JPH01170854A - Production of carrier particle for immobilizing physiologically active material - Google Patents
Production of carrier particle for immobilizing physiologically active materialInfo
- Publication number
- JPH01170854A JPH01170854A JP62331024A JP33102487A JPH01170854A JP H01170854 A JPH01170854 A JP H01170854A JP 62331024 A JP62331024 A JP 62331024A JP 33102487 A JP33102487 A JP 33102487A JP H01170854 A JPH01170854 A JP H01170854A
- Authority
- JP
- Japan
- Prior art keywords
- acrylic acid
- weight
- latex
- monomer mixture
- particles
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 239000002245 particle Substances 0.000 title claims abstract description 87
- 230000003100 immobilizing effect Effects 0.000 title claims description 11
- 238000004519 manufacturing process Methods 0.000 title claims description 9
- 239000011149 active material Substances 0.000 title 1
- 239000004816 latex Substances 0.000 claims abstract description 67
- 229920000126 latex Polymers 0.000 claims abstract description 67
- 239000000203 mixture Substances 0.000 claims abstract description 38
- 239000000178 monomer Substances 0.000 claims abstract description 37
- NIXOWILDQLNWCW-UHFFFAOYSA-N 2-Propenoic acid Natural products OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 claims abstract description 35
- -1 acrylic fluoroalkyl ester Chemical class 0.000 claims abstract description 19
- 239000000839 emulsion Substances 0.000 claims abstract description 10
- 238000006116 polymerization reaction Methods 0.000 claims description 45
- 150000001252 acrylic acid derivatives Chemical class 0.000 claims description 24
- 239000013543 active substance Substances 0.000 claims description 19
- 229920000642 polymer Polymers 0.000 claims description 19
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 17
- 239000003995 emulsifying agent Substances 0.000 claims description 16
- 239000001257 hydrogen Substances 0.000 claims description 16
- 229910052739 hydrogen Inorganic materials 0.000 claims description 16
- 239000012736 aqueous medium Substances 0.000 claims description 11
- 125000000217 alkyl group Chemical group 0.000 claims description 10
- 238000000034 method Methods 0.000 claims description 10
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 7
- 150000002431 hydrogen Chemical class 0.000 claims description 5
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 3
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 3
- 125000003545 alkoxy group Chemical group 0.000 claims description 3
- 239000011737 fluorine Substances 0.000 claims description 3
- 229910052731 fluorine Inorganic materials 0.000 claims description 3
- 239000000126 substance Substances 0.000 claims description 2
- 229920002959 polymer blend Polymers 0.000 claims 1
- SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 abstract description 19
- 238000007334 copolymerization reaction Methods 0.000 abstract description 11
- 229920001577 copolymer Polymers 0.000 abstract description 5
- 239000003999 initiator Substances 0.000 abstract 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 36
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 31
- 239000012153 distilled water Substances 0.000 description 28
- ROOXNKNUYICQNP-UHFFFAOYSA-N ammonium persulfate Chemical compound [NH4+].[NH4+].[O-]S(=O)(=O)OOS([O-])(=O)=O ROOXNKNUYICQNP-UHFFFAOYSA-N 0.000 description 20
- 229910052757 nitrogen Inorganic materials 0.000 description 18
- 239000007864 aqueous solution Substances 0.000 description 17
- 239000007787 solid Substances 0.000 description 12
- 238000003756 stirring Methods 0.000 description 12
- QTKPMCIBUROOGY-UHFFFAOYSA-N 2,2,2-trifluoroethyl 2-methylprop-2-enoate Chemical compound CC(=C)C(=O)OCC(F)(F)F QTKPMCIBUROOGY-UHFFFAOYSA-N 0.000 description 11
- 229910001870 ammonium persulfate Inorganic materials 0.000 description 10
- 239000006185 dispersion Substances 0.000 description 10
- 230000002776 aggregation Effects 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 9
- 230000000052 comparative effect Effects 0.000 description 8
- 238000004220 aggregation Methods 0.000 description 7
- 230000004520 agglutination Effects 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 239000003505 polymerization initiator Substances 0.000 description 5
- 210000002966 serum Anatomy 0.000 description 5
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 4
- 239000000427 antigen Substances 0.000 description 4
- 102000036639 antigens Human genes 0.000 description 4
- 108091007433 antigens Proteins 0.000 description 4
- 239000007853 buffer solution Substances 0.000 description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 4
- 239000002504 physiological saline solution Substances 0.000 description 4
- 238000004062 sedimentation Methods 0.000 description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- JAHNSTQSQJOJLO-UHFFFAOYSA-N 2-(3-fluorophenyl)-1h-imidazole Chemical compound FC1=CC=CC(C=2NC=CN=2)=C1 JAHNSTQSQJOJLO-UHFFFAOYSA-N 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 229910021538 borax Inorganic materials 0.000 description 3
- 239000000872 buffer Substances 0.000 description 3
- 238000009826 distribution Methods 0.000 description 3
- LVHBHZANLOWSRM-UHFFFAOYSA-N methylenebutanedioic acid Natural products OC(=O)CC(=C)C(O)=O LVHBHZANLOWSRM-UHFFFAOYSA-N 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 102000004169 proteins and genes Human genes 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- 235000010339 sodium tetraborate Nutrition 0.000 description 3
- 238000001179 sorption measurement Methods 0.000 description 3
- BSVBQGMMJUBVOD-UHFFFAOYSA-N trisodium borate Chemical compound [Na+].[Na+].[Na+].[O-]B([O-])[O-] BSVBQGMMJUBVOD-UHFFFAOYSA-N 0.000 description 3
- 210000002700 urine Anatomy 0.000 description 3
- 102000004856 Lectins Human genes 0.000 description 2
- 108090001090 Lectins Proteins 0.000 description 2
- CERQOIWHTDAKMF-UHFFFAOYSA-N Methacrylic acid Chemical compound CC(=C)C(O)=O CERQOIWHTDAKMF-UHFFFAOYSA-N 0.000 description 2
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 description 2
- 241000283973 Oryctolagus cuniculus Species 0.000 description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 2
- PPBRXRYQALVLMV-UHFFFAOYSA-N Styrene Chemical compound C=CC1=CC=CC=C1 PPBRXRYQALVLMV-UHFFFAOYSA-N 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 238000005054 agglomeration Methods 0.000 description 2
- 238000005842 biochemical reaction Methods 0.000 description 2
- 150000001718 carbodiimides Chemical class 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000007720 emulsion polymerization reaction Methods 0.000 description 2
- 239000001530 fumaric acid Substances 0.000 description 2
- 230000004927 fusion Effects 0.000 description 2
- 239000002523 lectin Substances 0.000 description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 2
- 239000011976 maleic acid Substances 0.000 description 2
- 239000000693 micelle Substances 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- JRKICGRDRMAZLK-UHFFFAOYSA-L persulfate group Chemical group S(=O)(=O)([O-])OOS(=O)(=O)[O-] JRKICGRDRMAZLK-UHFFFAOYSA-L 0.000 description 2
- USHAGKDGDHPEEY-UHFFFAOYSA-L potassium persulfate Chemical compound [K+].[K+].[O-]S(=O)(=O)OOS([O-])(=O)=O USHAGKDGDHPEEY-UHFFFAOYSA-L 0.000 description 2
- 239000007870 radical polymerization initiator Substances 0.000 description 2
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
- 238000002336 sorption--desorption measurement Methods 0.000 description 2
- 235000000346 sugar Nutrition 0.000 description 2
- 150000008163 sugars Chemical class 0.000 description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 2
- LCPVQAHEFVXVKT-UHFFFAOYSA-N 2-(2,4-difluorophenoxy)pyridin-3-amine Chemical compound NC1=CC=CN=C1OC1=CC=C(F)C=C1F LCPVQAHEFVXVKT-UHFFFAOYSA-N 0.000 description 1
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 108010093096 Immobilized Enzymes Proteins 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- 239000004793 Polystyrene Substances 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-N Sulfurous acid Chemical compound OS(O)=O LSNNMFCWUKXFEE-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 229920001222 biopolymer Polymers 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 125000006364 carbonyl oxy methylene group Chemical group [H]C([H])([*:2])OC([*:1])=O 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000005515 coenzyme Substances 0.000 description 1
- JZCCFEFSEZPSOG-UHFFFAOYSA-L copper(II) sulfate pentahydrate Chemical compound O.O.O.O.O.[Cu+2].[O-]S([O-])(=O)=O JZCCFEFSEZPSOG-UHFFFAOYSA-L 0.000 description 1
- LDHQCZJRKDOVOX-NSCUHMNNSA-N crotonic acid Chemical compound C\C=C\C(O)=O LDHQCZJRKDOVOX-NSCUHMNNSA-N 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 229940039227 diagnostic agent Drugs 0.000 description 1
- 239000000032 diagnostic agent Substances 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- FGRVOLIFQGXPCT-UHFFFAOYSA-L dipotassium;dioxido-oxo-sulfanylidene-$l^{6}-sulfane Chemical compound [K+].[K+].[O-]S([O-])(=O)=S FGRVOLIFQGXPCT-UHFFFAOYSA-L 0.000 description 1
- 238000006911 enzymatic reaction Methods 0.000 description 1
- 230000005484 gravity Effects 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 230000001900 immune effect Effects 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- SNVLJLYUUXKWOJ-UHFFFAOYSA-N methylidenecarbene Chemical compound C=[C] SNVLJLYUUXKWOJ-UHFFFAOYSA-N 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 229920002223 polystyrene Polymers 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000007717 redox polymerization reaction Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- CHQMHPLRPQMAMX-UHFFFAOYSA-L sodium persulfate Substances [Na+].[Na+].[O-]S(=O)(=O)OOS([O-])(=O)=O CHQMHPLRPQMAMX-UHFFFAOYSA-L 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- PODWXQQNRWNDGD-UHFFFAOYSA-L sodium thiosulfate pentahydrate Chemical compound O.O.O.O.O.[Na+].[Na+].[O-]S([S-])(=O)=O PODWXQQNRWNDGD-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- 125000006850 spacer group Chemical group 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-L sulfite Chemical class [O-]S([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-L 0.000 description 1
- 239000002344 surface layer Substances 0.000 description 1
- 150000004764 thiosulfuric acid derivatives Chemical class 0.000 description 1
- LDHQCZJRKDOVOX-UHFFFAOYSA-N trans-crotonic acid Natural products CC=CC(O)=O LDHQCZJRKDOVOX-UHFFFAOYSA-N 0.000 description 1
Landscapes
- Immobilizing And Processing Of Enzymes And Microorganisms (AREA)
- Polymerisation Methods In General (AREA)
- Addition Polymer Or Copolymer, Post-Treatments, Or Chemical Modifications (AREA)
Abstract
Description
【発明の詳細な説明】
産業上の利用分野
本発明は、生理活性物質固定化用担体粒子としての重合
体粒子の製造方法に関し、詳しくは、その製造時には重
合安定性にすぐれると共に、酵素、抗体等のような生理
活性物質を例えば共有結合にて固定化し、これを緩衝液
、生理食塩水、血清、尿、その他高分子溶質を含む水溶
液等に分散させた場合にも、分散安定性にすぐれるアク
リル酸誘導体−アクリル酸フルオロアルキルエステル誘
導体共重合体粒子からなる生理活性物質固定化用担体粒
子の製造方法に関する。DETAILED DESCRIPTION OF THE INVENTION Field of Industrial Application The present invention relates to a method for manufacturing polymer particles as carrier particles for immobilizing physiologically active substances. Even when physiologically active substances such as antibodies are immobilized by covalent bonds and dispersed in buffer solutions, physiological saline, serum, urine, and other aqueous solutions containing polymeric solutes, dispersion stability remains The present invention relates to a method for producing carrier particles for immobilizing physiologically active substances comprising excellent acrylic acid derivative-acrylic acid fluoroalkyl ester derivative copolymer particles.
従来の技術
生理活性物質、例えば、酵素を水不溶性のラテックス粒
子に固定化してなる固定化酵素は、その回収が容易であ
ると共に、酵素の変性や失活が起こり難いために、近年
、工業的な酵素反応に広く用いられている。また、生理
活性物質としてレクチンをラテックス粒子に固定化した
ものは、レクチンの糖類との結合能力を利用して、糖類
の分離や精製に用いられる。更に、生理活性物質として
抗原若しくはハプテン、又は抗体をラテックス粒子に結
合したものは、対応する抗体、又は抗原若しくはハプテ
ンをラテックス凝集反応として検出するための免疫学的
診断試薬として広く実用化されている。Conventional technology Immobilized enzymes, which are made by immobilizing physiologically active substances, such as enzymes, on water-insoluble latex particles, have been used industrially in recent years because they are easy to recover and are difficult to denature or deactivate. It is widely used in enzymatic reactions. Furthermore, lectin immobilized as a physiologically active substance on latex particles is used to separate and purify sugars by utilizing the lectin's ability to bind sugars. Furthermore, antigens, haptens, or antibodies bound to latex particles as physiologically active substances have been widely put into practical use as immunodiagnostic reagents for detecting the corresponding antibodies, antigens, or haptens as a latex agglutination reaction. .
このような生理活性物質固定化用担体粒子は、従来、種
々の単量体を用い、これを乳化共重合させることによっ
て製造されている。Such carrier particles for immobilizing physiologically active substances have conventionally been produced by emulsion copolymerization using various monomers.
例えば、従来の代表的なラテックスは、乳化剤及び水溶
性ラジカル重合開始剤の存在下に、例えばスチレンのよ
うな水難溶性ラジカル重合性単量体を乳化共重合させて
製造されている。ここに、上記乳化剤は、水難溶性の単
量体をミセル状態にすることによって水に可溶化せしめ
、ミセル内にて単量体をラジカル重合させるものであり
、また、得られる重合体粒子の表面に付着することによ
って、それを水性媒体中で沈降させず、安定に分散させ
ることができるという効果を有するものである。For example, a typical conventional latex is produced by emulsion copolymerizing a poorly water-soluble radically polymerizable monomer, such as styrene, in the presence of an emulsifier and a water-soluble radical polymerization initiator. Here, the emulsifier is an agent that solubilizes poorly water-soluble monomers in water by converting them into micelles, and radically polymerizes the monomers within the micelles. By adhering to the aqueous medium, it has the effect that it can be stably dispersed without settling in the aqueous medium.
このような重合体粒子の分散安定化作用については、必
ずしも明らかではないが、一般には、乳化剤の一部が重
合体粒子に吸着されており、残余はラテックス中に遊離
の状態で存在し、このようにラテックス中において、こ
れら重合体粒子に吸着された乳化剤と遊離の乳化剤との
間に吸着脱着平衡が存在し、かかる平衡の結果として、
ラテックスの安定化が達成されるとされている。従って
、このように乳化剤を含むラテックスは、これを緩衝液
や生理食塩水中に分散させたとき、ラテツク −ス中の
乳化剤の前記したような吸着脱着平衡がくずれる結果、
ラテックスの安定性が損なわれて、重合体粒子間での融
着、凝集が起こり、沈降しやすくなる。また、融着によ
る上記粒子の凝集を防止するために、多官能性の単量体
を乳化剤の存在下に共重合させて、内部凝集力を高める
方法も行なわれているが、若干の改善はみられるものの
、安定性を前記乳化剤の吸着肌着平衡によっているため
に、上記緩衝液等に分散させた場合、粒子の凝集、沈降
を生じることがある。The dispersion stabilizing effect of such polymer particles is not necessarily clear, but in general, a part of the emulsifier is adsorbed to the polymer particles, and the remainder exists in the latex in a free state. Thus, in latex, an adsorption-desorption equilibrium exists between the emulsifier adsorbed on these polymer particles and the free emulsifier, and as a result of this equilibrium,
Latex stabilization is said to be achieved. Therefore, when a latex containing an emulsifier is dispersed in a buffer solution or physiological saline, the above-mentioned adsorption-desorption equilibrium of the emulsifier in the latex is disrupted.
The stability of the latex is impaired, causing fusion and aggregation between polymer particles, making it easier to settle. In addition, in order to prevent agglomeration of the particles due to fusion, a method has been used in which polyfunctional monomers are copolymerized in the presence of an emulsifier to increase the internal cohesive force, but some improvements have been made. However, since the stability depends on the adsorption equilibrium of the emulsifier, when dispersed in the buffer solution, etc., particles may aggregate or settle.
そこで、近年、上記のような悪影響を示す乳化剤も用い
ずに、乳化剤の不存在下に乳化重合を行なう所謂無乳化
剤重合が注目されているが、乳化剤が存在しないために
、安定に重合反応が進行せずに、重合体粒子の製造時に
凝集を起こすことが多く、重合体粒子を再現性よく安定
に製造することが困難である。Therefore, in recent years, so-called emulsifier-free polymerization, in which emulsion polymerization is carried out in the absence of emulsifiers without using emulsifiers that have the above-mentioned adverse effects, has been attracting attention. The process does not progress and agglomeration often occurs during the production of polymer particles, making it difficult to stably produce polymer particles with good reproducibility.
また、このような無乳化剤重合によるラテックスとして
も、ポリスチレンラテックスが最もよく知られているが
、生理食塩水、血清、尿等中でタンパク質等の生体高分
子のラテックスへの非特異吸着が起こり、非特異凝集が
生じて、分散安定性に劣る。特に、この分散の不安定性
は、粒子表面にスベーザ基を結合したり、粒子に生理活
性物質を固定化したとき等に著しい。In addition, polystyrene latex is the most well-known latex produced by polymerization without emulsifiers, but non-specific adsorption of biopolymers such as proteins to latex occurs in physiological saline, serum, urine, etc. Non-specific aggregation occurs and dispersion stability is poor. In particular, the instability of this dispersion is significant when a subeza group is bonded to the particle surface or when a physiologically active substance is immobilized on the particle.
更に、マイクロタイター法を用いる免疫学的診断薬にお
いては、抗体若しくは抗原を付けたラテックスの凝集沈
降反応像の大きさを観測することによって、診断がなさ
れる。従って、僅かな自然凝集によっても、その沈降像
が著しく崩れる。Furthermore, in immunological diagnostic agents using the microtiter method, diagnosis is made by observing the size of the agglutination-sedimentation reaction image of latex to which antibodies or antigens have been attached. Therefore, even a slight amount of natural aggregation significantly disrupts the sedimentation image.
発明が解決しようとする問題点
本発明は上記した問題を解決するためになされたもので
あって、その製造において、乳化剤を用いずとも、乳化
重合時の重合安定性にすぐれると共に、酵素、抗体等の
ような生理活性物質を例えば共有結合にて固定化し、こ
れを緩衝液、生理食塩水、血清、尿、その他高分子溶質
を含む水溶液等に分散させた場合にも、非特異凝集が少
なく、分散安定性にすぐれるアクリル酸誘導体−アクリ
ル酸フルオロアルキルエステル誘導体共重合体粒子から
なり、所要の粒径を有せしめることができる生理活性物
質固定化用担体粒子の製造方法を提供することを目的と
する。Problems to be Solved by the Invention The present invention has been made to solve the above-mentioned problems.In its production, it has excellent polymerization stability during emulsion polymerization without using an emulsifier, and also uses enzymes, Nonspecific aggregation also occurs when physiologically active substances such as antibodies are immobilized by covalent bonds and dispersed in buffer solutions, physiological saline, serum, urine, and other aqueous solutions containing polymeric solutes. To provide a method for producing carrier particles for immobilizing a physiologically active substance, which are made of acrylic acid derivative-acrylic acid fluoroalkyl ester derivative copolymer particles with a small amount of particles and have excellent dispersion stability, and can have a desired particle size. With the goal.
ュ、占をｐンするための
本発明による生理活性物質固定化用担体粒子の製造方法
は、
（ａ）一般式
％式％
（但し、Ｒ１は水素、低級アルキル基又はカルボキシル
基を示し、Ｒ２は水素又は低級アルキル基を示し、Ｒ１
が水素又は低級アルキル基のときは、Ｒ２はカルボ低級
アルコキシ基であってもよい。）で表わされるアクリル
酸誘導体０．１〜２０重量％と、
（ｂｌ一般式
％式％
（但し、Ｒ３は水素又は低級アルキル基を示し、Ｒ４は
−（ＣＨｚ）□−又は−（ＣＨ２）ＸＣＨ（ＣＨ□）ｙ
−ＯＲ’
（但し、ｍば０〜１２の整数を示し、Ｘ ＋ ｙ −ｍ
−１であり、Ｒ５は水素又はアセチル基を示す。）を示
し、Ａはそれぞれ独立に水素、フッ素又はＣＦ３を示し
、ｎは０〜１２の整数を示す。）で表わされるアクリル
酸フルオロアルキルエステル誘導体９９．１〜８０重量
％とを水性媒体中で乳化共重合させて、生理活性物質固
定化用担体粒子を製造する方法において、
第１段として、アクリル酸誘導体とアクリル酸フルオロ
アルキルエステル誘導体との単量体混合物の合計量にお
いて、アクリル酸誘導体を０〜１０重量％の範囲として
共重合させ、後続段においては、前段よりも単量体混合
物の合計量におけるアクリル酸誘導体の量を少なくとも
０．５重量％増加させて、最終的に平均粒径０．２〜２
μｍ、表面にカルボキシル基を０．５〜２０μモル／ｒ
ｒｌの密度にて有する水分散型高分子重合体粒子を得る
ことを特徴とする。The method for producing a carrier particle for immobilizing a physiologically active substance according to the present invention for improving the concentration is as follows: represents hydrogen or a lower alkyl group, R1
When is hydrogen or a lower alkyl group, R2 may be a carbo-lower alkoxy group. 0.1 to 20% by weight of an acrylic acid derivative represented by (CH□)y
-OR' (where m is an integer from 0 to 12, X + y -m
-1, and R5 represents hydrogen or an acetyl group. ), A each independently represents hydrogen, fluorine or CF3, and n represents an integer of 0 to 12. ) in an aqueous medium to emulsion copolymerize with 99.1 to 80% by weight of an acrylic acid fluoroalkyl ester derivative represented by In the total amount of the monomer mixture of the derivative and the acrylic acid fluoroalkyl ester derivative, the acrylic acid derivative is copolymerized in the range of 0 to 10% by weight, and in the subsequent stage, the total amount of the monomer mixture is lower than that in the previous stage. by increasing the amount of acrylic acid derivative by at least 0.5% by weight to reach a final average particle size of 0.2-2.
μm, carboxyl group on the surface 0.5 to 20 μmol/r
The method is characterized in that water-dispersed polymer particles having a density of rl are obtained.
本発明において、生理活性物質とは、前述した酵素、補
酵素や、抗体若しくはハプテン、抗原、ホルモン等のよ
うに、生物学的又は生化学的な反応活性を有する有機物
質、通常、高分子量タンパク質を意味する。In the present invention, physiologically active substances are organic substances that have biological or biochemical reaction activity, such as the aforementioned enzymes, coenzymes, antibodies or haptens, antigens, hormones, etc., and usually high molecular weight proteins. means.
本発明においては、水分散型高分子重合体粒子を構成す
る単量体成分の一つであるアクリル酸誘導体は、一般式
％式％
（但し、Ｒ１は水素、低級アルキル基又はカルボキシル
基を示し、Ｒ２は水素又は低級アルキル基を示し、Ｒ１
が水素又は低級アルキル基のときは、Ｒ２はカルボ低級
アルコキシ基であってもよい。）で表わされる。In the present invention, the acrylic acid derivative, which is one of the monomer components constituting the water-dispersed polymer particles, has the general formula % (where R1 represents hydrogen, a lower alkyl group, or a carboxyl group). , R2 represents hydrogen or a lower alkyl group, R1
When is hydrogen or a lower alkyl group, R2 may be a carbo-lower alkoxy group. ).
上記アクリル酸誘導体としては、例えば、アクリル酸、
メタクリル酸、イタコン酸、クロトン酸、マレイン酸、
フマル酸、モノアルキルマレイン酸、モノアルキルフマ
ル酸、モノアルキルイタコン酸等を好ましい例として挙
げることができるが、特に、アクリル酸、メタクリル酸
及びイタコン酸の１種又は２種以上の混合物が好ましく
用いられる。Examples of the acrylic acid derivatives include acrylic acid,
Methacrylic acid, itaconic acid, crotonic acid, maleic acid,
Preferred examples include fumaric acid, monoalkyl maleic acid, monoalkyl fumaric acid, monoalkyl itaconic acid, etc., and in particular, one type or a mixture of two or more of acrylic acid, methacrylic acid, and itaconic acid is preferably used. It will be done.
これらアクリル酸誘導体は、乳化共重合時の重合安定性
にすぐれ、また、水性媒体中での分散安定性にすぐれる
水分散型高分子重合体粒子を得るために必要な単量体成
分であり、更に、例えば、カルボジイミドやＮ−ヒドロ
キシスクシンイミドにて活性化し、或いはスペーサ基を
結合するためのカルボキシル基を担体粒子に付与するた
めに必要な単量体成分である。These acrylic acid derivatives are monomer components necessary to obtain water-dispersed polymer particles that have excellent polymerization stability during emulsion copolymerization and excellent dispersion stability in aqueous media. Furthermore, it is a monomer component necessary for, for example, activation with carbodiimide or N-hydroxysuccinimide, or for imparting a carboxyl group for bonding a spacer group to the carrier particles.
そのために、本発明においては、アクリル酸誘導体は、
反応に用いる全単量体のうち、少なくとも０．１重量％
を必要とする。しかし、過多に共重合単量体成分として
用いるときは、却って重合安定性と、得られる重合体粒
子の分散安定性を損なうので、反応に用いる全単量体に
おいて、２０重量％以下の範囲で用いられる。特に好ま
しい範囲は、０．５〜１０重量％である。Therefore, in the present invention, the acrylic acid derivative is
At least 0.1% by weight of all monomers used in the reaction
Requires. However, if too much is used as a copolymerization monomer component, it will actually impair polymerization stability and dispersion stability of the resulting polymer particles. used. A particularly preferred range is 0.5 to 10% by weight.
また、水分散型高分子重合体粒子を構成する単量体成分
の他の一つであるアクリル酸フルオロアルキルエステル
誘導体は、一般式
％式％
（但し、Ｒ３は水素又は低級アルキル基を示し、Ｒ４は
、
−（ＣＨ２）。−又は−（ＣＨ２） ＸＣＨ（ＣＨ２）
ｙ＝Ｒ５
（但し、ｍは０〜１２の整数を示し、Ｘ ＋ ｙ ＝
ｍ−１であり、Ｒ５は水素又はアセチル基を示す。）を
示し、Ａはそれぞれ独立に水素、フッ素又はＣＦ３を示
し、ｎは０〜１２の整数を示す。）で表わされる。In addition, the acrylic acid fluoroalkyl ester derivative, which is another monomer component constituting the water-dispersed polymer particles, has the general formula % (where R3 represents hydrogen or a lower alkyl group, R4 is -(CH2).- or -(CH2) XCH(CH2)
y=R5 (However, m represents an integer from 0 to 12, and X + y =
m-1, and R5 represents hydrogen or an acetyl group. ), A each independently represents hydrogen, fluorine or CF3, and n represents an integer of 0 to 12. ).
かかるアクリル酸フルオロアルキルエステル誘導体は、
好ましくは、一般式
％式％（１）
（但し、Ｒ３、Ｒ５、ｍ及びｎは前記と同じである。）
で表わされ、従って、特に、好ましく用いることができ
るアクリル酸フルオロアルキルエステル誘導体の具体例
として、例えば、
ＣＨ２＝Ｃ（ＣＨ３）Ｃ００ＣＨ２ＣＦ３
（５１ＣＨ□＝Ｃ（ＣＩ＋３）ＣＯＯＣＨ２（
ＣＦＺ） ２Ｈ（６１ＣＨｚ＝Ｃ（ＣＬ）ＣＯＯＣＨｚ
（ＣＦｚ）Ｊ （７）ＣＨｚ＝Ｃ（ＣＨ
３） Ｃｏｏ （Ｃ１ｌｚ） ｚ （ＣＦ、） ｅＦ
（８）等を例示することができる。Such acrylic acid fluoroalkyl ester derivatives are
Preferably, the general formula % formula % (1) (However, R3, R5, m and n are the same as above.)
As a specific example of the acrylic acid fluoroalkyl ester derivative which can be particularly preferably used, for example, CH2=C(CH3)C00CH2CF3
(51CH□=C(CI+3)COOCH2(
CFZ) 2H (61CHHz=C(CL)COOCHz
(CFz)J (7)CHz=C(CH
3) Coo (C1lz) z (CF,) eF
(8) etc. can be exemplified.
これらアクリル酸フルオロアルキルエステル誘導体は、
本発明による生理活性物質固定化用担体粒子において、
長期間にわたる保存安定性や、水性媒体中ですぐれた分
散性を有するために必要であるのみならす、その活性化
時や、或いは活性化担体粒子への生理活性物質の固定化
時の水性分散系において、粒子に安定な分散性を保たし
める効果を有する。These acrylic acid fluoroalkyl ester derivatives are
In the carrier particles for immobilizing a physiologically active substance according to the present invention,
Aqueous dispersion systems necessary for long-term storage stability and excellent dispersibility in aqueous media during activation or immobilization of physiologically active substances on activated carrier particles. It has the effect of maintaining stable dispersibility in the particles.
このような効果を有効に得るためには、アクリル酸フル
オロアルキルエステル誘導体は、用いる全単量体におい
て９９．９〜８０重量％、好ましくは９９．５〜９０重
量％の範囲で用いられる。In order to effectively obtain such effects, the acrylic acid fluoroalkyl ester derivative is used in an amount of 99.9 to 80% by weight, preferably 99.5 to 90% by weight of the total monomers used.
本発明の方法においては、アクリル酸誘導体とアクリル
酸フルオロアルキルエステル誘導体との共重合体からな
る担体粒子を製造するに際して、アクリル酸誘導体とア
クリル酸フルオロアルキルエステル誘導体とのそれぞれ
の仕込み量を変化させつつ、乳化剤の不存在下で段階的
に水性媒体中で乳化共重合させる。In the method of the present invention, when producing carrier particles made of a copolymer of an acrylic acid derivative and an acrylic acid fluoroalkyl ester derivative, the amounts of the acrylic acid derivative and the acrylic acid fluoroalkyl ester derivative are varied. At the same time, the emulsion copolymerization is carried out stepwise in an aqueous medium in the absence of an emulsifier.
１’１
第１段の共重合においては、アクリル酸誘導体とアクリ
ル酸フルオロアルキルエステル誘導体との単量体混合物
の合計量において、アクリル酸誘導体は０〜１０重量％
の範囲で仕込み、第２段以降の後続段においては、前段
よりも単量体混合物の合計量におけるアクリル酸誘導体
量を少なくとも０．５重量％増加し、このようにして、
複数段にて段階的に共重合を行なって、最終的には、粒
子径ｏ、２〜２μｍ、表面にカルボキシル基を０．５〜
２０μモル／イの密度にて有する水分散型高分子重合体
粒子を得る。それぞれの段階で仕込む単量体の比率及び
量を調整することによって、最終的に得られる水分散型
高分子重合体粒子の平均粒径及び粒子表面のカルボキシ
ル基量を所要の範囲にすることができる。1'1 In the first stage copolymerization, the acrylic acid derivative is 0 to 10% by weight in the total amount of the monomer mixture of the acrylic acid derivative and the acrylic acid fluoroalkyl ester derivative.
In the subsequent stages after the second stage, the amount of acrylic acid derivative in the total amount of the monomer mixture is increased by at least 0.5% by weight compared to the previous stage, and in this way,
Copolymerization is carried out stepwise in multiple stages, and the final particle size is o, 2 to 2 μm, and the carboxyl group on the surface is 0.5 to 2 μm.
Water-dispersed polymer particles having a density of 20 μmol/I are obtained. By adjusting the ratio and amount of monomers charged in each step, the average particle diameter and the amount of carboxyl groups on the particle surface of the final water-dispersed polymer particles can be adjusted to the desired range. can.
特に、本発明の方法においては、アクリル酸誘導体とア
クリル酸フルオロアルキルエステル誘導体の単量体混合
物は、第１段の重合においては、アクリル酸誘導体を０
〜１０重量％の範囲で含む単量体混合物を用い、第２段
の重合では、アクリル酸誘導体を１〜２０重量％の範囲
で含む単量体混合物を用い、第３段の重合では、アクリ
ル酸誘導体を２重量％以上含む単量体混合物を用い、且
つ、後続段では、前段よりもアクリル酸誘導体量の比率
の多い単量体混合物を用いるのが有利である。最終段で
は、単量体混合物におけるアクリル酸量を５０〜１００
重量％とすることもできる。In particular, in the method of the present invention, the monomer mixture of an acrylic acid derivative and an acrylic acid fluoroalkyl ester derivative is used in the first stage of polymerization.
In the second stage polymerization, a monomer mixture containing an acrylic acid derivative in a range of 1 to 20% by weight was used, and in the third stage polymerization, a monomer mixture containing an acrylic acid derivative in a range of 1 to 20% by weight was used. It is advantageous to use a monomer mixture containing 2% by weight or more of an acid derivative, and to use a monomer mixture containing a higher proportion of acrylic acid derivative in the subsequent stage than in the previous stage. In the final stage, the amount of acrylic acid in the monomer mixture is adjusted to 50 to 100.
It can also be expressed as % by weight.
本発明の方法においては、各段階にて、単量体混合物は
、−括して反応容器内に加えて、所定時間反応させた後
、後続段の重合を行なってもよく、また、単量体混合物
をある時間にわたって反応容器内に滴下し、滴下終了後
、適宜時間反応混合物を攪拌して熟成し、この後、後続
段の重合のために、単量体混合物を反応容器内に滴下、
共重合させてもよい。In the method of the present invention, at each stage, the monomer mixture may be added to the reaction vessel all at once and reacted for a predetermined time, and then the subsequent stage of polymerization may be carried out. The monomer mixture is dropped into the reaction vessel over a certain period of time, and after the completion of the dropping, the reaction mixture is stirred for an appropriate time to ripen, and then the monomer mixture is dropped into the reaction vessel for the subsequent stage of polymerization.
They may also be copolymerized.
また、本発明においては、予め調製したシード・ラテッ
クスの存在下に上記したような段階的な共重合を行なう
ことによって、重合安定性を一層高めることができると
共に、得られる粒子の最終的な粒径を、より正確に制御
することができる。In addition, in the present invention, by performing the stepwise copolymerization as described above in the presence of a seed latex prepared in advance, the polymerization stability can be further increased, and the final particles of the obtained particles can be further improved. The diameter can be controlled more precisely.
上記シード・ラテックスは、通常、アクリル酸誘導体１
〜１０重量％とアクリル酸フルオロアルキルエステル９
９〜９０重量％からなる単量体混合物を乳化共重合させ
ることによって得ることができる。The above seed latex is usually an acrylic acid derivative 1
~10% by weight of acrylic acid fluoroalkyl ester 9
It can be obtained by emulsion copolymerization of a monomer mixture consisting of 9 to 90% by weight.
各段階及びシード・ラテックスの調製のためのアクリル
酸誘導体とアクリル酸フルオロアルキルエステル誘導体
との共重合は、乳化剤の不存在下に重合開始剤を用いて
行なわれる。重合開始剤としては、水溶性ラジカル重合
開始剤が用いられる。The copolymerization of acrylic acid derivatives and acrylic acid fluoroalkyl ester derivatives for each step and for the preparation of the seed latex is carried out using a polymerization initiator in the absence of emulsifiers. As the polymerization initiator, a water-soluble radical polymerization initiator is used.
通常、過硫酸カリウム、過硫酸ナトリウム、過硫酸アン
モニウム等の過硫酸塩や、これら過硫酸塩とチオ硫酸ナ
トリウム、チオ硫酸カリウム、千オ硫酸水素ナトリウム
等のようなチオ硫酸塩、又は亜硫酸ナトリウム、亜硫酸
カリウム、亜硫酸水素ナトリウム等のような亜硫酸塩と
のレドックス系重合開始剤が好ましく用いられるが、こ
れらに限定されるものではない。これら重合開始剤の使
用量は、単量体混合物に対して０．０１〜１重量％の範
囲が好適である。重合の雰囲気も、特に制限されないが
、好ましくは酸素を除いた不活性ガス雰囲気が用いられ
る。また、重合温度は、特に制限されないが、通常、２
０〜１００°Ｃ１好ましくは４０〜９０°Ｃの範囲であ
る。Usually, persulfates such as potassium persulfate, sodium persulfate, ammonium persulfate, these persulfates and thiosulfates such as sodium thiosulfate, potassium thiosulfate, sodium perthiosulfate, etc., or sodium sulfite, sulfite, etc. Redox polymerization initiators with sulfites such as potassium, sodium bisulfite, etc. are preferably used, but are not limited thereto. The amount of these polymerization initiators used is preferably in the range of 0.01 to 1% by weight based on the monomer mixture. The atmosphere for polymerization is also not particularly limited, but preferably an inert gas atmosphere excluding oxygen is used. In addition, the polymerization temperature is not particularly limited, but is usually 2
It is in the range of 0 to 100°C, preferably 40 to 90°C.
本発明において、最終的に得られる水分散型高分子重合
体粒子は、その平均粒径が０．２〜２μｍの範囲にある
と共に、その比重は０．９〜１．５の範囲にあることが
好ましい。。In the present invention, the water-dispersed polymer particles finally obtained have an average particle diameter in the range of 0.2 to 2 μm and a specific gravity in the range of 0.9 to 1.5. is preferred. .
更に、重合体粒子は、水性媒体中で安定した分散状態を
確保し得るように、その表面に０．５〜２０μモル／イ
の密度にてカルボキシル基を有する。Furthermore, the polymer particles have carboxyl groups on their surfaces at a density of 0.5 to 20 μmol/I so as to ensure a stable dispersion state in an aqueous medium.
重合体粒子の有するカルボキシル基数が余りに少ないと
きは、粒子が水性媒体中での分散性に劣り、凝集を起こ
しやすいと共に、例えばその活性化に際して、十分な量
のカルボジイミドやＮ−ヒドロキシスクシンイミドを結
合させることができず、延いては、得られる活性化担体
粒子に十分な量の生理活性物質を固定化することができ
ない。他方、重合体粒子の有するカルボキシル基数が余
りに多いときも、水性媒体中にて凝集することがあり、
或いは生理活性物質を固定化したときに、その生化学的
反応を阻害するおそれがある。When the number of carboxyl groups in the polymer particles is too small, the particles have poor dispersibility in an aqueous medium and tend to aggregate, and at the same time, for example, when activating the particles, a sufficient amount of carbodiimide or N-hydroxysuccinimide must be bound. Furthermore, a sufficient amount of the physiologically active substance cannot be immobilized on the obtained activated carrier particles. On the other hand, when polymer particles have too many carboxyl groups, they may aggregate in an aqueous medium.
Alternatively, when a physiologically active substance is immobilized, its biochemical reaction may be inhibited.
両所■四果
以上のように、本発明の方法によれば、アクリル酸誘導
体のアクリル酸フルオロアルキルエステル誘導体に対す
る割合を増やしながら、複数段にわたって段階的に乳化
共重合を行なって、共重合体粒子を得るので、例えば、
診断用ラテックスとして、粒子径が均一であり、更に、
タンパク質の非特異吸着が少なく、且つ、抗体等の固定
化後も、分散安定性にすぐれるラテックス粒子を高い重
合安定性の下で製造することができる。As described above, according to the method of the present invention, emulsion copolymerization is carried out stepwise over multiple stages while increasing the ratio of the acrylic acid derivative to the acrylic acid fluoroalkyl ester derivative to form a copolymer. Since we obtain particles, e.g.
As a diagnostic latex, it has a uniform particle size and
Latex particles with low non-specific adsorption of proteins and excellent dispersion stability even after immobilization of antibodies and the like can be produced with high polymerization stability.
実施例
以下に実施例を挙げて本発明を説明するが、本発明はこ
れら実施例によって何ら制限されるものではない。EXAMPLES The present invention will be explained below with reference to Examples, but the present invention is not limited to these Examples in any way.
実施例１
（シード・ラテックスの調製）
アクリル酸５重量％及びメタクリル酸トリフルオロエチ
ル９５重量％からなる単量体混合物１２０ｇを蒸留水３
４０ｇに加え、窒素気流下に６５°Ｃに昇温した後、６
０分間攪拌した。Example 1 (Preparation of seed latex) 120 g of a monomer mixture consisting of 5% by weight of acrylic acid and 95% by weight of trifluoroethyl methacrylate was mixed with 3% of distilled water.
40g and heated to 65°C under a nitrogen stream, 6
Stirred for 0 minutes.
硫酸銅５水和物１２■を水５ｍｌに溶解させた水溶液と
チオ硫酸ナトリウム５水和物６０■を水５ｍｌに溶解さ
せた水溶液を上記単量体混合物に加え、これに直ちに重
合開始剤として、過硫酸カリウム０．６ｇを蒸留水１０
ｍ１に溶解させた水溶液を窒素気流下に加えた後、２０
Ｏｒｐｍにて攪拌しつつ、４時間重合させて、重合率９
９％にて平均粒子径０、２４．０μｍのラテックスを得
た。重合反応後の凝集物は皆無であった。An aqueous solution of 12 μl of copper sulfate pentahydrate dissolved in 5 ml of water and an aqueous solution of 60 μl of sodium thiosulfate pentahydrate dissolved in 5 ml of water were added to the above monomer mixture, and immediately added to this as a polymerization initiator. , 0.6 g of potassium persulfate in 10 g of distilled water
After adding an aqueous solution dissolved in ml under a nitrogen stream, 20
Polymerization was carried out for 4 hours while stirring at Orpm, and the polymerization rate was 9.
At 9%, a latex with an average particle size of 0.24.0 μm was obtained. There were no aggregates after the polymerization reaction.
このラテックスを遠心分離し、蒸留水にて洗浄した後、
再度、蒸留水に固形分濃度５重量％に分散させて、シー
ド・ラテックスとした。After centrifuging this latex and washing it with distilled water,
The seed latex was again dispersed in distilled water to a solid content concentration of 5% by weight.
（第１段の重合）
上記ラテックス４３．９ ｇを蒸留水３００ｇに加えた
後、メタクリル酸トリフルオロエチル３７．８ｇ（１０
，０重量％）を加え、７０”Ｃに昇温し、窒素気流下に
４０分間、２２Ｏｒｐｍにて攪拌した。(First stage polymerization) After adding 43.9 g of the above latex to 300 g of distilled water, 37.8 g of trifluoroethyl methacrylate (10
, 0% by weight) was added, the temperature was raised to 70''C, and the mixture was stirred at 22Orpm for 40 minutes under a nitrogen stream.
次いで、過硫酸アンモニウム０．２ｇを蒸留水１Ｏｒｎ
ｌに溶解させた水溶液を窒素気流下に加えた後、２２０
ｒｐｍにて攪拌しつつ、６時間重合させて、重合率９
９％にて平均粒子径０．６５μｍのラテックスを得た。Next, add 0.2 g of ammonium persulfate to 1 liter of distilled water.
After adding an aqueous solution dissolved in 220 liters under a nitrogen stream,
Polymerization was carried out for 6 hours while stirring at rpm, and the polymerization rate was 9.
A latex with an average particle size of 0.65 μm was obtained at 9%.
重合反応後の凝集物は、固形分に対して０．０８重量％
であった。The aggregate after the polymerization reaction is 0.08% by weight based on the solid content.
Met.
このラテックスを遠心分離し、蒸留水にて洗浄した後、
再度、蒸留水に固形分濃度５重量％に分散させた。After centrifuging this latex and washing it with distilled water,
It was again dispersed in distilled water to a solid content concentration of 5% by weight.
比較例１
（第１段の重合）
実施例１にて得たシード・ラテックス２８．５ ｇを蒸
留水３４２ｇに加えた後、これにアクリル酸７．１ｇ（
１２，０重量％）とメタクリル酸トリフルオロエチル５
２．１ｇ（８８，０重量％）とを加え、７０°Ｃに昇温
し、窒素気流下に６０分間、２２０ｒｐｍにて攪拌した
。Comparative Example 1 (First Stage Polymerization) After adding 28.5 g of the seed latex obtained in Example 1 to 342 g of distilled water, 7.1 g of acrylic acid (
12,0% by weight) and trifluoroethyl methacrylate 5
2.1 g (88.0% by weight) was added, the temperature was raised to 70°C, and the mixture was stirred at 220 rpm for 60 minutes under a nitrogen stream.
次いで、過硫酸アンモニウム０．３０ ｇを蒸留水１０
ｍ１に溶解させた水溶液を窒素気流下に加えた後、２２
Ｏｒｐｍにて攪拌しつつ、８時間重合させて、重合率９
２％にて平均粒子径０．８８μｍ、表面カルボキシル基
量１２．０μモル／、（のラテックスを得た。しかし、
このラテックスにおいて、は、粒子の粒径分布が広く、
１．１〜１．５μｍの粒径を有する粒子が個数にて５．
０％、０．３８〜０．５６μｍの粒径を有する粒子が３
．２％生成していることが確認された。Next, 0.30 g of ammonium persulfate was added to 10 g of distilled water.
After adding an aqueous solution dissolved in ml under a nitrogen stream, 22
Polymerization was carried out for 8 hours while stirring at Orpm, and the polymerization rate was 9.
At 2%, a latex was obtained with an average particle diameter of 0.88 μm and a surface carboxyl group content of 12.0 μmol/.However,
In this latex, the particle size distribution is wide;
The number of particles having a particle size of 1.1 to 1.5 μm is 5.
0%, 3 particles with a particle size of 0.38-0.56 μm
．． It was confirmed that 2% was produced.
比較例２
（第２段の重合）
実施例１にて第１段で得たラテックス１８７ｇを蒸留水
１２０ｇに加えた後、これにアクリル酸０．０４７ ｇ
（０，３０重量％）とメタクリル酸トリフルオロエ
チル１５．８ｇ（９９，７重量％）とを加え、７０℃に
昇温し、窒素気流下に６０分間、２２０ｒｐｍにて攪拌
した。Comparative Example 2 (Second Stage Polymerization) After adding 187 g of the latex obtained in the first stage of Example 1 to 120 g of distilled water, 0.047 g of acrylic acid was added thereto.
(0.30% by weight) and 15.8 g (99.7% by weight) of trifluoroethyl methacrylate were added, the temperature was raised to 70°C, and the mixture was stirred at 220 rpm for 60 minutes under a nitrogen stream.
次いで、過硫酸アンモニウム０．０８ ｇを蒸留水１０
ｍ】に溶解させた水溶液を窒素気流下に加えた後、２２
０ｒｐｍにて攪拌しつつ、５時間重合させて、重合率９
５％にて粒径分布が０．６０〜２．８μｍにわたるラテ
ックスを得た。重合反応後の凝集物は約４６％であった
。また、ラテックス粒子の表面カルボキシル基量は０．
３８ｇモル／Ｍであった。Next, 0.08 g of ammonium persulfate was added to 10 g of distilled water.
After adding an aqueous solution dissolved in 22 m] under a nitrogen stream,
Polymerization was carried out for 5 hours while stirring at 0 rpm, and the polymerization rate was 9.
At 5%, a latex with a particle size distribution ranging from 0.60 to 2.8 μm was obtained. The amount of aggregates after the polymerization reaction was about 46%. Furthermore, the surface carboxyl group content of the latex particles is 0.
It was 38 gmol/M.
実施例−
（第２段の重合）
前記実施例の第１段で得たラテックス１８７ｇを蒸留水
１２０ｇに加えた後、これにアクリル酸０．５２ｇ（３
，３重量％）とメタクリル酸トリフルオロエチル１５．
３ｇ（９６，７重量％）とを加え、７０℃に昇温し、窒
素気流下に６０分間、２２０ｒｐｍにて攪拌した。Example - (Second Stage Polymerization) After adding 187 g of the latex obtained in the first stage of the above Example to 120 g of distilled water, 0.52 g of acrylic acid (3
, 3% by weight) and trifluoroethyl methacrylate 15.
3g (96.7% by weight) was added, the temperature was raised to 70°C, and the mixture was stirred at 220 rpm for 60 minutes under a nitrogen stream.
次いで、過硫酸アンモニウム０．０８ ｇを蒸留水１０
ｍ１に溶解させた水溶液を窒素気流下に加えた後、２２
０ｒｐｍにて攪拌しつつ、５時間重合させて、重合率９
６％にて平均粒子径０．８９μｍ、表面カルボキシル基
量５．８μモル／Ｍの粒径の均一なラテックスを得た。Next, 0.08 g of ammonium persulfate was added to 10 g of distilled water.
After adding an aqueous solution dissolved in ml under a nitrogen stream, 22
Polymerization was carried out for 5 hours while stirring at 0 rpm, and the polymerization rate was 9.
At 6%, a uniform latex with an average particle diameter of 0.89 μm and a surface carboxyl group content of 5.8 μmol/M was obtained.
重合反応後の凝集物は、固形分に対して０．９８重量％
であった。The aggregate after the polymerization reaction is 0.98% by weight based on the solid content.
Met.
このラテックスを遠心分離し、蒸留水にて洗浄した後、
再度、蒸留水に固形分濃度５重量％に分散させた。After centrifuging this latex and washing it with distilled water,
It was again dispersed in distilled water to a solid content concentration of 5% by weight.
実施例３
実施例２において得たラテックス２４０ｇを蒸留水６２
．０ ｇに加え、これに更にアクリル酸５．０ｇ（３８
，２重量％）とメタクリル酸トリフルオロエチル８．１
ｇ（６１，８重量％）とを加え、７０℃に昇温し、窒素
気流下に６０分間、２２Ｏｒｐｍにて攪拌した。Example 3 240 g of latex obtained in Example 2 was mixed with 62 g of distilled water.
．． In addition to 0 g, acrylic acid 5.0 g (38
, 2% by weight) and trifluoroethyl methacrylate 8.1
g (61.8% by weight), the temperature was raised to 70° C., and the mixture was stirred at 22 Orpm for 60 minutes under a nitrogen stream.
次いで、過硫酸アンモニウム０．０６５ ｇを蒸留水１
０ｍ１に溶解させた水溶液を窒素気流下に加えた後、２
２０ｒｐｍにて攪拌しつつ、６時間重合させて、重合率
９７％にて平均粒子径１．２０μｍ、表面カルボキシル
基量１８．５μモル／Ｍの粒径の均一なラテックスを得
た。Next, 0.065 g of ammonium persulfate was added to 1 liter of distilled water.
After adding an aqueous solution dissolved in 0ml under a nitrogen stream,
Polymerization was carried out for 6 hours while stirring at 20 rpm to obtain a uniform latex with an average particle diameter of 1.20 μm and a surface carboxyl group content of 18.5 μmol/M at a polymerization rate of 97%.
比較例３
実施例２にて得たラテックス２４０ｇを蒸留水６２、０
ｇ、アクリル酸０．３３ｇ（２，５重量％）及びメタ
クリル酸トリフルオロエチル１２．８ｇ（９７，５重量
％）と混合し、６０°Ｃに昇温し、窒素気流下に７０分
間、２２０ｒｐｍにて攪拌した。Comparative Example 3 240 g of latex obtained in Example 2 was mixed with distilled water 62.0 g.
g, mixed with 0.33 g (2.5% by weight) of acrylic acid and 12.8 g (97.5% by weight) of trifluoroethyl methacrylate, heated to 60°C, and heated at 220 rpm for 70 minutes under nitrogen flow. The mixture was stirred at
次いで、過硫酸アンモニウム０．０６５ ｇを蒸留水１
０ｍ１に溶解させた水溶液を窒素気流下に加えた後、２
２０ｒｐｍにて攪拌しつつ、６時間重合させて、重合率
８８％にてラテックスを得た。このラテックスにおいて
は、粒径分布は０．２〜２．１μｍにわたり、また、凝
集物も、固形分に対して３゜２％であった。表面カルボ
キシル基量２７μモル／Ｍであった。Next, 0.065 g of ammonium persulfate was added to 1 liter of distilled water.
After adding an aqueous solution dissolved in 0ml under a nitrogen stream,
Polymerization was carried out for 6 hours while stirring at 20 rpm to obtain latex at a polymerization rate of 88%. In this latex, the particle size distribution ranged from 0.2 to 2.1 μm, and the aggregate content was 3.2% based on the solid content. The surface carboxyl group amount was 27 μmol/M.
実施例４
（シード・ラテックスの調製）
アクリル酸２重量％及びメタクリル酸トリフルオロエチ
ル９８重量％からなる単量体混合物１２６ｇを蒸留水２
９４ｇに加え、７０°Ｃに昇温した後、４５分間攪拌し
た。この後、過硫酸アンモニウム０．６１ ｇを蒸留水
１０ｍ１に薄解させた水溶液を窒素気流下に加えた後、
２００ｒｐｍにて攪拌しつつ、６時間重合させて、重合
率９９．８％にて平均粒子径０．３７４μｍのラテック
スを得た。重合反応後の凝集物は皆無であった。Example 4 (Preparation of seed latex) 126 g of a monomer mixture consisting of 2% by weight of acrylic acid and 98% by weight of trifluoroethyl methacrylate was mixed with 2% of distilled water.
The mixture was added to 94 g, heated to 70°C, and stirred for 45 minutes. After this, an aqueous solution prepared by dissolving 0.61 g of ammonium persulfate in 10 ml of distilled water was added under a nitrogen stream.
The mixture was polymerized for 6 hours while stirring at 200 rpm to obtain a latex with a polymerization rate of 99.8% and an average particle diameter of 0.374 μm. There were no aggregates after the polymerization reaction.
このラテックスにその３０ｍ１当りについてＩＮ水酸化
ナトリウム水溶液０．５ｍｌを加え、十分に攪拌した後
、蒸留水にて３回洗浄した。これを蒸留水に固形分濃度
１６．１重量％に分散させて、シード・ラテックスとし
た。0.5 ml of IN sodium hydroxide aqueous solution was added to this latex per 30 ml of the latex, and after stirring thoroughly, the mixture was washed three times with distilled water. This was dispersed in distilled water to a solid content concentration of 16.1% by weight to obtain a seed latex.
（第１段の重合）
上記シード・ラテックス１８．３ ｇを蒸留水３３５ｇ
に加えた後、７０°Ｃに昇温した。過硫酸アンモニウム
０．４４ ｇを蒸留水１０ｍ１に溶解させた水溶液を窒
素気流下に加え、２２Ｏｒｐｍにて攪拌しつつ、直ちに
アクリル酸０．８７ｇ（１，３重量％）とメタクリル酸
トリフルオロエチル６４．４ｇ（９８，７重量％）との
混合物を滴下速度１８ｇ／時にて加え、滴下終了後、２
０分間攪拌熟成した。(1st stage polymerization) 18.3 g of the above seed latex was mixed with 335 g of distilled water.
The temperature was raised to 70°C. An aqueous solution of 0.44 g of ammonium persulfate dissolved in 10 ml of distilled water was added under a nitrogen stream, and while stirring at 22 rpm, 0.87 g (1.3% by weight) of acrylic acid and 64.0 g of trifluoroethyl methacrylate were immediately added. 4g (98.7% by weight) was added at a dropping rate of 18g/hour, and after the completion of the dropping, 2
The mixture was stirred and aged for 0 minutes.
（第２段の重合）
次いで、上記反応混合物にアクリル酸３．５ｇ（１６，
１重量％）とメタクリル酸トリフルオロエチル１８．３
ｇ（８３，９重量％）との混合物を１８ｇ／時にて滴下
し、滴下終了後、直ちに８０°Ｃに昇温しで、２時間熟
成した。(Second stage polymerization) Next, 3.5 g of acrylic acid (16,
1% by weight) and trifluoroethyl methacrylate 18.3
g (83.9% by weight) was added dropwise at a rate of 18 g/hour, and immediately after the addition, the temperature was raised to 80° C. and aged for 2 hours.
その結果、重合率９８％にて平均粒子径１．２１μｍ、
表面カルボキシル基量１６．９μモル／Ｍの均一なラテ
ックスを得た。重合反応後の凝集物は、固形分に対して
０．４６重量％であった。As a result, the average particle diameter was 1.21 μm at a polymerization rate of 98%.
A uniform latex with a surface carboxyl group content of 16.9 μmol/M was obtained. The amount of aggregate after the polymerization reaction was 0.46% by weight based on the solid content.
このラテックス粒子の内部をＴＥＭにて観察した結果、
粒子表面から表層部は、均一な構造をもたず、ミクロド
メイン構造といわれる相分離構造を有していた。As a result of observing the inside of this latex particle with TEM,
The surface layer part from the particle surface did not have a uniform structure, but had a phase-separated structure called a microdomain structure.
比較例４
実施例４において得たシード・ラテックス２１゜３ｇを
蒸留水３３４ｇに加えた後、７０°Ｃに昇温し、窒素気
流下に７０分間、２２０ｒｐｍにて攪拌した。Comparative Example 4 After adding 21.3 g of the seed latex obtained in Example 4 to 334 g of distilled water, the mixture was heated to 70° C. and stirred at 220 rpm for 70 minutes under a nitrogen stream.
次いで、過硫酸アンモニウム０．４３ ｇを蒸留水１０
ｍ１に溶解させた水溶液を窒素気流下に加えた後、直ち
にアクリル酸９．８ｇ（１１，３重量％）とメタクリル
酸トリフルオロエチル７６．８ｇ（８８゜７重量％）と
の混合物を滴下速度１８ｇ／時にて加えた。滴下終了後
、直ちに８０℃に昇温し、２時間熟成した。Next, 0.43 g of ammonium persulfate was added to 10 g of distilled water.
Immediately after adding the aqueous solution dissolved in ml under a nitrogen stream, a mixture of 9.8 g (11.3% by weight) of acrylic acid and 76.8 g (88°7% by weight) of trifluoroethyl methacrylate was added at a dropwise rate. Added at 18g/hour. Immediately after the dropwise addition was completed, the temperature was raised to 80°C and aged for 2 hours.
この結果、重合率９７％にて平均粒子径１．２０７１
ｍ 、表面カルボキシル基量１６．９ ｔｔモル／♂の
ラテックスを得た。重合反応後の凝集物は、固形分に対
して０．５４重量％であった。As a result, the average particle diameter was 1.2071 at a polymerization rate of 97%.
A latex with a surface carboxyl group content of 16.9 tt mol/male was obtained. The amount of aggregate after the polymerization reaction was 0.54% by weight based on the solid content.
このラテックス粒子の内部をＴＥＭにて観察した結果、
実施例４で得たラテックス粒子のような相分離構造は認
められなかった。As a result of observing the inside of this latex particle with TEM,
A phase-separated structure like the latex particles obtained in Example 4 was not observed.
参考例
上記実施例及び比較例で得た固形分濃度５重量％ラテッ
クスのそれぞれ３．０ｍｌ、５■／ｍｌ濃度の水溶性カ
ルボジイミド水溶液０．３ｍｌ、４■／ ｍ Ｉ ｔａ
度のウサギＩｇＧ １． Ｏｍｌ及びホウ酸ナトリウム
緩衝液（０，０１Ｍ、 ｐＨ８，２） １．８ｍｌを混
合し、攪拌しながら、１０℃で１７時間反応させた後、
１０％リジン水溶液２．５ｔｎｌを加えて、１０℃で１
時間攪拌して、反応を停止させた。次いで、遠心洗浄を
３回繰り返して、それぞれのラテックス粒子にウサギＩ
ｇＧを固定化した。Reference Example: 3.0 ml of latex with a solid content concentration of 5% by weight obtained in the above Examples and Comparative Examples, 0.3 ml of a water-soluble carbodiimide aqueous solution with a concentration of 5 μ/ml, and 4 μ/m I ta
Rabbit IgG 1. After mixing Oml and 1.8ml of sodium borate buffer (0.01M, pH 8.2) and reacting at 10°C for 17 hours with stirring,
Add 2.5 tnl of 10% lysine aqueous solution and incubate at 10°C.
The reaction was stopped by stirring for an hour. Then, centrifugal washing was repeated three times to inject rabbit I into each latex particle.
gG was immobilized.
それぞれのラテックスを固形分濃度０．２５％に調整し
、その２０μβをホウ酸ナトリウム緩衝液（０，０１Ｍ
、ｐＨ８，２） １００μβに加え、撹拌した後、１
０分間静置して、光学顕微鏡にてラテックス粒子の凝集
を調べたところ、比較例２を除いて、いずれのラテック
スも非特異凝集反応は認められなかった。比較例２にお
いては、多数の凝集塊の生成が認められた。Each latex was adjusted to a solid content concentration of 0.25%, and 20μβ of the latex was added to a sodium borate buffer (0.01M
, pH 8, 2) and stirred, 1
When the latex particles were allowed to stand for 0 minutes and examined for aggregation using an optical microscope, no non-specific agglutination reaction was observed in any of the latexes except for Comparative Example 2. In Comparative Example 2, formation of many aggregates was observed.
次に、それぞれのラテックスを固形分濃度０．２５％に
調整し、その２０μβをホウ酸ナトリウム緩衝液（０，
ＯＩ Ｍ、 ｐＨ８，２）にて所定の倍率で希釈したヒ
ト血清１００μρに加え、攪拌した後、１０分間静置し
て、光学顕微鏡にてラテックス粒子の凝集を調べた。結
果を第１表に示す。Next, each latex was adjusted to a solid content concentration of 0.25%, and 20μβ of the latex was added to a sodium borate buffer (0,
The mixture was added to 100 μρ of human serum diluted at a predetermined ratio with OIM (pH 8, 2), stirred, and allowed to stand for 10 minutes, and the aggregation of latex particles was examined using an optical microscope. The results are shown in Table 1.
尚、本参考例においては、相互に凝集している粒子の割
合が個数にて１０％を越えるとき、有意な非特異凝集反
応が生じたとし、表中には十で表示し、相互に凝集して
いる粒子の割合が個数にて１０％以下のとき、非特異凝
集が生じないとして、−で表示した。In this reference example, when the proportion of mutually agglomerated particles exceeds 10% in number, it is assumed that a significant non-specific agglutination reaction has occurred, and this is indicated by a 10 in the table. When the proportion of particles with the above-mentioned conditions was 10% or less in terms of number, it was determined that non-specific aggregation did not occur, and this was indicated by a minus sign.
更に、それぞれのラテックスをマイクロタイター板のウ
ェル中でその沈降凝集像を肉眼で観察したところ、本発
明の実施例１〜４によるラテックスでは、いずれも非特
異な沈降凝集像は、ヒト血清希釈倍数１０以下であった
のに対して、比較例１〜４によるラテックス粒子では、
いずれも４０倍以上まで認められた。Furthermore, when the sedimentation and agglutination images of each latex were observed with the naked eye in the wells of a microtiter plate, it was found that for the latexes according to Examples 1 to 4 of the present invention, non-specific sedimentation and agglutination images were observed at the human serum dilution factor. 10 or less, whereas in the latex particles according to Comparative Examples 1 to 4,
In both cases, it was observed to be more than 40 times higher.
特許出願人 日東電気工業株式会社 代理人 弁理士 牧 野 逸 部Patent applicant: Nitto Electric Industry Co., Ltd. Agent Patent Attorney Itsu Makino
Claims (2)
ル基を示し、Ｒ＾２は水素又は低級アルキル基を示し、
Ｒ＾１が水素又は低級アルキル基のときは、Ｒ＾２はカ
ルボ低級アルコキシ基であつてもよい。） で表わされるアクリル酸誘導体０．１〜２０重量％と、 （ｂ）一般式 ＣＨ＿２＝ＣＲ＾３ＣＯＯＲ＾４（ＣＦ＿２）＿ｎＣＦ
Ａ＿２（但し、Ｒ＾３は水素又は低級アルキル基を示し
、Ｒ＾４は ▲数式、化学式、表等があります▼ （但し、ｍは０〜１２の整数を示し、ｘ＋ｙ＝ｍ−１で
あり、Ｒ＾５は水素又はアセチル基を示す。）を示し、
Ａはそれぞれ独立に水素、フッ素又はＣＦ＿３を示し、
ｎは０〜１２の整数を示す。） で表わされるアクリル酸フルオロアルキルエステル誘導
体９９．１〜８０重量％とを水性媒体中で乳化剤の不存
在下に乳化共重合させて、生理活性物質固定化用担体粒
子を製造する方法において、 第１段として、アクリル酸誘導体とアクリル酸フルオロ
アルキルエステル誘導体との単量体混合物の合計量にお
いて、アクリル酸誘導体を０〜１０重量％の範囲として
共重合させ、後続段においては、前段よりも単量体混合
物の合計量におけるアクリル酸誘導体の量を少なくとも
０．５重量％増加させて、最終的に平均粒径０．２〜２
μｍ、表面にカルボキシル基を０．５〜２０μモル／ｍ
＾２の密度にて有する水分散型高分子重合体粒子を得る
ことを特徴とする生理活性物質固定化用担体粒子の製造
方法。(1) (a) General formula R^1CH=CR^2COOH (However, R^1 represents hydrogen, a lower alkyl group, or a carboxyl group, and R^2 represents hydrogen or a lower alkyl group,
When R^1 is hydrogen or a lower alkyl group, R^2 may be a carbo-lower alkoxy group. ) 0.1 to 20% by weight of an acrylic acid derivative represented by (b) general formula CH_2=CR^3COOR^4(CF_2)_nCF
A_2 (However, R^3 represents hydrogen or a lower alkyl group, and R^4 has a ▲ mathematical formula, chemical formula, table, etc.) (However, m represents an integer from 0 to 12, and x + y = m-1. , R^5 represents hydrogen or an acetyl group),
A each independently represents hydrogen, fluorine or CF_3,
n represents an integer of 0 to 12. ) in an aqueous medium in the absence of an emulsifier to produce carrier particles for immobilizing a physiologically active substance, comprising: In the first stage, the acrylic acid derivative is copolymerized in a range of 0 to 10% by weight based on the total amount of the monomer mixture of the acrylic acid derivative and the acrylic acid fluoroalkyl ester derivative, and in the subsequent stage, the monomer mixture is copolymerized in a proportion of 0 to 10% by weight. The amount of acrylic acid derivative in the total amount of the polymer mixture is increased by at least 0.5% by weight to obtain a final average particle size of 0.2 to 2.
μm, carboxyl group on the surface 0.5 to 20 μmol/m
A method for producing carrier particles for immobilizing a physiologically active substance, the method comprising obtaining water-dispersed polymer particles having a density of ^2.
ルオロアルキルエステル誘導体９９〜９０重量％からな
る単量体混合物を水性媒体中で乳化共重合させてなるシ
ード・ラテックスの存在下に、第１段の重合を行なうこ
とを特徴とする特許請求の範囲第１項記載の生理活性物
質固定化用担体粒子の製造方法。(2) In the presence of a seed latex obtained by emulsion copolymerizing a monomer mixture consisting of 1 to 10% by weight of an acrylic acid derivative and 99 to 90% by weight of an acrylic acid fluoroalkyl ester derivative in an aqueous medium, the first 2. The method for producing carrier particles for immobilizing a physiologically active substance according to claim 1, which comprises performing step-by-step polymerization.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP62331024A JPH01170854A (en) | 1987-12-25 | 1987-12-25 | Production of carrier particle for immobilizing physiologically active material |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP62331024A JPH01170854A (en) | 1987-12-25 | 1987-12-25 | Production of carrier particle for immobilizing physiologically active material |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH01170854A true JPH01170854A (en) | 1989-07-05 |
Family
ID=18238969
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP62331024A Pending JPH01170854A (en) | 1987-12-25 | 1987-12-25 | Production of carrier particle for immobilizing physiologically active material |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH01170854A (en) |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH0517538A (en) * | 1991-07-11 | 1993-01-26 | Hoechst Gosei Kk | Method for producing fluorine-containing acryl copolymer aqueous emulsion and composition therefor |
| EP0708120A1 (en) | 1994-10-18 | 1996-04-24 | Elf Atochem S.A. | Latexes and blends of fluorinated acrylic and methacrylic latexes |
| AU2012202761B2 (en) * | 2011-05-17 | 2013-04-18 | Rohm And Haas Company | Latex particles imbibed with a thermoplastic polymer |
| JPWO2013027849A1 (en) * | 2011-08-25 | 2015-03-23 | 積水化成品工業株式会社 | Oval shaped resin particles, method for producing the same, and use thereof |
| JP2020083905A (en) * | 2018-11-15 | 2020-06-04 | 花王株式会社 | Production method of polymer emulsion |
-
1987
- 1987-12-25 JP JP62331024A patent/JPH01170854A/en active Pending
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH0517538A (en) * | 1991-07-11 | 1993-01-26 | Hoechst Gosei Kk | Method for producing fluorine-containing acryl copolymer aqueous emulsion and composition therefor |
| EP0708120A1 (en) | 1994-10-18 | 1996-04-24 | Elf Atochem S.A. | Latexes and blends of fluorinated acrylic and methacrylic latexes |
| AU2012202761B2 (en) * | 2011-05-17 | 2013-04-18 | Rohm And Haas Company | Latex particles imbibed with a thermoplastic polymer |
| JPWO2013027849A1 (en) * | 2011-08-25 | 2015-03-23 | 積水化成品工業株式会社 | Oval shaped resin particles, method for producing the same, and use thereof |
| JP2020083905A (en) * | 2018-11-15 | 2020-06-04 | 花王株式会社 | Production method of polymer emulsion |
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