JP4780710B2 - Core-shell type polymer gel fine particles and method for producing the same - Google Patents
Core-shell type polymer gel fine particles and method for producing the same Download PDFInfo
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- JP4780710B2 JP4780710B2 JP2006072646A JP2006072646A JP4780710B2 JP 4780710 B2 JP4780710 B2 JP 4780710B2 JP 2006072646 A JP2006072646 A JP 2006072646A JP 2006072646 A JP2006072646 A JP 2006072646A JP 4780710 B2 JP4780710 B2 JP 4780710B2
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- 229920000642 polymer Polymers 0.000 title claims description 192
- 239000010419 fine particle Substances 0.000 title claims description 180
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- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 3
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- 239000002202 Polyethylene glycol Substances 0.000 description 2
- PPBRXRYQALVLMV-UHFFFAOYSA-N Styrene Chemical compound C=CC1=CC=CC=C1 PPBRXRYQALVLMV-UHFFFAOYSA-N 0.000 description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
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- XGZNHFPFJRZBBT-UHFFFAOYSA-N ethanol;titanium Chemical compound [Ti].CCO.CCO.CCO.CCO XGZNHFPFJRZBBT-UHFFFAOYSA-N 0.000 description 2
- FJKIXWOMBXYWOQ-UHFFFAOYSA-N ethenoxyethane Chemical compound CCOC=C FJKIXWOMBXYWOQ-UHFFFAOYSA-N 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 238000010304 firing Methods 0.000 description 2
- VOZRXNHHFUQHIL-UHFFFAOYSA-N glycidyl methacrylate Chemical compound CC(=C)C(=O)OCC1CO1 VOZRXNHHFUQHIL-UHFFFAOYSA-N 0.000 description 2
- 150000002430 hydrocarbons Chemical group 0.000 description 2
- 239000003999 initiator Substances 0.000 description 2
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- ZUEKXCXHTXJYAR-UHFFFAOYSA-N tetrapropan-2-yl silicate Chemical compound CC(C)O[Si](OC(C)C)(OC(C)C)OC(C)C ZUEKXCXHTXJYAR-UHFFFAOYSA-N 0.000 description 2
- VXUYXOFXAQZZMF-UHFFFAOYSA-N titanium(IV) isopropoxide Chemical compound CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C VXUYXOFXAQZZMF-UHFFFAOYSA-N 0.000 description 2
- 229930195735 unsaturated hydrocarbon Natural products 0.000 description 2
- 229920002818 (Hydroxyethyl)methacrylate Polymers 0.000 description 1
- MIZLGWKEZAPEFJ-UHFFFAOYSA-N 1,1,2-trifluoroethene Chemical group FC=C(F)F MIZLGWKEZAPEFJ-UHFFFAOYSA-N 0.000 description 1
- BQCIDUSAKPWEOX-UHFFFAOYSA-N 1,1-Difluoroethene Chemical group FC(F)=C BQCIDUSAKPWEOX-UHFFFAOYSA-N 0.000 description 1
- KOMNUTZXSVSERR-UHFFFAOYSA-N 1,3,5-tris(prop-2-enyl)-1,3,5-triazinane-2,4,6-trione Chemical compound C=CCN1C(=O)N(CC=C)C(=O)N(CC=C)C1=O KOMNUTZXSVSERR-UHFFFAOYSA-N 0.000 description 1
- KWKAKUADMBZCLK-UHFFFAOYSA-N 1-octene Chemical compound CCCCCCC=C KWKAKUADMBZCLK-UHFFFAOYSA-N 0.000 description 1
- ZCXVJRGWDAFVTK-UHFFFAOYSA-N 2,3-dihydroxyocta-2,6-dienediamide Chemical compound NC(=O)C=CCCC(O)=C(O)C(N)=O ZCXVJRGWDAFVTK-UHFFFAOYSA-N 0.000 description 1
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 description 1
- ZNQVEEAIQZEUHB-UHFFFAOYSA-N 2-ethoxyethanol Chemical compound CCOCCO ZNQVEEAIQZEUHB-UHFFFAOYSA-N 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-M Acrylate Chemical compound [O-]C(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-M 0.000 description 1
- WOBHKFSMXKNTIM-UHFFFAOYSA-N Hydroxyethyl methacrylate Chemical compound CC(=C)C(=O)OCCO WOBHKFSMXKNTIM-UHFFFAOYSA-N 0.000 description 1
- CERQOIWHTDAKMF-UHFFFAOYSA-M Methacrylate Chemical compound CC(=C)C([O-])=O CERQOIWHTDAKMF-UHFFFAOYSA-M 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- 239000004820 Pressure-sensitive adhesive Substances 0.000 description 1
- RTAQQCXQSZGOHL-UHFFFAOYSA-N Titanium Chemical compound [Ti] RTAQQCXQSZGOHL-UHFFFAOYSA-N 0.000 description 1
- DAKWPKUUDNSNPN-UHFFFAOYSA-N Trimethylolpropane triacrylate Chemical compound C=CC(=O)OCC(CC)(COC(=O)C=C)COC(=O)C=C DAKWPKUUDNSNPN-UHFFFAOYSA-N 0.000 description 1
- QYKIQEUNHZKYBP-UHFFFAOYSA-N Vinyl ether Chemical class C=COC=C QYKIQEUNHZKYBP-UHFFFAOYSA-N 0.000 description 1
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- JUDXBRVLWDGRBC-UHFFFAOYSA-N [2-(hydroxymethyl)-3-(2-methylprop-2-enoyloxy)-2-(2-methylprop-2-enoyloxymethyl)propyl] 2-methylprop-2-enoate Chemical compound CC(=C)C(=O)OCC(CO)(COC(=O)C(C)=C)COC(=O)C(C)=C JUDXBRVLWDGRBC-UHFFFAOYSA-N 0.000 description 1
- HVVWZTWDBSEWIH-UHFFFAOYSA-N [2-(hydroxymethyl)-3-prop-2-enoyloxy-2-(prop-2-enoyloxymethyl)propyl] prop-2-enoate Chemical compound C=CC(=O)OCC(CO)(COC(=O)C=C)COC(=O)C=C HVVWZTWDBSEWIH-UHFFFAOYSA-N 0.000 description 1
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- NIXOWILDQLNWCW-UHFFFAOYSA-N acrylic acid group Chemical group C(C=C)(=O)O NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 1
- 125000003647 acryloyl group Chemical group O=C([*])C([H])=C([H])[H] 0.000 description 1
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- 239000008280 blood Substances 0.000 description 1
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- FPCJKVGGYOAWIZ-UHFFFAOYSA-N butan-1-ol;titanium Chemical compound [Ti].CCCCO.CCCCO.CCCCO.CCCCO FPCJKVGGYOAWIZ-UHFFFAOYSA-N 0.000 description 1
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- GLVVKKSPKXTQRB-UHFFFAOYSA-N ethenyl dodecanoate Chemical compound CCCCCCCCCCCC(=O)OC=C GLVVKKSPKXTQRB-UHFFFAOYSA-N 0.000 description 1
- LZWYWAIOTBEZFN-UHFFFAOYSA-N ethenyl hexanoate Chemical compound CCCCCC(=O)OC=C LZWYWAIOTBEZFN-UHFFFAOYSA-N 0.000 description 1
- 125000005678 ethenylene group Chemical group [H]C([*:1])=C([H])[*:2] 0.000 description 1
- 125000002573 ethenylidene group Chemical group [*]=C=C([H])[H] 0.000 description 1
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- XUCNUKMRBVNAPB-UHFFFAOYSA-N fluoroethene Chemical group FC=C XUCNUKMRBVNAPB-UHFFFAOYSA-N 0.000 description 1
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- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
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- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- LFQCEHFDDXELDD-UHFFFAOYSA-N tetramethyl orthosilicate Chemical compound CO[Si](OC)(OC)OC LFQCEHFDDXELDD-UHFFFAOYSA-N 0.000 description 1
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- PLCFYBDYBCOLSP-UHFFFAOYSA-N tris(prop-2-enyl) 2-hydroxypropane-1,2,3-tricarboxylate Chemical compound C=CCOC(=O)CC(O)(CC(=O)OCC=C)C(=O)OCC=C PLCFYBDYBCOLSP-UHFFFAOYSA-N 0.000 description 1
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Description
本発明は、コア−シェル型高分子ゲル微粒子及びその製造方法に関する。また、本発明は、該コア−シェル型高分子ゲル微粒子を用いて修飾された微粒子及びその製造方法に関する。 The present invention relates to a core-shell type polymer gel fine particle and a method for producing the same. The present invention also relates to fine particles modified with the core-shell type polymer gel fine particles and a method for producing the same.
コア（核）−シェル（殻）型高分子微粒子は、粒子の表面と内部が異なった高分子で構成された微粒子であり、表面の高分子は主に媒体中での分散に寄与し、内部に異なる高分子を包含する。内部の高分子に薬剤を包含させたり、感温性等の機能をもたせることで、媒体中における分散に優れた機能性微粒子を提供することができる。そのため、コア−シェル型高分子微粒子の製造方法は非常に注目を集めている。 Core (shell) type polymer fine particles are fine particles composed of a polymer whose surface is different from the inside of the particle, and the surface polymer mainly contributes to dispersion in the medium, and the inside. Includes different polymers. Functional fine particles excellent in dispersion in a medium can be provided by incorporating a drug in the internal polymer and having functions such as temperature sensitivity. Therefore, the method for producing core-shell type polymer fine particles has attracted a great deal of attention.
コアシェル型高分子微粒子は、一般的な高分子微粒子の製造法と同様に、界面活性剤を用いる乳化重合法によって合成できるが、この場合、二回以上の重合が必要となる。また、余剰の界面活性剤が環境に負荷を与える等の欠点がある。 The core-shell type polymer fine particles can be synthesized by an emulsion polymerization method using a surfactant in the same manner as a general method for producing polymer fine particles. In this case, two or more polymerizations are required. Moreover, there exists a fault that an excess surfactant gives load to an environment.
他のコアシェル型高分子微粒子の合成方法として、例えば、シェル部形成の原料として極性高分子末端（ポリエチレングリコール）に重合性のビニル基やメタクリロキシ基を導入したマクロモノマーを用い、該マクロモノマーとメチルメタクリレートとを分散重合、乳化重合する方法がある（非特許文献１）。 As another method for synthesizing the core-shell polymer fine particles, for example, a macromonomer in which a polymerizable vinyl group or methacryloxy group is introduced into a polar polymer terminal (polyethylene glycol) is used as a raw material for forming a shell portion. There is a method of dispersion polymerization and emulsion polymerization of methacrylate (Non-patent Document 1).
しかし、上記の末端重合性マクロモノマーを用いた場合、別途水溶性重合開始剤が必要となる。また、反応活性点が高分子末端にあるためミセル形成が不安定であり粒子形成しない場合や、モノマーと反応せずに活性を失いフリーのポリマーを形成し易い傾向がある。さらに、ナノスフェアーが得られる組成範囲（溶液組成及びモノマー/マクロモノマー比の組成範囲）が限定される等の欠点を有していた。 However, when the above terminal polymerizable macromonomer is used, a water-soluble polymerization initiator is separately required. In addition, since the reaction active site is at the polymer terminal, micelle formation is unstable and particles are not formed, or there is a tendency to lose activity and form a free polymer without reacting with the monomer. Furthermore, the composition range (solution composition and composition range of monomer / macromonomer ratio) in which nanospheres can be obtained is limited.
本発明者らは、上記の問題を解決するために、ＰＥＧ含有高分子アゾ重合開始剤及び疎水性ビニル系モノマーを、水及び／またはアルコール中でソープフリー乳化重合させることを特徴とするコア−シェル型高分子微粒子の製造方法を開発している（非特許文献２）
本発明は、上記コア−シェル型高分子微粒子の利点を維持しつつ、溶媒、温度等に対して高い安定性を有する等の特徴をさらに有するコア−シェル型高分子ゲル微粒子を提供することを目的とする。 The present invention provides a core-shell type polymer gel fine particle further having characteristics such as high stability with respect to a solvent, temperature, etc. while maintaining the advantages of the core-shell type fine polymer particle. Objective.
本発明者は、上記の課題を解決するために鋭意研究を行った結果、ＰＥＧ含有高分子アゾ重合開始剤及び多官能性モノマーを、水及び／またはアルコール中で重合させることにより、粒子内に架橋による三次元網目構造を有するコア−シェル型高分子ゲル微粒子を製造できることを見出した。本発明者は、当該コア−シェル型高分子ゲル微粒子が従来のコア−シェル型高分子微粒子の利点を維持しつつ、温度、溶媒等に対する高い安定性等の新たな特徴を有することを見出した。本発明者は、かかる知見に基づき、さらに研究を重ねた結果、本発明を完成するに至った。 As a result of diligent research to solve the above-mentioned problems, the present inventor has polymerized a PEG-containing polymer azo polymerization initiator and a polyfunctional monomer in water and / or alcohol to form particles. It has been found that core-shell type polymer gel fine particles having a three-dimensional network structure by crosslinking can be produced. The present inventor has found that the core-shell type polymer gel fine particles have new characteristics such as high stability to temperature, solvent, etc. while maintaining the advantages of the conventional core-shell type polymer fine particles. . As a result of further research based on this knowledge, the present inventor has completed the present invention.
即ち、本発明は、次に示すコア−シェル型高分子ゲル微粒子、その製造方法等を提供する。 That is, the present invention provides the following core-shell type polymer gel fine particles, a production method thereof, and the like.
項１．ＰＥＧ含有高分子アゾ重合開始剤及び多官能性モノマーを、水及び／またはアルコール中で重合させることを特徴とする平均粒子径２０ｎｍ〜３０００ｎｍ程度のコア−シェル型高分子ゲル微粒子の製造方法；
項２．ＰＥＧ含有高分子アゾ重合開始剤が一般式（Ｉ）：
Item 1. A method for producing core-shell type polymer gel fine particles having an average particle size of about 20 nm to 3000 nm, wherein a PEG-containing polymer azo polymerization initiator and a polyfunctional monomer are polymerized in water and / or alcohol;
Item 2. The PEG-containing polymeric azo polymerization initiator is represented by the general formula (I):
で表される繰り返し単位を含む高分子化合物である請求項１に記載の製造方法；
項３．作製されるコア−シェル型高分子ゲル微粒子が表面に凹凸を有する、請求項１または２に記載の製造方法；
項４．ＰＥＧ含有高分子アゾ重合開始剤におけるＰＥＧ換算のモル数に対する多官能性モノマーのモル数の比が、前者１に対して後者が０.５〜１５０程度である請求項１〜３のいずれかに記載の製造方法；
項５．多官能性モノマーが、エチレングリコールジメタクリレート、メチレンビスアクリルアミド、トリエチレングリコールジメタクリレート及びエチレンビスアクリルアミドからなる群より選ばれる少なくとも１種である請求項１〜３のいずれかに記載の製造方法；
項６．請求項１〜５のいずれかに記載の製造方法により製造される平均粒子径２０ｎｍ〜３０００ｎｍ程度のコア−シェル型高分子ゲル微粒子；
項７．多官能性モノマーが重合してなる高分子を含むコア部と、ＰＥＧ含有高分子を含むシェル部からなるコア−シェル型高分子ゲル微粒子であって、該微粒子の平均粒子径に対する粒子径の標準偏差の比が、前者１に対して後者が０．０５〜０．６程度であるコア−シェル型高分子ゲル微粒子；
項８．請求項１〜５のいずれかの製造方法で得られるコア−シェル型高分子ゲル微粒子を核として用い、水及び／またはアルコール中で、ビニル系モノマーを重合させることを特徴とする高分子層で被覆されたコア−シェル型高分子ゲル微粒子の製造方法；
項９．請求項８に記載の製造方法により製造される高分子層で被覆されたコア−シェル型高分子ゲル微粒子；
項１０．請求項１〜５のいずれかの製造方法で得られるコア−シェル型高分子ゲル微粒子を核として用い、水及び／またはアルコール中で、金属アルコキシドを反応させることを特徴とする金属酸化物層で被覆されたコア−シェル型高分子ゲル微粒子の製造方法；
項１１．請求項１０に記載の製造方法により製造される金属酸化物層で被覆されたコア−シェル型高分子ゲル微粒子；
項１２．請求項１０に記載の製造方法により製造される金属酸化物層で被覆されたコア−シェル型高分子ゲル微粒子を加熱処理することを特徴とする中空金属酸化物微粒子の製造方法；
項１３．請求項１２に記載の製造方法により製造される中空金属酸化物微粒子。
The production method according to claim 1, wherein the polymer compound comprises a repeating unit represented by:
Item 3. The production method according to claim 1 or 2, wherein the core-shell type polymer gel fine particles to be produced have irregularities on the surface;
Item 4. The ratio of the number of moles of the polyfunctional monomer to the number of moles in terms of PEG in the PEG-containing polymer azo polymerization initiator is such that the latter is about 0.5 to 150 with respect to the former 1. The manufacturing method as described;
Item 5. The production method according to any one of claims 1 to 3, wherein the polyfunctional monomer is at least one selected from the group consisting of ethylene glycol dimethacrylate, methylene bisacrylamide, triethylene glycol dimethacrylate and ethylene bisacrylamide.
Item 6. Core-shell type polymer gel fine particles having an average particle diameter of about 20 nm to 3000 nm produced by the production method according to claim 1;
Item 7. A core-shell type polymer gel fine particle comprising a core part containing a polymer formed by polymerization of a polyfunctional monomer and a shell part containing a PEG-containing polymer, and a standard particle diameter with respect to the average particle diameter of the fine particles Core-shell type polymer gel fine particles whose deviation ratio is about 0.05 to 0.6 with respect to the former 1;
Item 8. A polymer layer characterized by polymerizing a vinyl monomer in water and / or alcohol using the core-shell type polymer gel fine particles obtained by the production method according to claim 1 as a nucleus. Method for producing coated core-shell type polymer gel fine particles;
Item 9. Core-shell type polymer gel fine particles coated with a polymer layer produced by the production method according to claim 8;
Item 10. A metal oxide layer characterized by reacting a metal alkoxide in water and / or alcohol using the core-shell type polymer gel fine particles obtained by the production method according to claim 1 as a nucleus. Method for producing coated core-shell type polymer gel fine particles;
Item 12. A method for producing hollow metal oxide fine particles, wherein the core-shell type polymer gel fine particles coated with the metal oxide layer produced by the production method according to claim 10 are heat-treated;
Item 13. Hollow metal oxide fine particles produced by the production method according to claim 12.
以下、本発明を詳述する。
Ｉ．コア−シェル型高分子ゲル微粒子
本発明のコア−シェル型高分子ゲル微粒子は、ポリエチレングリコール（以下、「ＰＥＧ」とも表記する）含有高分子アゾ重合開始剤及び多官能性モノマーを、水及び／またはアルコール中で重合させて製造することができる。
The present invention is described in detail below.
I. Core-shell type polymer gel fine particle The core-shell type polymer gel fine particle of the present invention comprises a polyethylene glycol (hereinafter also referred to as “PEG”)-containing polymer azo polymerization initiator and a polyfunctional monomer, water and / or Alternatively, it can be produced by polymerization in alcohol.
本明細書において、コア−シェル型高分子微粒子とは、粒子の表面（シェル）と内部（コア）が異なった高分子で構成された微粒子を意味する。 In this specification, the core-shell type polymer fine particles mean fine particles composed of polymers having different surface (shell) and inside (core) of the particles.
本発明においてゲル微粒子とは、当該粒子中に三次元網目構造を有する高分子微粒子であり、溶媒の種類によっては、その三次元網目構造中に溶媒を含んで膨潤し、粒子内部に有機物を貯蔵することができる微粒子である。 In the present invention, the gel fine particles are polymer fine particles having a three-dimensional network structure in the particles, and depending on the type of the solvent, the three-dimensional network structure swells containing a solvent and stores organic matter inside the particles. Fine particles that can be made.
従って、本発明におけるコア−シェル型高分子ゲル微粒子は、多官能性モノマーが重合してなる高分子を含むコア部と、ＰＥＧ含有高分子を含むシェル部とからなり、架橋による三次元網目構造を有するコア−シェル型高分子微粒子であって、そのコア部に三次元網目構造を有し、溶媒の種類によっては、その三次元網目構造中に溶媒を含んで膨潤し、粒子内部に有機物を貯蔵することができる微粒子である。本発明における「コア−シェル型高分子ゲル微粒子」は、コア部だけでなくシェル部にも三次元網目構造を有し得る。 Accordingly, the core-shell type polymer gel fine particle in the present invention comprises a core part containing a polymer obtained by polymerizing a polyfunctional monomer and a shell part containing a PEG-containing polymer, and has a three-dimensional network structure by crosslinking. Core-shell type polymer fine particles having a three-dimensional network structure in the core part, and depending on the type of the solvent, the three-dimensional network structure swells containing a solvent, and organic substances are contained inside the particles. Fine particles that can be stored. The “core-shell type polymer gel fine particles” in the present invention may have a three-dimensional network structure not only in the core part but also in the shell part.
なお、本発明において、用語「ゲル微粒子」「コア−シェル型高分子ゲル微粒子」は、その三次元網目構造に溶媒分子を保持していない状態のものも包含し得る。 In the present invention, the terms “gel fine particles” and “core-shell type polymer gel fine particles” may include those having no solvent molecules in their three-dimensional network structure.
本発明のコア−シェル型高分子ゲル微粒子の原料であるＰＥＧ含有高分子アゾ重合開始剤とは、分子内にＰＥＧ及びアゾ基（−Ｎ＝Ｎ−）を含有する繰り返し単位を含む高分子化合物である。具体的には、一般式（Ｉ）： The PEG-containing polymer azo polymerization initiator that is a raw material of the core-shell type polymer gel fine particles of the present invention is a polymer compound containing a repeating unit containing PEG and an azo group (—N═N—) in the molecule. It is. Specifically, the general formula (I):
で表される繰り返し単位を含む高分子化合物である。
It is a high molecular compound containing the repeating unit represented by these.
一般式（Ｉ）において、ｍは３０〜２００の整数が好ましく、４０〜１５０の整数がより好ましい。また、ｎは４〜４０の整数が好ましく、５〜２０の整数がより好ましい。 In general formula (I), m is preferably an integer of 30 to 200, and more preferably an integer of 40 to 150. N is preferably an integer of 4 to 40, and more preferably an integer of 5 to 20.
より具体的には、一般式（ＩＩ）： More specifically, the general formula (II):
で表される高分子化合物である。
It is a high molecular compound represented by these.
一般式（ＩＩ）において、ｍは３０〜２００の整数が好ましく、４０〜１５０の整数がより好ましい。また、ｎは４〜４０の整数が好ましく、５〜２０の整数がより好ましい。 In general formula (II), m is preferably an integer of 30 to 200, more preferably an integer of 40 to 150. N is preferably an integer of 4 to 40, and more preferably an integer of 5 to 20.
一般式（ＩＩ）において、Ｒ1で示されるアルキル基としては、炭素数１〜４のアルキ
ル基が好ましく、具体的にはメチル、エチル、イソプロピル等が挙げられる。特に、メチル基が好ましい。
In the general formula (II), the alkyl group represented by R 1 is preferably an alkyl group having 1 to 4 carbon atoms, and specific examples include methyl, ethyl, isopropyl and the like. A methyl group is particularly preferable.
一般式（ＩＩ）において、Ｒ2で示されるアルキル基としては、炭素数１〜４のアルキ
ル基が好ましく、具体的にはメチル、エチル、イソプロピル等が挙げられる。特に、メチル基が好ましい。
In the general formula (II), the alkyl group represented by R 2 is preferably an alkyl group having 1 to 4 carbon atoms, and specific examples include methyl, ethyl, isopropyl and the like. A methyl group is particularly preferable.
ＰＥＧ含有高分子アゾ重合開始剤の分子量は、5000〜１０万程度、好ましくは１万〜５万であればよい。また、該開始剤のＰＥＧ部分の分子量は、800〜1万程度、好ましくは1000〜8000程度であればよい。 The molecular weight of the PEG-containing polymeric azo polymerization initiator may be about 5,000 to 100,000, preferably 10,000 to 50,000. The molecular weight of the PEG moiety of the initiator may be about 800 to 10,000, preferably about 1000 to 8000.
このＰＥＧ含有高分子アゾ重合開始剤は、ＰＥＧを有しているため重合反応の媒体である水及び／またはアルコール中に良好に溶解することができ、また、分子鎖骨格中に重合開始部分（ラジカル発生部分：―Ｎ＝Ｎ−）を有しているため、別途水溶性重合開始剤を使用する必要がない。さらに溶媒に溶解しない多官能性モノマーを添加した場合にミセルを形成する組成範囲（溶媒中の水／アルコール比と多官能性モノマー／PEG含有高分子アゾ重合開始剤との比）が広いという特徴を有している。しかも、分子骨格中にラジカル発生部分であるアゾ基を有しているため、末端反応性マクロモノマーに比べてラジカルの反応性、安定性が高いという特徴をも有している。 Since this PEG-containing polymeric azo polymerization initiator has PEG, it can be dissolved well in water and / or alcohol, which is a medium for the polymerization reaction, and the polymerization initiating moiety ( Since it has a radical generating portion: -N = N-), it is not necessary to use a separate water-soluble polymerization initiator. Furthermore, the composition range (ratio of water / alcohol ratio in solvent and polyfunctional monomer / PEG-containing polymer azo polymerization initiator) that forms micelles when a polyfunctional monomer that does not dissolve in the solvent is added is wide have. In addition, since it has an azo group that is a radical generating moiety in the molecular skeleton, it has a feature that the reactivity and stability of the radical are higher than those of the terminal reactive macromonomer.
ＰＥＧ含有高分子アゾ重合開始剤の具体例としては、和光純薬製の高分子アゾ重合開始剤VPE0201（PEG部分の分子量2000）、VPE0401（PEG部分の分子量4000）VPE0601（PEG部分の分子量6000）等が例示される。高分子アゾ重合開始剤VPEシリーズの合成方法は、例えば、J.J.Laverty and Z.G.Gardlund, J.Polym.Sci., Polym. Chem.Ed., 15, 2001 (1977)、A.Ueda, S.Nagai, J.Polym.Sci., Polym. Chem.Ed., 24, 405 (1986)等の文献に記載されている。 Specific examples of PEG-containing polymeric azo polymerization initiators include: Wako Pure Chemicals Polymer Azo Polymerization Initiator VPE0201 (molecular weight of PEG moiety 2000), VPE0401 (molecular weight of PEG moiety 4000) VPE0601 (molecular weight of PEG moiety 6000) Etc. are exemplified. Synthetic methods of the polymer azo polymerization initiator VPE series are described in, for example, JJ Laverty and ZGGardlund, J. Polym. Sci., Polym. Chem. Ed., 15, 2001 (1977), A. Ueda, S. Nagai, J. Polym. Sci., Polym. Chem. Ed., 24, 405 (1986).
本発明のコア−シェル型高分子ゲル微粒子の原料である多官能性モノマーとは、二重結合を有する官能基を分子内に２個以上、好ましくは２〜5個、より好ましくは２〜3個有しているモノマーである。この多官能性モノマーは、重合反応によりコア−シェル型高分子ゲル微粒子のコア部を形成する。当該多官能性モノマーに起因して、本発明のコア−シェル型高分子ゲル微粒子は、その構成成分である高分子が架橋されてなる三次元網目構造を有することとなる。 The polyfunctional monomer that is a raw material of the core-shell type polymer gel fine particles of the present invention is two or more, preferably 2 to 5, more preferably 2 to 3 functional groups having a double bond in the molecule. It is a monomer that has one. This polyfunctional monomer forms a core part of core-shell type polymer gel fine particles by a polymerization reaction. Due to the polyfunctional monomer, the core-shell type polymer gel fine particles of the present invention have a three-dimensional network structure formed by crosslinking the constituent polymers.
官能基としては、例えば、ビニル基、アリル基、プロペニル基、ビニリデン基、ビニレン基、等の不飽和炭化水素基、（メタ）アクリロイル基、（メタ）アクリルアミド基、等の不飽和エステル、不飽和アミド、フルオロエチレン基、フッ化ビニリデン基、トリフルオロエチレン基等のフッ素系炭化水素基が挙げられるがこれらに限定されない。 Examples of the functional group include unsaturated hydrocarbon groups such as vinyl group, allyl group, propenyl group, vinylidene group and vinylene group, unsaturated esters such as (meth) acryloyl group and (meth) acrylamide group, and unsaturated groups. Examples thereof include, but are not limited to, fluorinated hydrocarbon groups such as amide, fluoroethylene group, vinylidene fluoride group, and trifluoroethylene group.
このような多官能性モノマーとしては、例えば、エチレングリコールジメタクリレート、メチレンビスアクリルアミド、エチレンビスアクリルアミド、トリエチレングリコールジメタクリレート、ジヒドロキシエチレンビスアクリルアミド、ジビニルベンゼン、トリメチロールプロパントリアクリレート、ペンタエリスリトールトリアクリレート、ペンタエリスリトールトリメタクリレート、トリアリルイソシアヌレート、トリアリルサイトレート、エチレングリコールジアクリレート、フェニレンジグリコールジアクリレート等を例示できる。 Examples of such polyfunctional monomers include ethylene glycol dimethacrylate, methylene bisacrylamide, ethylene bisacrylamide, triethylene glycol dimethacrylate, dihydroxyethylene bisacrylamide, divinylbenzene, trimethylolpropane triacrylate, pentaerythritol triacrylate, Examples include pentaerythritol trimethacrylate, triallyl isocyanurate, triallyl citrate, ethylene glycol diacrylate, phenylene diglycol diacrylate, and the like.
多官能性モノマーは、上記のうちの１種、或いは上記のうちから選ばれる２種以上を選択することができる。本発明の多官能性モノマーとしては、微粒子の形成し易さの点から、比較的極性の高い分子が好ましい。 As the polyfunctional monomer, one of the above or two or more selected from the above can be selected. The polyfunctional monomer of the present invention is preferably a molecule having a relatively high polarity from the viewpoint of easy formation of fine particles.
本発明の重合反応の媒体は、水及び／またはアルコールが用いられる。水は、塩を含まないイオン交換水を用いることが好ましい。アルコールとしては、エタノール、メタノール、n−プロパノール、イソプロパノール、ｔ−ブタノール等の炭素数１〜４のアルコールが好適である。好ましい媒体としては、水を主成分とするものが好ましく、水とアルコールの体積比が95／5〜40／60程度、好ましくは90／10〜40／60程度の混合媒体が好適である。なお、水及びアルコールに加えて、N，N−ジメチルホルムアミド、N，N−ジメチルアセトアミド、エチレングリコール、エチレングリコールモノメチルエーテル、エチレングリコールモノエチルエーテル等の他の溶媒を用いてもよいが、媒体全体の体積の60体積％以下であることが好ましい。 Water and / or alcohol is used as the medium for the polymerization reaction of the present invention. As the water, it is preferable to use ion-exchanged water containing no salt. As alcohol, C1-C4 alcohol, such as ethanol, methanol, n-propanol, isopropanol, t-butanol, is suitable. As a preferable medium, a medium mainly composed of water is preferable, and a mixed medium having a volume ratio of water to alcohol of about 95/5 to 40/60, preferably about 90/10 to 40/60 is suitable. In addition to water and alcohol, other solvents such as N, N-dimethylformamide, N, N-dimethylacetamide, ethylene glycol, ethylene glycol monomethyl ether, and ethylene glycol monoethyl ether may be used. It is preferable that it is 60 volume% or less of the volume of this.
重合反応における媒体の使用量は、溶液中の85〜99.9wt%程度であればよい。 The amount of medium used in the polymerization reaction may be about 85-99.9 wt% in the solution.
重合反応に際し、原料である多官能性モノマー及びＰＥＧ含有高分子アゾ重合開始剤は、多官能性モノマーのモル数とＰＥＧ含有高分子アゾ重合開始剤におけるＰＥＧ換算のモル数との比が、０．５：１〜１５０：１程度、好ましくは０.５：１〜１００：１程度になるように配合される。 In the polymerization reaction, the polyfunctional monomer and the PEG-containing polymer azo polymerization initiator as raw materials have a ratio of the number of moles of the multifunctional monomer to the number of moles in terms of PEG in the PEG-containing polymer azo polymerization initiator is 0. .5: 1 to about 150: 1, preferably about 0.5: 1 to about 100: 1.
ここで、「ＰＥＧ含有高分子アゾ重合開始剤におけるＰＥＧ換算のモル数」とは、PEG換算分子量を[PEG部分の分子量+226]として、（ＰＥＧ含有高分子アゾ重合開始剤の使用量ｇ）／（PEG換算分子量[PEG部分の分子量+226]）で算出される値を意味する。 Here, “the number of moles in terms of PEG in a PEG-containing polymer azo polymerization initiator” means that the molecular weight in terms of PEG is [molecular weight of PEG moiety + 226] (amount of PEG-containing polymer azo polymerization initiator used g) / (Mean PEG equivalent molecular weight [molecular weight of PEG moiety +226]).
また、多官能性モノマー及びＰＥＧ含有高分子アゾ重合開始剤は、反応溶液中の多官能性モノマーとＰＥＧ含有高分子アゾ重合開始剤の濃度の合計が、０.１-１５ｗｔ％程度、好ましくは０.２-１０ｗｔ％程度、より好ましくは０.５-６ｗｔ％程度となるように配合される。 The polyfunctional monomer and the PEG-containing polymer azo polymerization initiator have a total concentration of the polyfunctional monomer and the PEG-containing polymer azo polymerization initiator in the reaction solution of about 0.1 to 15 wt%, preferably It is blended so as to be about 0.2-10 wt%, more preferably about 0.5-6 wt%.
多官能性モノマー及びＰＥＧ含有高分子アゾ重合開始剤を上記のような条件で配合することによって、実質的に球状でありかつ表面に凹凸を有するコア−シェル型高分子ゲル微粒子の分散粒子を製造することができる。 By blending a polyfunctional monomer and a PEG-containing polymer azo polymerization initiator under the conditions as described above, a core-shell type polymer gel fine particle dispersed particle having a substantially spherical shape and irregularities on the surface is produced. can do.
本発明において、「表面に凹凸を有する」とは、表面に複数の突起及び／またはへこみを有することを示し、「表面に複数の突起を有する」、「金平糖型」等と同様の概念を包含する。 In the present invention, “having irregularities on the surface” means that the surface has a plurality of protrusions and / or dents, and includes the same concept as “having a plurality of protrusions on the surface”, “Kanpeira type”, etc. To do.
粒子表面に凹凸を有することによって、例えば、診断薬用途において、粒子１個あたりにより多くの抗原タンパクを結合させることができるようになる等の利点が生じる。 By having irregularities on the particle surface, there is an advantage that, for example, more antigenic proteins can be bound per particle in diagnostic drug applications.
さらに、上記重合反応の際に、上記の多官能性モノマーに加えて、一官能性モノマーを添加してもよい。 Furthermore, in the polymerization reaction, a monofunctional monomer may be added in addition to the polyfunctional monomer.
ここで、一官能性モノマーとは、二重結合を有する官能基を分子内に１個有するモノマーである。 Here, the monofunctional monomer is a monomer having one functional group having a double bond in the molecule.
一官能性モノマーの具体例としては、例えば、メチル（メタ）アクリレートなどの（メタ）アクリル酸エステル類、（メタ）アクリルアミド、Ｎ−イソプロピル（メタ）アクリルアミドなどの（メタ）アクリルアミド類、ヘキサン酸ビニル、ラウリル酸ビニルなどのビニルエステル類、オクテン、スチレン、などの不飽和炭化水素、エチルビニルエーテルなどのビニルエーテル、（メタ）アクリル酸などの不飽和カルボン酸、等が挙げられる。 Specific examples of monofunctional monomers include, for example, (meth) acrylic esters such as methyl (meth) acrylate, (meth) acrylamides such as (meth) acrylamide and N-isopropyl (meth) acrylamide, and vinyl hexanoate. And vinyl esters such as vinyl laurate, unsaturated hydrocarbons such as octene and styrene, vinyl ethers such as ethyl vinyl ether, unsaturated carboxylic acids such as (meth) acrylic acid, and the like.
一官能性モノマーを添加する場合、多官能性モノマーと一官能性モノマーとの使用割合は、前者１モルに対して、後者が通常約2モル以下、好ましくは約1モル以下である。 When the monofunctional monomer is added, the ratio of the polyfunctional monomer and the monofunctional monomer used is usually about 2 mol or less, preferably about 1 mol or less, with respect to 1 mol of the former.
また、一官能性モノマーを添加する場合、重合反応に際し、原料である多官能性モノマー及びＰＥＧ含有高分子アゾ重合開始剤は、多官能性モノマー及び一官能性モノマーのモル数の合計とＰＥＧ含有高分子アゾ重合開始剤におけるＰＥＧ換算のモル数との比が、０．５：１〜１５０：１程度、好ましくは０.５：１〜１００：１程度になるように配合される。 In addition, when a monofunctional monomer is added, the polyfunctional monomer and PEG-containing polymer azo polymerization initiator, which are raw materials, are added to the total number of moles of the polyfunctional monomer and the monofunctional monomer and PEG-containing in the polymerization reaction. The polymer azo polymerization initiator is blended so that the ratio with respect to the number of moles in terms of PEG is about 0.5: 1 to 150: 1, preferably about 0.5: 1 to 100: 1.
また、この場合、反応溶液中の多官能性モノマー、ＰＥＧ含有高分子アゾ重合開始剤及び一官能性モノマーの濃度の総和が、０.１-１５ｗｔ％程度、好ましくは０.２-１０ｗｔ％程度、より好ましくは０.５-６ｗｔ％程度となるように配合される。 In this case, the total concentration of the polyfunctional monomer, the PEG-containing polymer azo polymerization initiator and the monofunctional monomer in the reaction solution is about 0.1-15 wt%, preferably about 0.2-10 wt%. More preferably, it is blended so as to be about 0.5-6 wt%.
この場合、多官能性モノマー、ＰＥＧ含有高分子アゾ重合開始剤及び一官能性モノマーを上記のような条件で配合することによって、実質的に球状でありかつ表面に凹凸を有するコア−シェル型高分子ゲル微粒子の分散粒子を製造することができる。 In this case, by blending the polyfunctional monomer, the PEG-containing polymer azo polymerization initiator and the monofunctional monomer under the conditions as described above, the core-shell type Dispersion particles of molecular gel fine particles can be produced.
本発明のコア−シェル型高分子ゲル微粒子は、ＰＥＧ含有高分子アゾ重合開始剤及び多官能性モノマーを、水及び／またはアルコール中で重合させることにより製造することができる。具体的には、例えば、上記した配合量に基づき、次のようにして実施することができる。 The core-shell type polymer gel fine particles of the present invention can be produced by polymerizing a PEG-containing polymer azo polymerization initiator and a polyfunctional monomer in water and / or alcohol. Specifically, for example, it can be carried out as follows based on the blending amount described above.
ＰＥＧ含有高分子アゾ重合開始剤を水（特に、イオン交換水）に溶解（分散）した後、アルコール（特に、エタノールまたはイソプロパノール）及び多官能性モノマーを加えて溶解（分散）させ、６０〜１００℃（好ましくは65〜85℃）に加熱して攪拌する。加熱攪拌は、窒素ガスを連続的にバブリングさせて行う。窒素ガス導入後約１５から６０分程度で反応溶液は乳白色に濁りはじめ、その後窒素気流下５〜２４時間加熱攪拌を続ける。 The PEG-containing polymer azo polymerization initiator is dissolved (dispersed) in water (especially ion-exchanged water), and then alcohol (especially ethanol or isopropanol) and a polyfunctional monomer are added and dissolved (dispersed). Heat to ℃ (preferably 65-85 ℃) and stir. The stirring with heating is performed by continuously bubbling nitrogen gas. About 15 to 60 minutes after the introduction of nitrogen gas, the reaction solution starts to become milky white, and then the heating and stirring are continued under a nitrogen stream for 5 to 24 hours.
上記操作において、ＰＥＧ含有高分子アゾ重合開始剤及び多官能性モノマーは、分散重合、ソープフリー乳化重合等のような形態の重合反応をする。 In the above operation, the PEG-containing polymer azo polymerization initiator and the polyfunctional monomer undergo a polymerization reaction such as dispersion polymerization, soap-free emulsion polymerization, and the like.
ここで、ソープフリー乳化重合とは、ＰＥＧ含有高分子アゾ重合開始剤以外の界面活性剤を含まない系における乳化重合を意味する。 Here, the soap-free emulsion polymerization means emulsion polymerization in a system that does not contain a surfactant other than the PEG-containing polymer azo polymerization initiator.
得られた混合物を、遠心分離と透析（分子量１０００以下を通す透析膜を用いて水に対して透析）を行うことにより三次元網目構造を有するコア−シェル型高分子ゲル微粒子を得る。ここで、水に対して透析とは、透析膜に合成して得た混合溶液を入れ、透析膜ごと水中に放置しておく（ビーカー等に入れて）と、浸透圧で水と低分子量成分が入れ替わり、架橋による三次元網目構造を有するコア−シェル型高分子ゲル微粒子の水分散液が得られるとするものである。この製造方法の模式図を図１に示す。 The obtained mixture is subjected to centrifugation and dialysis (dialysis against water using a dialysis membrane that passes a molecular weight of 1000 or less) to obtain core-shell type polymer gel fine particles having a three-dimensional network structure. Here, dialysis against water means that a mixed solution obtained by synthesizing into a dialysis membrane is put, and the dialysis membrane is left in water (in a beaker or the like). Are replaced, and an aqueous dispersion of core-shell type polymer gel fine particles having a three-dimensional network structure by crosslinking is obtained. A schematic diagram of this manufacturing method is shown in FIG.
本発明では、ＰＥＧ含有高分子アゾ重合開始剤は、活性点（ラジカル開始点）を主鎖骨格中に有しているため活性点が安定であり、また１分子中に数個の活性点を有しているためモノマーと反応しやすい。したがって高い収率で本発明のコア−シェル型高分子ゲル微粒子を得ることができる。また広い溶媒組成、モノマー・高分子アゾ重合開始剤比の組成範囲においてコア−シェル型高分子ゲル微粒子を得ることができる。 In the present invention, since the PEG-containing polymer azo polymerization initiator has an active site (radical start site) in the main chain skeleton, the active site is stable, and several active sites are present in one molecule. It has a tendency to react with the monomer. Therefore, the core-shell type polymer gel fine particles of the present invention can be obtained with a high yield. Moreover, core-shell type polymer gel fine particles can be obtained in a wide solvent composition and a composition range of a monomer / polymer azo polymerization initiator ratio.
得られる本発明のコア−シェル型高分子ゲル微粒子の平均粒子径は、２０〜３０００nm程度、好ましくは９０〜１０００nm程度であり、平均粒子径に対する粒子径の標準偏差の比が前者１に対して後者が０．０３〜０．６程度、特に０．０５〜０．３程度と、個々の微粒子がほぼ均一の大きさであり、単分散に近い分布をしている。なお、平均粒子径は、動的光散乱法による粒度分布測定により行う。 The average particle size of the obtained core-shell type polymer gel fine particles of the present invention is about 20 to 3000 nm, preferably about 90 to 1000 nm, and the ratio of the standard deviation of the particle size to the average particle size is relative to the former 1. The latter is about 0.03 to 0.6, particularly about 0.05 to 0.3, and the individual fine particles are almost uniform in size and have a distribution close to monodispersion. The average particle diameter is determined by measuring the particle size distribution by the dynamic light scattering method.
また、本発明において、原料であるＰＥＧ含有高分子アゾ重合開始剤におけるＰＥＧ換算のモル数に対する多官能性モノマーのモル数の比を、前者１に対して後者が０.５〜１５０程度の範囲で調節することにより、製造される本発明のコア−シェル型高分子ゲル微粒子の平均粒子径を２０〜１０００ｎｍ程度の範囲に制御できるという利点がある。通常、疎水性ビニル系モノマーのモル数に対し、ＰＥＧ換算のモル数が大きくなると、本発明のコア−シェル型高分子ゲル微粒子の平均粒子径が減少していく。 In the present invention, the ratio of the number of moles of the polyfunctional monomer to the number of moles of PEG conversion in the raw material PEG-containing polymer azo polymerization initiator is such that the latter is in the range of about 0.5 to 150 with respect to the former 1. By adjusting in step (b), there is an advantage that the average particle size of the produced core-shell type polymer gel fine particles of the present invention can be controlled in the range of about 20 to 1000 nm. Usually, when the number of moles in terms of PEG is larger than the number of moles of the hydrophobic vinyl monomer, the average particle size of the core-shell type polymer gel fine particles of the present invention decreases.
また、原料であるＰＥＧ含有高分子アゾ重合開始剤におけるＰＥＧ換算のモル数に対する疎水性ビニル系モノマーのモル数の比を変えることによって、生成される本発明のコア−シェル型高分子ゲル微粒子の膨潤度を変化させることもできる。すなわち、ＰＥＧ換算のモル数に対するビニル系モノマーのモル数の比が小さくなるほど、膨潤度は大きくなる傾向が見られた。これは、モノマーに対してＰＥＧ含有高分子アゾ重合開始剤の濃度が高くなるほど、三次元架橋の架橋密度が小さくなることに加えて分岐が起きやすくなるためと考えられる。 Further, by changing the ratio of the number of moles of the hydrophobic vinyl monomer to the number of moles in terms of PEG in the raw material PEG-containing polymer azo polymerization initiator, The degree of swelling can also be changed. That is, the degree of swelling tended to increase as the ratio of the number of moles of vinyl monomer to the number of moles in terms of PEG decreased. This is presumably because the higher the concentration of the PEG-containing polymer azo polymerization initiator with respect to the monomer, the smaller the cross-linking density of the three-dimensional cross-linking, and the easier the branching.
本発明のコア−シェル型高分子ゲル微粒子は、複数の高分子が、共有結合により架橋されて一体となった構造を有する。従って、本発明のコア−シェル型高分子ゲル微粒子は、温度及び溶媒に対して安定である。すなわち、加熱しても溶融、熱分解しにくく、また溶媒中に分散させた際に良溶媒であっても溶解しないという特徴を有する。本発明者らは多官能性モノマーによる架橋構造を含まないコア−シェル型高分子微粒子をＰＥＧ含有高分子アゾ重合開始剤及び疎水性ビニル系モノマーから製造する方法を開発しているが、同程度の配合のもの同士を比較した場合、本発明による架橋構造を有するコア−シェル型高分子ゲル微粒子の方が熱分解開始温度（5％減量時の温度）は約20℃高い。また、架橋構造のないコア−シェル型高分子微粒子はトルエンなどに溶解するが、架橋構造を有するコア−シェル型高分子ゲル微粒子では膨潤はするが、溶解はしない。
II．コア−シェル型高分子ゲル微粒子の修飾
上記で得られる本発明のコア−シェル型高分子ゲル微粒子を、次のようにして修飾することも可能である。
The core-shell type polymer gel fine particles of the present invention have a structure in which a plurality of polymers are integrated by covalent bonding. Therefore, the core-shell type polymer gel fine particles of the present invention are stable with respect to temperature and solvent. That is, it is difficult to melt and pyrolyze even when heated, and does not dissolve even if it is a good solvent when dispersed in a solvent. The present inventors have developed a method for producing core-shell type polymer fine particles that do not contain a cross-linked structure of a polyfunctional monomer from a PEG-containing polymer azo polymerization initiator and a hydrophobic vinyl-based monomer. In comparison, the core-shell type polymer gel fine particles having a crosslinked structure according to the present invention have a higher thermal decomposition starting temperature (temperature at 5% weight loss) of about 20 ° C. Further, the core-shell type polymer fine particles having no crosslinked structure are dissolved in toluene or the like, but the core-shell type polymer gel fine particles having a crosslinked structure are swollen but not dissolved.
II. Modification of core-shell type polymer gel fine particles The core-shell type polymer gel fine particles of the present invention obtained above can be modified as follows.
例えば、本発明のコア−シェル型高分子ゲル微粒子を核として用い、水及び／またはアルコール中で、ビニル系モノマーを重合させて高分子層で少なくとも一部が被覆されたコア−シェル型高分子ゲル微粒子を製造することができる。この場合、1）溶媒中に分散されたコア−シェル型高分子ゲル微粒子を核として重合により高分子層を被覆することもできるが、2）あらかじめビニル系モノマーを用いてコア−シェル型高分子ゲル微粒子を膨潤させておき、その後余分なビニル系モノマーを除去した後、膨潤したコア−シェル型高分子ゲル微粒子を溶媒中に分散させて、適宜触媒を加えることで、コア−シェル型高分子ゲル微粒子に新たな高分子層を複合化させることもできる。 For example, the core-shell type polymer gel fine particle of the present invention is used as a nucleus, and a vinyl-type monomer is polymerized in water and / or alcohol to be at least partially coated with a polymer layer. Gel fine particles can be produced. In this case, the polymer layer can be coated by polymerization using 1) core-shell type polymer gel fine particles dispersed in a solvent as a nucleus, but 2) a core-shell type polymer using a vinyl monomer in advance. After the gel fine particles are swollen and then the excess vinyl monomer is removed, the swollen core-shell polymer gel fine particles are dispersed in a solvent, and a catalyst is added as appropriate. A new polymer layer can be combined with the gel fine particles.
用いるビニル系モノマーは、その目的に応じて適宜選択することができ、疎水性または親水性のいずれのものでもよい。具体例としては、グリシジルメタクリレート（ＧＭＡ）、（メタ）アクリル酸、メタクリル酸ヒドロキシエチル等が好適に用いられる。ビニル系モノマーの添加量は、コア−シェル型高分子ゲル微粒子に対して、1）の方法では0.5〜10wt%程度、好ましくは1〜5wt%程度、2）の方法では100〜5000wt%程度、好ましくは200〜4000wt%程度であればよい。 The vinyl monomer to be used can be appropriately selected according to the purpose, and may be either hydrophobic or hydrophilic. As specific examples, glycidyl methacrylate (GMA), (meth) acrylic acid, hydroxyethyl methacrylate and the like are preferably used. The addition amount of the vinyl monomer is about 0.5 to 10 wt%, preferably about 1 to 5 wt% in the method 1), and about 100 to 5000 wt% in the method 2) with respect to the core-shell type polymer gel fine particles. Preferably, it may be about 200 to 4000 wt%.
重合反応は、溶液重合、分散重合、乳化重合等の公知の反応を用いることができる。例えば、コア−シェル型高分子ゲル微粒子の水／エタノール分散液にビニル系モノマー（例えば、ＧＭＡ等）を加えて、窒素気流下７０〜９０℃で５〜２０時間程度加熱処理することにより、コア−シェル型高分子ゲル微粒子の外側にビニル系モノマー由来の高分子層を有する複合微粒子が製造される。 As the polymerization reaction, known reactions such as solution polymerization, dispersion polymerization, and emulsion polymerization can be used. For example, by adding a vinyl monomer (for example, GMA or the like) to a water / ethanol dispersion of core-shell type polymer gel fine particles and heat-treating at 70 to 90 ° C. for about 5 to 20 hours under a nitrogen stream, the core is obtained. -Composite fine particles having a polymer layer derived from a vinyl monomer outside the shell type polymer gel fine particles are produced.
また、コア−シェル型高分子ゲル微粒子を核として用い、金属アルコキシドを反応させて金属酸化物層で少なくとも１部が被覆されたコア−シェル型高分子ゲル微粒子を製造することができる。この場合、1）溶媒中に分散されたコア−シェル型高分子ゲル微粒子を核として金属酸化物層を被覆することもできるが、2）あらかじめ金属アルコキシドを用いてコア−シェル型高分子ゲル微粒子を膨潤させておき、その後余分な金属アルコキシドを除去した後、膨潤したコア−シェル型高分子ゲル微粒子を溶媒中に分散させて、適宜触媒を加えることで、コア−シェル型高分子ゲル微粒子に金属酸化物を複合化させることもできる。 Further, core-shell type polymer gel fine particles in which at least one part is coated with a metal oxide layer by reacting metal alkoxide using core-shell type polymer gel fine particles as nuclei can be produced. In this case, 1) the core-shell type polymer gel fine particles dispersed in the solvent can be used as a core to coat the metal oxide layer, but 2) the core-shell type polymer gel fine particles are previously used using a metal alkoxide. After the excess metal alkoxide is removed, the swollen core-shell type polymer gel fine particles are dispersed in a solvent, and an appropriate catalyst is added to form the core-shell type polymer gel fine particles. Metal oxides can also be combined.
用いる金属アルコキシドとしては、テトラアルコキシシラン、テトラアルコキシチタン、トリアルコキシアルミニウム等が例示される。 Examples of the metal alkoxide to be used include tetraalkoxysilane, tetraalkoxytitanium, trialkoxyaluminum and the like.
テトラアルコキシシランとしては、テトラメトキシシラン、テトラエトキシシラン（ＴＥＯＳ）、テトライソプロポキシシラン、テトラｎ−ブトキシシラン等が挙げられ、好ましくは、ＴＥＯＳ、テトライソプロポキシシラン、テトラｎ−ブトキシシランである。また、テトラアルコキシチタンとしては、テトラエトキシチタン、テトライソプロポキシチタン、テトラｎ−ブトキシチタン等が挙げられ、好ましくは、テトラエトキシチタンまたはテトライソプロポキシチタンである。 Examples of the tetraalkoxysilane include tetramethoxysilane, tetraethoxysilane (TEOS), tetraisopropoxysilane, tetra n-butoxysilane, and the like, and preferably TEOS, tetraisopropoxysilane, and tetra n-butoxysilane. Examples of the tetraalkoxy titanium include tetraethoxy titanium, tetraisopropoxy titanium, tetra n-butoxy titanium and the like, and tetraethoxy titanium or tetraisopropoxy titanium is preferable.
溶媒としてはアルコール（メタノール、エタノール、ｎ−プロパノール、イソプロパノール、ｎ−ブタノール等）またはアルコール／水混合系（100/0〜50/50程度）が用いられる。 As the solvent, alcohol (methanol, ethanol, n-propanol, isopropanol, n-butanol, etc.) or an alcohol / water mixed system (about 100/0 to 50/50) is used.
金属アルコキシドの添加量は、微粒子全重量中の金属酸化物の重量分率が、1）の方法では10〜90wt%程度、好ましくは20〜75wt%程度、2）の方法では100〜5000wt%程度、好ましくは200〜4000wt%程度になるように添加すればよい。 The amount of metal alkoxide added is such that the weight fraction of the metal oxide in the total weight of the fine particles is about 10 to 90 wt% in the method 1), preferably about 20 to 75 wt%, and about 100 to 5000 wt% in the method 2). Preferably, it may be added so as to be about 200 to 4000 wt%.
金属酸化物層の形成は、ゾル−ゲル法等の公知の反応を用いることができる。例えば、本発明のコア−シェル型高分子ゲル微粒子に金属アルコキシド（例えば、ＴＥＯＳ等）を加えて室温で膨潤させた後、余分な金属アルコキシドを除去し、エタノール中に分散させた後、触媒量のアンモニア水溶液を加えて、これを室温で２〜１０時間程度撹拌する。得られた混合物を遠心分離にかけて分離して、金属酸化物層で被覆されたコア−シェル型高分子ゲル微粒子が製造される。 For the formation of the metal oxide layer, a known reaction such as a sol-gel method can be used. For example, after adding a metal alkoxide (for example, TEOS) to the core-shell type polymer gel fine particles of the present invention to swell at room temperature, excess metal alkoxide is removed and dispersed in ethanol. Aqueous ammonia solution is added and stirred at room temperature for about 2 to 10 hours. The obtained mixture is separated by centrifuging to produce core-shell type polymer gel fine particles coated with a metal oxide layer.
更に上記で製造される金属酸化物層で被覆されたコア−シェル型高分子ゲル微粒子を加熱処理することにより有機成分を除去して中空金属酸化物微粒子を製造することもできる。本発明において用語「加熱処理」は、焼成処理を包含する。加熱処理は、４００〜1000℃の温度で、1〜7時間程度であればよい。
III．用途
本発明の架橋による三次元網目構造を有するコア−シェル型高分子ゲル微粒子は、平均粒子径の分布が狭く、均質な微粒子である。
Furthermore, by subjecting the core-shell type polymer gel fine particles coated with the metal oxide layer produced as described above to heat treatment, the organic component can be removed to produce hollow metal oxide fine particles. In the present invention, the term “heat treatment” includes baking treatment. The heat treatment may be performed at a temperature of 400 to 1000 ° C. for about 1 to 7 hours.
III. Use The core-shell type polymer gel fine particles having a three-dimensional network structure formed by crosslinking according to the present invention are homogeneous fine particles having a narrow average particle size distribution.
本発明のコア−シェル型高分子ゲル微粒子は、そのコア部に目的の物質を保持させることによりカプセル化微粒子を製造することができる。この用途においては、本発明のコア−シェル型高分子ゲル微粒子は、より簡便かつ高効率にカプセル化微粒子を製造することができる。 The core-shell type polymer gel fine particles of the present invention can produce encapsulated fine particles by holding the target substance in the core portion. In this application, the core-shell type polymer gel fine particles of the present invention can produce encapsulated fine particles more easily and efficiently.
例えば、カプセル化微粒子は、本発明のコア−シェル型高分子ゲル微粒子を構成するコア部及びシェル部ならびにカプセル化させたい物質の全てに親和性の高いいわゆる良溶媒に、本発明のコア−シェル型高分子ゲル微粒子及び目的物質を溶解することによって製造することができる。この操作により、本発明のコア−シェル型高分子ゲル微粒子は、その三次元網目構造内に溶媒及び目的物質を取り込んで膨潤し、カプセル化微粒子となる。 For example, the encapsulated fine particles are used in the so-called good solvent having a high affinity for the core portion and the shell portion constituting the core-shell type polymer gel fine particles of the present invention and all the substances to be encapsulated. Can be produced by dissolving the fine polymer gel particles and the target substance. By this operation, the core-shell type polymer gel fine particles of the present invention take the solvent and the target substance into the three-dimensional network structure and swell to become encapsulated fine particles.
上記製造方法において本発明のコア−シェル型高分子ゲル微粒子の替わりに、架橋構造のない微粒子を用いると、良溶媒に溶解した段階で、当該微粒子が、その構成する高分子1分子までほぐれて、溶媒中に当該高分子と目的物質が溶解した溶液となる。従って、これをカプセル化微粒子の形状にするためには、この後に、良溶媒から貧溶媒への溶媒の置換により高分子と目的物質を共沈殿させる工程及び精製工程という追加の工程が必要となる。 In the above production method, instead of the core-shell type polymer gel fine particles of the present invention, when fine particles having no cross-linked structure are used, the fine particles are loosened up to one molecule of the constituent polymer when dissolved in a good solvent. A solution in which the polymer and the target substance are dissolved in a solvent is obtained. Therefore, in order to make this into the shape of encapsulated fine particles, an additional step of a coprecipitation of a polymer and a target substance by substitution of a solvent from a good solvent to a poor solvent and an additional purification step are required thereafter. .
また、本発明のコア−シェル型高分子ゲル微粒子は、シェル部に親水性ポリマーを有していることから、シェル部に抗原タンパクを結合させて血液等の診断薬として用いることができる。抗体の検出により、抗原−抗体反応によって粒子同士が凝集することから、透過率を測定することによって容易に診断が可能となる。特に、表面に凹凸を有するコア−シェル型高分子ゲル微粒子は、粒子１個当りにより多くの抗原タンパク質を結合させられるため有用である。 Further, since the core-shell type polymer gel fine particles of the present invention have a hydrophilic polymer in the shell part, the antigen protein can be bound to the shell part and used as a diagnostic agent for blood or the like. Since the particles are aggregated due to the antigen-antibody reaction due to the detection of the antibody, it is possible to easily diagnose by measuring the transmittance. In particular, core-shell type polymer gel fine particles having irregularities on the surface are useful because more antigenic proteins can be bound per particle.
また、コア部に用いる高分子の選択によって、特定温度以上で収縮する感温性のゲル微粒子、コア内に不安定な薬効成分を包含させて患部に達した際に効果を発揮させるドラッグデリバリーシステム、コア内に診断に有効な発光性微粒子あるいは磁気微粒子を包含させた診断剤等の応用が可能である。粒子径分布が狭く、容易にコア−シェル微粒子を得ることができるため、上記のような従来のコア−シェル微粒子の使用用途において、より高性能な使用が可能となり、用途拡大が期待される。たとえば、診断精度の向上、感温性ゲル微粒子の場合の収縮温度範囲を狭くする等である。 Also, drug delivery system that exerts effects when it reaches the affected area by containing thermosensitive gel fine particles that shrink at a specific temperature or higher, and unstable medicinal ingredients in the core, by selecting the polymer used for the core In addition, it is possible to apply a diagnostic agent in which luminescent fine particles or magnetic fine particles effective for diagnosis are included in the core. Since the particle size distribution is narrow and the core-shell fine particles can be easily obtained, the above-described conventional use of the core-shell fine particles can be used with higher performance, and the application is expected to be expanded. For example, improvement of diagnostic accuracy, narrowing of the contraction temperature range in the case of thermosensitive gel fine particles, and the like.
さらに凹凸を有するコア−シェル型高分子ゲル微粒子については、凹凸形状を利用することでナノ粒子の分別や除去、ウイルスの除去などが可能なフィルターへの応用も期待できる。 Furthermore, the core-shell type polymer gel fine particles having irregularities can be expected to be applied to filters capable of separating and removing nanoparticles and removing viruses by utilizing the irregular shapes.
その他、エマルションあるいは分散溶液として、粘着剤、塗料、フィルム形成材、インク、繊維処理剤、紙処理剤、固形分としてブロッキング防止剤、クロマト充填材等従来の工業製品、にも用いることが可能であり、同様に高性能化、用途拡大が期待される。 In addition, it can also be used in conventional industrial products such as pressure sensitive adhesives, paints, film forming materials, inks, fiber processing agents, paper processing agents, anti-blocking agents and chromatographic fillers as solids as emulsions or dispersion solutions. In the same way, high performance and application expansion are expected.
本発明によれば、簡便かつ効率的に粒子径分布が狭いコア−シェル型高分子ゲル微粒子を製造することができる。ＰＥＧ含有高分子アゾ重合開始剤は、ＰＥＧを有しているため水性媒体に分散しやすく、分子鎖骨格中に重合開始部分を有しているため、別途水溶性重合開始剤を使用する必要がない。しかも、ラジカルの反応性、安定性が高いという特徴を有している。 According to the present invention, core-shell type polymer gel fine particles having a narrow particle size distribution can be produced simply and efficiently. Since PEG-containing polymer azo polymerization initiator has PEG, it is easy to disperse in an aqueous medium, and since it has a polymerization initiation part in the molecular chain skeleton, it is necessary to use a separate water-soluble polymerization initiator. Absent. In addition, it has a feature of high radical reactivity and stability.
さらに、本発明のコア−シェル型高分子ゲル微粒子は、構成成分である高分子が架橋により互いに結合されているので、微粒子としての安定性が高い。従って、本発明のコア−シェル型高分子ゲル微粒子は、これを用いることによって、簡便かつ高効率にカプセル化微粒子を製造することができるという利点も有している。 Furthermore, the core-shell type polymer gel fine particles of the present invention have high stability as fine particles because the constituent polymers are bonded to each other by crosslinking. Therefore, the core-shell type polymer gel fine particles of the present invention also have an advantage that the encapsulated fine particles can be produced easily and efficiently by using this.
また、ＰＥＧ含有高分子アゾ重合開始剤と多官能性モノマーとのモル比を変えることで、所望の膨張度、粒子径のコア−シェル型高分子ゲル微粒子を製造することができる。 Further, by changing the molar ratio of the PEG-containing polymer azo polymerization initiator and the polyfunctional monomer, core-shell type polymer gel fine particles having a desired degree of expansion and particle diameter can be produced.
さらに、凹凸を有するコア−シェル型高分子ゲル微粒子は、体積に対する比表面積が高いことに起因して、シェル部により多くの分子を吸着させることができる等の利点を有する。 Furthermore, the core-shell type polymer gel fine particles having irregularities have an advantage that more molecules can be adsorbed by the shell part due to the high specific surface area relative to the volume.
上記のような特徴を有する本発明のコア−シェル型高分子ゲル微粒子は、広範な用途に用いることができる。 The core-shell type polymer gel fine particles of the present invention having the above characteristics can be used for a wide range of applications.
次に本発明を、以下の実施例及び比較例を用いて詳細に説明するが、これによって本発明が限定されるわけではない。 Next, the present invention will be described in detail using the following examples and comparative examples, but the present invention is not limited thereby.
実施例１
200ｍｌ四つ口フラスコに高分子アゾ開始剤VPE0201（和光純薬製、PEG部分の分子量2000）0.452ｇ（PEG換算のモル数2.0Ｘ10-4モル）を入れ、イオン交換水60ｍｌに完全に溶かした後、この溶液にエタノール（以下EtOH）40ｍｌ、エチレングリコールジメタクリレート（以下EGDMA）1.982ｇ（1Ｘ１０-2モル）を加えて攪拌した。EGDMAのモル数／PEG換算のモル数＝50であった。
Example 1
In a 200 ml four-necked flask, 0.452 g of polymer azo initiator VPE0201 (manufactured by Wako Pure Chemical Industries, PEG molecular weight 2000) (mol of PEG equivalent 2.0 × 10 −4 mol) was completely dissolved in 60 ml of ion-exchanged water. Thereafter, 40 ml of ethanol (hereinafter EtOH) and 1.982 g (1 × 10 −2 mol) of ethylene glycol dimethacrylate (hereinafter EGDMA) were added to the solution and stirred. The number of moles of EGDMA / number of moles in terms of PEG = 50.
この四つ口フラスコに窒素ガス導入用キャピラリー管、攪拌羽根、冷却管を取り付け、オイルバス中において、四つ口フラスコ中の溶液を加熱攪拌し、75℃に達した後、窒素ガスを連続的にバブリングさせた。窒素ガス導入後50分程度で、反応溶液は乳白色に濁りはじめた。その後窒素気流下15時間加熱攪拌を続けた。反応溶液の遠心分離と透析（分子量1000以下を通す透析膜を用いて水に対して透析）によりEGDMAコア/PEGシェルの凹凸を有するコア−シェル型高分子ゲル微粒子を得た。 A capillary tube for introducing nitrogen gas, a stirring blade, and a cooling tube are attached to this four-necked flask, and the solution in the four-necked flask is heated and stirred in an oil bath, and after reaching 75 ° C, nitrogen gas is continuously added. Bubbling. About 50 minutes after the introduction of nitrogen gas, the reaction solution began to become milky white. Thereafter, heating and stirring were continued for 15 hours under a nitrogen stream. Centrifugation of the reaction solution and dialysis (dialysis against water using a dialysis membrane that passes a molecular weight of 1000 or less) yielded core-shell type polymer gel fine particles having EGDMA core / PEG shell irregularities.
動的光散乱法による粒度分布測定（大塚電子製ELS-8000HW）により得られた粒子径は388±57.8nm（個数分布）であった。この値は走査型電子顕微鏡（SEM）の結果とほぼ一致した。トルエンを用いた膨潤度測定の結果は、4.38であった。 The particle size obtained by particle size distribution measurement by dynamic light scattering method (ELS-8000HW manufactured by Otsuka Electronics) was 388 ± 57.8 nm (number distribution). This value almost coincided with the result of scanning electron microscope (SEM). The result of swelling degree measurement using toluene was 4.38.
得られたコア−シェル型高分子ゲル微粒子のSEM像を図２に示す。 The SEM image of the obtained core-shell type polymer gel fine particles is shown in FIG.
実施例2
実施例１におけるVPE0201添加量を1.131g (PEG換算のモル数5X10-4mol) とし、他の条件は変えずに合成を行った。EGDMAのモル数／PEG換算のモル数＝20であった。その結果、粒子径179±29.9nm（個数分布）の凹凸を有するコアシェル型高分子ゲル微粒子を得た。トルエンを用いた膨潤度は4.43であった。VPE0201モル数に対するモノマーモル数の比が小さい場合には粒子径は小さく、比を大きくすると粒子径は大きくなる傾向にあった。得られたコア−シェル型高分子ゲル微粒子のSEM像を図３に示す。
Example 2
The VPE0201 addition amount in Example 1 was 1.131 g (number of moles in terms of PEG: 5 × 10 −4 mol), and synthesis was performed without changing other conditions. The number of moles of EGDMA / number of moles in terms of PEG = 20. As a result, core-shell type polymer gel fine particles having irregularities with a particle diameter of 179 ± 29.9 nm (number distribution) were obtained. The degree of swelling with toluene was 4.43. When the ratio of the number of moles of monomer to the number of moles of VPE0201 is small, the particle diameter is small, and when the ratio is large, the particle diameter tends to be large. The SEM image of the obtained core-shell type polymer gel fine particles is shown in FIG.
比較例１
実施例１におけるVPE0201添加量0.5655g（PEG換算のモル数2.5Ｘ10-4モル）、EGDMAの添加量9.911g（5Ｘ10-2モル）とし、他の条件は変えずに合成を行った。EGDMAのモル数／PEG換算のモル数＝200であった。その結果、合成開始後約3時間でポリマーがゲル状に析出し、攪拌が不可能となった。これは、粒子内での架橋だけでなく、粒子間での架橋がおこり、マクロゲル化したことによるものと考えられる。VPE0201モル数に対するモノマーモル数の比が、150程度より大きい場合にはマクロゲル化する傾向が見られた。
Comparative Example 1
The VPE0201 addition amount in Example 1 was 0.5655 g (number of moles in terms of PEG: 2.5 × 10 −4 mol) and the addition amount of EGDMA was 9.911 g (5 × 10 −2 mol), and the synthesis was carried out without changing other conditions. The number of moles of EGDMA / number of moles in terms of PEG = 200. As a result, about 3 hours after the start of synthesis, the polymer precipitated in a gel state, and stirring was impossible. This is considered to be caused not only by the cross-linking within the particles but also by the cross-linking between the particles, resulting in macro gelation. When the ratio of the number of moles of monomer to the number of moles of VPE0201 was greater than about 150, a tendency to macrogel was observed.
比較例2
実施例１におけるVPE0201添加量1.414g（PEG換算のモル数6.25Ｘ10-4モル）、EGDMAのかわりにMMAを10.0g（1Ｘ10-2モル）用い、イオン交換水48ml, EtOH 32ml （水：EtOH=60：40）として、75℃11時間合成を行った。MMAのモル数／PEG換算のモル数＝160であった。その結果、粒子径194.0±28.8nm（個数分布）の凹凸のない球状コア−シェル型高分子微粒子が得られた（SEM像を図４に示す）。得られた微粒子はコア部分に架橋を有しないため、トルエン、テトラヒドロフランなどの溶媒に溶解した。
Comparative Example 2
The amount of VPE0201 added in Example 1 was 1.414 g (number of moles in terms of PEG: 6.25 × 10 −4 mol), 10.0 g (1 × 10 −2 mol) of MMA was used instead of EGDMA, ion-exchanged water 48 ml, EtOH 32 ml (water: EtOH = 60:40) and the synthesis was carried out at 75 ° C. for 11 hours. The number of moles of MMA / the number of moles in terms of PEG = 160. As a result, spherical core-shell type polymer fine particles having a particle size of 194.0 ± 28.8 nm (number distribution) and no irregularities were obtained (SEM image is shown in FIG. 4). Since the obtained fine particles did not have cross-linking in the core portion, they were dissolved in a solvent such as toluene or tetrahydrofuran.
トルエンに溶解させた後、再度水：EtOH=60：40に添加させると、再度微粒子が分散した状態となった。しかし、粒度分布測定およびSEM観察の結果（SEM像を図5に示す）から、（溶解-再分散させる前の）もとの粒子よりも粒度分布が広くなっていることがわかった。 When dissolved in toluene and then added again to water: EtOH = 60: 40, the fine particles were dispersed again. However, from the results of particle size distribution measurement and SEM observation (SEM image shown in FIG. 5), it was found that the particle size distribution was wider than the original particles (before dissolution-redispersion).
一方、実施例２で得られたコア−シェル型高分子ゲル微粒子を同様にトルエンに分散させると、これは架橋構造を有するため、膨潤するが、溶解しない。膨潤した微粒子を遠心分離により回収し、粒度分布測定および乾燥後にSEM観察した結果（図6）、粒子径および粒子径分布は（トルエンで膨潤させる前の）もとの微粒子とほぼ同じであった。 On the other hand, when the core-shell type polymer gel fine particles obtained in Example 2 are similarly dispersed in toluene, this has a crosslinked structure, so that it swells but does not dissolve. The swollen fine particles were collected by centrifugation, and as a result of particle size distribution measurement and SEM observation after drying (Fig. 6), the particle size and particle size distribution were almost the same as the original fine particles (before swelling with toluene) .
以上の結果から、コア−シェル型高分子微粒子をカプセル材料として用いる場合、架橋構造のない微粒子では、内包させる化合物とともに共溶解、再分散、回収、精製、といったプロセスを経る必要がある。また、用いる溶媒によっては、もとの粒度分布を保持していない場合があり、思考錯誤が必要となるものと考えられる。一方、本発明により得られるコア−シェル型高分子ゲル微粒子を用いる場合、内包させる化合物とともに良溶媒に溶解（架橋微粒子は分散、膨潤）させ、遠心分離などにより回収するだけで、もとの粒度分布を保ったカプセル化粒子を容易に調製することができる。 From the above results, when the core-shell type polymer fine particles are used as the capsule material, the fine particles having no crosslinked structure need to undergo processes such as co-dissolution, redispersion, recovery, and purification together with the compound to be encapsulated. Also, depending on the solvent used, the original particle size distribution may not be maintained, and thought and error is considered necessary. On the other hand, when the core-shell type polymer gel fine particles obtained by the present invention are used, the original particle size can be obtained simply by dissolving them in a good solvent together with the compound to be encapsulated (cross-linked fine particles are dispersed and swollen) and collecting them by centrifugation or the like. Encapsulated particles having a distribution can be easily prepared.
実施例３（コアシェル微粒子の外側にシリカ層を有する複合微粒子）
（１）実施例２で得られた微粒子0.05ｇを10ｍｌのサンプル管にとり、テトラブトキシシラン(TBOS)２ccとともに混合して密封したまま、室温にて24時間保持して膨潤させた。その後上記試料の上澄みを除去し沈降した微粒子のみを100ccエルレンマイヤーフラスコに入れ、MeOH 50ｍｌを加えて超音波洗浄器を用いて再分散させた。分散後、アンモニア水溶液（２８％）2ｍｌを加え、マグネチックスターラーで室温において5時間攪拌を続けた。得られた微粒子を遠心分離により分離させた。コアシェル微粒子の外側にシリカ層を有する複合微粒子を得た。得られた複合微粒子のSEM像を図７に示す。
Example 3 (composite fine particles having a silica layer outside the core-shell fine particles)
(1) 0.05 g of the fine particles obtained in Example 2 were taken in a 10 ml sample tube, mixed with 2 cc of tetrabutoxysilane (TBOS) and kept sealed at room temperature for 24 hours to swell. Thereafter, the supernatant of the sample was removed, and only the settled fine particles were placed in a 100 cc Erlenmeyer flask, 50 ml of MeOH was added, and redispersed using an ultrasonic cleaner. After the dispersion, 2 ml of an aqueous ammonia solution (28%) was added, and stirring was continued for 5 hours at room temperature with a magnetic stirrer. The resulting microparticles were separated by centrifugation. Composite fine particles having a silica layer outside the core-shell fine particles were obtained. An SEM image of the obtained composite fine particles is shown in FIG.
25℃における粒子径551±88.9nm（個数分布）。示差熱熱天秤測定による750℃での残渣から、シリカ成分は約57wt％であった。
（２）600℃、3時間で焼成後もSEM観察による粒子形状などに変化は見られず、焼成によって中空微粒子が得られたものと考えられる。得られた微粒子のSEM像を図８に示す。
Particle size 551 ± 88.9nm at 25 ° C (number distribution). From the residue at 750 ° C. by differential thermothermal balance measurement, the silica component was about 57 wt%.
(2) Even after firing at 600 ° C. for 3 hours, there was no change in the particle shape or the like by SEM observation, and it is considered that hollow fine particles were obtained by firing. The SEM image of the obtained fine particles is shown in FIG.
実施例４
実施例２におけるVPE0201添加量およびEGDMAの添加量は変えず、用いる溶媒をイオン交換水70ｍｌ、EtOH 30ｍｌとして合成を行った。その結果、粒子径400.7±82.5nm（個数分布）の凹凸を有するコア−シェル型高分子ゲル微粒子を得た。得られた微粒子のSEM像を図９に示す。（SEMによりえられた粒子径と粒度分布の結果は一致していないが、粒度分布測定では、粒子が膨潤しているためと考えられる）。トルエンを用いた膨潤度は5.76であった。用いる溶媒としてEtOHとイオン交換水の比率を変えた場合、水含有率が60vol%程度で粒子径が極小を示した。水含有率が40-60vol%の範囲では粒子径の変化は大きくなかったが、60vol%を越えると急激に粒子径は大きくなった。これはモノマーおよびポリマーの溶解性が関係しているものと考えられる。
Example 4
The VPE0201 addition amount and EGDMA addition amount in Example 2 were not changed, and the synthesis was carried out using 70 ml of ion-exchanged water and 30 ml of EtOH. As a result, core-shell type polymer gel fine particles having irregularities with a particle diameter of 400.7 ± 82.5 nm (number distribution) were obtained. FIG. 9 shows an SEM image of the obtained fine particles. (The particle size and particle size distribution obtained by SEM do not match, but in the particle size distribution measurement, it is considered that the particles are swollen). The degree of swelling with toluene was 5.76. When the ratio of EtOH and ion-exchanged water was changed as the solvent to be used, the water content was about 60 vol% and the particle size was minimal. The change in particle size was not large when the water content was in the range of 40-60 vol%, but the particle size suddenly increased beyond 60 vol%. This is thought to be related to the solubility of the monomer and polymer.
実施例５
実施例１において、モノマーとしてEGDMA0.991ｇ（5×10-3モル）およびメタクリル酸メチル（MMA）0.501ｇ（5Ｘ１０-3モル）を用い、他の条件は変えずに合成を行った。（EGDMA+MMAのモル数）／PEG換算のモル数＝50（（EGDMAのモル数）／PEG換算のモル数＝25）であった。その結果、粒子径177±28.9nm（個数分布）の凹凸を有するコア−シェル型高分子ゲル微粒子を得た。得られた微粒子のSEM像を図１０に示す。トルエンを用いた膨潤度は4.85であった。また、用いるモノマーの内MMAの割合を変えて微粒子の合成を行った結果、用いるモノマーの内MMAの割合が50％以下であれば得られたコア−シェル型高分子ゲル微粒子は凹凸を有することがわかった。
Example 5
In Example 1, EGDMA 0.991 g (5 × 10 −3 mol) and methyl methacrylate (MMA) 0.501 g (5 × 10 −3 mol) were used as monomers, and the synthesis was performed without changing other conditions. It was (number of moles of EGDMA + MMA) / number of moles in terms of PEG = 50 ((number of moles of EGDMA) / number of moles in terms of PEG = 25). As a result, core-shell type polymer gel fine particles having irregularities with a particle size of 177 ± 28.9 nm (number distribution) were obtained. The SEM image of the obtained fine particles is shown in FIG. The degree of swelling with toluene was 4.85. In addition, as a result of synthesizing fine particles by changing the proportion of MMA in the monomer to be used, the core-shell type polymer gel fine particles obtained should have irregularities if the proportion of MMA in the monomer to be used is 50% or less. I understood.
実施例６
実施例２におけるVPE0201の代わりにVPE0601（和光純薬製、PEG部分の分子量6000）3.131ｇ（PEG換算のモル数5.0×10-4モル）を用い、EGDMA添加量を1.982ｇ（1×10-2モル）とし、イオン交換水60ｍｌ、EtOH 40ｍｌを用いて75℃15時間加熱攪拌により合成を行った。MMAのモル数／PEG換算のモル数＝20であった。その結果、粒子径251±47.0nm（個数分布）の凹凸を有するコア−シェル型高分子ゲル微粒子を得た。
Example 6
Instead VPE0601 (manufactured by Wako Pure Chemical Industries, Ltd., molecular weight 6000 PEG moiety) of VPE0201 in Example 2 3.131G used (mole number 5.0 × 10 -4 mol of PEG terms), EGDMA amount of 1.982g (1 × 10 - 2 mol), and synthesized by heating and stirring at 75 ° C. for 15 hours using 60 ml of ion exchange water and 40 ml of EtOH. The number of moles of MMA / number of moles in terms of PEG = 20. As a result, core-shell type polymer gel fine particles having irregularities with a particle diameter of 251 ± 47.0 nm (number distribution) were obtained.
得られた微粒子のSEM像を図１１に示す。 FIG. 11 shows an SEM image of the obtained fine particles.
実施例7
実施例1においてVPE0201 1.131ｇ（PEG換算のモル数5×10-4モル）、EGDMAの代わりにメチレンビスアクリルアミド(MBAA) 1.54ｇ（1×10-2モル）を用い、他の条件は変えずに合成を行った。MBAAのモル数／PEG換算のモル数＝20であった。
Example 7
In Example 1, 1.131 g of VPE0201 (5 × 10 −4 mol in terms of PEG) and 1.54 g (1 × 10 −2 mol) of methylenebisacrylamide (MBAA) were used instead of EGDMA, and other conditions were not changed. Was synthesized. The number of moles of MBAA / number of moles in terms of PEG = 20.
その結果、粒子径170±34.3nm（個数分布）の凹凸を有するコアシェル型高分子ゲル微粒子を得た。 As a result, core-shell type polymer gel fine particles having irregularities with a particle size of 170 ± 34.3 nm (number distribution) were obtained.
得られた微粒子のSEM像を図１２に示す。 FIG. 12 shows an SEM image of the obtained fine particles.
Claims (10)
多官能性モノマーが、エチレングリコールジメタクリレート、メチレンビスアクリルアミド、ジビニルベンゼン、トリエチレングリコールジメタクリレート及びエチレンビスアクリルアミドからなる群より選ばれる少なくとも１種であるコア−シェル型高分子ゲル微粒子の製造方法。 A core-shell type polymer gel fine particle having an average particle size of 20 nm to 3000 nm, wherein a PEG-containing polymer azo polymerization initiator and a monomer composed only of a polyfunctional monomer are polymerized in water and / or alcohol. A manufacturing method comprising:
A method for producing core-shell type polymer gel fine particles, wherein the polyfunctional monomer is at least one selected from the group consisting of ethylene glycol dimethacrylate, methylene bisacrylamide, divinylbenzene, triethylene glycol dimethacrylate, and ethylene bisacrylamide .
（式中、ｍは２０〜２５０の整数、ｎは４〜５０の整数を示す。）
で表される繰り返し単位を含む高分子化合物である請求項１に記載の製造方法。 The PEG-containing polymeric azo polymerization initiator is represented by the general formula (I):
(In the formula, m represents an integer of 20 to 250, and n represents an integer of 4 to 50.)
The manufacturing method of Claim 1 which is a high molecular compound containing the repeating unit represented by these.
多官能性モノマーが、エチレングリコールジメタクリレート、メチレンビスアクリルアミド、ジビニルベンゼン、トリエチレングリコールジメタクリレート及びエチレンビスアクリルアミドからなる群より選ばれる少なくとも１種であるコア−シェル型高分子ゲル微粒子。 A core-shell type polymer gel fine particle comprising a core part comprising a polymer obtained by polymerizing a monomer composed only of a polyfunctional monomer and a shell part comprising a PEG-containing polymer, the average particle diameter of the fine particle The ratio of the standard deviation of the particle diameter is a core-shell type polymer gel fine particle in which the latter is 0.05 to 0.6 with respect to the former 1,
Core-shell type polymer gel fine particles, wherein the polyfunctional monomer is at least one selected from the group consisting of ethylene glycol dimethacrylate, methylene bisacrylamide, divinylbenzene, triethylene glycol dimethacrylate, and ethylene bisacrylamide .
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