JP4465465B2 - Spherical biodegradable polymer / ceramic composite having porous structure inside and method for producing the same - Google Patents
Spherical biodegradable polymer / ceramic composite having porous structure inside and method for producing the same Download PDFInfo
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- JP4465465B2 JP4465465B2 JP2004101820A JP2004101820A JP4465465B2 JP 4465465 B2 JP4465465 B2 JP 4465465B2 JP 2004101820 A JP2004101820 A JP 2004101820A JP 2004101820 A JP2004101820 A JP 2004101820A JP 4465465 B2 JP4465465 B2 JP 4465465B2
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- 229920002988 biodegradable polymer Polymers 0.000 title claims description 79
- 239000004621 biodegradable polymer Substances 0.000 title claims description 79
- 239000002131 composite material Substances 0.000 title claims description 47
- 239000000919 ceramic Substances 0.000 title claims description 42
- 238000004519 manufacturing process Methods 0.000 title claims description 18
- 239000000243 solution Substances 0.000 claims description 27
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 claims description 20
- 229910001424 calcium ion Inorganic materials 0.000 claims description 20
- 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 claims description 20
- 239000011148 porous material Substances 0.000 claims description 17
- 239000002904 solvent Substances 0.000 claims description 16
- 239000003814 drug Substances 0.000 claims description 15
- 238000000034 method Methods 0.000 claims description 15
- 229940079593 drug Drugs 0.000 claims description 14
- 229920000747 poly(lactic acid) Polymers 0.000 claims description 14
- 239000004626 polylactic acid Substances 0.000 claims description 14
- 239000000839 emulsion Substances 0.000 claims description 13
- 125000000524 functional group Chemical group 0.000 claims description 13
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 12
- 239000000945 filler Substances 0.000 claims description 11
- 239000011259 mixed solution Substances 0.000 claims description 10
- 239000003995 emulsifying agent Substances 0.000 claims description 6
- 229920001577 copolymer Polymers 0.000 claims description 5
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical group [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 4
- 230000010478 bone regeneration Effects 0.000 claims description 4
- 239000007788 liquid Substances 0.000 claims description 4
- 125000000129 anionic group Chemical group 0.000 claims description 3
- 229920000954 Polyglycolide Polymers 0.000 claims description 2
- 230000032683 aging Effects 0.000 claims description 2
- 239000011575 calcium Substances 0.000 claims description 2
- 229920006237 degradable polymer Polymers 0.000 claims description 2
- 230000006911 nucleation Effects 0.000 claims description 2
- 238000010899 nucleation Methods 0.000 claims description 2
- 125000004437 phosphorous atom Chemical group 0.000 claims description 2
- 239000004633 polyglycolic acid Substances 0.000 claims description 2
- 210000001519 tissue Anatomy 0.000 claims description 2
- 238000003756 stirring Methods 0.000 description 32
- 210000000988 bone and bone Anatomy 0.000 description 29
- 239000007864 aqueous solution Substances 0.000 description 28
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 24
- 239000001506 calcium phosphate Substances 0.000 description 18
- 229910000389 calcium phosphate Inorganic materials 0.000 description 18
- 235000011010 calcium phosphates Nutrition 0.000 description 18
- 239000004068 calcium phosphate ceramic Substances 0.000 description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 14
- 239000000843 powder Substances 0.000 description 10
- 239000012071 phase Substances 0.000 description 9
- 239000012153 distilled water Substances 0.000 description 8
- 239000000047 product Substances 0.000 description 7
- MNNHAPBLZZVQHP-UHFFFAOYSA-N diammonium hydrogen phosphate Chemical compound [NH4+].[NH4+].OP([O-])([O-])=O MNNHAPBLZZVQHP-UHFFFAOYSA-N 0.000 description 6
- 229910000388 diammonium phosphate Inorganic materials 0.000 description 6
- 235000019838 diammonium phosphate Nutrition 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- 239000004094 surface-active agent Substances 0.000 description 6
- VSGNNIFQASZAOI-UHFFFAOYSA-L calcium acetate Chemical compound [Ca+2].CC([O-])=O.CC([O-])=O VSGNNIFQASZAOI-UHFFFAOYSA-L 0.000 description 5
- 239000001639 calcium acetate Substances 0.000 description 5
- 235000011092 calcium acetate Nutrition 0.000 description 5
- 229960005147 calcium acetate Drugs 0.000 description 5
- 238000004108 freeze drying Methods 0.000 description 5
- 238000011049 filling Methods 0.000 description 4
- 239000008247 solid mixture Substances 0.000 description 4
- 208000001132 Osteoporosis Diseases 0.000 description 3
- 229910052586 apatite Inorganic materials 0.000 description 3
- 239000008346 aqueous phase Substances 0.000 description 3
- 239000012237 artificial material Substances 0.000 description 3
- 230000017531 blood circulation Effects 0.000 description 3
- 238000004113 cell culture Methods 0.000 description 3
- 230000007547 defect Effects 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 230000009545 invasion Effects 0.000 description 3
- 229910052751 metal Inorganic materials 0.000 description 3
- 239000002184 metal Substances 0.000 description 3
- 239000002245 particle Substances 0.000 description 3
- VSIIXMUUUJUKCM-UHFFFAOYSA-D pentacalcium;fluoride;triphosphate Chemical compound [F-].[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 VSIIXMUUUJUKCM-UHFFFAOYSA-D 0.000 description 3
- 229920000642 polymer Polymers 0.000 description 3
- 238000000634 powder X-ray diffraction Methods 0.000 description 3
- 238000001556 precipitation Methods 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 210000002805 bone matrix Anatomy 0.000 description 2
- 239000004568 cement Substances 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 230000007423 decrease Effects 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 238000005304 joining Methods 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 2
- WHQOKFZWSDOTQP-UHFFFAOYSA-N 2,3-dihydroxypropyl 4-aminobenzoate Chemical compound NC1=CC=C(C(=O)OCC(O)CO)C=C1 WHQOKFZWSDOTQP-UHFFFAOYSA-N 0.000 description 1
- 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 1
- 208000006386 Bone Resorption Diseases 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- 206010007269 Carcinogenicity Diseases 0.000 description 1
- 229920000742 Cotton Polymers 0.000 description 1
- 229930012538 Paclitaxel Natural products 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 230000000172 allergic effect Effects 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- LFVGISIMTYGQHF-UHFFFAOYSA-N ammonium dihydrogen phosphate Chemical compound [NH4+].OP(O)([O-])=O LFVGISIMTYGQHF-UHFFFAOYSA-N 0.000 description 1
- 229910000387 ammonium dihydrogen phosphate Inorganic materials 0.000 description 1
- 229940035676 analgesics Drugs 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000000730 antalgic agent Substances 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 229940124599 anti-inflammatory drug Drugs 0.000 description 1
- 229940124350 antibacterial drug Drugs 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 208000010668 atopic eczema Diseases 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 230000024279 bone resorption Effects 0.000 description 1
- 239000000316 bone substitute Substances 0.000 description 1
- 229910001622 calcium bromide Inorganic materials 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- WGEFECGEFUFIQW-UHFFFAOYSA-L calcium dibromide Chemical compound [Ca+2].[Br-].[Br-] WGEFECGEFUFIQW-UHFFFAOYSA-L 0.000 description 1
- OSILKTNFXJYZTB-UHFFFAOYSA-L calcium;dichlorate;dihydrate Chemical compound O.O.[Ca+2].[O-]Cl(=O)=O.[O-]Cl(=O)=O OSILKTNFXJYZTB-UHFFFAOYSA-L 0.000 description 1
- YMIFCOGYMQTQBP-UHFFFAOYSA-L calcium;dichloride;hydrate Chemical compound O.[Cl-].[Cl-].[Ca+2] YMIFCOGYMQTQBP-UHFFFAOYSA-L 0.000 description 1
- 230000007670 carcinogenicity Effects 0.000 description 1
- 231100000260 carcinogenicity Toxicity 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 238000004581 coalescence Methods 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000000835 fiber Substances 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000003094 microcapsule Substances 0.000 description 1
- 239000004005 microsphere Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 235000019837 monoammonium phosphate Nutrition 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 235000019796 monopotassium phosphate Nutrition 0.000 description 1
- 239000004745 nonwoven fabric Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000011164 ossification Effects 0.000 description 1
- 229960001592 paclitaxel Drugs 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 229940085991 phosphate ion Drugs 0.000 description 1
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000001172 regenerating effect Effects 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- BBMHARZCALWXSL-UHFFFAOYSA-M sodium dihydrogenphosphate monohydrate Chemical compound O.[Na+].OP(O)([O-])=O BBMHARZCALWXSL-UHFFFAOYSA-M 0.000 description 1
- VBJGJHBYWREJQD-UHFFFAOYSA-M sodium;dihydrogen phosphate;dihydrate Chemical compound O.O.[Na+].OP(O)([O-])=O VBJGJHBYWREJQD-UHFFFAOYSA-M 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 1
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- Materials For Medical Uses (AREA)
Description
本発明は、内部に孔構造を有する球状生体内分解性高分子／セラミックス複合体及びその製造方法に関するものであり、更に詳しくは、骨充填剤として好適に利用することが可能な、内部に多孔構造を有する生体内分解性高分子とリン酸カルシウム系セラミックスとの結合体、その製造方法及びその応用製品に関するものである。本発明は、生体の骨再生医療の技術分野において、従来法による生体内分解性高分子とリン酸カルシウム系セラミックスとの複合体では、例えば、球状に加工すること及び多孔体にすることが困難であったこと、また、多孔状にする工程が複雑であったこと等の問題があり、その解決が求められていたことを踏まえ、それらの従来技術の問題点を確実に解消すると共に、内部に多孔構造を有する球状生体内分解性高分子／セラミックス複合体を効率良く製造することが可能な新規複合体の製造方法及びその製品を提供するものであり、例えば、骨再生を目的とした骨欠損部・骨折部補修用、骨粗鬆症に対する注入剤、金属製人工材料と骨母床間の間隙充填用の充填剤、ＤＤＳ担体、細胞培養担体等として好適な内部に孔構造を有する球状生体内分解性高分子／セラミックス複合体を効率よく製造し、提供するものとして有用である。 The present invention relates to a spherical biodegradable polymer / ceramic composite having a pore structure inside and a method for producing the same, and more specifically, the inside porous material which can be suitably used as a bone filler. The present invention relates to a combined body of a biodegradable polymer having a structure and a calcium phosphate ceramic, a production method thereof, and an applied product thereof. In the technical field of biological bone regenerative medicine, the present invention has been difficult to process into a spherical body and to form a porous body, for example, by a conventional biodegradable polymer-calcium phosphate ceramic composite. Moreover, based on the fact that the process of making the porous structure was complicated and the solution to that problem was sought, the problems of the conventional technology were surely solved, and the porous structure inside. A method for producing a novel composite capable of efficiently producing a spherical biodegradable polymer / ceramic composite having a structure and a product thereof, for example, a bone defect portion for the purpose of bone regeneration・ Spherical living body having pore structure inside suitable for fracture fracture repair, injection for osteoporosis, filler for filling gap between metal artificial material and bone matrix, DDS carrier, cell culture carrier, etc. The degradable polymer / ceramic composite efficiently produced, which is useful for providing.
従来より、リン酸カルシウム系セラミックスは、自家骨との接合を期待できる骨代替物として利用されている。リン酸カルシウム系セラミックスとして実用化されている製品の形状としては、例えば、緻密体、多孔体、自己硬化性セメントなどが多い。この中で、緻密体は、自家骨との置換がほとんど期待できず、生体内にセラミックスが異物として残存し、更に、周辺に存在する自家骨より機械的強度が高いために、自家骨を破壊したり、自家骨の吸収を促したりするという問題がある。また、自己硬化性セメントは、経皮的に注入することができ、低侵襲な手術法として注目されているが、血液存在下で硬化しにくいという欠点がある。 Conventionally, calcium phosphate ceramics have been used as a bone substitute that can be expected to be joined to autologous bone. Examples of the shape of products that are put into practical use as calcium phosphate ceramics include dense bodies, porous bodies, and self-curing cements. Among these, the compact body can hardly be expected to replace the autologous bone, ceramics remain as a foreign substance in the living body, and because the mechanical strength is higher than the autologous bone present in the surrounding area, the autologous bone is destroyed. Or promote resorption of autologous bone. Self-curing cement can be injected percutaneously and has attracted attention as a minimally invasive surgical method, but has a drawback that it is difficult to cure in the presence of blood.
更に、多孔体は、その孔に新生骨を侵入させることができるため、自家骨との接合に優れている上、血流を遮断しないので、骨の早期再生が可能であるという点で優れているが、リン酸カルシウム系セラミックスのみで作られた多孔体の場合、孔の存在により機械的強度が低いという問題がある。また、多孔体を骨充填剤として応用する際には、多孔体を不定形に砕いたものを充填することが多いが、この際にできる粉は、細胞毒性があるとされている。このため、リン酸カルシウム系セラミックスを骨充填剤として利用するためには、その形態は、球状の多孔体であることが好ましい。更に、生体内分解性高分子は、リン酸カルシウム系セラミックスとの複合体として生体内に埋入すると、分解吸収され、骨組織と置換されることが報告されているため、骨充填剤としては、生体内分解性高分子とリン酸カルシウム系セラミックスとの複合体が好ましい。 Furthermore, since the porous body can infiltrate new bone into its pores, it is excellent in joining with autologous bone, and it is excellent in that bone can be regenerated early because it does not block blood flow. However, in the case of a porous body made only of calcium phosphate ceramics, there is a problem that the mechanical strength is low due to the presence of pores. Further, when the porous body is applied as a bone filler, it is often filled with an irregularly pulverized porous body, and the powder produced at this time is considered to be cytotoxic. For this reason, in order to use calcium phosphate ceramics as a bone filler, the form is preferably a spherical porous body. Furthermore, biodegradable polymers have been reported to be decomposed and absorbed and replaced with bone tissue when implanted in vivo as a complex with calcium phosphate ceramics. A composite of a biodegradable polymer and a calcium phosphate ceramic is preferred.
骨充填剤やＤＤＳ担体として好適な材料としては、基本的には、内部に多孔構造を有すること、球状であること、リン酸カルシウムと生体内分解性高分子が強固に結合した複合体であること、及びリン酸カルシウムが球状表面に存在していること、があげられる。従来技術では、このようなリン酸カルシウム系セラミックスと生体内分解性高分子との複合体として、例えば、薬物とポリ乳酸とリン酸カルシウムとからなる骨内部埋め込み用製剤が提案されているが（特許文献１参照）、これは、ポリ乳酸とリン酸カルシウムの粉体を混合し、圧縮して得た成形体であり、この種の手法では、球状に加工すること及び多孔体にすることが困難である。 As a material suitable as a bone filler or DDS carrier, basically, it has a porous structure inside, is spherical, is a complex in which calcium phosphate and a biodegradable polymer are firmly bound, And the presence of calcium phosphate on the spherical surface. In the prior art, as a composite of such a calcium phosphate ceramic and a biodegradable polymer, for example, a preparation for implanting into bone comprising a drug, polylactic acid and calcium phosphate has been proposed (see Patent Document 1). This is a molded body obtained by mixing and compressing powders of polylactic acid and calcium phosphate, and it is difficult to process into a spherical shape and to make a porous body by this type of technique.
また、先行技術文献には、繊維状や不織布状、綿状のポリ乳酸とリン酸カルシウムとの複合型骨充填材が開示されているが（特許文献２参照）、この種の手法では、生体内でポリ乳酸が分解吸収された後に有効な気孔が形成されることになるため、ポリ乳酸分解前の充填初期には新生骨の侵入や血流の確保を許可しない。更に、他の先行技術文献には、生体内分解性ポリマーをイオン水溶液に浸漬して得られるアパタイト被覆固形組成物が開示されているが（特許文献３参照）、固形組成物を多孔体状にする手法は記載されていない上、その方法は、固形組成物を成形した後にアパタイトを被覆させるという２段階での製法であるため、被覆するアパタイトと固形組成物との結合力は弱いという問題がある。 Further, the prior art document discloses a composite bone filler of polylactic acid and calcium phosphate in the form of fibers, nonwoven fabrics, and cotton (see Patent Document 2). Since effective pores are formed after polylactic acid is decomposed and absorbed, invasion of new bone and securing of blood flow are not permitted at the initial filling stage before polylactic acid decomposition. Further, other prior art documents disclose an apatite-coated solid composition obtained by immersing a biodegradable polymer in an ionic aqueous solution (see Patent Document 3), but the solid composition is made into a porous body. In addition, the method is not described, and the method is a two-stage production method in which the apatite is coated after the solid composition is molded. Therefore, there is a problem that the bonding force between the apatite to be coated and the solid composition is weak. is there.
このような状況の中で、本発明者らは、上記従来技術に鑑みて、内部に多孔構造を有する球状生体内分解性高分子／セラミックス複合体を効率よく製造することが可能な新しい方法を確立することを目標として鋭意研究を積み重ねた結果、揮発性溶媒に溶解させた生体内分解性高分子を水中に入れた後に撹拌し、その後カルシウムイオンを含む溶液を加え、更に、リン酸イオンを含む溶液を滴下したものを熟成させ、その生成物を固−液分離することにより所期の目的を達成し得ることを見出し、更に研究を重ねて、本発明を完成した。 Under such circumstances, the present inventors, in view of the above prior art, have developed a new method capable of efficiently producing a spherical biodegradable polymer / ceramic composite having a porous structure inside. As a result of intensive research aimed at establishing, biodegradable polymer dissolved in volatile solvent was put in water and stirred, then solution containing calcium ion was added, and phosphate ion was further added It was found that the intended purpose could be achieved by aging the solution containing the added solution dropwise and subjecting the product to solid-liquid separation, and further research was completed to complete the present invention.
本発明は、内部に多孔構造を有する球状生体内分解性高分子／セラミックス複合体を効率よく製造する方法を提供することを目的とするものである。
また、本発明は、骨充填剤やＤＤＳ担体として有用な内部に多孔構造を有する球状生体内分解性高分子／セラミックス複合体を提供することを目的とするものである。
An object of the present invention is to provide a method for efficiently producing a spherical biodegradable polymer / ceramic composite having a porous structure therein.
Another object of the present invention is to provide a spherical biodegradable polymer / ceramic composite having a porous structure inside which is useful as a bone filler or a DDS carrier.
上記課題を解決するための本発明は、揮発性溶媒に溶解させた生体内分解性高分子を水中に入れた後に撹拌し、その後カルシウムイオンを含む溶液を加え、更に、リン酸イオンを含む溶液を滴下したものを熟成させ、その生成物を固−液分離することを特徴とする内部に多孔構造を有する球状生体内分解性高分子／セラミックス複合体の製造方法である。 In order to solve the above problems, the present invention provides a biodegradable polymer dissolved in a volatile solvent, which is then stirred, and then added with a solution containing calcium ions, and further a solution containing phosphate ions Is a method for producing a spherical biodegradable polymer / ceramic composite having a porous structure inside, wherein the product is aged and the product is solid-liquid separated.
また、本発明は、生体内分解性高分子が、難水溶性揮発性溶媒に溶解し、末端官能基もしくは側鎖官能基の少なくともどちらか一方がアニオン性の官能基である高分子の１種又は２種以上であること、及び混合溶液中のカルシウム原子の濃度が、２×１０-4ｍｏｌ／ｌ〜８×１０-2ｍｏｌ／ｌであることを望ましい様態としてもいる。
また、本発明は、上記方法により製造された、内部に多孔構造を有する球状生体内分解性高分子／セラミックス複合体である。
The present invention also provides a biodegradable polymer that is dissolved in a poorly water-soluble volatile solvent and at least one of a terminal functional group or a side chain functional group is an anionic functional group. Alternatively, it is desirable that the number of calcium atoms in the mixed solution is 2 × 10 −4 mol / l to 8 × 10 −2 mol / l.
In addition, the present invention is a spherical biodegradable polymer / ceramic composite produced by the above method and having a porous structure inside.
本発明では、先ず、生体内分解性高分子を揮発性溶媒を用いて溶解させる。この際、原料として用いられる生体内分解性高分子としては、例えば、ジクロロメタン、四塩化炭素、クロロホルム、などの難水溶性揮発性溶媒に溶解し、末端官能基もしくは側鎖官能基の少なくともどちらか一方がアニオン性の官能基である高分子が例示される。これらの高分子としては、ポリ乳酸、乳酸−グリコール酸共重合体、ポリグリコール酸が使用される。これらの高分子は、１種類だけではなく、２種類以上を組み合わせて用いることもできる。次に、揮発性溶媒は、難水溶性かつ１００℃以下の沸点の有機溶媒であれば特に限定されるものではないが、特に、生体内分解性ポリマーとして、ポリ乳酸もしくは乳酸−グリコール酸共重合体を用いる場合には、ジクロロメタンが好ましい。更に、薬物を生体内分解性高分子内部に担持させる場合には、好適には、例えば、生体内分解性高分子を揮発性溶媒に溶解する際に薬物を添加する。薬物は、難水溶性のものを用いることが好ましい。薬物の種類としては、例えば、骨形成促進作用物質、骨吸収抑制作用物質、抗腫瘍薬、抗生物質、抗菌薬、抗炎症薬、及び鎮痛剤などを好ましいものとしてあげることができる。 In the present invention, first, the biodegradable polymer is dissolved using a volatile solvent. In this case, the biodegradable polymer used as a raw material is, for example, dissolved in a poorly water-soluble volatile solvent such as dichloromethane, carbon tetrachloride, chloroform, and at least one of a terminal functional group and a side chain functional group. Examples are polymers in which one is an anionic functional group. These polymers, polylactic acid, lactic acid - glycolic acid copolymer, polyglycolic acid is used. These polymers can be used alone or in combination of two or more. Next, the volatile solvent is not particularly limited as long as it is a poorly water-soluble organic solvent having a boiling point of 100 ° C. or lower, and in particular, as a biodegradable polymer, polylactic acid or lactic acid-glycolic acid copolymer is used. When a coalescence is used, dichloromethane is preferred. Further, when the drug is carried inside the biodegradable polymer, the drug is preferably added when, for example, the biodegradable polymer is dissolved in a volatile solvent. It is preferable to use a poorly water-soluble drug. Preferred examples of the drug include bone formation promoting substances, bone resorption inhibiting substances, antitumor drugs, antibiotics, antibacterial drugs, anti-inflammatory drugs, and analgesics.
次に、球状生体内分解性高分子懸濁液の調製方法について説明する。即ち、前述の生体内分解性高分子を揮発性溶媒中で溶解し、これを蒸留水中に加え、撹拌し、Ｏ／Ｗ型エマルションを形成させる。この撹拌は、例えば、プロペラ型撹拌機、マグネティックスターラーやホモジナイザーなどで容易に行うことができる。この際の水相の体積は、油相の体積の１倍以上から選ばれる。更に、好ましくは、約２倍から約５０００倍から選ばれる。このとき、多くの製法では、エマルションを安定させるために、界面活性剤や乳化剤を添加するが、本発明の製法では、界面活性剤や乳化剤などは使用しない。界面活性剤や乳化剤を用いる製法で得られるマイクロスフェアやマイクロカプセルでは、最終製品にも界面活性剤や乳化剤が残留することが指摘されており、それによるアレルギー症状の誘発やガン原性の疑いが報告されている。本発明の製法は、エマルジョンに添加するカルシウムイオンを含む水溶液及びリン酸イオンを含む水溶液の存在によって、界面活性剤や乳化剤を用いることなく、エマルションを安定させるため、界面活性剤や乳化剤の残留の可能性をまったく排除できることが特徴である。蒸留水中での撹拌時間は、油相が十分に分散し、且つ生体内分解性高分子が揮発性溶媒中で流動可能な状態であれば良く、撹拌方法、撹拌速度や撹拌容器の大きさによって異なるため特に限定されるものではないが、０．１分から１００分の間が好ましい。 Next, a method for preparing a spherical biodegradable polymer suspension will be described. That is, the aforementioned biodegradable polymer is dissolved in a volatile solvent, and this is added to distilled water and stirred to form an O / W emulsion. This stirring can be easily performed with, for example, a propeller type stirrer, a magnetic stirrer, a homogenizer, or the like. The volume of the aqueous phase at this time is selected from one or more times the volume of the oil phase. Furthermore, it is preferably selected from about 2 times to about 5000 times. At this time, in many production methods, a surfactant or an emulsifier is added to stabilize the emulsion, but in the production method of the present invention, a surfactant or an emulsifier is not used. It has been pointed out that surfactants and emulsifiers remain in the final product of microspheres and microcapsules obtained by the production method using surfactants and emulsifiers, which may cause allergic symptoms and suspected carcinogenicity. It has been reported. In the production method of the present invention, the presence of an aqueous solution containing calcium ions and an aqueous solution containing phosphate ions added to the emulsion stabilizes the emulsion without using a surfactant or an emulsifier. The feature is that the possibility can be completely eliminated. The stirring time in distilled water is not limited as long as the oil phase is sufficiently dispersed and the biodegradable polymer can flow in the volatile solvent, and depends on the stirring method, the stirring speed, and the size of the stirring container. Since it differs, it is not particularly limited, but it is preferably between 0.1 minutes and 100 minutes.
このようにして得られたＯ／Ｗ型エマルションの撹拌を継続しながらカルシウムイオンを含む溶液を添加するが、このときＯ／Ｗ型エマルションの油相と水相の界面において、油相中に溶解している生体内分解性高分子の親水性官能基と水相中に含まれるカルシウムイオンが直接的に化学結合する。カルシウムイオンを含む溶液としては、例えば、硝酸カルシウム四水和物水溶液、塩化カルシウム水溶液、塩化カルシウム一水和物水溶液、塩素酸カルシウム二水和物水溶液、過塩素酸カルシウム水溶液、臭化カルシウム水溶液、及び酢酸カルシウム水溶液が好適なものとして例示されるが、これらに限らず、これらと同効のものであれば適宜のものが使用される。このカルシウムイオンを含む溶液の濃度は、Ｏ／Ｗ型エマルションと混合した後の混合溶液のカルシウムイオン濃度が２×１０-4ｍｏｌ／ｌ以上となるように調整する。これ以下のカルシウムイオン濃度では、Ｏ／Ｗ型エマルションの油相と水相の界面が安定せず、生体内分解性高分子同士が凝集して塊状になるか、もしくは生体内分解性高分子が撹拌機や撹拌容器に付着して収率が下がる。 A solution containing calcium ions is added while continuing stirring of the O / W emulsion thus obtained. At this time, the O / W emulsion dissolves in the oil phase at the interface between the oil phase and the water phase. The hydrophilic functional group of the biodegradable polymer is directly chemically bonded to the calcium ions contained in the aqueous phase. Examples of the solution containing calcium ions include calcium nitrate tetrahydrate aqueous solution, calcium chloride aqueous solution, calcium chloride monohydrate aqueous solution, calcium chlorate dihydrate aqueous solution, calcium perchlorate aqueous solution, calcium bromide aqueous solution, And calcium acetate aqueous solution are exemplified as suitable ones, but not limited thereto, and any suitable one may be used as long as it has the same effect as these. The concentration of the solution containing calcium ions is adjusted so that the calcium ion concentration of the mixed solution after mixing with the O / W emulsion is 2 × 10 −4 mol / l or more. When the calcium ion concentration is lower than this, the interface between the oil phase and the aqueous phase of the O / W emulsion is not stable, and the biodegradable polymers aggregate together to form a lump, or the biodegradable polymer The yield decreases due to adhesion to a stirrer and a stirring vessel.
更に、このカルシウムイオンを含むＯ／Ｗ型エマルションの撹拌を継続しながらリン酸イオンを含む溶液を滴下する。リン酸イオンを含む溶液を滴下することによって、生体内分解性高分子の親水性官能基と結合したカルシウムイオンを核生成サイトとしてリン酸カルシウムが析出し、この析出したリン酸カルシウムがＯ／Ｗエマルションを安定化する働きを有する。リン酸イオンを含む溶液を滴下する速度は特に限定されるものではないが、少量ずつ滴下することにより、生体内分解性高分子上へ均一にリン酸カルシウムを被覆させることができる。リン酸イオンを含む溶液は、滴下後に生じた溶液中のカルシウム原子のリン原子に対する原子比（Ｃａ／Ｐ比）が１．０〜２０となるように調製することが好ましい。リン酸イオンを含む溶液としては、例えば、リン酸水素二アンモニウム水溶液、リン酸二水素アンモニウム水溶液、リン酸水素二ナトリウム水溶液、リン酸二水素ナトリウム一水和物水溶液、リン酸二水素ナトリウム二水和物水溶液、リン酸カリウム水溶液、リン酸水素二カリウム水溶液、リン酸二水素カリウム水溶液、及びリン酸水溶液が好適なものとして例示されるが、これらに限らず、これらと同効のものであれば適宜のものが使用される。リン酸イオンを含む水溶液滴下後も撹拌を続けるが、この撹拌時間は、揮発性溶媒が完全に揮発されれば良く、特に限定されるものではないが、室温で常圧であれば１時間から７２時間が好ましく、更に、３時間から４８時間が好ましい。 Further, a solution containing phosphate ions is dropped while continuing stirring of the O / W type emulsion containing calcium ions. By dropping a solution containing phosphate ions, calcium phosphate is precipitated using calcium ions bound to the hydrophilic functional group of the biodegradable polymer as nucleation sites, and this precipitated calcium phosphate stabilizes the O / W emulsion. Has the function of The speed at which the solution containing phosphate ions is dropped is not particularly limited, but calcium phosphate can be uniformly coated on the biodegradable polymer by dropping little by little. The solution containing phosphate ions is preferably prepared such that the atomic ratio (Ca / P ratio) of calcium atoms to phosphorus atoms in the solution generated after the dropping is 1.0 to 20. Examples of the solution containing phosphate ions include diammonium hydrogen phosphate aqueous solution, ammonium dihydrogen phosphate aqueous solution, disodium hydrogen phosphate aqueous solution, sodium dihydrogen phosphate monohydrate aqueous solution, sodium dihydrogen phosphate diwater. Japanese aqueous solutions, potassium phosphate aqueous solutions, dipotassium hydrogen phosphate aqueous solutions, potassium dihydrogen phosphate aqueous solutions, and aqueous phosphoric acid aqueous solutions are exemplified as preferred ones, but not limited thereto, and those having the same effect as these. An appropriate one is used. Stirring is continued even after dropwise addition of the aqueous solution containing phosphate ions, and this stirring time is not particularly limited as long as the volatile solvent is completely volatilized. 72 hours are preferred, and further 3 to 48 hours are preferred.
最終的な球状生体内分解性高分子／セラミックス複合体の直径は、揮発性溶媒の量、生体内分解性高分子の量、水の量、カルシウムイオンを含む溶液の量、撹拌速度を変化させることにより、０．０５〜３０００μｍの範囲、典型的には０．１〜１０００μｍの範囲で容易に制御することができる。球状生体内分解性高分子／セラミックス複合体の大きさは、Ｏ／Ｗエマルションを調製する際の条件によって変化させることが可能であり、例えば、揮発性溶媒に対する水の量及びカルシウムイオンを含む溶液の量、撹拌速度、などが増加すると小さくなり、生体内分解性高分子の量などが増加すると大きくなる傾向がある。例えば、生体内分解性高分子を０．３６ｇ、揮発性溶媒を２０ｍｌ、水を３００ｍｌ、カルシウムイオンを含む溶液を１００ｍｌ、用いて、撹拌速度を毎分３００回転とした場合には、約３００μｍの大きさの球状生体内分解性高分子／セラミックス複合体が得られる。このように、揮発性溶媒を揮発させた後、混合溶液中の固形分を、濾過や遠心分離などの手段によって取り出し、乾燥処理することによって、内部に多孔構造を有する球状生体内分解性高分子／セラミックス複合体が得られる。 The diameter of the final spherical biodegradable polymer / ceramic composite varies the amount of volatile solvent, the amount of biodegradable polymer, the amount of water, the amount of solution containing calcium ions, and the stirring speed Therefore, it can be easily controlled in the range of 0.05 to 3000 μm, typically in the range of 0.1 to 1000 μm. The size of the spherical biodegradable polymer / ceramic composite can be changed depending on the conditions for preparing the O / W emulsion, for example, a solution containing water and calcium ions with respect to a volatile solvent. When the amount of agitation, the stirring speed, etc. increase, it decreases, and when the amount of biodegradable polymer increases, it tends to increase. For example, when the biodegradable polymer is 0.36 g, the volatile solvent is 20 ml, the water is 300 ml, the solution containing calcium ions is 100 ml, and the stirring speed is 300 revolutions per minute, about 300 μm A spherical biodegradable polymer / ceramic composite of a size is obtained. In this way, after volatilizing the volatile solvent, the solid content in the mixed solution is taken out by means such as filtration or centrifugation, and dried to give a spherical biodegradable polymer having a porous structure inside. / Ceramic composite is obtained.
本発明により、生体内分解性高分子の親水性官能基がカルシウムイオンと結合する作用によって、生体内分解性高分子の球状化と内部の多孔構造化、リン酸カルシウムの析出を同時に行うことが可能である。更に、リン酸カルシウムの析出によりＯ／Ｗ型エマルションの分散相が安定化し、界面活性剤フリーで球状に組織化した、内部に多孔構造を有する球状生体内分解性高分子／セラミックス複合体が得られる。カルシウムイオンを含む溶液を添加することにより、生体内分解性高分子内部に多孔構造を生じさせることから、生体内分解性高分子とカルシウムイオンとの結合が多孔構造に必要であると考えられる。ＳＥＭ観察では、球の表面に析出物の存在が確認され、分析の結果から、析出物は、低結晶性のリン酸カルシウムセラミックスであることがわかった。更に、球状複合体の破断面のＳＥＭ観察により、内部の多孔構造が球状組織によって構成された多孔構造であり、孔を形成する球の直径は、０．０１〜１０００μｍの範囲、典型的には０．０５〜５００μｍの範囲であり、気孔率は１０％以上であることがわかった。 According to the present invention, the biodegradable polymer can be spheroidized and porous inside, and calcium phosphate can be precipitated simultaneously by the action of the hydrophilic functional group of the biodegradable polymer binding to calcium ions. is there. Furthermore, the dispersed phase of the O / W emulsion is stabilized by the precipitation of calcium phosphate, and a spherical biodegradable polymer / ceramic composite having a porous structure inside and having a spherical structure with no surfactant is obtained. By adding a solution containing calcium ions, a porous structure is generated inside the biodegradable polymer. Therefore, it is considered that a bond between the biodegradable polymer and calcium ions is necessary for the porous structure. In SEM observation, the presence of precipitates was confirmed on the surface of the sphere, and the results of analysis revealed that the precipitates were low crystalline calcium phosphate ceramics. Further, by SEM observation of the fracture surface of the spherical composite, the inner porous structure is a porous structure constituted by a spherical structure, and the diameter of the sphere forming the pore is in the range of 0.01 to 1000 μm, typically It was in the range of 0.05 to 500 μm, and the porosity was found to be 10% or more.
本発明の、内部に多孔構造を有する球状生体内分解性高分子／セラミックス複合体は、球表面に存在するリン酸カルシウムセラミックスが自家骨と直接的に接合する能力を持ち、球内部に存在する孔が新生骨の侵入を可能にし、自家骨との接合を促進させる。更に、この複合体は、球状であることによって充填が容易な上、内部の生体内分解性高分子に薬物を保持させて生体内で薬物を徐放することができる。 The spherical biodegradable polymer / ceramics composite of the present invention having a porous structure inside has the ability of the calcium phosphate ceramics present on the sphere surface to directly join the autologous bone, and the pores present inside the sphere Allows new bones to invade and promotes joining with autologous bone. Furthermore, since this composite is spherical, it can be easily filled, and the drug can be gradually released in vivo by holding the drug in the internal biodegradable polymer.
本発明により、１）内部に多孔構造を有する球状生体内分解性高分子／セラミックス複合体が得られる、２）リン酸カルシウムの析出により分散相が安定化される、３）界面活性剤フリーで、球状に組織化された生体内分解性高分子／リン酸カルシウム複合体が得られる、４）リン酸カルシウムが表面に存在する球状生体内分解性高分子／セラミックス複合体を効率よく製造することができる、５）自家骨と直接結合する能力を有するリン酸カルシウムが表面に存在する内部に多孔構造を有する球状生体内分解性高分子／セラミックス複合体を製造することができる、６）本製法により得られた、内部に多孔構造を有する球状生体内分解性高分子／セラミックス複合体は、表面のリン酸カルシウムが自家骨と直接結合する能力をもち、内部の多孔構造は、血流や組織液の侵入を確保すると共に、細胞やタンパク質、新生骨の侵入を容易にし、また、生体内分解性高分子中に薬物を保持すれば薬物を徐々に放出するという利点を有するので、骨再生を目的とした骨欠損部・骨折部補修用、骨粗鬆症に対する注入剤、金属製人工材料と骨母床間の間隙充填用の充填剤、ＤＤＳ担体、細胞培養担体等として有用である、という格別の効果が奏される。 According to the present invention, 1) a spherical biodegradable polymer / ceramic composite having a porous structure is obtained, 2) the dispersed phase is stabilized by precipitation of calcium phosphate, and 3) a surfactant-free, spherical shape. To obtain a biodegradable polymer / calcium phosphate complex that is organized into 4), and 4) a spherical biodegradable polymer / ceramic complex in which calcium phosphate is present on the surface can be efficiently produced. A spherical biodegradable polymer / ceramics composite having a porous structure in the interior of which calcium phosphate having the ability to directly bind to bone exists on the surface can be produced. 6) Porous inside obtained by this production method Spherical biodegradable polymer / ceramic composites with the structure have the ability of the surface calcium phosphate to bind directly to the autologous bone, The pore structure ensures the invasion of blood flow and tissue fluid, facilitates the invasion of cells, proteins, and new bone, and has the advantage of gradually releasing the drug if it is retained in the biodegradable polymer It is useful as a bone defect / fracture repair for bone regeneration, an injection for osteoporosis, a filler for filling the gap between the metal artificial material and the bone matrix, a DDS carrier, a cell culture carrier, etc. This is an exceptional effect.
次に、実施例に基づいて本発明を具体的に説明するが、本発明は、以下の実施例によって何ら限定されるものではない。 EXAMPLES Next, although this invention is demonstrated concretely based on an Example, this invention is not limited at all by the following Examples.
２０ｍｌのジクロロメタンで溶解した分子量２０，０００のポリ乳酸０．３６ｇを、蒸留水３００ｍｌ中で毎分３００回転で３分間撹拌し、撹拌を続けながら０．０１３ｍｏｌ／ｌの酢酸カルシウム水溶液１００ｍｌ中を添加した。添加後１０分撹拌した後、更に、撹拌を続けながら得られた混合溶液に、０．００８ｍｏｌ／ｌのリン酸水素二アンモニウム水溶液１００ｍｌを滴下した。更に、２４時間撹拌を続けた後、ろ過後、凍結乾燥で乾燥した。 0.36 g of polylactic acid having a molecular weight of 20,000 dissolved in 20 ml of dichloromethane was stirred in 300 ml of distilled water at 300 rpm for 3 minutes, and added to 100 ml of 0.013 mol / l calcium acetate aqueous solution while continuing stirring. did. After stirring for 10 minutes after the addition, 100 ml of 0.008 mol / l diammonium hydrogen phosphate aqueous solution was added dropwise to the mixed solution obtained while continuing the stirring. Furthermore, stirring was continued for 24 hours, followed by filtration and lyophilization.
このようにして得られた粉体は、走査型電子顕微鏡と実体顕微鏡及び粉末Ｘ線回折の結果より、平均粒子径が約３００μｍの大きさで、内部に直径５〜２００μｍの孔が多数存在し、表面にリン酸カルシウムセラミックスが存在する球状生体内分解性高分子／セラミックス複合体であることがわかった。 The powder thus obtained has a mean particle diameter of about 300 μm and a large number of pores having a diameter of 5 to 200 μm inside from the results of scanning electron microscope, stereomicroscope and powder X-ray diffraction. It was found to be a spherical biodegradable polymer / ceramic composite with calcium phosphate ceramics on the surface.
２０ｍｌのジクロロメタンで溶解した、共重合体比７５：２５で、分子量２０，０００の乳酸−グリコール酸共重合体で分子量２０，０００のポリ乳酸０．３６ｇを、蒸留水３００ｍｌ中で毎分３００回転で３分間撹拌し、撹拌を続けながら０．０１７ｍｏｌ／ｌの酢酸カルシウム水溶液１００ｍｌを添加した。添加後１０分撹拌した後、更に、撹拌を続けながら得られた混合溶液に０．０１０ｍｏｌ／ｌのリン酸水素二アンモニウム水溶液１００ｍｌを滴下した。更に、２４時間撹拌を続けた後、ろ過後、凍結乾燥で乾燥した。 A lactic acid-glycolic acid copolymer having a copolymer ratio of 75:25, dissolved in 20 ml of dichloromethane, and having a molecular weight of 20,000, 0.36 g of polylactic acid having a molecular weight of 20,000 is 300 revolutions per minute in 300 ml of distilled water. For 3 minutes, and 100 ml of 0.017 mol / l calcium acetate aqueous solution was added while continuing the stirring. After the addition, the mixture was stirred for 10 minutes, and further, 100 ml of an aqueous 0.010 mol / l diammonium hydrogen phosphate solution was added dropwise to the resulting mixed solution while continuing stirring. Furthermore, stirring was continued for 24 hours, followed by filtration and lyophilization.
このようにして得られた粉体は、走査型電子顕微鏡と実体顕微鏡及び粉末Ｘ線回折の結果より、平均粒子径が約１００μｍの大きさで、内部に直径５〜１００μｍの孔が多数存在し、表面にリン酸カルシウムセラミックスが存在する球状生体内分解性高分子／セラミックス複合体であることがわかった。 The powder thus obtained has a mean particle size of about 100 μm and a large number of pores with a diameter of 5 to 100 μm in the result of scanning electron microscope, stereomicroscope and powder X-ray diffraction. It was found to be a spherical biodegradable polymer / ceramic composite with calcium phosphate ceramics on the surface.
２０ｍｌのジクロロメタンで溶解した分子量２０，０００のポリ乳酸０．１８ｇを、蒸留水３００ｍｌ中で毎分４００回転で２分間撹拌し、撹拌を続けながら０．００８ｍｏｌ／ｌの酢酸カルシウム水溶液１００ｍｌを添加した。添加後１０分撹拌した後、更に、撹拌を続けながら得られた混合溶液に、０．００５ｍｏｌ／ｌのリン酸水素二アンモニウム水溶液１００ｍｌを滴下した。更に、２４時間撹拌を続けた後、ろ過後、凍結乾燥で乾燥した。 0.18 g of polylactic acid having a molecular weight of 20,000 dissolved in 20 ml of dichloromethane was stirred at 300 rpm for 2 minutes in 300 ml of distilled water, and 100 ml of 0.008 mol / l calcium acetate aqueous solution was added while stirring was continued. . After stirring for 10 minutes after the addition, 100 ml of a 0.005 mol / l diammonium hydrogen phosphate aqueous solution was added dropwise to the obtained mixed solution while continuing stirring. Furthermore, stirring was continued for 24 hours, followed by filtration and lyophilization.
このようにして得られた粉体は、走査型電子顕微鏡と実体顕微鏡及び粉末Ｘ線回折の結果より、平均粒子径が約１００μｍの大きさで、内部に直径５〜２００μｍの孔が多数存在し、表面にリン酸カルシウムセラミックスが存在する球状生体内分解性高分子／セラミックス複合体であることがわかった。 The powder obtained in this manner has an average particle size of about 100 μm and a large number of pores with a diameter of 5 to 200 μm inside from the results of scanning electron microscope, stereomicroscope and powder X-ray diffraction. It was found to be a spherical biodegradable polymer / ceramic composite with calcium phosphate ceramics on the surface.
２０ｍｌのジクロロメタンで溶解した分子量２０，０００のポリ乳酸０．３６ｇと、パクリタキセル４０ｍｇを、蒸留水３００ｍｌ中で毎分３００回転で３分間撹拌し、撹拌を続けながら０．０１３ｍｏｌ／ｌの酢酸カルシウム水溶液１００ｍｌを添加した。添加後１０分撹拌した後、更に、撹拌を続けながら得られた混合溶液に、０．００８ｍｏｌ／ｌのリン酸水素二アンモニウム水溶液１００ｍｌを滴下した。更に、２４時間撹拌を続けた後、ろ過後、凍結乾燥で乾燥した。 0.36 g of polylactic acid having a molecular weight of 20,000 dissolved in 20 ml of dichloromethane and 40 mg of paclitaxel were stirred in 300 ml of distilled water at 300 rpm for 3 minutes, and 0.013 mol / l calcium acetate aqueous solution with continued stirring. 100 ml was added. After stirring for 10 minutes after the addition, 100 ml of 0.008 mol / l diammonium hydrogen phosphate aqueous solution was added dropwise to the mixed solution obtained while continuing the stirring. Furthermore, stirring was continued for 24 hours, followed by filtration and lyophilization.
このようにして得られた粉体２０ｍｇを、リン酸緩衝液（ｐＨ７．４）１５ｍｌ中に入れて密封し、３７℃の恒温槽で振とうした。振とう開始２時間後及び１、２、５日後に溶液の一部を採取し、高速液体クロマトグラフィーで薬物の放出量を定量した。図３は、薬物の放出量を時間に対するグラフにしたものであるが、これより、薬物が持続的に放出されていることがわかる。 20 mg of the powder thus obtained was put in 15 ml of a phosphate buffer (pH 7.4), sealed, and shaken in a 37 ° C. constant temperature bath. A part of the solution was collected 2 hours after the start of shaking and 1, 2, 5 days later, and the amount of drug released was quantified by high performance liquid chromatography. FIG. 3 is a graph showing the amount of drug released versus time, which shows that the drug is released continuously.
比較例１
２０ｍｌのジクロロメタンで溶解した分子量２０，０００のポリ乳酸０．３６ｇを、蒸留水５００ｍｌ中で毎分３００回転で２４時間撹拌を続けた。このような方法で調製した結果、生体内分解性高分子のほとんどは撹拌羽根やビーカーに付着し、粉体として有用な収量を得ることはできなかった。更に、得られたわずかな量の粉体を実体顕微鏡で観察した結果、内部に孔は存在しないことがわかった。
Comparative Example 1
0.36 g of polylactic acid having a molecular weight of 20,000 dissolved in 20 ml of dichloromethane was continuously stirred for 24 hours at 500 rpm in 500 ml of distilled water. As a result of the preparation by such a method, most of the biodegradable polymers adhered to the stirring blades and beakers, and a useful yield as a powder could not be obtained. Furthermore, as a result of observing a small amount of the obtained powder with a stereomicroscope, it was found that there were no pores inside.
比較例２
２０ｍｌのジクロロメタンで溶解した分子量２０，０００のポリ乳酸０．３６ｇを、蒸留水４００ｍｌ中で毎分３００回転で１０分撹拌した後、更に、撹拌を続けながら得られた混合溶液に０．００８ｍｏｌ／ｌのリン酸水素二アンモニウム水溶液１００ｍｌを滴下した。更に、２４時間撹拌を続けた後、ろ過後、凍結乾燥で乾燥した。
Comparative Example 2
After 0.36 g of polylactic acid having a molecular weight of 20,000 dissolved in 20 ml of dichloromethane was stirred in 400 ml of distilled water at 300 rpm for 10 minutes, 0.008 mol / mol was added to the resulting mixed solution while stirring was continued. 100 ml of 1 diammonium hydrogen phosphate aqueous solution was added dropwise. Furthermore, stirring was continued for 24 hours, followed by filtration and lyophilization.
このような方法で調製した結果、生体内分解性高分子のほとんどは撹拌羽根やビーカーに付着し、粉体として有用な収量を得ることはできなかった。更に、得られたわずかな量の粉体を実体顕微鏡で観察した結果、内部に孔は存在しないことがわかった。 As a result of the preparation by such a method, most of the biodegradable polymers adhered to the stirring blades and beakers, and a useful yield as a powder could not be obtained. Furthermore, as a result of observing a small amount of the obtained powder with a stereomicroscope, it was found that there were no pores inside.
本発明は、揮発性溶媒に溶解させた生体内分解性高分子を水中に入れた後に撹拌し、その後、カルシウムイオンを含む溶液を加え、更に、リン酸イオンを含む溶液を滴下したものを熟成させ、その生成物を固−液分離することを特徴とする内部に多孔構造を有する球状生体内分解性高分子／セラミックス複合体の製造方法及びその内部に多孔構造を有する球状生体内分解性高分子／セラミックス複合体に係るものであり、本発明により、内部に多孔構造を有する球状生体内分解性高分子／セラミックス複合体が得られる。リン酸カルシウムの析出により分散相が安定化される。界面活性剤フリーで、球状に組織化された生体内分解性高分子／リン酸カルシウム複合体が得られる。リン酸カルシウムが表面に存在する球状生体内分解性高分子／セラミックス複合体を効率よく製造することができる。自家骨と直接結合する能力を有するリン酸カルシウムが表面に存在する内部に多孔構造を有する球状生体内分解性高分子／セラミックス複合体を製造することができる。本発明で得られる内部に孔構造を有する球状生体内分解性高分子／セラミックス複合体は、例えば、骨再生を目的とした骨欠損部・骨折部補修用、骨粗鬆症に対する注入剤、金属製人工材料と骨母床間の間隙充填用の充填剤、ＤＤＳ担体、細胞培養担体等として適用できる。 In the present invention, a biodegradable polymer dissolved in a volatile solvent is stirred in water, then a solution containing calcium ions is added, and a solution containing phosphate ions is further dropped. And a method for producing a spherical biodegradable polymer / ceramics composite having a porous structure inside, and a spherical biodegradability high having a porous structure inside thereof, characterized by solid-liquid separation of the product According to the present invention, a spherical biodegradable polymer / ceramic composite having a porous structure is obtained. The dispersed phase is stabilized by the precipitation of calcium phosphate. A surfactant-free, biodegradable polymer / calcium phosphate complex organized in a spherical shape is obtained. A spherical biodegradable polymer / ceramic composite having calcium phosphate on the surface can be efficiently produced. A spherical biodegradable polymer / ceramic composite having a porous structure in the inside of which calcium phosphate having the ability to directly bond with autologous bone is present can be produced. The spherical biodegradable polymer / ceramic composite having a pore structure inside obtained in the present invention is, for example, for bone defect / fracture repair for the purpose of bone regeneration, an injection for osteoporosis, and a metal artificial material It can be applied as a filler for filling the gap between the bone and the mother bed, DDS carrier, cell culture carrier and the like.
Claims (8)
末端官能基もしくは側鎖官能基の少なくともどちらか一方がアニオン性の官能基である生体内分解性高分子を揮発性溶媒に溶解させたものを水中に入れて撹拌してＯ／Ｗ型エマルジョンを形成し、その後、この混合溶液にカルシウムイオンを含む溶液を加え、更に、リン酸イオンを含む溶液を滴下して生体内分解性高分子の親水性官能基と結合したカルシウムイオンを核生成サイトとしてリン酸カルシウムを析出させたものを熟成させ、その生成物を固−液分離すること、上記生体内分解性高分子が、ポリ乳酸、ポリグリコール酸、及び乳酸−グリコール酸共重合体から選択された少なくとも１種であること、を特徴とする内部に多孔構造を有する球状生体内分解性高分子／セラミックス複合体の製造方法。 A method for producing a spherical biodegradable polymer / ceramic composite without using an emulsifier and having a porous structure formed inside,
A biodegradable polymer in which at least one of the terminal functional group or the side chain functional group is an anionic functional group is dissolved in a volatile solvent, and stirred in an O / W emulsion. After that, a solution containing calcium ions is added to this mixed solution, and a solution containing phosphate ions is added dropwise, and calcium ions bound to the hydrophilic functional group of the biodegradable polymer are used as nucleation sites. Aging the precipitated calcium phosphate, solid-liquid separating the product , the biodegradable polymer is at least selected from polylactic acid, polyglycolic acid, and lactic acid-glycolic acid copolymer A method for producing a spherical biodegradable polymer / ceramics composite having a porous structure inside, characterized by being one type .
球状生体内分解性高分子／セラミックス複合体の直径が、０．０５〜３０００μｍの範囲であり、内部の多孔構造が球状組織によって構成された多孔構造であり、孔を形成する球の直径が、０．０１〜１０００μｍの範囲であることを特徴とする球状生体内分解性高分子／セラミックス複合体。 Claims made by the method as set forth in claim 1 in any of 5, a spherical shape biodegradable polymer / ceramic composite that having a porous structure constituted by spherical tissue therein,
The diameter of the spherical biodegradable polymer / ceramic composite is in the range of 0.05 to 3000 μm, the internal porous structure is a porous structure constituted by a spherical structure, and the diameter of the sphere forming the pore is A spherical biodegradable polymer / ceramic composite characterized by being in the range of 0.01 to 1000 μm.
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