical compound O=[Zr]=O MCMNRKCIXSYSNV-UHFFFAOYSA-N 0.000 description 4
- 229910001424 calcium ion Inorganic materials 0.000 description 4
- 238000000635 electron micrograph Methods 0.000 description 4
- 238000010298 pulverizing process Methods 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 239000004809 Teflon Substances 0.000 description 3
- 229920006362 Teflon® Polymers 0.000 description 3
- 229910052588 hydroxylapatite Inorganic materials 0.000 description 3
- 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 description 3
- 239000002002 slurry Substances 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 229910021642 ultra pure water Inorganic materials 0.000 description 3
- 239000012498 ultrapure water Substances 0.000 description 3
- 239000013585 weight reducing agent Substances 0.000 description 3
- 241000238557 Decapoda Species 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 239000002639 bone cement Substances 0.000 description 2
- 239000000316 bone substitute Substances 0.000 description 2
- 229910000019 calcium carbonate Inorganic materials 0.000 description 2
- 238000009826 distribution Methods 0.000 description 2
- 238000007580 dry-mixing Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 239000004570 mortar (masonry) Substances 0.000 description 2
- LFULEKSKNZEWOE-UHFFFAOYSA-N propanil Chemical compound CCC(=O)NC1=CC=C(Cl)C(Cl)=C1 LFULEKSKNZEWOE-UHFFFAOYSA-N 0.000 description 2
- 235000001674 Agaricus brunnescens Nutrition 0.000 description 1
- 208000018084 Bone neoplasm Diseases 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 229920002101 Chitin Polymers 0.000 description 1
- 206010010214 Compression fracture Diseases 0.000 description 1
- 241000238424 Crustacea Species 0.000 description 1
- 206010017076 Fracture Diseases 0.000 description 1
- 241001288468 Melita Species 0.000 description 1
- 208000001132 Osteoporosis Diseases 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 229910000831 Steel Inorganic materials 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- 210000001124 body fluid Anatomy 0.000 description 1
- 239000010839 body fluid Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- FUFJGUQYACFECW-UHFFFAOYSA-L calcium hydrogenphosphate Chemical compound [Ca+2].OP([O-])([O-])=O FUFJGUQYACFECW-UHFFFAOYSA-L 0.000 description 1
- -1 calcium phosphate compound Chemical class 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 210000002421 cell wall Anatomy 0.000 description 1
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- 239000002131 composite material Substances 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
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- NEFBYIFKOOEVPA-UHFFFAOYSA-K dicalcium phosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])([O-])=O NEFBYIFKOOEVPA-UHFFFAOYSA-K 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
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- 238000010828 elution Methods 0.000 description 1
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- 230000002538 fungal effect Effects 0.000 description 1
- 230000036571 hydration Effects 0.000 description 1
- 238000002513 implantation Methods 0.000 description 1
- 238000007373 indentation Methods 0.000 description 1
- 238000004898 kneading Methods 0.000 description 1
- 239000000178 monomer Substances 0.000 description 1
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- 239000013642 negative control Substances 0.000 description 1
- 230000011164 ossification Effects 0.000 description 1
- 210000000963 osteoblast Anatomy 0.000 description 1
- 238000006116 polymerization reaction Methods 0.000 description 1
- 230000002250 progressing effect Effects 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000004904 shortening Methods 0.000 description 1
- 238000010334 sieve classification Methods 0.000 description 1
- 238000007873 sieving Methods 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000010959 steel Substances 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
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- 231100000419 toxicity Toxicity 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
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Abstract
Description
本発明は、自己硬化型リン酸カルシウム組成物、該組成物を製造するためのキットおよび該組成物の製造方法に関する。 The present invention relates to a self-curing calcium phosphate composition, a kit for producing the composition, and a method for producing the composition.
近年、疾患や事故などによる骨折や骨欠損の修復のために、生体内で水和硬化する骨補填材を用いることが一般に行われるようになっている。例えば、骨粗鬆症や骨腫瘍による椎体の圧迫骨折では、骨補填材としての骨セメントを穿刺針により経皮的に椎体内に注入して椎体を再建する経皮的椎体形成術が行われている。 In recent years, in order to repair fractures or bone defects due to diseases or accidents, it has become common to use bone filling materials that are hydrated and cured in vivo. For example, in compression fracture of the vertebral body due to osteoporosis or bone tumor, percutaneous vertebroplasty is performed in which bone cement as a bone replacement material is percutaneously injected into the vertebral body with a puncture needle and the vertebral body is reconstructed. It has been broken.
骨セメントとしては、現在、ポリメチルメタクリレート(PMMA)セメントまたはリン酸カルシウムセメント(CPC)が主に用いられている。PMMAセメントは、硬化速度および硬化後の強度に優れているが、骨伝導能がないため骨組織との親和性に乏しい。さらに、PMMAセメントには、未反応モノマーの毒性や、重合熱の発生による周辺組織の損傷などの問題もある。一方、CPCは、PMMAセメントに比べて硬化速度および硬化後の強度の点で劣るが、生体内で骨類似ハイドロキシアパタイトに転化するので骨伝導能に優れている。CPCの材料であるリン酸カルシウム系化合物には、生体内で分解・吸収されることによって自然に消滅し、自家骨と置換されるという性質を有するものが多いことから、骨置換型のCPCの開発も進んでいる。また、非特許文献１に開示されるような、生体適合性物質であるキトサンをCPCに配合することにより、機械的特性を改善したCPCも開発されている。 Currently, polymethyl methacrylate (PMMA) cement or calcium phosphate cement (CPC) is mainly used as bone cement. PMMA cement is excellent in curing speed and strength after curing, but lacks osteoconductivity and has poor affinity with bone tissue. Furthermore, PMMA cement has problems such as toxicity of unreacted monomers and damage of surrounding tissues due to generation of polymerization heat. On the other hand, CPC is inferior to PMMA cement in terms of curing speed and strength after curing, but is excellent in osteoconductivity because it is converted into bone-like hydroxyapatite in vivo. Since many calcium phosphate compounds, which are CPC materials, have the property of self-disappearing by being decomposed and absorbed in vivo and replaced with autologous bone, development of bone-replacement type CPC is also possible. Progressing. Moreover, CPC which improved the mechanical characteristic by mix | blending chitosan which is a biocompatible substance with CPC which is disclosed by the nonpatent literature 1 is also developed.
また、近年では、内部に気孔と呼ばれる微小な空隙を多数有する多孔質のCPCも開発されている。このような多孔体では、気孔内に骨芽細胞や新生骨などが進入することにより気孔内で骨形成がなされ、母床骨と一体化することが期待される。また、多孔質とすることにより表面積が増大するので、生体内での骨置換が起こりやすくなる。そのような多孔質のCPCとしては、例えば、特許文献１に記載の多孔質硬化体が挙げられる。また、特許文献２には、ハイドロキシアパタイトなどのリン酸カルシウム系化合物を主成分とし、生体内で分解・吸収される物質を含む補填材が記載されている。特許文献２の補填材は、生体内に用いられた後、上記の物質が生体内で分解・吸収されることにより多孔化する。 In recent years, porous CPCs having a large number of minute voids called pores have been developed. In such a porous body, it is expected that osteoblasts, new bones, and the like enter the pores to form bone in the pores and to be integrated with the mother bone. In addition, since the surface area is increased by using a porous material, bone replacement in a living body is likely to occur. As such porous CPC, for example, a porous cured body described in Patent Document 1 can be mentioned. Patent Document 2 describes a filling material containing a substance that is mainly composed of a calcium phosphate compound such as hydroxyapatite and is decomposed and absorbed in a living body. After the filling material of Patent Document 2 is used in a living body, the material is made porous by being decomposed and absorbed in the living body.
しかし、上記のような多孔質のCPCでは、その気孔内で骨形成がなされて強度が向上するまでには、通常２〜３ヶ月程度を要する。そのため、特許文献１の多孔質硬化体は、生体への移植直後の初期強度が十分とはいえない。また、特許文献１では、セメント粉末と硬化液とを混合してから40分かけて多孔質硬化体を得ており、硬化速度も満足できるものではない。特許文献２に記載の補填材についても、人工体液中で３日間の水和硬化後の圧縮強度は約５〜13 MPaであり、改善の余地がある。 However, in the porous CPC as described above, it usually takes about 2 to 3 months for the bone formation in the pores to improve the strength. Therefore, the porous cured body of Patent Document 1 cannot be said to have sufficient initial strength immediately after transplantation into a living body. Moreover, in patent document 1, the porous hardened | cured material is obtained over 40 minutes after mixing cement powder and a hardening liquid, and a cure rate is not satisfactory. The filling material described in Patent Document 2 also has room for improvement because the compressive strength after hydration curing for 3 days in an artificial body fluid is about 5 to 13 MPa.
そこで、本発明は、硬化速度および硬化後の強度に優れ、且つ、生体内で多孔化するとともに自家骨に置換される硬化体を得ることが可能な自己硬化型リン酸カルシウム組成物を提供することを目的とする。また、本発明は、そのような組成物を製造するためのキットおよび製造方法を提供することも目的とする。 Therefore, the present invention provides a self-curing calcium phosphate composition that is excellent in curing speed and strength after curing, and that can obtain a cured body that becomes porous in vivo and is replaced with autologous bone. Objective. Another object of the present invention is to provide a kit and a production method for producing such a composition.
本発明者は、分級によって得た、互いに異なる粒径を有する２つの群のリン酸四カルシウムと、リン酸水素カルシウムと、キトサンと、硬化液としてのリンゴ酸水溶液とを原料に用いてCPCを製造したところ、比較的短時間で硬化し、硬化後の強度も良好であることを見出した。また、得られたCPCが生理食塩水中で多孔化することを見出した。これらの知見に基づいて、本発明者は、本発明を完成した。 The present inventor uses two groups of tetracalcium phosphate having different particle sizes obtained by classification, calcium hydrogen phosphate, chitosan, and malic acid aqueous solution as a hardening solution as raw materials. As a result of the production, it was found that the composition was cured in a relatively short time and the strength after curing was also good. It was also found that the obtained CPC becomes porous in physiological saline. Based on these findings, the present inventor has completed the present invention.
よって、本発明は、互いに異なる粒径を有する２つの群のリン酸四カルシウムと、リン酸水素カルシウム二水和物と、キトサンと、硬化液としてのリンゴ酸水溶液とを混和してなり、該リン酸四カルシウムの２つの群が、分級により得られた、300μm未満の粒径を有する少なくとも３つの群から選択されたものである、自己硬化型リン酸カルシウム組成物を提供する。 Therefore, the present invention comprises mixing two groups of tetracalcium phosphate having different particle sizes, calcium hydrogen phosphate dihydrate, chitosan, and malic acid aqueous solution as a hardening solution, A self-hardening calcium phosphate composition is provided wherein the two groups of tetracalcium phosphate are selected from at least three groups obtained by classification and having a particle size of less than 300 μm.
また、本発明は、互いに異なる粒径を有する２つの群のリン酸四カルシウム、およびリン酸水素カルシウム二水和物を含む粉体と、キトサンおよびリンゴ酸を含む硬化液とを含み、該リン酸四カルシウムの２つの群が、分級により得られた、300μm未満の粒径を有する少なくとも３つの群から選択されたものである、自己硬化型リン酸カルシウム組成物を製造するためのキットを提供する。 The present invention also includes a powder containing two groups of tetracalcium phosphate and calcium hydrogen phosphate dihydrate having different particle diameters, and a hardening liquid containing chitosan and malic acid. Provided is a kit for producing a self-curing calcium phosphate composition, wherein the two groups of tetracalcium acid are selected from at least three groups obtained by classification and having a particle size of less than 300 μm.
さらに、本発明は、互いに異なる粒径を有する２つの群のリン酸四カルシウムと、リン酸水素カルシウム二水和物と、キトサンと、硬化液としてのリンゴ酸水溶液とを混和する工程を含み、
上記のリン酸四カルシウムの２つの群が、分級により得られた、300μm未満の粒径を有する少なくとも３つの群から選択されたものである、
自己硬化型リン酸カルシウム組成物の製造方法を提供する。
Furthermore, the present invention includes a step of mixing two groups of tetracalcium phosphate having different particle sizes, calcium hydrogen phosphate dihydrate, chitosan, and malic acid aqueous solution as a hardening solution,
The two groups of tetracalcium phosphate are selected from at least three groups obtained by classification and having a particle size of less than 300 μm.
A method for producing a self-curing calcium phosphate composition is provided.
本発明によれば、硬化速度および硬化後の強度に優れた自己硬化型リン酸カルシウム組成物を得ることができる。また、該組成物の硬化体は、生体内で多孔化するとともに自家骨に置換されることが可能である。 According to the present invention, a self-curing calcium phosphate composition excellent in curing speed and strength after curing can be obtained. In addition, the cured product of the composition can be made porous in vivo and replaced with autologous bone.
[自己硬化型リン酸カルシウム組成物およびその製造方法]
本発明の自己硬化型リン酸カルシウム組成物(以下、単に「組成物」ともいう)は、リン酸四カルシウムと、リン酸水素カルシウム二水和物と、キトサンと、硬化液としてのリンゴ酸水溶液とを混和してなる、ペーストもしくはスラリーのような不定形混合物である。混和直後の本発明の組成物は、任意の形状に変えることやチューブへの充填などの操作が可能である。そして、本発明の組成物は、時間経過にしたがって自己硬化する。硬化した本発明の組成物は、水中または生体内で水和反応によりさらに硬化して、CPCの一種である硬化体になる。したがって、本発明の組成物は、骨補填材として好適に用いることが可能である。
[Self-curing calcium phosphate composition and method for producing the same]
The self-curing calcium phosphate composition of the present invention (hereinafter also simply referred to as “composition”) comprises tetracalcium phosphate, calcium hydrogen phosphate dihydrate, chitosan, and an aqueous malic acid solution as a curing solution. It is an amorphous mixture such as paste or slurry. The composition of the present invention immediately after mixing can be changed into an arbitrary shape or filled into a tube. And the composition of this invention self-hardens with time passage. The cured composition of the present invention is further cured by a hydration reaction in water or in vivo to become a cured product which is a kind of CPC. Therefore, the composition of the present invention can be suitably used as a bone substitute material.
本発明において、リン酸四カルシウム(TeCP)は、互いに異なる粒径を有する２つの群の粉体を用いる。そのような２つの群のTeCPは、分級により得られた、300μm未満の粒径を有する少なくとも３つの群から選択される。ここで、分級の方法は特に限定されず、公知の分級装置を用いてもよいし、ふるいにより分級してもよい。本発明の実施形態においては、ふるい分級が好ましい。 In the present invention, tetracalcium phosphate (TeCP) uses two groups of powders having different particle sizes. Such two groups of TeCPs are selected from at least three groups obtained by classification and having a particle size of less than 300 μm. Here, the classification method is not particularly limited, and a known classification device may be used, or classification may be performed using a sieve. In the embodiment of the present invention, sieve classification is preferred.
分級により得られた、300μm未満の粒径を有する少なくとも３つの群としては、例えば、45μm未満の粒径の群、45μm以上且つ75μm未満の粒径の群および75μm以上且つ300μm未満の粒径の群が挙げられる。これらの３つの群のTeCP粉体から２つを選択して組み合わせることにより、本発明の組成物から得られる硬化体の圧縮強度が向上する。 The at least three groups having a particle size of less than 300 μm obtained by classification include, for example, a group of particle sizes of less than 45 μm, a group of particle sizes of 45 μm or more and less than 75 μm, and a particle size of 75 μm or more and less than 300 μm. Groups. By selecting and combining two of these three groups of TeCP powder, the compression strength of the cured product obtained from the composition of the present invention is improved.
本発明の実施形態においては、上記の45μm未満の粒径の群が、25μm未満の粒径の群および25μm以上且つ45μm未満の粒径の群のいずれか１つであり、また、上記の75μm以上且つ300μm未満の粒径の群が、75μm以上且つ150μm未満の粒径の群および150μm以上且つ300μm未満の粒径の群のいずれか１つであることがより好ましい。この場合、TeCPの２つ群の組み合わせとしては、硬化体の圧縮強度を向上させる観点から、以下の組み合わせが特に好ましい：
25μm未満の粒径の群と75μm以上且つ150μm未満の粒径の群との組み合わせ；
25μm未満の粒径の群と150μm以上且つ300μm未満の粒径の群との組み合わせ；
25μm以上且つ45μm未満の粒径の群と45μm以上且つ75μm未満の粒径の群との組み合わせ；
25μm以上且つ45μm未満の粒径の群と75μm以上且つ150μm未満の粒径の群との組み合わせ；
25μm以上且つ45μm未満の粒径の群と150μm以上且つ300μm未満の粒径の群との組み合わせ；
45μm以上且つ75μm未満の粒径の群と75μm以上且つ150μm未満の粒径の群との組み合わせ；および
45μm以上且つ75μm未満の粒径の群と150μm以上且つ300μm未満の粒径の群との組み合わせ。
In an embodiment of the present invention, the group having a particle size of less than 45 μm is one of a group having a particle size of less than 25 μm and a group having a particle size of 25 μm or more and less than 45 μm, and the above-mentioned 75 μm. More preferably, the group having a particle diameter of 300 μm or less is any one of a group of particle diameters of 75 μm or more and less than 150 μm and a group of particle diameters of 150 μm or more and less than 300 μm. In this case, the combination of the two groups of TeCP is particularly preferable from the viewpoint of improving the compression strength of the cured body:
A combination of a group having a particle size of less than 25 μm and a group having a particle size of 75 μm or more and less than 150 μm;
A combination of a group having a particle size of less than 25 μm and a group having a particle size of 150 μm or more and less than 300 μm;
A combination of a group of particle sizes of 25 μm or more and less than 45 μm and a group of particle sizes of 45 μm or more and less than 75 μm;
A combination of a group of particle sizes of 25 μm or more and less than 45 μm and a group of particle sizes of 75 μm or more and less than 150 μm;
A combination of a group of particle sizes of 25 μm or more and less than 45 μm and a group of particle sizes of 150 μm or more and less than 300 μm;
A combination of a group of particle sizes greater than or equal to 45 μm and less than 75 μm and a group of particle sizes greater than or equal to 75 μm and less than 150 μm; and
A combination of a group having a particle size of 45 μm or more and less than 75 μm and a group having a particle size of 150 μm or more and less than 300 μm.
本発明の組成物に用いられるTeCPは、市販のものを用いてもよいし、自ら製造したものを用いてもよい。TeCPの製造方法自体は公知であり、いずれの製造方法を用いてもよいが、例えば、次のようにして得ることができる。炭酸カルシウムの粉体とリン酸水素カルシウム二水和物の粉体とを、水を溶媒として湿式混合し、得られた混合物を1200〜1700℃で３〜６時間焼成する。そして、得られた焼成物を粉砕することで、TeCPの粉体を得ることができる。このTeCPの粉体を分級することにより、互いに異なる粒径を有する２つの群のTeCPの粉体を得ることができる。 As the TeCP used in the composition of the present invention, a commercially available product or a product produced by itself may be used. The TeCP production method itself is known, and any production method may be used. For example, it can be obtained as follows. Calcium carbonate powder and calcium hydrogen phosphate dihydrate powder are wet-mixed using water as a solvent, and the resulting mixture is fired at 1200-1700 ° C. for 3-6 hours. Then, by pulverizing the obtained fired product, TeCP powder can be obtained. By classifying the TeCP powder, two groups of TeCP powders having different particle sizes can be obtained.
本発明の組成物においては、リン酸水素カルシウム二水和物(DCPD)をTeCPとともに配合することで、自己硬化した組成物の水和反応による硬化が進むとともに、得られる硬化体においてTeCPとDCPDとが反応してハイドロキシアパタイトへと徐々に転化する。なお、本発明の実施形態においては、DCPDに替えて、その無水物であるリン酸水素カルシウム(DCPA)を用いることもできる。DCPDおよびDCPAは市販のものを用いることができる。 In the composition of the present invention, by blending calcium hydrogen phosphate dihydrate (DCPD) together with TeCP, curing by the hydration reaction of the self-cured composition proceeds, and TeCP and DCPD are obtained in the obtained cured product. Reacts gradually with hydroxyapatite. In the embodiment of the present invention, the anhydrous calcium calcium phosphate (DCPA) may be used instead of DCPD. Commercially available DCPD and DCPA can be used.
本発明の実施形態においては、DCPDの粒径は特に限定されないが、好ましくは0.2〜10μmであり、より好ましくは0.5〜５μmである。なお、市販のDCPDの粉体の粒径が好ましい大きさでない場合は、湿式粉砕などの公知の粉砕方法で粉砕して粒径を調節することができる。 In the embodiment of the present invention, the particle size of DCPD is not particularly limited, but is preferably 0.2 to 10 μm, more preferably 0.5 to 5 μm. In addition, when the particle size of commercially available DCPD powder is not a preferred size, the particle size can be adjusted by pulverization by a known pulverization method such as wet pulverization.
本発明の実施形態においては、TeCPおよびDCPTのそれぞれ等モル量を乾式混合して、セメント粉を得ることが好ましい。このようなセメント粉とすることにより、均一な組成物を得ることができる。 In the embodiment of the present invention, it is preferable to obtain a cement powder by dry mixing equimolar amounts of TeCP and DCPT. By using such cement powder, a uniform composition can be obtained.
本発明の組成物においては、硬化時間の短縮の観点から、硬化液としてリンゴ酸水溶液が好適に用いられる。本発明の組成物中のリンゴ酸の濃度は、硬化時間および硬化体の圧縮強度を考慮すると、1.0重量％以上2.5重量％以下の範囲、特に1.0重量％以上2.0重量％以下の範囲から選択されることが望ましい。なお、硬化液中のリンゴ酸濃度が2.0重量％以下であると、後述のキトサンを該硬化液に溶解することができないので、組成物中のリンゴ酸濃度を0.5重量％以下とすることは困難である。また、組成物中のリンゴ酸濃度が2.5重量％より大きい場合、組成物の硬化時間が短すぎて混和することができなくなる。 In the composition of the present invention, an aqueous malic acid solution is suitably used as the curing liquid from the viewpoint of shortening the curing time. The concentration of malic acid in the composition of the present invention is selected from the range of 1.0% by weight to 2.5% by weight, particularly 1.0% by weight to 2.0% by weight in consideration of the curing time and the compression strength of the cured product. It is desirable. When the malic acid concentration in the hardening liquid is 2.0% by weight or less, since chitosan described later cannot be dissolved in the hardening liquid, it is difficult to make the malic acid concentration in the composition 0.5% by weight or less. It is. On the other hand, when the malic acid concentration in the composition is larger than 2.5% by weight, the curing time of the composition is too short to be mixed.
本発明において、キトサンは、自己硬化型リン酸カルシウム組成物の硬化速度およびその硬化体の圧縮強度を向上させる目的で、また、硬化体を生体内に注入もしくは埋入した後に溶出させて該硬化体を多孔化させる目的で添加される。キトサンは、カニやエビなどの甲殻類の外骨格およびキノコなどの菌類の細胞壁に含まれるキチンを濃アルカリによって脱アセチル化することで得られる天然高分子として知られているが、本発明の実施形態においては、キトサンの由来は特に限定されない。 In the present invention, chitosan is used for the purpose of improving the curing rate of the self-curing calcium phosphate composition and the compressive strength of the cured product, and by eluting the cured product after injection or implantation into a living body, It is added for the purpose of making it porous. Chitosan is known as a natural polymer obtained by deacetylation of chitin contained in crustacean exoskeletons such as crabs and shrimps and fungal cell walls such as mushrooms with concentrated alkali. In the form, the origin of chitosan is not particularly limited.
本発明の実施形態においては、キトサンの形態は特に限定されず、粉体の形態であってもよいし、溶液の形態であってもよい。キトサンを溶液の形態で用いて本発明の組成物を調製する場合、キトサンは、硬化液としてのリンゴ酸水溶液に溶解していることが望ましい。 In the embodiment of the present invention, the form of chitosan is not particularly limited, and may be a powder form or a solution form. When preparing the composition of this invention using chitosan in the form of a solution, it is desirable for chitosan to melt | dissolve in malic acid aqueous solution as a hardening | curing liquid.
本発明に用いられるキトサンの平均分子量は、上記のTeCPおよびDCPTのセメント粉と硬化液との混和が可能な範囲であればよいが、好ましくは、粘度に基づく分子量として10,000以上310,000以下である。なお、キトサンの分子量は、該キトサンの溶液の粘度に比例することが知られている。本明細書においては、粘度は、１％酢酸水溶液にキトサンを１重量％となるように溶解させて得たキトサン溶液について、溶液温度20℃にてＢ型回転粘度計により測定するものとする。そして、測定した粘度に基づいてキトサンの固有粘度を算出し、Mark-Houwink-Sakuradaの式より、キトサンの分子量を算出する。 The average molecular weight of the chitosan used in the present invention may be within a range in which the above-mentioned TeCP and DCPT cement powder and the hardening liquid can be mixed, but preferably has a molecular weight based on viscosity of 10,000 to 310,000. It is known that the molecular weight of chitosan is proportional to the viscosity of the chitosan solution. In the present specification, the viscosity is measured with a B-type rotational viscometer at a solution temperature of 20 ° C. with respect to a chitosan solution obtained by dissolving chitosan in a 1% aqueous acetic acid solution to 1% by weight. Then, the intrinsic viscosity of chitosan is calculated based on the measured viscosity, and the molecular weight of chitosan is calculated from the Mark-Houwink-Sakurada equation.
本発明の実施形態においては、キトサンの脱アセチル化度は特に限定されないが、好ましくは70〜100％である。 In the embodiment of the present invention, the degree of deacetylation of chitosan is not particularly limited, but is preferably 70 to 100%.
本発明の実施形態においては、組成物中のキトサンの濃度は、該組成物の機械的強度および多孔化の観点から、1.0重量％以上10.0重量％以下の範囲、特に1.25重量％以上3．75重量％以下の範囲であることが望ましい。なお、硬化液中のキトサン濃度が20重量％以上であると、水分が少なくなり、該硬化液と上記のTeCPおよびDCPTのセメント粉との混和ができなくなるので、組成物中のキトサン濃度を11.0重量％以上とすることは困難である。 In an embodiment of the present invention, the concentration of chitosan in the composition ranges from 1.0% by weight to 10.0% by weight, particularly from 1.25% by weight to 3.75%, from the viewpoint of mechanical strength and porosity of the composition. It is desirable that the amount be in the range of weight percent or less. When the chitosan concentration in the hardening liquid is 20% by weight or more, the water content decreases, and the hardening liquid and the above-mentioned TeCP and DCPT cement powder cannot be mixed, so the chitosan concentration in the composition is 11.0 It is difficult to make it more than% by weight.
本発明の実施形態においては、上記のTeCPおよびDCPTのセメント粉と、リンゴ酸水溶液およびキトサンを含む硬化液とを混合することにより組成物を得ることが好ましい。ここで、セメント粉と硬化液との混合の際の粉液比(粉(g)/液(g))は、通常0.8〜５であり、好ましくは２〜４であり、特に好ましくは３である。なお、混合手段は特に限定されず、混合量などに応じて公知の混合手段から適宜選択すればよい。 In an embodiment of the present invention, it is preferable to obtain a composition by mixing the above-mentioned TeCP and DCPT cement powder with a malic acid aqueous solution and a hardening liquid containing chitosan. Here, the powder-liquid ratio (powder (g) / liquid (g)) at the time of mixing cement powder and hardening liquid is 0.8-5 normally, Preferably it is 2-4, Most preferably, it is 3. is there. The mixing means is not particularly limited, and may be appropriately selected from known mixing means according to the mixing amount.
上記のセメント粉と硬化液との混合後、本発明の組成物は、通常３〜20分程度で自己硬化が完了する(初期硬化)。このときの温度および湿度の条件は、一般的なCPCの調製条件と特に変わるところはないが、通常、20〜40℃の温度且つ50〜100％の湿度であればよい。 After mixing the above cement powder and the curing liquid, the composition of the present invention usually completes self-curing in about 3 to 20 minutes (initial curing). The conditions of temperature and humidity at this time are not particularly different from general CPC preparation conditions, but are usually 20 to 40 ° C. and 50 to 100% humidity.
得られた本発明の組成物は、上述のとおり、骨補填材として生体に用いることが可能である。そして、本発明の組成物は、生体内で水和反応により硬化体となる。水和反応により本発明の組成物から得られる硬化体は、少なくとも15 MPa、好ましくは少なくとも17 MPa、より好ましくは少なくとも20 MPaの圧縮強度を示す。その後、硬化体に含まれるキトサンが生体内で溶出することにより、硬化体は多孔化する。なお、この多孔化は、硬化体を生理食塩水中に浸漬することによっても生じるので、多孔化の確認試験は、硬化体を生理食塩水中に浸漬した後、走査型電子顕微鏡などにより確認することができる。 The obtained composition of the present invention can be used in a living body as a bone grafting material as described above. And the composition of this invention turns into a hardening body by hydration reaction in the living body. The cured product obtained from the composition of the present invention by a hydration reaction exhibits a compressive strength of at least 15 MPa, preferably at least 17 MPa, more preferably at least 20 MPa. Thereafter, chitosan contained in the cured body elutes in vivo to make the cured body porous. In addition, since this porosity occurs also by immersing a hardening body in physiological saline, after the hardening body is immersed in physiological saline, it can confirm with a scanning electron microscope etc. it can.
[自己硬化型リン酸カルシウム組成物を製造するためのキット]
本発明の自己硬化型リン酸カルシウム組成物を製造するためのキット(以下、単に「キット」ともいう)は、互いに異なる粒径を有する２つの群のTeCP、およびDCPDを含む粉体と、キトサンおよびリンゴ酸を含む硬化液とを含む。
[Kit for producing self-curing calcium phosphate composition]
A kit for producing the self-curing calcium phosphate composition of the present invention (hereinafter also simply referred to as “kit”) includes two groups of TeCP having different particle diameters and powders containing DCPD, chitosan and apple And a curable liquid containing an acid.
互いに異なる粒径を有する２つの群のTeCPは、上記の本発明の組成物の説明において述べたことと同じである。すなわち、分級により得られた、300μm未満の粒径を有する少なくとも３つの群から選択された２つの群であればよい。本発明の実施形態において、互いに異なる粒径を有する２つの群のTeCP、およびDCPDを含む粉体は、上述した、TeCPおよびDCPTのそれぞれ等モル量を乾式混合して得られるセメント粉が好ましい。なお、TeCPおよびDCPTのそれぞれの詳細については、上記の本発明の組成物の説明において述べたことと同じである。 The two groups of TeCPs having different particle sizes are the same as described in the description of the composition of the present invention above. That is, it may be two groups selected from at least three groups obtained by classification and having a particle size of less than 300 μm. In the embodiment of the present invention, the powder containing two groups of TeCP and DCPD having different particle sizes is preferably a cement powder obtained by dry-mixing equimolar amounts of TeCP and DCPT described above. The details of TeCP and DCPT are the same as those described in the description of the composition of the present invention.
本発明の実施形態において、キトサンおよびリンゴ酸を含む硬化液は、上述した、キトサンが溶解したリンゴ酸水溶液が好ましい。なお、キトサンおよびリンゴ酸のそれぞれの詳細については、上記の本発明の組成物の説明において述べたことと同じである。また、硬化液中のリンゴ酸濃度やキトサン濃度についても、上記の本発明の組成物の説明において述べたことと同じである。 In the embodiment of the present invention, the hardening liquid containing chitosan and malic acid is preferably the above-described malic acid aqueous solution in which chitosan is dissolved. The details of each of chitosan and malic acid are the same as those described in the description of the composition of the present invention. Further, the malic acid concentration and chitosan concentration in the curable liquid are the same as those described in the description of the composition of the present invention.
本発明の実施形態において、キットは、TeCPおよびDCPDを含む粉体と、キトサンおよびリンゴ酸を含む硬化液とがそれぞれ別個の容器に収められた二試薬型のキットであることが好ましい。そのような容器の形状は特に限定されず、例えば、TeCPおよびDCPDを含む粉体は、硬化液との混和が可能な混練注入器に収め、硬化液も注入器に収めることなどが挙げられる。この場合、本発明のキットは、注入針をさらに含んでいてもよい。また、本発明のキットは、得られる組成物の粘度を調整するための水をさらに含んでいてもよい。 In the embodiment of the present invention, the kit is preferably a two-reagent kit in which a powder containing TeCP and DCPD and a hardening liquid containing chitosan and malic acid are contained in separate containers. The shape of such a container is not particularly limited, and for example, the powder containing TeCP and DCPD is stored in a kneading injector that can be mixed with the curable liquid, and the curable liquid is also stored in the injector. In this case, the kit of the present invention may further include an injection needle. Moreover, the kit of this invention may further contain the water for adjusting the viscosity of the composition obtained.
以下に、本発明を実施例により詳細に説明するが、本発明はこれらの実施例に限定されるものではない。 EXAMPLES The present invention will be described in detail below by examples, but the present invention is not limited to these examples.
＜実施例１＞
本実施例では、セメント粉の粒径と硬化体の圧縮強度との関連を検討した。
(１)材料
・リン酸四カルシウム(TeCP)
炭酸カルシウム(11.032 g (0.110 mol)、和光純薬工業株式会社)と、リン酸水素カルシウム二水和物(18.968 g (0.110 mol)、和光純薬工業株式会社)と、超純水(180 mL)とを、ジルコニアボール(200 g、アズワン株式会社製)と共にポットミルHD-A-4(アズワン株式会社製)に入れ、室温にて110 rpmの回転速度で24時間湿式混合した。得られたスラリーをろ紙5C(桐山製作所製)にのせ、アスピレーターA-3S(EYELA社製)で吸引ろ過した。ろ過物をシャーレに入れ，定温乾燥機DOV-450P(アズワン株式会社製)で、50℃にて24時間乾燥した。乾燥物を粉砕し、得られた粉末を内径14 mmの熱プレス機用金型1-6002-18(アズワン株式会社製)に入れ、プレス(ジャスコエンジニアリング社製)を用いて1,100 kgf/cm2で一軸加圧して、高さ12 mm程度の円柱形状試料を得た。得られた試料をアルミナ製ボートSSA‐H2B(株式会社ニッカトー製)に入れ、電気炉(丸祥電器株式会社製)を用いて、大気中、1500℃にて５時間焼成した。昇降温速度は10℃/minとした。焼成後、試料を電気炉から取り出し、超硬質鋼乳鉢(WD型、伊藤製作所製)で粉砕し、さらにめのう乳鉢で微粉砕して、TeCPの粉体を得た。得られたTeCPの粉体を、５つのふるいを備えたふるい振とう機MVS-1(アズワン株式会社製)を用いて分級した。なお、ふるい振とう機の振動数は10 rpsとした。また、各ふるいの目開きは、25μm、45μm、75μm、150μmおよび300μmであった。分級により、次の５つの群のTeCPを得た：25μm未満の群、25μm以上且つ45μm未満の群、45μm以上且つ75μm未満の群、75μm以上且つ150μm未満の群、および150μm以上且つ300μm未満の群。
<Example 1>
In this example, the relationship between the particle size of cement powder and the compressive strength of the cured body was examined.
(1) Materials: Tetracalcium phosphate (TeCP)
Calcium carbonate (11.032 g (0.110 mol), Wako Pure Chemical Industries, Ltd.), calcium hydrogen phosphate dihydrate (18.968 g (0.110 mol), Wako Pure Chemical Industries, Ltd.), and ultrapure water (180 mL ) Together with zirconia balls (200 g, manufactured by ASONE CORPORATION) in a pot mill HD-A-4 (manufactured by ASONE CORPORATION) and wet-mixed at room temperature for 24 hours at a rotation speed of 110 rpm. The obtained slurry was placed on filter paper 5C (manufactured by Kiriyama Seisakusho) and suction filtered with an aspirator A-3S (manufactured by EYELA). The filtrate was put in a petri dish and dried at 50 ° C. for 24 hours with a constant temperature dryer DOV-450P (manufactured by ASONE Corporation). The dried product is pulverized, and the obtained powder is placed in a hot press machine mold 1-6002-18 (manufactured by ASONE Co., Ltd.) having an inner diameter of 14 mm, and 1,100 kgf / cm 2 using a press (manufactured by Jusco Engineering). A cylindrical sample having a height of about 12 mm was obtained. The obtained sample was placed in an alumina boat SSA-H2B (manufactured by Nikkato Co., Ltd.) and baked in the atmosphere at 1500 ° C. for 5 hours using an electric furnace (manufactured by Marusho Denki Co., Ltd.). The temperature raising / lowering rate was 10 ° C / min. After firing, the sample was taken out of the electric furnace, pulverized with a super hard steel mortar (WD type, manufactured by Ito Seisakusho), and further finely pulverized with an agate mortar to obtain TeCP powder. The obtained TeCP powder was classified using a sieve shaker MVS-1 (manufactured by ASONE CORPORATION) equipped with five sieves. The frequency of the sieve shaker was 10 rps. The openings of each sieve were 25 μm, 45 μm, 75 μm, 150 μm and 300 μm. By classification, the following five groups of TeCP were obtained: groups less than 25 μm, groups greater than 25 μm and less than 45 μm, groups greater than 45 μm and less than 75 μm, groups greater than 75 μm and less than 150 μm, and greater than 150 μm and less than 300 μm group.
・リン酸水素カルシウム二水和物(DCPD)
リン酸水素カルシウム二水和物(15.00 g、和光純薬工業株式会社)と超純水(180 mL)とを、ジルコニアボール(500 g、アズワン株式会社製)と共にポットミルHD-A-4(アズワン株式会社製)に入れ、室温にて110 rpmの回転速度で48時間湿式粉砕した。得られたスラリーをろ紙5C(桐山製作所製)にのせ、アスピレーターA-3S(EYELA社製)で吸引ろ過した。ろ過物をシャーレに入れ，定温乾燥機DOV-450P(アズワン株式会社製)で、50℃にて24時間乾燥した。乾燥物を粉砕して、平均粒径2.5±2.2μmのDCPDの粉体を得た。
・ Calcium hydrogen phosphate dihydrate (DCPD)
Calcium hydrogen phosphate dihydrate (15.00 g, Wako Pure Chemical Industries, Ltd.) and ultrapure water (180 mL) together with zirconia balls (500 g, manufactured by As One Corporation), Pot Mill HD-A-4 (As One And was wet-ground for 48 hours at a rotation speed of 110 rpm at room temperature. The obtained slurry was placed on filter paper 5C (manufactured by Kiriyama Seisakusho) and suction filtered with an aspirator A-3S (manufactured by EYELA). The filtrate was put in a petri dish and dried at 50 ° C. for 24 hours with a constant temperature dryer DOV-450P (manufactured by ASONE Corporation). The dried product was pulverized to obtain a DCPD powder having an average particle size of 2.5 ± 2.2 μm.
・硬化液
硬化液として、リンゴ酸(和光純薬工業株式会社)を10重量％、およびキトサン(平均分子量50,000〜190,000、脱アセチル化度約81.3％、ARDRICH Chemistry社)を10重量％含む水溶液を用いた。
・ Curing solution As a curing solution, an aqueous solution containing 10% by weight of malic acid (Wako Pure Chemical Industries, Ltd.) and 10% by weight of chitosan (average molecular weight 50,000 to 190,000, degree of deacetylation about 81.3%, ARDRICH Chemistry) Using.
(２)自己硬化型リン酸カルシウム組成物およびその硬化体の調製
TeCPの粉体として、上記の各群を単独で、または所定の２つの群を組み合わせたものを用いた。TeCPの粉体(6.80 g(0.186 mol))とDCPDの粉体(3.20 g(0.186 mol))とを、Mini Blender (メリタ社製)を用いて１分間混合してセメント粉を得た。セメント粉の粒度分布をレーザー回折／散乱式粒度分布測定装置LA-920(株式会社堀場製作所製)で調べた。セメント粉と硬化液とを、粉液比(粉(g)/液(g))が３となるように90秒間混和して、自己硬化型リン酸カルシウム組成物(リンゴ酸2.5重量％、キトサン2.5重量％含有)を得た。この組成物をテフロン製割型(内径６mm、高さ12 mm)に注入し、37℃、湿度100％の環境下で１時間静置して、初期硬化体を得た。そして、初期硬化体を型から取り出し、超純水中に24時間浸漬して水和硬化させ、硬化体を得た。以降、得られた硬化体を試料として圧縮強度の測定に付した。なお、各試料について、TeCPの２つの群を組み合わせ、並びにセメント粉の平均直径および平均高さは、以下の表１に示した。
(2) Preparation of self-curing calcium phosphate composition and cured product thereof
As the TeCP powder, each of the above groups was used alone or a combination of two predetermined groups. TeCP powder (6.80 g (0.186 mol)) and DCPD powder (3.20 g (0.186 mol)) were mixed for 1 minute using Mini Blender (Melita) to obtain cement powder. The particle size distribution of the cement powder was examined with a laser diffraction / scattering type particle size distribution analyzer LA-920 (manufactured by Horiba, Ltd.). Cement powder and hardened liquid are mixed for 90 seconds so that the powder-liquid ratio (powder (g) / liquid (g)) is 3, self-setting calcium phosphate composition (malic acid 2.5 wt%, chitosan 2.5 wt%) % Content). This composition was poured into a Teflon split mold (inner diameter 6 mm, height 12 mm) and allowed to stand in an environment of 37 ° C. and 100% humidity for 1 hour to obtain an initial cured product. Then, the initial cured body was taken out of the mold and immersed in ultrapure water for 24 hours to be hydrated and cured to obtain a cured body. Thereafter, the obtained cured body was subjected to compression strength measurement as a sample. In addition, about each sample, two groups of TeCP were combined, and the average diameter and average height of cement powder were shown in Table 1 below.
(３)試料の分析
得られた試料の圧縮強度を、万能試験機AG-10(島津製作所製)を用いて、JIS規格(JIS T6602)に準拠して測定した。なお、この測定では５kNロードセルを用い、試験速度は0.50 mm/秒とした。なお、測定は、各試料について６回ずつ行い、測定値に基づいて圧縮強度の平均値と標準誤差を算出した。結果を表１に示す。
(3) Analysis of sample The compressive strength of the obtained sample was measured according to JIS standard (JIS T6602) using a universal testing machine AG-10 (manufactured by Shimadzu Corporation). In this measurement, a 5 kN load cell was used and the test speed was 0.50 mm / sec. The measurement was performed 6 times for each sample, and the average value and standard error of the compressive strength were calculated based on the measured values. The results are shown in Table 1.
(４)結果および考察
表１より、いずれのセメント粉においても粒子の平均直径および平均高さに大きな差は認められず、ほぼ均一なサイズであった。一方、得られた試料の圧縮強度は、セメント粉に用いたTeCPの粒径によって差が認められた。ふるいにより分級した各群を単独で用いた場合は、150μm以上且つ300μm未満の粒径の群では圧縮強度が約４MPaと比較的小さく、それ以外の群では約10〜18 MPaの圧縮強度の試料が得られた(表１のNo.１〜５参照)。
(4) Results and discussion From Table 1, no significant difference was observed in the average diameter and average height of the particles in any cement powder, and the sizes were almost uniform. On the other hand, a difference in the compressive strength of the obtained samples was observed depending on the particle size of TeCP used for the cement powder. When each group classified by sieving is used alone, a sample with a particle size of 150 μm or more and less than 300 μm has a relatively small compressive strength of about 4 MPa, and the other group has a compressive strength of about 10 to 18 MPa. Was obtained (see Nos. 1 to 5 in Table 1).
表１より、互いに粒径の異なる２つの群を組み合わせた場合では、25μm未満の粒径の群と、25μm以上且つ45μm未満の粒径の群または45μm以上且つ75μm未満の粒径の群との組み合わせ、あるいは、45μm以上且つ75μm未満の粒径の群と、150μm以上且つ300μm未満の粒径の群との組み合わせを用いたときに、約15〜18 MPaの圧縮強度の試料が得られた(表１のNo.６、７および14参照)。一方、75μm以上且つ150μm未満の粒径の群と、150μm以上且つ300μm未満の粒径の群との組み合わせでは、得られた試料の圧縮強度は約４MPaと比較的小さかった(表１のNo.15参照)。 From Table 1, when two groups having different particle sizes are combined, a group having a particle size of less than 25 μm and a group having a particle size of 25 μm or more and less than 45 μm or a group having a particle size of 45 μm or more and less than 75 μm When a combination or a combination of a group having a particle size of 45 μm or more and less than 75 μm and a group having a particle size of 150 μm or more and less than 300 μm was used, a sample having a compressive strength of about 15 to 18 MPa was obtained ( (See No. 6, 7, and 14 in Table 1). On the other hand, in the combination of a group having a particle size of 75 μm or more and less than 150 μm and a group having a particle size of 150 μm or more and less than 300 μm, the compression strength of the obtained sample was relatively small at about 4 MPa (No. in Table 1). 15).
以下の組み合わせを用いた場合では、得られた硬化体の圧縮強度が20 MPa以上と特に良好な値であった(表１のNo.８〜13参照)：
25μm未満の粒径の群と75μm以上且つ150μm未満の粒径の群との組み合わせ、
25μm未満の粒径の群と150μm以上且つ300μm未満の粒径の群との組み合わせ、
25μm以上且つ45μm未満の粒径の群と45μm以上且つ75μm未満の粒径の群との組み合わせ、
25μm以上且つ45μm未満の粒径の群と75μm以上且つ150μm未満の粒径の群との組み合わせ、
25μm以上且つ45μm未満の粒径の群と150μm以上且つ300μm未満の粒径の群との組み合わせ、
45μm以上且つ75μm未満の粒径の群と75μm以上且つ150μm未満の粒径の群との組み合わせ、および
45μm以上且つ75μm未満の粒径の群と150μm以上且つ300μm未満の粒径の群との組み合わせ。
In the case of using the following combinations, the obtained cured product had a particularly good compressive strength of 20 MPa or more (see Nos. 8 to 13 in Table 1):
A combination of a group having a particle size of less than 25 μm and a group having a particle size of 75 μm or more and less than 150 μm,
A combination of a group having a particle size of less than 25 μm and a group having a particle size of 150 μm or more and less than 300 μm,
A combination of a group having a particle size of 25 μm or more and less than 45 μm and a group having a particle size of 45 μm or more and less than 75 μm,
A combination of a group having a particle size of 25 μm or more and less than 45 μm and a group having a particle size of 75 μm or more and less than 150 μm,
A combination of a group having a particle size of 25 μm or more and less than 45 μm and a group having a particle size of 150 μm or more and less than 300 μm,
A combination of a group of particle sizes of 45 μm or more and less than 75 μm with a group of particle sizes of 75 μm or more and less than 150 μm, and
A combination of a group having a particle size of 45 μm or more and less than 75 μm and a group having a particle size of 150 μm or more and less than 300 μm.
以上のことから、TeCPの互いに異なる粒径を有する２つの群としては、ふるいにより分級された、粒径が45μm未満の比較的小さい粒子の群、粒径が45μm以上且つ75μm未満の比較的中程度の粒子の群、および粒径が75μm以上且つ300μm未満の比較的大きい粒子の群から選択される２つの群を組み合わせれば、良好な圧縮強度の硬化体となる自己硬化型リン酸カルシウム組成物が得られると考えられる。 Based on the above, two groups of TeCP having different particle sizes are classified as a group of relatively small particles classified by a sieve and having a particle size of less than 45 μm, and a relatively medium particle size of 45 μm or more and less than 75 μm. A self-curing calcium phosphate composition that provides a cured product with good compressive strength by combining two groups selected from a group of particles having a size and a group of relatively large particles having a particle size of 75 μm or more and less than 300 μm. It is thought that it is obtained.
＜実施例２＞
本実施例では、硬化体が多孔化するか否かを生理食塩水中で試験した。
<Example 2>
In this example, it was tested in physiological saline to determine whether the cured body was porous.
(１)材料
・TeCPおよびDCPD
TeCPおよびDCPDは、実施例１と同様にして得られたものを用いた。なお、TeCPの粉体として、75μm未満の粒径の群を用いた。
(1) Materials, TeCP and DCPD
TeCP and DCPD obtained in the same manner as in Example 1 were used. In addition, a group having a particle size of less than 75 μm was used as TeCP powder.
・硬化液
硬化液として、リンゴ酸(和光純薬工業株式会社)を10重量％、およびキトサン(平均分子量190,000〜310,000、脱アセチル化度約78.8％、ARDRICH Chemistry社)を10重量％含む水溶液を用いた。また、陰性対照として、キトサンを含まない硬化液(10重量％リンゴ酸水溶液)を用いた。
・ Curing solution As the curing solution, an aqueous solution containing 10% by weight of malic acid (Wako Pure Chemical Industries, Ltd.) and 10% by weight of chitosan (average molecular weight 190,000-310,000, degree of deacetylation about 78.8%, ARDICRH Chemistry) Using. Further, as a negative control, a curable liquid containing no chitosan (10% by weight aqueous malic acid solution) was used.
(２)自己硬化型リン酸カルシウム組成物および硬化体の調製
実施例１と同様にして、TeCPおよびDCPDからセメント粉を調製した。得られたセメント粉と上記の硬化液とを用いて、粉液比(粉(g)/液(g))が３となるように90秒間混和して、自己硬化型リン酸カルシウム組成物(リンゴ酸2.5重量％、キトサン2.5重量％含有)を得た。この組成物をテフロン製型枠(内径10 mm、高さ２mm)に注入し、37℃、湿度100％の環境下で１時間静置して、初期硬化体を得た。
(2) Preparation of self-curing calcium phosphate composition and cured body Cement powder was prepared from TeCP and DCPD in the same manner as in Example 1. Using the obtained cement powder and the above-mentioned hardening liquid, the mixture is mixed for 90 seconds so that the powder-liquid ratio (powder (g) / liquid (g)) is 3, and the self-hardening calcium phosphate composition (malic acid 2.5% by weight and 2.5% by weight of chitosan). This composition was poured into a Teflon mold (inner diameter 10 mm, height 2 mm) and allowed to stand in an environment of 37 ° C. and 100% humidity for 1 hour to obtain an initial cured product.
(３)試料の分析
得られた硬化体を生理食塩水(37℃)に浸漬して、該硬化体から生理食塩水中に溶出したカルシウムイオンの量を、浸漬後300分まで経時的に測定した。より具体的には、浸漬後60分までは５分おきに測定し、浸漬後60分から150分までは15分おきに測定し、浸漬後150分から300分までは30分おきに測定した。なお、測定には、カルシウムイオン電極(Metrohm社製)を用いた。結果を図１に示す。また、生理食塩水に浸漬して１日後および７日後に、硬化体を電界放出型走査型電子顕微鏡JSM-6500F(日本電子株式会社製)で観察した。得られた電子顕微鏡写真を図２ＡおよびＢに示す。
(3) Analysis of sample The obtained cured body was immersed in physiological saline (37 ° C), and the amount of calcium ions eluted from the cured body into physiological saline was measured over time until 300 minutes after immersion. . More specifically, measurement was performed every 5 minutes up to 60 minutes after immersion, measurement was performed every 15 minutes from 60 minutes to 150 minutes after immersion, and measurement was performed every 30 minutes from 150 minutes to 300 minutes after immersion. For the measurement, a calcium ion electrode (manufactured by Metrohm) was used. The results are shown in FIG. The cured product was observed with a field emission scanning electron microscope JSM-6500F (manufactured by JEOL Ltd.) 1 day and 7 days after immersion in physiological saline. The obtained electron micrographs are shown in FIGS.
(４)結果および考察
図１より、生理食塩水中のカルシウムイオン濃度、すなわち硬化体からのカルシウム溶出量は、時間経過に従って、キトサンを含まない硬化液を用いて得た硬化体の方が、キトサンを含む硬化液を用いて得た硬化体よりも高くなっていくことがわかった。他方で、各硬化体の浸漬前後の重量を測定して、重量減少量(浸漬前の重量−浸漬後の重量)を算出したところ、キトサンを含む硬化液を用いて得た硬化体の重量減少量の方が、キトサンを含まない硬化液を用いて得た硬化体の重量減少量よりも大きかった。これらのことから、キトサンを含む硬化液を用いて得た硬化体では、生理食塩水中でキトサンが優先的に溶出していることが示唆される。また、図２ＡおよびＢの電子顕微鏡写真より、キトサンを含む硬化液を用いて得た硬化体は、生理食塩水中で多孔化していることが示された。
(4) Results and Consideration From FIG. 1, the calcium ion concentration in physiological saline, that is, the amount of calcium elution from the cured body, shows that the cured body obtained by using a hardening liquid not containing chitosan is more chitosan over time. It turned out that it becomes higher than the hardening body obtained using the hardening liquid containing this. On the other hand, when the weight before and after immersion of each cured body was measured and the weight reduction amount (weight before immersion-weight after immersion) was calculated, the weight reduction of the cured body obtained using the curing liquid containing chitosan The amount was larger than the weight reduction amount of the cured product obtained using the curable liquid containing no chitosan. From these facts, it is suggested that chitosan is preferentially eluted in physiological saline in a cured product obtained using a curable liquid containing chitosan. Moreover, from the electron micrographs of FIGS. 2A and B, it was shown that the cured product obtained using the curable liquid containing chitosan was porous in physiological saline.
＜実施例３＞
本実施例では、硬化液中のリンゴ酸濃度と、硬化時間との関連を検討した。
<Example 3>
In this example, the relationship between the malic acid concentration in the curable liquid and the curing time was examined.
(１)材料
・TeCPおよびDCPD
TeCPおよびDCPDは、実施例１と同様にして得られたものを用いた。なお、TeCPの粉体として、75μm未満の粒径の群を用いた。
(1) Materials, TeCP and DCPD
TeCP and DCPD obtained in the same manner as in Example 1 were used. In addition, a group having a particle size of less than 75 μm was used as TeCP powder.
・硬化液
硬化液として、リンゴ酸を４、６、８、10または12重量％、およびキトサン(平均分子量50,000〜190,000、脱アセチル化度約81.3％、ARDRICH Chemistry社)を10重量％含む水溶液を用いた。なお、本実施例では、リンゴ酸濃度が２重量％の硬化液の調製も試みたが、この濃度のリンゴ酸水溶液ではキトサンを溶解させることができかった。
・ Curing solution As the curing solution, an aqueous solution containing 4, 6, 8, 10 or 12% by weight of malic acid and 10% by weight of chitosan (average molecular weight 50,000 to 190,000, deacetylation degree: 81.3%, ARDICRH Chemistry) Using. In this example, preparation of a hardened solution having a malic acid concentration of 2% by weight was also attempted, but chitosan could not be dissolved with an aqueous malic acid solution having this concentration.
(２)自己硬化型リン酸カルシウム組成物および硬化体の調製
実施例１と同様にして、TeCPおよびDCPDからセメント粉を調製した。得られたセメント粉に各硬化液を、粉液比(粉(g)/液(g))が３となるように添加した。ここで、リンゴ酸を４〜10重量％で含む硬化液を用いた場合は、セメント粉と70秒間混和して自己硬化型リン酸カルシウム組成物が得られた。しかし、リンゴ酸を12重量％で含む硬化液を用いた場合は、硬化時間が極めて短かったため混和することができなかった。以降、リンゴ酸を1.0〜10重量％で含む組成物を試料として、硬化時間の測定に付した。
(2) Preparation of self-curing calcium phosphate composition and cured body Cement powder was prepared from TeCP and DCPD in the same manner as in Example 1. Each hardening liquid was added to the obtained cement powder so that a powder-liquid ratio (powder (g) / liquid (g)) might be set to 3. Here, when a hardening liquid containing malic acid at 4 to 10% by weight was used, a self-setting calcium phosphate composition was obtained by mixing with cement powder for 70 seconds. However, when a curing solution containing 12% by weight of malic acid was used, the curing time was extremely short, so that mixing was impossible. Thereafter, the composition containing 1.0 to 10% by weight of malic acid was used as a sample and subjected to measurement of the curing time.
(３)硬化時間の測定
混和開始から90秒以内に、各試料をテフロン型(内径10 mm、高さ５mm)に入れた。そして、混和開始の２分後から30秒おきにビカー針試験機(株式会社日本メック製)の針(300 g、先端断面積２mm2)を試料表面に落とし、該表面に圧痕が残らなくなるまでの時間を記録した。なお、ビカー針試験機による試験時以外は、各試料を、水を含んだスポンジを底部に備えた密閉容器内に37℃で保管した。本実施例では、密閉容器内の湿度を100％とみなした。測定は各試料について３回ずつ行い、測定値(分)に基づいて硬化時間の平均値および標準誤差を算出した。結果を表２に示す。
(3) Measurement of curing time Within 90 seconds from the start of mixing, each sample was placed in a Teflon mold (inner diameter 10 mm, height 5 mm). Then, after 30 minutes from the start of mixing, the needle (300 g, tip cross-sectional area 2 mm 2 ) of the Vicat needle tester (manufactured by Nippon Mec Co., Ltd.) is dropped on the sample surface until no indentation remains on the surface. The time was recorded. In addition, except at the time of the test by a Vicat needle tester, each sample was stored at 37 ° C. in a closed container equipped with a sponge containing water at the bottom. In this example, the humidity in the sealed container was regarded as 100%. The measurement was performed three times for each sample, and the average value and standard error of the curing time were calculated based on the measured value (minute). The results are shown in Table 2.
(４)結果および考察
表２より、硬化時間は、硬化液に含まれるリンゴ酸濃度が増加するにつれて短くなる傾向を示した。臨床現場では、CPCを用いる場合、一般に５分程度の操作時間を要するとされていることから、本発明の組成物に含まれるリンゴ酸濃度としては、1.0〜2.0重量％の範囲内が特に好ましいと考えられる。
(4) Results and Discussion From Table 2, the curing time tended to be shorter as the concentration of malic acid contained in the curable liquid increased. In clinical practice, when CPC is used, it is generally considered that an operation time of about 5 minutes is required. Therefore, the malic acid concentration contained in the composition of the present invention is particularly preferably in the range of 1.0 to 2.0% by weight. it is conceivable that.
Claims (9)
前記リン酸四カルシウムの２つの群が、分級により得られた、300μm未満の粒径を有する少なくとも３つの群から選択されたものである、
自己硬化型リン酸カルシウム組成物。 Two groups of tetracalcium phosphate having different particle sizes, calcium hydrogen phosphate dihydrate, chitosan, and malic acid aqueous solution as a hardening solution are mixed.
The two groups of tetracalcium phosphate are selected from at least three groups obtained by classification and having a particle size of less than 300 μm;
Self-curing calcium phosphate composition.
前記75μm以上且つ300μm未満の粒径の群が、75μm以上且つ150μm未満の粒径の群および150μm以上且つ300μm未満の粒径の群のいずれか１つである
請求項２に記載の自己硬化型リン酸カルシウム組成物。 The group having a particle size of less than 45 μm is one of a group of particle sizes of less than 25 μm and a group of particle sizes of 25 μm or more and less than 45 μm;
3. The self-curing type according to claim 2, wherein the group having a particle diameter of 75 μm or more and less than 300 μm is one of a group of particle diameters of 75 μm or more and less than 150 μm and a group of particle diameters of 150 μm or more and less than 300 μm. Calcium phosphate composition.
前記リン酸四カルシウムの２つの群が、分級により得られた、300μm未満の粒径を有する少なくとも３つの群から選択されたものである、
自己硬化型リン酸カルシウム組成物を製造するためのキット。 A powder comprising two groups of tetracalcium phosphate having different particle sizes and calcium hydrogen phosphate dihydrate, and a hardening liquid comprising chitosan and malic acid,
The two groups of tetracalcium phosphate are selected from at least three groups obtained by classification and having a particle size of less than 300 μm;
A kit for producing a self-curing calcium phosphate composition.
前記リン酸四カルシウムの２つの群が、分級により得られた、300μm未満の粒径を有する少なくとも３つの群から選択されたものである、
自己硬化型リン酸カルシウム組成物の製造方法。 Mixing two groups of tetracalcium phosphate having different particle sizes, calcium hydrogen phosphate dihydrate, chitosan, and malic acid aqueous solution as a hardening solution,
The two groups of tetracalcium phosphate are selected from at least three groups obtained by classification and having a particle size of less than 300 μm;
A method for producing a self-curing calcium phosphate composition.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2018038590A (en) * | 2016-09-07 | 2018-03-15 | 公立大学法人大阪市立大学 | Bioactive cement paste and kit for producing bioactive cement, bioactive cement paste and production method thereof |
| CN117122733A (en) * | 2023-04-28 | 2023-11-28 | 鹏拓生物科技(杭州)有限公司 | High-strength quick-curing phosphate bone cement and preparation method thereof |
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| JPH0277261A (en) * | 1987-12-28 | 1990-03-16 | Asahi Optical Co Ltd | Composite composition for producing cured body of calcium phosphate system and production of cured body |
| JPH05168692A (en) * | 1991-06-26 | 1993-07-02 | Nitta Gelatin Inc | Curable material for restoration of hard biotissue |
| JPH06321515A (en) * | 1993-05-18 | 1994-11-22 | Osaka Cement Co Ltd | High-strength hardenable material |
| JP2003524635A (en) * | 1999-12-23 | 2003-08-19 | アイヴリア インコーポレイテッド | Chitosan biopolymer for topical delivery of active agents |
| JP2008136603A (en) * | 2006-11-30 | 2008-06-19 | Kuraray Medical Inc | Calcium phosphate composition and its application |
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Patent Citations (5)
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|---|---|---|---|---|
| JPH0277261A (en) * | 1987-12-28 | 1990-03-16 | Asahi Optical Co Ltd | Composite composition for producing cured body of calcium phosphate system and production of cured body |
| JPH05168692A (en) * | 1991-06-26 | 1993-07-02 | Nitta Gelatin Inc | Curable material for restoration of hard biotissue |
| JPH06321515A (en) * | 1993-05-18 | 1994-11-22 | Osaka Cement Co Ltd | High-strength hardenable material |
| JP2003524635A (en) * | 1999-12-23 | 2003-08-19 | アイヴリア インコーポレイテッド | Chitosan biopolymer for topical delivery of active agents |
| JP2008136603A (en) * | 2006-11-30 | 2008-06-19 | Kuraray Medical Inc | Calcium phosphate composition and its application |
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| 公益社団法人日本セラミックス協会２０１３年年会講演予稿集, JPN6018005092, 2013, pages 2J05 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2018038590A (en) * | 2016-09-07 | 2018-03-15 | 公立大学法人大阪市立大学 | Bioactive cement paste and kit for producing bioactive cement, bioactive cement paste and production method thereof |
| CN117122733A (en) * | 2023-04-28 | 2023-11-28 | 鹏拓生物科技(杭州)有限公司 | High-strength quick-curing phosphate bone cement and preparation method thereof |
| CN117122733B (en) * | 2023-04-28 | 2024-05-17 | 鹏拓生物科技(杭州)有限公司 | High-strength quick-curing phosphate bone cement and preparation method thereof |
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