JP6051903B2 - Aggregation accelerator for latex agglutination reaction, target substance detection method and kit for use in target substance detection - Google Patents
Aggregation accelerator for latex agglutination reaction, target substance detection method and kit for use in target substance detection Download PDFInfo
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- JP6051903B2 JP6051903B2 JP2013021148A JP2013021148A JP6051903B2 JP 6051903 B2 JP6051903 B2 JP 6051903B2 JP 2013021148 A JP2013021148 A JP 2013021148A JP 2013021148 A JP2013021148 A JP 2013021148A JP 6051903 B2 JP6051903 B2 JP 6051903B2
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- 238000004220 aggregation Methods 0.000 title claims description 76
- 230000002776 aggregation Effects 0.000 title claims description 76
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- 238000006243 chemical reaction Methods 0.000 title claims description 50
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- 230000004520 agglutination Effects 0.000 title claims description 23
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 9
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- 238000002955 isolation Methods 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
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- FPYJFEHAWHCUMM-UHFFFAOYSA-N maleic anhydride Chemical compound O=C1OC(=O)C=C1 FPYJFEHAWHCUMM-UHFFFAOYSA-N 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- LULAYUGMBFYYEX-UHFFFAOYSA-N metachloroperbenzoic acid Natural products OC(=O)C1=CC=CC(Cl)=C1 LULAYUGMBFYYEX-UHFFFAOYSA-N 0.000 description 1
- ZQMHJBXHRFJKOT-UHFFFAOYSA-N methyl 2-[(1-methoxy-2-methyl-1-oxopropan-2-yl)diazenyl]-2-methylpropanoate Chemical compound COC(=O)C(C)(C)N=NC(C)(C)C(=O)OC ZQMHJBXHRFJKOT-UHFFFAOYSA-N 0.000 description 1
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- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
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- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
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- 229960004793 sucrose Drugs 0.000 description 1
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- 125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 description 1
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- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 1
- RKHXQBLJXBGEKF-UHFFFAOYSA-M tetrabutylphosphanium;bromide Chemical compound [Br-].CCCC[P+](CCCC)(CCCC)CCCC RKHXQBLJXBGEKF-UHFFFAOYSA-M 0.000 description 1
- IBWGNZVCJVLSHB-UHFFFAOYSA-M tetrabutylphosphanium;chloride Chemical compound [Cl-].CCCC[P+](CCCC)(CCCC)CCCC IBWGNZVCJVLSHB-UHFFFAOYSA-M 0.000 description 1
- 125000000383 tetramethylene group Chemical group [H]C([H])([*:1])C([H])([H])C([H])([H])C([H])([H])[*:2] 0.000 description 1
- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
- LDHQCZJRKDOVOX-UHFFFAOYSA-N trans-crotonic acid Natural products CC=CC(O)=O LDHQCZJRKDOVOX-UHFFFAOYSA-N 0.000 description 1
- 125000003258 trimethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])[*:1] 0.000 description 1
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Landscapes
- Addition Polymer Or Copolymer, Post-Treatments, Or Chemical Modifications (AREA)
Description
本発明は、ラテックス凝集反応用凝集促進剤、標的物質の検出方法および標的物質の検出に用いるためのキットに関する。 The present invention relates to an aggregation accelerator for latex aggregation reaction, a method for detecting a target substance, and a kit for use in detecting a target substance.
標的物質である抗原(抗体)と、これに対する抗体(抗原)との間で生じる凝集反応を利用した免疫ラテックス凝集測定法が、臨床検査、生化学研究等の領域において広く活用されているが、この測定法は、他の測定方法(酵素増幅法、化学発光測定法等)と比較して検出感度不足が指摘されることがある。 An immunolatex agglutination measurement method that utilizes an agglutination reaction that occurs between an antigen (antibody) that is a target substance and an antibody (antigen) against it is widely used in areas such as clinical tests and biochemical research. This measurement method may point to a lack of detection sensitivity compared to other measurement methods (enzyme amplification method, chemiluminescence measurement method, etc.).
そのため、ラテックス凝集反応の凝集促進剤が提案されている。このような凝集促進剤として、ポリエチレングリコール、多価アルコール、ポリビニルピロリドン、カルボキシメチルセルロース、サッカロース、デキストラン、ポリアミノ酸、アルギン酸、アミノエタンスルホン酸誘導体、アミノプロパンスルン酸誘導体等の水溶性高分子が用いられている(特許文献1〜4)。 Therefore, an aggregation accelerator for latex aggregation reaction has been proposed. As such an aggregation accelerator, water-soluble polymers such as polyethylene glycol, polyhydric alcohol, polyvinyl pyrrolidone, carboxymethyl cellulose, saccharose, dextran, polyamino acid, alginic acid, aminoethanesulfonic acid derivative, aminopropane sulfonic acid derivative are used. (Patent Documents 1 to 4).
本発明が解決しようとする課題は、凝集促進効果に優れるラテックス凝集反応用凝集促進剤、標的物質の検出方法および標的物質の検出に用いるためのキットを提供することにある。 The problem to be solved by the present invention is to provide an aggregation accelerator for latex aggregation reaction that is excellent in the aggregation promotion effect, a method for detecting a target substance, and a kit for use in detecting a target substance.
そこで、本発明者らは、スルフィニル基を側鎖に有する繰り返し単位を有する重合体が、ラテックス凝集反応の凝集促進効果に優れることを見出し、本発明を完成した。 Thus, the present inventors have found that a polymer having a repeating unit having a sulfinyl group in the side chain is excellent in the aggregation promoting effect of latex aggregation reaction, and completed the present invention.
すなわち、本発明は、スルフィニル基を側鎖に有する繰り返し単位を有する重合体を含有するラテックス凝集反応用凝集促進剤を提供するものである。 That is, the present invention provides an aggregation accelerator for latex aggregation reaction, which contains a polymer having a repeating unit having a sulfinyl group in the side chain.
また、本発明は、ラテックス凝集法による検体中の標的物質の検出方法であって、スルフィニル基を側鎖に有する繰り返し単位を有する重合体の存在下で、標的物質に対する抗原または抗体が固定化された粒子と、標的物質を含む可能性のある検体とを混合することを特徴とする検出方法を提供するものである。 The present invention also relates to a method for detecting a target substance in a specimen by a latex agglutination method, wherein an antigen or antibody against the target substance is immobilized in the presence of a polymer having a repeating unit having a sulfinyl group in the side chain. The detection method is characterized by mixing the prepared particles and a specimen that may contain a target substance.
更に、本発明は、ラテックス凝集法による検体中の標的物質の検出に用いるためのキットであって、スルフィニル基を側鎖に有する繰り返し単位を有する重合体を含有するラテックス凝集反応用凝集促進剤を少なくとも備えることを特徴とするキットを提供するものである。 Furthermore, the present invention provides a kit for use in detecting a target substance in a specimen by a latex agglutination method, comprising an aggregation accelerator for latex agglutination reaction containing a polymer having a repeating unit having a sulfinyl group in the side chain. A kit characterized by comprising at least the above is provided.
本発明のラテックス凝集反応用凝集促進剤は、ラテックス凝集反応の凝集促進効果に優れる。
また、本発明の標的物質の検出方法及び標的物質の検出に用いるためのキットは、高い検出感度を有する。
The aggregation accelerator for latex aggregation reaction of the present invention is excellent in the aggregation promotion effect of latex aggregation reaction.
In addition, the target substance detection method and the kit for use in detection of the target substance of the present invention have high detection sensitivity.
〔ラテックス凝集反応用凝集促進剤〕
本発明のラテックス凝集反応用凝集促進剤は、スルフィニル基を側鎖に有する繰り返し単位(以下、繰り返し単位(A)とも称する)を有する重合体を含有するものである。
[Aggregation accelerator for latex agglutination reaction]
The aggregation accelerator for latex aggregation reaction of the present invention contains a polymer having a repeating unit having a sulfinyl group in the side chain (hereinafter also referred to as a repeating unit (A)).
<繰り返し単位(A)>
上記繰り返し単位(A)としては親水性を示すものが好ましい。ここで、本明細書において、親水性とは、水との親和力が強い性質を持つことを意味する。具体的には1種の繰り返し単位のみからなるホモポリマー(実施例の測定法による数平均分子量が1万〜10万程度のもの)が、常温(25℃)において純水100gに対して1g以上溶解する場合にはその繰り返し単位は親水性である。
また、上記繰り返し単位(A)としては、親水疎水の尺度を示すHydrophile−Lipophile Balance(HLB値)が10以上のものが好ましい。高い親水性を得る場合には、HLB値は15以上がより好ましく、20〜40がさらに好ましく、20〜30が特に好ましい。
また、本明細書において、HLB値は、化合物の有機性の値と無機性の値の比率から算出されるもの(小田式)を意味し、「Formulation Design with Organic Conception Diagram」[1998年、NIHON EMULSION CO.,LTD]に記載の計算方法により算出できる。例えば、後述する実施例に記載のN−1−1の共重合体に含まれる繰り返し単位(A)のHLB値は、(60×1+140×1+100×3)/(20×10+40×1+(−10)×3)×10=23.8である。
<Repeating unit (A)>
As said repeating unit (A), what shows hydrophilic property is preferable. Here, in this specification, hydrophilic means that it has a property with strong affinity with water. Specifically, a homopolymer consisting of only one type of repeating unit (having a number average molecular weight of about 10,000 to 100,000 by the measurement method of the Examples) is 1 g or more per 100 g of pure water at room temperature (25 ° C.). When dissolved, the repeating unit is hydrophilic.
Moreover, as said repeating unit (A), the thing of Hydrophile-Lipophile Balance (HLB value) which shows the scale of hydrophilicity hydrophobicity is 10 or more is preferable. In the case of obtaining high hydrophilicity, the HLB value is more preferably 15 or more, further preferably 20 to 40, and particularly preferably 20 to 30.
Further, in this specification, the HLB value means a value calculated from the ratio of the organic value and the inorganic value of the compound (Oda equation), and “Formation Design with Organic Concept Diagram” [1998, NIHON]. EMULSION CO. , LTD]. For example, the HLB value of the repeating unit (A) contained in the copolymer of N-1-1 described in Examples described later is (60 × 1 + 140 × 1 + 100 × 3) / (20 × 10 + 40 × 1 + (− 10 ) × 3) × 10 = 23.8.
また、繰り返し単位(A)は特に限定されないが、ノニオン性のものが好ましい。
また、繰り返し単位(A)は、スルフィニル基の他に、ヒドロキシ基、カルボキシ基、アミノ基、スルホ基、チオール基、リン酸基、アルデヒド基等の親水性基を有していてもよい。また、斯かる親水性基の位置および個数は任意であるが、その位置は好ましくは重合体の側鎖である。一方、スルフィニル基以外の親水性基の個数としては、適度な親水性を得る観点から、繰り返し単位1個中に、0〜12個が好ましく、0〜10個がより好ましく、0〜5個が更に好ましく、0〜3個が更に好ましく、1〜3個が更に好ましく、2または3個が特に好ましい。また、上記親水性基の中でも、適度な親水性を得る観点から、ヒドロキシ基が好ましい。なお、本発明の効果が失われない範囲で、重合体に含まれる複数のスルフィニル基の一部がスルフィド基やスルホニル基となっていてもよい。
The repeating unit (A) is not particularly limited, but nonionic ones are preferred.
In addition to the sulfinyl group, the repeating unit (A) may have a hydrophilic group such as a hydroxy group, a carboxy group, an amino group, a sulfo group, a thiol group, a phosphoric acid group, or an aldehyde group. Further, the position and the number of such hydrophilic groups are arbitrary, but the position is preferably a side chain of the polymer. On the other hand, the number of hydrophilic groups other than sulfinyl groups is preferably 0 to 12, more preferably 0 to 10, more preferably 0 to 5 in one repeating unit from the viewpoint of obtaining appropriate hydrophilicity. More preferably, 0 to 3 is more preferable, 1 to 3 is more preferable, and 2 or 3 is particularly preferable. Among the hydrophilic groups, a hydroxy group is preferable from the viewpoint of obtaining appropriate hydrophilicity. In addition, as long as the effect of this invention is not lost, some sulfinyl groups contained in a polymer may be sulfide groups or sulfonyl groups.
また、上記繰り返し単位(A)の好適な具体例としては、下記式(1)で表される構造を側鎖中に少なくとも1つ含む繰り返し単位が挙げられる。式(1)で表される構造を側鎖中に有する繰り返し単位となるポリマー種としては公知のものを用いることができ、中でも(メタ)アクリレート系のポリマー種、(メタ)アクリルアミド系のポリマー種、スチレン系のポリマー種等が好ましい。より具体的には、下記式(2)で表される繰り返し単位が挙げられる。 Specific examples of the repeating unit (A) include a repeating unit containing at least one structure represented by the following formula (1) in the side chain. As the polymer species to be a repeating unit having the structure represented by the formula (1) in the side chain, known polymers can be used, among which (meth) acrylate polymer species and (meth) acrylamide polymer species Styrene-based polymer species are preferred. More specifically, a repeating unit represented by the following formula (2) is exemplified.
〔式(1)中、R3は、直接結合または炭素数1〜24の2価の有機基を示し、R4は、炭素数1〜10の有機基を示す。〕 [In Formula (1), R < 3 > shows a direct bond or a C1-C24 bivalent organic group, and R < 4 > shows a C1-C10 organic group. ]
〔式(2)中、R1は、水素原子またはメチル基を示し、R2は、基−O−、基*−(C=O)−O−、基*−(C=O)−NR5−、基*−NR5−(C=O)−(R5は、水素原子または炭素数1〜10の有機基を示し、*は、式(2)中のR1が結合している炭素原子と結合する位置を示す)またはフェニレン基を示し、R3およびR4は前記と同義である。〕
ここで、式(1)および(2)中の各記号について詳細に説明する。
[In formula (2), R 1 represents a hydrogen atom or a methyl group, R 2 is a group -O-, a group * - (C = O) -O- , group * - (C = O) -NR 5 -, group * -NR 5 - (C = O) - (R 5 is a hydrogen atom or an organic group having 1 to 10 carbon atoms, and *, R 1 in the formula (2) is attached R represents a position bonded to a carbon atom) or a phenylene group, and R 3 and R 4 are as defined above. ]
Here, each symbol in the formulas (1) and (2) will be described in detail.
R1は、水素原子またはメチル基を示すが、メチル基が好ましい。 R 1 represents a hydrogen atom or a methyl group, preferably a methyl group.
また、R2は、基−O−、基*−(C=O)−O−、基*−(C=O)−NR5−、基*−NR5−(C=O)−またはフェニレン基を示す。斯かるフェニレン基としては、1,2−フェニレン基、1,3−フェニレン基、1,4−フェニレン基が挙げられる。 R 2 represents a group —O—, a group * — (C═O) —O—, a group * — (C═O) —NR 5 —, a group * —NR 5 — (C═O) — or phenylene. Indicates a group. Examples of such a phenylene group include a 1,2-phenylene group, a 1,3-phenylene group, and a 1,4-phenylene group.
また、上記R5で示される有機基の炭素数は、好ましくは1〜10であり、より好ましくは2〜8であり、更に好ましくは2〜6である。上記有機基としては、炭化水素基が挙げられる。斯かる炭化水素基は、脂肪族炭化水素基、脂環式炭化水素基および芳香族炭化水素基を包含する概念である。 The number of carbon atoms of the organic group represented by the R 5 is preferably 1 to 10, more preferably from 2 to 8, more preferably from 2 to 6. Examples of the organic group include hydrocarbon groups. Such a hydrocarbon group is a concept including an aliphatic hydrocarbon group, an alicyclic hydrocarbon group, and an aromatic hydrocarbon group.
上記R5における脂肪族炭化水素基は直鎖状でも分岐状でもよく、具体的には、メチル基、エチル基、n−プロピル基、イソプロピル基、n−ブチル基、イソブチル基、sec−ブチル基、tert−ブチル基、ペンチル基、ヘキシル基、ヘプチル基、オクチル基等のアルキル基が挙げられる。
また、上記脂環式炭化水素基は、単環の脂環式炭化水素基と橋かけ環炭化水素基に大別される。上記単環の脂環式炭化水素基としては、シクロプロピル基、シクロヘキシル基等のシクロアルキル基が挙げられる。また、橋かけ環炭化水素基としては、イソボルニル基等が挙げられる。
また、上記芳香族炭化水素基としては、フェニル基等のアリール基が挙げられる。
The aliphatic hydrocarbon group in R 5 may be linear or branched, and specifically includes a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, and a sec-butyl group. Alkyl groups such as tert-butyl group, pentyl group, hexyl group, heptyl group and octyl group.
The alicyclic hydrocarbon group is roughly classified into a monocyclic alicyclic hydrocarbon group and a bridged ring hydrocarbon group. Examples of the monocyclic alicyclic hydrocarbon group include cycloalkyl groups such as a cyclopropyl group and a cyclohexyl group. Examples of the bridged ring hydrocarbon group include an isobornyl group.
Examples of the aromatic hydrocarbon group include aryl groups such as a phenyl group.
上述のようなR2の中でも、凝集促進効果の観点から、基*−(C=O)−O−、フェニレン基が好ましく、基*−(C=O)−O−が特に好ましい。 Among R 2 as described above, the group * — (C═O) —O— and the phenylene group are preferable, and the group * — (C═O) —O— is particularly preferable from the viewpoint of the aggregation promoting effect.
R3は、直接結合または炭素数1〜24の2価の有機基を示す。斯かる直接結合としては、単結合が挙げられる。 R 3 represents a direct bond or a divalent organic group having 1 to 24 carbon atoms. Such direct bonds include single bonds.
斯様なR3の中でも、炭素数1〜24の2価の有機基が好ましい。斯かる2価の有機基の炭素数は、好ましくは2〜18であり、より好ましくは2〜10であり、更に好ましくは2〜9であり、特に好ましくは3〜6である。 Among such R 3, a divalent organic group having 1 to 24 carbon atoms is preferable. The carbon number of such a divalent organic group is preferably 2 to 18, more preferably 2 to 10, still more preferably 2 to 9, and particularly preferably 3 to 6.
上記2価の有機基としては、2価の炭化水素基が挙げられる。2価の炭化水素基は、好ましくは2価の脂肪族炭化水素基であり、直鎖状でも分岐状でもよい。具体的には、メタン−1,1−ジイル基、エタン−1,1−ジイル基、エタン−1,2−ジイル基、プロパン−1,1−ジイル基、プロパン−1,2−ジイル基、プロパン−1,3−ジイル基、プロパン−2,2−ジイル基、ブタン−1,2−ジイル基、ブタン−1,3−ジイル基、ブタン−1,4−ジイル基、ペンタン−1,4−ジイル基、ペンタン−1,5−ジイル基、ヘキサン−1,5−ジイル基、ヘキサン−1,6−ジイル基、ヘプタン−1,7−ジイル基、オクタン−1,8−ジイル基等のアルカンジイル基が挙げられる。 Examples of the divalent organic group include a divalent hydrocarbon group. The divalent hydrocarbon group is preferably a divalent aliphatic hydrocarbon group and may be linear or branched. Specifically, methane-1,1-diyl group, ethane-1,1-diyl group, ethane-1,2-diyl group, propane-1,1-diyl group, propane-1,2-diyl group, Propane-1,3-diyl group, propane-2,2-diyl group, butane-1,2-diyl group, butane-1,3-diyl group, butane-1,4-diyl group, pentane-1,4 -Diyl group, pentane-1,5-diyl group, hexane-1,5-diyl group, hexane-1,6-diyl group, heptane-1,7-diyl group, octane-1,8-diyl group, etc. An alkanediyl group may be mentioned.
また、上記2価の炭化水素基は、置換基を有していてもよく、炭素−炭素結合間にエーテル結合を含んでいてもよい。
上記2価の炭化水素基が有していてもよい置換基としては、前記親水性基が挙げられる。該置換基の個数は、好ましくは1〜5であり、より好ましくは1〜3であり、更に好ましくは1または2である。
また、上記2価の炭化水素基が含んでいてもよいエーテル結合の個数としては、0〜5が好ましく、0〜3がより好ましい。
The divalent hydrocarbon group may have a substituent and may contain an ether bond between carbon-carbon bonds.
Examples of the substituent that the divalent hydrocarbon group may have include the hydrophilic group. The number of the substituents is preferably 1 to 5, more preferably 1 to 3, and further preferably 1 or 2.
Moreover, as the number of the ether bonds which the said bivalent hydrocarbon group may contain, 0-5 are preferable and 0-3 are more preferable.
また、2価の有機基の好適な具体例としては、下記式(3)で表される連結基、炭素数1〜24のアルカンジイル基が挙げられ、より好ましくは式(3)で表される連結基である。 Specific examples of the divalent organic group include a linking group represented by the following formula (3) and an alkanediyl group having 1 to 24 carbon atoms, and more preferably represented by the formula (3). A linking group.
〔式(3)中、R6は、単結合、基−R8−O−(R8は、炭素数1〜4のアルカンジイル基を示す)または下記式(4)で表される連結基を示し、R7は、炭素数1〜4のアルカンジイル基を示し、nは1または2を示し、**は、式(1)、(2)中のイオウ原子と結合する位置を示す。〕 [In Formula (3), R 6 is a single bond, a group —R 8 —O— (R 8 represents an alkanediyl group having 1 to 4 carbon atoms) or a linking group represented by the following Formula (4). R 7 represents an alkanediyl group having 1 to 4 carbon atoms, n represents 1 or 2, and ** represents a position bonded to a sulfur atom in the formulas (1) and (2). ]
〔式(4)中、R9は、炭素数1〜4のアルカンジイル基を示し、R10は、炭素数2または3のアルカンジイル基を示し、m1は1または2を示し、m2は1〜3の整数を示す。〕 [In the formula (4), R 9 represents an alkanediyl group having 1 to 4 carbon atoms, R 10 represents an alkanediyl group having 2 or 3 carbon atoms, m 1 represents 1 or 2, m 2 Represents an integer of 1 to 3. ]
上記R6としては、単結合、基−R8−O−が好ましく、単結合が特に好ましい。 R 6 is preferably a single bond or a group —R 8 —O—, and particularly preferably a single bond.
また、上記R7、R8およびR9で示されるアルカンジイル基の炭素数は1〜4であるが、1または2が好ましい。
また、上記アルカンジイル基は直鎖状でも分岐でもよく、前述のアルカンジイル基と同様のものが挙げられる。
The alkanediyl group represented by R 7 , R 8 and R 9 has 1 to 4 carbon atoms, but 1 or 2 is preferable.
The alkanediyl group may be linear or branched, and examples thereof include the same alkanediyl groups as described above.
また、上記R10で示されるアルカンジイル基の炭素数は、好ましくは2である。また、該アルカンジイル基としては、R7で示されるものと同様のものが挙げられる。なお、m2が2または3の場合、m2個のR10は同一であっても異なっていてもよい。
また、nおよびm1としては1が好ましく、m2としては1または2が好ましい。
The carbon number of the alkanediyl group represented by R 10 is preferably 2. Examples of the alkanediyl group include the same as those represented by R 7 . When m 2 is 2 or 3, m 2 R 10 may be the same or different.
Further, 1 is preferable as n and m 1, 1 or 2 is preferable as m 2.
また、R4は、炭素数1〜10の有機基を示す。斯かる有機基としては、R5で示されるものと同様のものが挙げられる。また、R4が炭化水素基である場合、斯かる炭化水素基は置換基を有していてもよく、該置換基およびその個数としては、前記2価の炭化水素基が有していてもよいものと同様のものが挙げられる。また、親水性の観点から、R4としては、シクロアルキル基、アリール基、アラルキル基等の環構造を含まないものが好ましい。 R 4 represents an organic group having 1 to 10 carbon atoms. Examples of such an organic group include the same groups as those represented by R 5 . In addition, when R 4 is a hydrocarbon group, such a hydrocarbon group may have a substituent, and the substituent and the number thereof may be the divalent hydrocarbon group. The thing similar to a good thing is mentioned. From the viewpoint of hydrophilicity, R 4 preferably does not contain a ring structure such as a cycloalkyl group, an aryl group, or an aralkyl group.
上述のようなR4の好適な具体例としては、前記親水性基を有する炭素数1〜10の有機基が挙げられ、より好ましくは下記式(5)で表される1価の基、炭素数1〜10のアルキル基であり、更に好ましくは式(5)で表される1価の基である。 Preferable specific examples of R 4 as described above include organic groups having 1 to 10 carbon atoms having the hydrophilic group, more preferably a monovalent group represented by the following formula (5), carbon. It is a C1-C10 alkyl group, More preferably, it is a monovalent group represented by Formula (5).
〔式(5)中、k1は、1〜4の整数を示し、k2は、0〜4の整数を示し、***は、式(1)、(2)中のイオウ原子と結合する位置を示す。〕 Wherein (5), k 1 represents an integer of 1 to 4, k 2 is an integer of 0 to 4, *** the formula (1), combined with the sulfur atom in (2) Indicates the position to perform. ]
式(5)中、k1としては、1または2が好ましい。また、k2としては、0〜2の整数が好ましく、0または1がより好ましい。 In formula (5), k 1 is preferably 1 or 2. As the k 2, preferably an integer of 0 to 2, 0 or 1 are more preferable.
また、繰り返し単位(A)の合計含有量の下限としては、水溶性の付与、凝集促進効果の観点から、全繰り返し単位中、10モル%以上が好ましく、20モル%以上がより好ましく、30モル%以上が更に好ましく、40モル%以上が更に好ましい。
一方、上限としては、重合体とラテックス粒子の疎水−疎水相互作用の観点から、全繰り返し単位中、99モル%以下が好ましく、90モル%以下がより好ましく、85モル%以下が更に好ましく、80モル%以下が更に好ましく、70モル%以下が更に好ましい。
なお、繰り返し単位(A)の含有量は13C−NMR等により測定可能である。
In addition, the lower limit of the total content of the repeating unit (A) is preferably 10 mol% or more, more preferably 20 mol% or more, more preferably 30 mol in all repeating units from the viewpoint of imparting water solubility and an effect of promoting aggregation. % Or more is more preferable, and 40 mol% or more is more preferable.
On the other hand, the upper limit is preferably 99 mol% or less, more preferably 90 mol% or less, still more preferably 85 mol% or less, from the viewpoint of hydrophobic-hydrophobic interaction between the polymer and latex particles. The mol% or less is more preferable, and the 70 mol% or less is more preferable.
The content of the repeating unit (A) can be measured by 13 C-NMR or the like.
<繰り返し単位(B)>
また、本発明で用いる重合体としては、更に疎水性繰り返し単位(以下、繰り返し単位(B)とも称する)を有するものが好ましい。ここで、疎水性とは、水との親和性が低い性質を持つことを意味する。具体的には、1種の繰り返し単位のみからなるホモポリマー(実施例の測定法による数平均分子量が1万〜10万程度のもの)が、常温(25℃)において純水100gに対して溶解する量が1g未満である場合にはその繰り返し単位は疎水性である。
また、上記繰り返し単位(B)のHLB値としては、高い疎水性を得る場合には、20未満が好ましく、15未満がより好ましく、0.1以上10未満が更に好ましく、0.1〜5が特に好ましい。
<Repeating unit (B)>
The polymer used in the present invention preferably further has a hydrophobic repeating unit (hereinafter also referred to as a repeating unit (B)). Here, “hydrophobic” means having a property of low affinity with water. Specifically, a homopolymer consisting of only one type of repeating unit (having a number average molecular weight of about 10,000 to 100,000 according to the measurement method in Examples) is dissolved in 100 g of pure water at room temperature (25 ° C.). If the amount is less than 1 g, the repeating unit is hydrophobic.
In addition, the HLB value of the repeating unit (B) is preferably less than 20, more preferably less than 15, more preferably less than 10 and less than 10, more preferably 0.1 to 5 in order to obtain high hydrophobicity. Particularly preferred.
繰り返し単位(B)としては、疎水性を示す公知のものが挙げられ、特に限定されないが、重合体とラテックス粒子の疎水−疎水相互作用の観点から、スチレン類、(メタ)アクリレート類および(メタ)アクリルアミド類から選ばれる1種以上の単量体に由来するものが好ましく、スチレン類に由来するものがより好ましい。 Examples of the repeating unit (B) include those known to exhibit hydrophobicity, and are not particularly limited. However, from the viewpoint of the hydrophobic-hydrophobic interaction between the polymer and latex particles, styrenes, (meth) acrylates, and (meta ) Those derived from one or more monomers selected from acrylamides are preferred, and those derived from styrenes are more preferred.
上記スチレン類に由来する繰り返し単位としては、下記式(6)で表される繰り返し単位が好ましい。 As the repeating unit derived from the styrenes, a repeating unit represented by the following formula (6) is preferable.
〔式(6)中、R11は、水素原子またはメチル基を示し、R12は、炭素数1〜10の有機基を示し、pは0〜5の整数を示す。〕 [In Formula (6), R < 11 > shows a hydrogen atom or a methyl group, R < 12 > shows a C1-C10 organic group, and p shows the integer of 0-5. ]
式(6)中、R12で示される有機基としては、R5で示されるものと同様のものが挙げられるが、その炭素数は、好ましくは1〜6であり、より好ましくは1〜3である。また、親水性基がないものが好ましい。なお、斯かる有機基は、炭素数1〜3のアルコキシ基等が置換していてもよい。また、pが2〜5の整数の場合、p個のR12は同一であっても異なっていてもよい。 In formula (6), examples of the organic group represented by R 12 include the same groups as those represented by R 5 , but the carbon number thereof is preferably 1 to 6, and more preferably 1 to 3. It is. Moreover, the thing without a hydrophilic group is preferable. Such an organic group may be substituted with an alkoxy group having 1 to 3 carbon atoms. Also, when p is integer of 2 to 5, p number of R 12 may be the same or different.
また、pは0〜5の整数を示すが、0〜3が好ましく、0がより好ましい。 Moreover, although p shows the integer of 0-5, 0-3 are preferable and 0 is more preferable.
スチレン類に由来する繰り返し単位の具体例としては、スチレン、4−メチルスチレン、2,4−ジメチルスチレン、2,4,6−トリメチルスチレン、4−エチルスチレン、4−イソプロピルスチレン、4−tert−ブチルスチレン、α―メチルスチレン等に由来する繰り返し単位が挙げられる。 Specific examples of the repeating unit derived from styrenes include styrene, 4-methylstyrene, 2,4-dimethylstyrene, 2,4,6-trimethylstyrene, 4-ethylstyrene, 4-isopropylstyrene, 4-tert- Examples thereof include repeating units derived from butylstyrene, α-methylstyrene and the like.
また、上記(メタ)アクリレート類としては、例えば、(メタ)アクリル酸メチル、(メタ)アクリル酸エチル、(メタ)アクリル酸イソブチル、(メタ)アクリル酸2−エチルヘキシル等の(メタ)アクリル酸C1-10アルキル;(メタ)アクリル酸シクロヘキシル等の(メタ)アクリル酸C6-10シクロアルキル;(メタ)アクリル酸1−メトキシエチル、(メタ)アクリル酸2−メトキシエチル等の(メタ)アクリル酸C1-10アルコキシC1-10アルキル;(メタ)アクリル酸1−アダマンチル、(メタ)アクリル酸1−メチル−(1−アダマンチルエチル)、(メタ)アクリル酸トリシクロ[5.2.1.02,6]デカン−8−イル等の炭素数8〜16の橋かけ環炭化水素基を有する(メタ)アクリル酸エステル等が挙げられる。また、これら(メタ)アクリレート類において、上記C1-10アルキル基としてはC1-8アルキル基が好ましく、上記C6-10シクロアルキル基としてはC6-8シクロアルキル基が好ましく、上記C1-10アルコキシ基としてはC1-6アルコキシ基が好ましく、炭素数8〜16の橋かけ環炭化水素基としては、炭素数8〜12の橋かけ環炭化水素基が好ましい。 Examples of the (meth) acrylates include (meth) acrylic acid C such as methyl (meth) acrylate, ethyl (meth) acrylate, isobutyl (meth) acrylate, and 2-ethylhexyl (meth) acrylate. 1-10 alkyl; (meth) acrylic acid C 6-10 cycloalkyl such as methacrylic cyclohexyl; (meth) acrylic such as 1-methoxyethyl (meth) acrylate and 2-methoxyethyl (meth) acrylate Acid C 1-10 alkoxy C 1-10 alkyl; (meth) acrylate 1-adamantyl, (meth) acrylate 1-methyl- (1-adamantylethyl), (meth) acrylate tricyclo [5.2.1. And (meth) acrylic acid ester having a bridged cyclic hydrocarbon group having 8 to 16 carbon atoms such as 0 2,6 ] decan-8-yl. In these (meth) acrylates, the C 1-10 alkyl group is preferably a C 1-8 alkyl group, and the C 6-10 cycloalkyl group is preferably a C 6-8 cycloalkyl group. The 1-10 alkoxy group is preferably a C 1-6 alkoxy group, and the bridged ring hydrocarbon group having 8 to 16 carbon atoms is preferably a bridged ring hydrocarbon group having 8 to 12 carbon atoms.
また、上記(メタ)アクリルアミド類としては、例えば、N,N−ジC1-10アルキル(メタ)アクリルアミド;N−イソプロピル(メタ)アクリルアミド等のN−C1-10アルキル(メタ)アクリルアミド;N−(1,1−ジメチル−2−アセチルエチル)(メタ)アクリルアミド等のN−C2-10アルカノイルC1-10アルキル(メタ)アクリルアミドの他、(メタ)アクリロイルピペリジン等が挙げられる。また、これら(メタ)アクリルアミド類において、上記C1-10アルキル基としては、C3-10アルキル基が好ましく、上記C2-10アルカノイル基としては、C2-6アルカノイル基が好ましい。 Examples of the (meth) acrylamides include N, N-diC 1-10 alkyl (meth) acrylamide; N-C 1-10 alkyl (meth) acrylamide such as N-isopropyl (meth) acrylamide; N In addition to N—C 2-10 alkanoyl C 1-10 alkyl (meth) acrylamide such as — (1,1-dimethyl-2-acetylethyl) (meth) acrylamide, (meth) acryloylpiperidine and the like can be mentioned. In these (meth) acrylamides, the C 1-10 alkyl group is preferably a C 3-10 alkyl group, and the C 2-10 alkanoyl group is preferably a C 2-6 alkanoyl group.
また、繰り返し単位(B)の合計含有量の下限としては、重合体とラテックス粒子の疎水−疎水相互作用の観点から、全繰り返し単位中、1モル%以上が好ましく、10モル%以上がより好ましく、15モル%以上が更に好ましく、20モル%以上が更に好ましく、30モル%以上が更に好ましい。
一方、上限としては、水溶性の付与、凝集促進効果の観点から、全繰り返し単位中、90モル%以下が好ましく、80モル%以下がより好ましく、70モル%以下が更に好ましく、60モル%以下が更に好ましい。
なお、繰り返し単位(B)の含有量は、繰り返し単位(A)の含有量と同様にして測定すればよい。
Further, the lower limit of the total content of the repeating unit (B) is preferably 1 mol% or more, more preferably 10 mol% or more in all repeating units from the viewpoint of the hydrophobic-hydrophobic interaction between the polymer and latex particles. 15 mol% or more is more preferable, 20 mol% or more is more preferable, and 30 mol% or more is more preferable.
On the other hand, the upper limit is preferably 90 mol% or less, more preferably 80 mol% or less, still more preferably 70 mol% or less, and even more preferably 60 mol% or less in all repeating units from the viewpoint of imparting water solubility and promoting aggregation. Is more preferable.
In addition, what is necessary is just to measure content of a repeating unit (B) similarly to content of a repeating unit (A).
また、重合体に含まれる繰り返し単位(A)と繰り返し単位(B)とのモル比〔(A):(B)〕としては、凝集促進効果の観点から、10:1〜10:30が好ましく、10:2〜10:20がより好ましく、10:3〜10:15が更に好ましい。 Further, the molar ratio [(A) :( B)] of the repeating unit (A) and the repeating unit (B) contained in the polymer is preferably 10: 1 to 10:30 from the viewpoint of the aggregation promoting effect. 10: 2 to 10:20 are more preferable, and 10: 3 to 10:15 are still more preferable.
また、本発明で用いる重合体は、前記繰り返し単位(A)及び(B)以外の親水性繰り返し単位(C)を有していてもよい。斯様な親水性繰り返し単位(C)としては、アニオン性の単量体(アニオン性モノマー)、カチオン性の単量体(カチオン性モノマー)、またはノニオン性の単量体(ノニオン性モノマー)に由来するものが挙げられ、これらを1種または2種以上含んでいてもよい。 The polymer used in the present invention may have a hydrophilic repeating unit (C) other than the repeating units (A) and (B). Such hydrophilic repeating unit (C) includes an anionic monomer (anionic monomer), a cationic monomer (cationic monomer), or a nonionic monomer (nonionic monomer). The thing which originates is mentioned, These 1 type or 2 types or more may be included.
上記アニオン性モノマーとしては、ビニル安息香酸、(メタ)アクリル酸等の不飽和カルボン酸モノマー;スチレンスルホン酸、2−アクリルアミド−2−メチルプロパンスルホン酸、イソプレンスルホン酸等の不飽和スルホン酸モノマーが挙げられる。 Examples of the anionic monomer include unsaturated carboxylic acid monomers such as vinyl benzoic acid and (meth) acrylic acid; unsaturated sulfonic acid monomers such as styrene sulfonic acid, 2-acrylamido-2-methylpropane sulfonic acid, and isoprene sulfonic acid. Can be mentioned.
また、カチオン性モノマーとしては、アリルアミン、アミノスチレン、N,N−ジメチルアミノプロピル(メタ)アクリルアミド塩化メチル4級塩等の1〜4級アミノ基と不飽和結合を有するものが挙げられる。 Examples of the cationic monomer include those having an unsaturated bond with a primary to quaternary amino group such as allylamine, aminostyrene, N, N-dimethylaminopropyl (meth) acrylamide methyl chloride quaternary salt and the like.
また、ノニオン性モノマーとしては、(メタ)アクリル酸ヒドロキシエチル、(メタ)アクリル酸グリセリル、(メタ)アクリル酸ポリオキシエチレン等のヒドロキシ基を有する不飽和カルボン酸エステルモノマー;N−(2−ヒドロキシエチル)(メタ)アクリルアミド等のヒドロキシ基を有する(メタ)アクリルアミドモノマーが挙げられる。 In addition, examples of nonionic monomers include unsaturated carboxylic acid ester monomers having a hydroxy group such as hydroxyethyl (meth) acrylate, glyceryl (meth) acrylate, and polyoxyethylene (meth) acrylate; N- (2-hydroxy And (meth) acrylamide monomers having a hydroxy group such as ethyl) (meth) acrylamide.
上記繰り返し単位(C)の合計含有量としては、全繰り返し単位中、0〜49モル%が好ましく、0〜20モル%がより好ましく、0〜10モル%が更に好ましく、0〜1モル%が特に好ましい。 The total content of the repeating unit (C) is preferably 0 to 49 mol%, more preferably 0 to 20 mol%, still more preferably 0 to 10 mol%, and 0 to 1 mol% in all repeating units. Particularly preferred.
また、本発明で用いる重合体が共重合体である場合、その繰り返し単位の配列の態様は特に限定されず、共重合体は、ブロック共重合体、グラフト共重合体、ランダム共重合体、交互共重合体のいずれであってもよい。 In addition, when the polymer used in the present invention is a copolymer, the arrangement of the repeating units is not particularly limited, and the copolymer may be a block copolymer, a graft copolymer, a random copolymer, an alternating copolymer, or the like. Any of copolymers may be used.
また、本発明で用いる重合体の数平均分子量(Mn)としては、5000〜100万が好ましく、7000〜20万がより好ましく、1万〜15万が特に好ましい。数平均分子量を5000以上とすることにより、凝集促進効果が向上し、一方、100万以下とすることにより、粘度が抑制され取扱いが容易になる。
また、本発明で用いる重合体の重量平均分子量(Mw)としては、5000〜500万が好ましく、7000〜100万がより好ましく、7000〜20万が更に好ましい。
また、分子量分布(Mw/Mn)としては、1.0〜5.0が好ましく、1.0〜4.0がより好ましく、1.0〜3.0が更に好ましく、1.5〜2.5が特に好ましい。
なお、上記数平均分子量および重量平均分子量は、後述する実施例に記載の方法に従い測定すればよい。
Moreover, as a number average molecular weight ( Mn ) of the polymer used by this invention, 5000-1 million are preferable, 7000-200000 are more preferable, and 10,000-150,000 are especially preferable. By setting the number average molecular weight to 5000 or more, the aggregation promoting effect is improved. On the other hand, by setting the number average molecular weight to 1 million or less, the viscosity is suppressed and handling becomes easy.
Moreover, as a weight average molecular weight ( Mw ) of the polymer used by this invention, 5000-5 million are preferable, 7000-1 million are more preferable, 7000-200,000 are still more preferable.
Moreover, as molecular weight distribution ( Mw / Mn ), 1.0-5.0 are preferable, 1.0-4.0 are more preferable, 1.0-3.0 are still more preferable, 1.5- 2.5 is particularly preferred.
In addition, what is necessary is just to measure the said number average molecular weight and a weight average molecular weight according to the method as described in the Example mentioned later.
また、本発明で用いる重合体としては、凝集促進効果の観点から、水溶性のものが好ましい。ここで、本明細書において、水溶性とは、1質量%のポリマー固形分となるように重合体を水(25℃)に添加・混合したときに、目視で透明となることをいう。
また、本発明で用いる重合体としては、ノニオン性のものが好ましい。
Moreover, as a polymer used by this invention, a water-soluble thing is preferable from a viewpoint of the aggregation promotion effect. Here, in the present specification, water-soluble means that the polymer becomes transparent when added to and mixed with water (25 ° C.) so that the polymer solid content is 1% by mass.
Moreover, as a polymer used by this invention, a nonionic thing is preferable.
また、本発明で用いる重合体としては、水溶性の付与、凝集促進効果の観点から、HLB値が10〜22の範囲であるものが好ましい。 Moreover, as a polymer used by this invention, the thing whose HLB value is the range of 10-22 is preferable from a viewpoint of provision of water solubility and an aggregation promotion effect.
次に、本発明で用いる重合体の製造方法について説明する。
本発明で用いる重合体は、(1)公知の重合体の側鎖中にスルフィド基を導入し、斯かるスルフィド基をスルフィニル基に変換すること、(2)重合させたときに側鎖となる部分にスルフィド基を有するモノマーを、重合または他のモノマーと共重合させ、得られた(共)重合体のスルフィド基をスルフィニル基に変換すること、(3)或いは重合させたときに側鎖となる部分にスルフィニル基を有するモノマーを、重合または他のモノマーと共重合させること等により製造できる。
上記製造方法を、下記共重合体(N−1)の製造方法を例に挙げて具体的に説明する。
すなわち、工程1−A−1および工程1−A−2により、或いは工程1−Bまたは工程1−Cにより、共重合体(S−1)を得、これを用いて共重合体(G−1)を経て共重合体(N−1)を得る。
Next, the manufacturing method of the polymer used by this invention is demonstrated.
The polymer used in the present invention is (1) introducing a sulfide group into the side chain of a known polymer and converting the sulfide group to a sulfinyl group, and (2) forming a side chain when polymerized. A monomer having a sulfide group in a portion thereof is polymerized or copolymerized with another monomer, and the sulfide group of the obtained (co) polymer is converted into a sulfinyl group, (3) or when the side chain is polymerized A monomer having a sulfinyl group in the portion can be produced by polymerization or copolymerization with other monomers.
The said manufacturing method is concretely demonstrated taking the example of the manufacturing method of the following copolymer (N-1).
That is, a copolymer (S-1) is obtained by the step 1-A-1 and the step 1-A-2, or by the step 1-B or the step 1-C, and the copolymer (G- A copolymer (N-1) is obtained through 1).
(式中の各記号は前記と同義である。) (Each symbol in the formula is as defined above.)
<工程1−A−1>
工程1−A−1は、化合物(A−1−1)と化合物(B−1)とを重合開始剤の存在下で重合させ、共重合体(M−1)を得る工程である。
化合物(A−1−1)としては、例えば、(メタ)アクリル酸等が挙げられ、これらは1種を単独でまたは2種以上を組み合わせて使用できる。
また、化合物(B−1)としては、前記スチレン類が挙げられ、その合計使用量としては、化合物(A−1−1)に対し、0.001〜1.5モル当量が好ましい。
<Step 1-A-1>
Step 1-A-1 is a step of obtaining a copolymer (M-1) by polymerizing the compound (A-1-1) and the compound (B-1) in the presence of a polymerization initiator.
Examples of the compound (A-1-1) include (meth) acrylic acid and the like, and these can be used alone or in combination of two or more.
Moreover, the said styrene is mentioned as a compound (B-1), As the total usage-amount, 0.001-1.5 molar equivalent is preferable with respect to a compound (A-1-1).
また、上記重合開始剤としては、例えば、2,2'−アゾビス(イソブチロニトリル)、ジメチル2,2'−アゾビス(2−メチルプロピオネート)、2,2'−アゾビス(4−メトキシ−2,4−ジメチルバレロニトリル等のアゾ系開始剤;ジ(3,5,5−トリメチルヘキサノイル)パーオキサイド、過酸化ベンゾイル等の過酸化物が挙げられ、これら重合開始剤は1種を単独でまたは2種以上を組み合わせて使用できる。
重合開始剤の合計使用量は、化合物(A−1−1)に対し、通常0.0002〜0.2質量倍程度である。
Examples of the polymerization initiator include 2,2′-azobis (isobutyronitrile), dimethyl 2,2′-azobis (2-methylpropionate), 2,2′-azobis (4-methoxy). Azo initiators such as -2,4-dimethylvaleronitrile; peroxides such as di (3,5,5-trimethylhexanoyl) peroxide and benzoyl peroxide. These polymerization initiators include one kind. It can be used alone or in combination of two or more.
The total amount of the polymerization initiator used is usually about 0.0002 to 0.2 times by mass with respect to the compound (A-1-1).
また、工程1−A−1には溶媒、連鎖移動剤を使用してもよい。溶媒としては、ジメチルホルムアミド、ジメチルアセトアミド、N−メチルピロリドン等のアミド系溶媒;ジメチルスルホキシド等のスルホキシド系溶媒;酢酸エチル、酢酸ブチル、γ−ブチロラクトン等のエステル系溶媒;トルエン、ベンゼン等の芳香族系溶媒;1、4−ジオキサン、ジエチルエーテル等のエーテル系溶媒が挙げられ、これら溶媒は1種を単独でまたは2種以上を組み合わせて使用できる。これら溶媒の合計使用量は、化合物(A−1−1)に対し、通常0.5〜15質量倍程度である。
また、上記連鎖移動剤としては、メルカプトエタノール、チオグリセロール、tert−ドデシルメルカプタン等が挙げられる。
Moreover, you may use a solvent and a chain transfer agent for process 1-A-1. Solvents include amide solvents such as dimethylformamide, dimethylacetamide and N-methylpyrrolidone; sulfoxide solvents such as dimethyl sulfoxide; ester solvents such as ethyl acetate, butyl acetate and γ-butyrolactone; aromatics such as toluene and benzene Type | system | group solvent; Ether type | system | group solvents, such as 1, 4- dioxane, diethyl ether, are mentioned, These solvents can be used individually by 1 type or in combination of 2 or more types. The total amount of these solvents used is usually about 0.5 to 15 times by mass relative to the compound (A-1-1).
Examples of the chain transfer agent include mercaptoethanol, thioglycerol, tert-dodecyl mercaptan, and the like.
また、工程1−A−1の反応時間は特に限定されないが、通常0.5〜24時間程度であり、反応温度は、溶媒の沸点以下で適宜選択すればよいが、通常0〜120℃程度である。 The reaction time in step 1-A-1 is not particularly limited, but is usually about 0.5 to 24 hours, and the reaction temperature may be appropriately selected below the boiling point of the solvent, but is usually about 0 to 120 ° C. It is.
<工程1−A−2>
工程1−A−2は、工程1−A−1で得た共重合体(M−1)の−R2を、化合物(C−1)のグリシジル基またはオキセタニル基に対し開環付加させ、共重合体(S−1)を得る工程である。
工程1−A−2で用いる化合物(C−1)としては、エチレングリコールジグリシジルエーテル、プロピレングリコールジグリシジルエーテル等が挙げられ、その合計使用量としては、共重合体(M−1)中の化合物(A−1−1)に由来する繰り返し単位に対し、1.5〜10モル当量が好ましい。
<Step 1-A-2>
Step 1-A-2, the copolymer obtained in Step 1-A-1 a -R 2 of (M-1), is ring-opening addition to a glycidyl group or an oxetanyl group of the compound (C-1), In this step, a copolymer (S-1) is obtained.
Examples of the compound (C-1) used in Step 1-A-2 include ethylene glycol diglycidyl ether, propylene glycol diglycidyl ether, and the total use amount thereof is in the copolymer (M-1). 1.5-10 molar equivalent is preferable with respect to the repeating unit derived from a compound (A-1-1).
また、工程1−A−2は、触媒存在下で行うのが好ましい。触媒としては、テトラブチルアンモニウムブロマイド等の四級アンモニウム塩;テトラブチルホスホニウムブロマイド、テトラブチルホスホニウムクロライド等の四級ホスホニウム塩が挙げられ、これら触媒は1種を単独でまたは2種以上を組み合わせて使用できる。
上記触媒の合計使用量は、共重合体(M−1)中の化合物(A−1−1)に由来する繰り返し単位に対し、通常0.01〜0.2モル当量程度である。
また、工程1−A−2で好適に使用される溶媒としては、工程1−A−1と同様のものが挙げられる。
Step 1-A-2 is preferably performed in the presence of a catalyst. Examples of the catalyst include quaternary ammonium salts such as tetrabutylammonium bromide; quaternary phosphonium salts such as tetrabutylphosphonium bromide and tetrabutylphosphonium chloride. These catalysts are used singly or in combination of two or more. it can.
The total amount of the catalyst used is usually about 0.01 to 0.2 molar equivalents with respect to the repeating unit derived from the compound (A-1-1) in the copolymer (M-1).
Moreover, as a solvent used suitably at process 1-A-2, the thing similar to process 1-A-1 is mentioned.
また、工程1−A−2の反応時間は特に限定されないが、通常1〜24時間程度であり、反応温度は、溶媒の沸点以下で適宜選択すればよいが、通常40〜200℃程度である。 The reaction time in step 1-A-2 is not particularly limited, but is usually about 1 to 24 hours, and the reaction temperature may be appropriately selected below the boiling point of the solvent, but is usually about 40 to 200 ° C. .
<工程1−Bおよび工程1−C>
工程1−Bおよび工程1−Cは、化合物(A−1−2)または化合物(A−1−3)と、化合物(B−1)とを重合開始剤の存在下で重合させ、共重合体(S−1)を得る工程である。
化合物(A−1−2)としては、例えば、グリシジル(メタ)アクリレート、オキセタニル(メタ)アクリレートが挙げられ、化合物(A−1−3)としては、ビニルベンジルグリシジルエーテル、4−ヒドロキシブチル(メタ)アクリレートグリシジルエーテル等が挙げられる。なお、これらは1種を単独でまたは2種以上を組み合わせて使用できる。
工程1−Bおよび工程1−Cは、上記工程1−A−1と同様にして行えばよい。
<Step 1-B and Step 1-C>
In step 1-B and step 1-C, compound (A-1-2) or compound (A-1-3) and compound (B-1) are polymerized in the presence of a polymerization initiator, This is a step of obtaining a coalescence (S-1).
Examples of the compound (A-1-2) include glycidyl (meth) acrylate and oxetanyl (meth) acrylate, and examples of the compound (A-1-3) include vinylbenzyl glycidyl ether, 4-hydroxybutyl (meta ) Acrylate glycidyl ether and the like. In addition, these can be used individually by 1 type or in combination of 2 or more types.
Step 1-B and step 1-C may be performed in the same manner as in step 1-A-1.
<工程2>
工程2は、工程1−A−2、工程1−Bまたは工程1−Cで得た共重合体(S−1)のグリシジル基またはオキセタニル基に対し、−SR4を開環付加させ、共重合体(G−1)を得る工程である。
工程2で用いるR4SHで表される化合物としては、チオグリセロール、メルカプトエタノールが挙げられるが、親水性向上の観点から、チオグリセロールが好ましい。
上記化合物の合計使用量は、化合物(A−1−1)、(A−1−2)または(A−1−3)に由来する繰り返し単位に対し、通常0.1〜20モル当量であり、好ましくは1〜10モル当量である。
<Step 2>
Step 2 includes ring-opening addition of —SR 4 to the glycidyl group or oxetanyl group of the copolymer (S-1) obtained in Step 1-A-2, Step 1-B or Step 1-C. In this step, a polymer (G-1) is obtained.
Examples of the compound represented by R 4 SH used in Step 2 include thioglycerol and mercaptoethanol, and thioglycerol is preferable from the viewpoint of improving hydrophilicity.
The total amount of the compound used is usually 0.1 to 20 molar equivalents relative to the repeating unit derived from the compound (A-1-1), (A-1-2) or (A-1-3). , Preferably 1 to 10 molar equivalents.
また、工程2は、触媒存在下で行うのが好ましい。触媒としては、トリエチルアミン、N,N−ジメチル−4−アミノピリジン等の塩基性触媒が挙げられ、これら触媒は1種を単独でまたは2種以上を組み合わせて使用できる。
上記触媒の合計使用量は、化合物(A−1−1)、(A−1−2)または(A−1−3)に由来する繰り返し単位に対し、通常0.01〜40モル当量である。
Step 2 is preferably performed in the presence of a catalyst. Examples of the catalyst include basic catalysts such as triethylamine and N, N-dimethyl-4-aminopyridine, and these catalysts can be used alone or in combination of two or more.
The total amount of the catalyst used is usually 0.01 to 40 molar equivalents with respect to the repeating unit derived from the compound (A-1-1), (A-1-2) or (A-1-3). .
また、工程2は、溶媒存在下で行うのが好ましい。溶媒としては、工程1で使用できる溶媒の他、エタノール、メタノール等のアルコール系溶媒、またはこれらの混合溶媒が挙げられ、その合計使用量は、共重合体(S−1)に対し、通常0.5〜20質量倍程度である。 Step 2 is preferably performed in the presence of a solvent. As the solvent, in addition to the solvent that can be used in Step 1, an alcohol solvent such as ethanol and methanol, or a mixed solvent thereof can be used, and the total amount used is usually 0 with respect to the copolymer (S-1). About 5 to 20 times the mass.
また、工程2の反応時間は特に限定されないが、通常1〜8時間程度であり、反応温度は、溶媒の沸点以下で適宜選択すればよいが、通常40〜100℃程度である。 The reaction time in step 2 is not particularly limited, but is usually about 1 to 8 hours, and the reaction temperature may be appropriately selected below the boiling point of the solvent, but is usually about 40 to 100 ° C.
なお、工程2を工程1−Bまたは工程1−Cの前に実施し、その後工程1−Bまたは工程1−Cの重合を実施してもよい。 Step 2 may be performed before step 1-B or step 1-C, and then polymerization of step 1-B or step 1-C may be performed.
<工程3>
工程3は、酸化剤を用いて、工程2で得た共重合体(G−1)のスルフィド基をスルフィニル基に変換し、共重合体(N−1)を得る工程である。なお、本発明の効果が失われない範囲で、共重合体中に含まれる複数のスルフィニル基の一部がスルフィド基やスルホニル基となってもよい。
<Step 3>
Step 3 is a step of obtaining a copolymer (N-1) by converting the sulfide group of the copolymer (G-1) obtained in Step 2 into a sulfinyl group using an oxidizing agent. In addition, as long as the effect of this invention is not lost, some sulfinyl groups contained in a copolymer may become a sulfide group or a sulfonyl group.
上記酸化剤は、有機酸化剤と無機酸化剤とに大別され、有機酸化剤としては、例えば、過酢酸、過安息香酸、メタクロロ過安息香酸等が挙げられる。一方、無機酸化剤としては、例えば、過酸化水素、クロム酸、過マンガン酸塩等が挙げられる。なお、これら酸化剤は1種を単独でまたは2種以上を組み合わせて使用できる。
また、酸化剤の使用量は、化合物(A−1−1)、(A−1−2)または(A−1−3)に由来する繰り返し単位に対し、通常1.0〜10.0モル当量程度である。
The oxidizing agent is roughly classified into an organic oxidizing agent and an inorganic oxidizing agent, and examples of the organic oxidizing agent include peracetic acid, perbenzoic acid, and metachloroperbenzoic acid. On the other hand, examples of the inorganic oxidizing agent include hydrogen peroxide, chromic acid, permanganate and the like. In addition, these oxidizing agents can be used individually by 1 type or in combination of 2 or more types.
Moreover, the usage-amount of an oxidizing agent is 1.0-10.0 mol normally with respect to the repeating unit derived from a compound (A-1-1), (A-1-2) or (A-1-3). It is about equivalent.
工程3は、溶媒存在下で行うのが好ましい。斯かる溶媒としては、水;ジメチルホルムアミド、ジメチルアセトアミド等のアミド系溶媒;メタノール、エタノール等のアルコール系溶媒等が挙げられ、これら溶媒は1種を単独でまたは2種以上を組み合わせて使用できるが、水、アルコール系溶媒が好ましい。
上記溶媒の合計使用量は、共重合体(G−1)に対し、通常1〜20質量倍程度である。
Step 3 is preferably performed in the presence of a solvent. Examples of such a solvent include water; amide solvents such as dimethylformamide and dimethylacetamide; alcohol solvents such as methanol and ethanol, and the like. These solvents can be used alone or in combination of two or more. Water and alcohol solvents are preferred.
The total amount of the solvent used is usually about 1 to 20 times by mass with respect to the copolymer (G-1).
また、工程3の反応時間は特に限定されないが、通常1〜24時間程度であり、反応温度は、溶媒の沸点以下で適宜選択すればよいが、通常25〜70℃程度である。 The reaction time in step 3 is not particularly limited, but is usually about 1 to 24 hours, and the reaction temperature may be appropriately selected below the boiling point of the solvent, but is usually about 25 to 70 ° C.
なお、前記各工程において、各反応生成物の単離は、必要に応じて、ろ過、洗浄、乾燥、再結晶、再沈殿、透析、遠心分離、各種溶媒による抽出、中和、クロマトグラフィー等の通常の手段を適宜組み合わせて行えばよい。 In each step, isolation of each reaction product may be performed by filtration, washing, drying, recrystallization, reprecipitation, dialysis, centrifugation, extraction with various solvents, neutralization, chromatography, etc., if necessary. Ordinary means may be combined as appropriate.
そして、後記実施例に示すように、上記のようにして得られるスルフィニル基を側鎖に有する繰り返し単位を有する重合体を、標的物質に対する抗原または抗体が固定化された粒子と標的物質を含む可能性のある検体とが存在する反応系に含有せしめることによって、ラテックス凝集反応が促進され、標的物質の検出感度が向上するため、標的物質が低濃度であるような場合であっても測定の再現性および精度を満足させることができる。
したがって、上記重合体は、ラテックス凝集反応用凝集促進剤(ラテックス凝集測定用増感剤)として有用である。また、上記重合体は、ラテックス凝集反応の凝集促進方法に使用することができる。
そして、斯かる重合体は、ラテックス凝集反応用凝集促進剤としてそのまま使用してもよく、ラテックス凝集反応用凝集促進剤を製造するための素材として使用することもできる。また、本発明のラテックス凝集反応用凝集促進剤は、溶媒への溶解性が良好なため取扱いが容易であり、経時劣化しにくく保存安定性にも優れる。
なお、本明細書において、ラテックス凝集反応とは、抗体(または抗原)が結合したラテックス粒子と、標的物質である抗原(または抗体)とが結合し、2粒子以上の凝集体を形成することをいう。
Then, as shown in the examples below, the polymer having a repeating unit having a sulfinyl group in the side chain obtained as described above may contain a particle to which an antigen or antibody against the target substance is immobilized and the target substance. Incorporation into a reaction system that has a characteristic analyte promotes latex agglutination and improves the detection sensitivity of the target substance. Therefore, even when the target substance is at a low concentration, measurement reproduction is possible. Performance and accuracy can be satisfied.
Therefore, the polymer is useful as an aggregation accelerator for latex aggregation reaction (sensitizer for measuring latex aggregation). Moreover, the said polymer can be used for the aggregation promotion method of latex aggregation reaction.
And such a polymer may be used as it is as an aggregation accelerator for latex aggregation reaction, and can also be used as a raw material for producing an aggregation accelerator for latex aggregation reaction. In addition, the aggregation accelerator for latex aggregation reaction of the present invention is easy to handle because of its good solubility in a solvent, hardly deteriorates with time, and has excellent storage stability.
In this specification, the latex agglutination reaction means that latex particles to which an antibody (or antigen) is bound and an antigen (or antibody) as a target substance bind to form an aggregate of two or more particles. Say.
また、本発明のラテックス凝集反応用凝集促進剤中の上記重合体の含有量は、0.001〜50質量%が好ましく、0.01〜10質量%がより好ましく、0.01〜5質量%が更に好ましい。斯様な低濃度であっても優れた凝集促進効果を奏する。 Moreover, 0.001-50 mass% is preferable, as for content of the said polymer in the aggregation accelerator for latex aggregation reaction of this invention, 0.01-10 mass% is more preferable, 0.01-5 mass% Is more preferable. Even at such a low concentration, an excellent aggregation promoting effect is exhibited.
また、本発明のラテックス凝集反応用凝集促進剤を使用するときの測定反応系に対する重合体の濃度は、好ましくは0.01〜20質量%であり、より好ましくは0.01〜5質量%である。斯様な低濃度であっても優れた凝集促進効果を奏する。
なお、ここで上記測定反応系とは、粒子と検体を混合しラテックス凝集反応を光学的に測定する系のことをいう。
Moreover, the concentration of the polymer with respect to the measurement reaction system when using the aggregation accelerator for latex aggregation reaction of the present invention is preferably 0.01 to 20% by mass, more preferably 0.01 to 5% by mass. is there. Even at such a low concentration, an excellent aggregation promoting effect is exhibited.
Here, the above measurement reaction system refers to a system that mixes particles and a specimen and optically measures a latex agglutination reaction.
本発明のラテックス凝集反応用凝集促進剤は上記重合体の他に、溶剤を含んでいてもよく、溶剤としては、水性媒体が挙げられる。水性媒体としては、水の他、リン酸緩衝液、グリシン緩衝液、グッド緩衝液、トリス緩衝液、アンモニア緩衝液等の各種緩衝液が挙げられ、これらを1種または2種以上含んでいてもよい。
また、本発明のラテックス凝集反応用凝集促進剤は、上記重合体と溶剤の他に、pH緩衝剤、界面活性剤、ブロッキング剤等を含んでいてもよい。該ブロッキング剤としては、牛血清アルブミン(BSA)等の生体由来の水溶性ポリマーや化学合成した水溶性ポリマー等が挙げられる。
The aggregation accelerator for latex aggregation reaction of the present invention may contain a solvent in addition to the above polymer, and examples of the solvent include an aqueous medium. Examples of the aqueous medium include various buffers such as a phosphate buffer, a glycine buffer, a Good buffer, a Tris buffer, and an ammonia buffer in addition to water, and may contain one or more of these. Good.
In addition, the aggregation accelerator for latex aggregation reaction of the present invention may contain a pH buffer, a surfactant, a blocking agent and the like in addition to the polymer and the solvent. Examples of the blocking agent include biologically derived water-soluble polymers such as bovine serum albumin (BSA), chemically synthesized water-soluble polymers, and the like.
〔標的物質の検出方法〕
本発明のラテックス凝集法による検体中の標的物質の検出方法は、上記スルフィニル基を側鎖に有する繰り返し単位を有する重合体の存在下で、標的物質に対する抗原または抗体が固定化された粒子と、標的物質を含む可能性のある検体とを混合することを特徴とするものである。本検出方法は、常法の免疫ラテックス凝集測定と同様にして行えばよい。
[Target substance detection method]
In the method for detecting a target substance in a specimen by the latex agglutination method of the present invention, particles in which an antigen or antibody against the target substance is immobilized in the presence of a polymer having a repeating unit having a sulfinyl group in its side chain, It mixes with the sample which may contain a target substance. This detection method may be carried out in the same manner as the conventional immunolatex aggregation measurement.
また、上記検体としては、通常、血清や血漿、尿、唾液等の各種生物学的液体サンプル、糞便や食品の検体粉砕物等が挙げられる。測定サンプルとして、pH緩衝液、タンパク質、アミノ酸等で検体を希釈した検体希釈液を用いてよい。
また、斯かる検体中に含まれる標的物質は、通常、レセプター、酵素、血中タンパク、感染症関連抗原、微生物、ウイルス、ホルモン、環境関係物質(例えば、環境ホルモン等)等の抗原や、これら抗原に対する抗体等であり、該抗体は、特定の抗原に対する結合性を有すればよく、抗体のフラグメントも含まれる。
Examples of the specimen usually include various biological fluid samples such as serum, plasma, urine, saliva, and crushed specimens of feces and foods. As a measurement sample, a sample diluent obtained by diluting a sample with a pH buffer solution, protein, amino acid, or the like may be used.
In addition, target substances contained in such specimens usually include antigens such as receptors, enzymes, blood proteins, infectious disease-related antigens, microorganisms, viruses, hormones, environmental substances (for example, environmental hormones), and the like. It is an antibody against an antigen, and the antibody only needs to have a binding property to a specific antigen, and includes an antibody fragment.
また、本検出方法で用いる標的物質に対する抗原または抗体としては上記抗原や抗体と同様のものが挙げられるが、これら抗原または抗体は粒子に固定化されたものである。
上記粒子は、免疫ラテックス凝集測定に使用されるもの(ラテックス粒子)であれば特に限定されないが、ポリマー粒子が挙げられる。斯かるポリマー粒子を構成するモノマーとしては、例えば、(メタ)アクリルアミド、N−ヒドロキシエチル(メタ)アクリルアミド、N,N−ジメチル(メタ)アクリルアミド、N−イソプロプル(メタ)アクリルアミド、(メタ)アクリロイルモルホリン、N,N−ジメチルアミノプロピルアクリルアミド、N,N−ジメチルアミノプロピルアクリルアミドのメチルクロライド4級塩、ダイアセトンアクリルアミド、N−ビニルアセトアミド等の(メタ)アクリルアミド化合物;(メタ)アクリル酸メトキシエチル、(メタ)アクリル酸メチル、(メタ)アクリル酸エチル、(メタ)アクリル酸プロピル、(メタ)アクリル酸ラウリル、(メタ)アクリル酸シクロヘキシル、(メタ)アクリル酸イソボルニル、(メタ)アクリル酸ベンジル、グリセロール(メタ)クリレート、ポリエチレングリコール(メタ)アクリレート、2−ヒドロキシエチル(メタ)アクリレート等の(メタ)アクリレート化合物;アクロレイン等の不飽和アルデヒド化合物;(メタ)アクリル酸、イタコン酸、無水マレイン酸、クロトン酸等の不飽和カルボン酸化合物または不飽和無水カルボン酸化合物;スチレンスルホン酸、イソプレンスルホン酸、2−アクリルアミド−2−メチルプロパンスルホン酸等の不飽和スルホン酸化合物;スチレン、アミノスチレン等のスチレン化合物の他、アリルアミン、N−ビニル−2−ピロリドン等が挙げられる。
斯様なポリマー粒子の中でも、スチレン化合物と不飽和カルボン酸化合物との共重合体であるものが好ましく、スチレンと、アクリル酸、メタクリル酸及びイタコン酸から選ばれる不飽和カルボン酸化合物との共重合体であるものがより好ましい。
Further, examples of the antigen or antibody against the target substance used in the present detection method include the same antigens and antibodies as those described above, but these antigens or antibodies are immobilized on particles.
Although the said particle | grain is not specifically limited if it is a thing (latex particle) used for an immune latex aggregation measurement, A polymer particle is mentioned. Examples of monomers constituting such polymer particles include (meth) acrylamide, N-hydroxyethyl (meth) acrylamide, N, N-dimethyl (meth) acrylamide, N-isopropyl (meth) acrylamide, and (meth) acryloylmorpholine. (Meth) acrylamide compounds such as N, N-dimethylaminopropylacrylamide, methyl chloride quaternary salt of N, N-dimethylaminopropylacrylamide, diacetone acrylamide and N-vinylacetamide; methoxyethyl (meth) acrylate, ( Methyl) methacrylate, ethyl (meth) acrylate, propyl (meth) acrylate, lauryl (meth) acrylate, cyclohexyl (meth) acrylate, isobornyl (meth) acrylate, benzyl (meth) acrylate , (Meth) acrylate compounds such as glycerol (meth) acrylate, polyethylene glycol (meth) acrylate, 2-hydroxyethyl (meth) acrylate; unsaturated aldehyde compounds such as acrolein; (meth) acrylic acid, itaconic acid, maleic anhydride , Unsaturated carboxylic acid compounds such as crotonic acid or unsaturated carboxylic acid compounds; unsaturated sulfonic acid compounds such as styrene sulfonic acid, isoprene sulfonic acid, 2-acrylamido-2-methylpropane sulfonic acid; styrene, aminostyrene, etc. In addition to styrene compounds, allylamine, N-vinyl-2-pyrrolidone and the like can be mentioned.
Among such polymer particles, those which are a copolymer of a styrene compound and an unsaturated carboxylic acid compound are preferred, and a copolymer of styrene and an unsaturated carboxylic acid compound selected from acrylic acid, methacrylic acid and itaconic acid. What is a coalescence is more preferable.
また、上記粒子の平均粒子径は、好ましくは0.01〜1μmである。
また、標的物質に対する抗原または抗体の粒子への固定化は、疎水−疎水相互作用による物理吸着、水溶性カルボジイミド系縮合剤を用いた化学的結合等の常法に従って行えばよい。
また、上記粒子は、牛血清アルブミン(BSA)等の生体由来の水溶性ポリマーや化学合成した水溶性ポリマー等のブロッキング剤がコーティングされていてもよい。該コーティングは、上記ブロッキング剤を含む溶液中に粒子を分散させた後、遠心分離を行い、上澄み液を除去し再度粒子を水または緩衝液により再分散させる等の常法に従って行えばよい。
The average particle size of the particles is preferably 0.01 to 1 μm.
Immobilization of the antigen or antibody to the target substance on the particles may be performed according to conventional methods such as physical adsorption by hydrophobic-hydrophobic interaction, chemical bonding using a water-soluble carbodiimide condensing agent, and the like.
The particles may be coated with a blocking agent such as a water-soluble polymer derived from a living body such as bovine serum albumin (BSA) or a chemically synthesized water-soluble polymer. The coating may be carried out according to a conventional method such as dispersing particles in a solution containing the blocking agent, then centrifuging, removing the supernatant, and redispersing the particles again with water or a buffer solution.
また、上記粒子と検体との混合は、pH4.0〜10の範囲で行うのが好ましい。また、混合温度は通常25〜45℃の範囲であり、混合時間は通常1〜20分である。
また、斯かる粒子と検体との混合は、上記スルフィニル基を側鎖に有する繰り返し単位を有する重合体の存在下で行われるものであるが、斯かる重合体とともに溶剤を使用するのが好ましい。溶剤としては、水性媒体として例示したものの他、エタノール、メタノール、イソプロパノール等の低級アルコール;アセトン、メチルエチルケトン、メチルイソブチルケトン等のケトン;酢酸エチル、酢酸ブチル等の酢酸エステル;ジメチルホルムアミド等のアミド;ジメチルスルホキシド等のスルホキシドが挙げられ、これらのうち1種を単独でまたは2種以上を組み合わせてもよい。溶剤を使用する場合、上記重合体の使用量としては、溶剤100質量部に対し、0.01〜20質量部が好ましく、0.01〜5質量部がより好ましい。
Moreover, it is preferable to mix the said particle | grain and a test substance in the range of pH 4.0-10. The mixing temperature is usually in the range of 25 to 45 ° C., and the mixing time is usually 1 to 20 minutes.
The mixing of the particles and the specimen is performed in the presence of a polymer having a repeating unit having a sulfinyl group in the side chain. It is preferable to use a solvent together with the polymer. Examples of the solvent include those exemplified as an aqueous medium, lower alcohols such as ethanol, methanol, and isopropanol; ketones such as acetone, methyl ethyl ketone, and methyl isobutyl ketone; acetate esters such as ethyl acetate and butyl acetate; amides such as dimethylformamide; dimethyl Examples thereof include sulfoxides such as sulfoxide, and one of these may be used alone or two or more of them may be combined. When using a solvent, as the usage-amount of the said polymer, 0.01-20 mass parts is preferable with respect to 100 mass parts of solvents, and 0.01-5 mass parts is more preferable.
そして、上記粒子と検体との混合の結果として生じる凝集反応を光学的に検出することで、検体中の標的物質が検出され、更に標的物質の濃度も測定できる。凝集反応の光学的な検出は、散乱光強度、透過光強度、吸光度等を検出できる光学機器を用いて常法に従い行えばよい。 The target substance in the specimen can be detected by optically detecting the agglutination reaction resulting from the mixing of the particles and the specimen, and the concentration of the target substance can also be measured. The optical detection of the agglutination reaction may be performed according to a conventional method using an optical instrument that can detect scattered light intensity, transmitted light intensity, absorbance, and the like.
〔標的物質の検出に用いるためのキット〕
本発明のラテックス凝集法による検体中の標的物質の検出に用いるためのキットは、上記スルフィニル基を側鎖に有する繰り返し単位を有する重合体を含有するラテックス凝集反応用凝集促進剤を少なくとも備えることを特徴とするものである。
本発明のキットとしては、上記ラテックス凝集反応用凝集促進剤(第1試薬とも称する)に加えて、上記標的物質に対する抗原または抗体が固定化された粒子を含む試薬(第2試薬とも称する)を更に備えるものが好ましい。
上記第2試薬は、上記標的物質に対する抗原または抗体が固定化された粒子の他に、溶剤を含んでいてもよい。該溶剤としては、各種緩衝液等の上記水性媒体が挙げられる。
また、本発明のキットは、上記第1試薬及び第2試薬の他に、陽性コントロール、陰性コントロール、血清希釈液等を備えていてもよい。陽性コントロール、陰性コントロールの媒体は、測定しうる標的物質が含まれていない血清、生理食塩水のほか、溶剤でもよい。該溶剤としては、各種緩衝液等の上記水性媒体が挙げられる。
[Kit for use in target substance detection]
A kit for use in detecting a target substance in a specimen by the latex agglutination method of the present invention comprises at least an aggregation accelerator for latex agglutination reaction containing a polymer having a repeating unit having a sulfinyl group in the side chain. It is a feature.
The kit of the present invention includes a reagent (also referred to as a second reagent) containing particles in which an antigen or antibody against the target substance is immobilized, in addition to the aggregation accelerator for latex aggregation reaction (also referred to as a first reagent). What is further provided is preferable.
The second reagent may contain a solvent in addition to the particles on which the antigen or antibody against the target substance is immobilized. Examples of the solvent include the above aqueous media such as various buffer solutions.
Moreover, the kit of this invention may be equipped with positive control, negative control, serum dilution liquid, etc. other than the said 1st reagent and 2nd reagent. The medium for the positive control and negative control may be a serum or physiological saline containing no measurable target substance, or a solvent. Examples of the solvent include the above aqueous media such as various buffer solutions.
本発明のキットは、通常のラテックス凝集法による検体中の標的物質の検出に用いるためのキットと同様にして、本発明の標的物質の検出方法に使用できる。また、常法に従い標的物質の濃度も測定できる。 The kit of the present invention can be used in the method for detecting a target substance of the present invention in the same manner as a kit for use in detecting a target substance in a specimen by a usual latex agglutination method. In addition, the concentration of the target substance can be measured according to a conventional method.
以下、実施例を挙げて本発明を詳細に説明するが、本発明はこれら実施例に限定されるものではない。 EXAMPLES Hereinafter, although an Example is given and this invention is demonstrated in detail, this invention is not limited to these Examples.
実施例における各分析条件は以下に示すとおりである。
<分子量測定>
重量平均分子量(Mw)および数平均分子量(Mn)は、東ソー社製 TSKgel α−Mカラムを用い、流量:0.5ミリリットル/分、溶出溶媒:NMP溶媒(H3PO4:0.016M、LiBr:0.030M)、カラム温度:40℃の分析条件で、ポリスチレンを標準とするゲルパーミエーションクロマトグラフィー(GPC)により測定した。
<NMRスペクトル>
13C−NMRスペクトルは、溶媒および内部標準物質としてd6−DMSOを用いて、BRUKER製モデルAVANCE500(500MHz)により測定した。
Each analysis condition in the examples is as follows.
<Molecular weight measurement>
Weight average molecular weight (Mw) and number average molecular weight (Mn) were measured using a TSKgel α-M column manufactured by Tosoh Corporation, flow rate: 0.5 ml / min, elution solvent: NMP solvent (H 3 PO 4 : 0.016M, LiBr: 0.030M), column temperature: Measured by gel permeation chromatography (GPC) using polystyrene as a standard under analysis conditions of 40 ° C.
<NMR spectrum>
The 13 C-NMR spectrum was measured by a model AVANCE 500 (500 MHz) manufactured by BRUKER using d6-DMSO as a solvent and an internal standard substance.
実施例1 共重合体(N−1−1)の合成
以下の合成経路に従い、共重合体(N−1−1)を得た。
Example 1 Synthesis of Copolymer (N-1-1) A copolymer (N-1-1) was obtained according to the following synthesis route.
グリシジルメタクリレート113gおよびスチレン113gと、重合開始剤として2,2'−アゾビス(イソブチロニトリル)6.8gと、N,N−ジメチルホルムアミド475gとを混合しフラスコに入れた。これに窒素を吹き込み、70℃まで昇温し、6時間重合させ、その後室温に冷却した。この溶液をメタノールによる再沈殿で精製し、減圧乾燥することで共重合体(S−1−1)を得た。
得られた共重合体(S−1−1)において、グリシジルメタクリレートに由来する繰り返し単位の含有量は48モル%であり、スチレンに由来する繰り返し単位の含有量は52モル%であった。なお、これら含有量は13C−NMRにより測定した。
113 g of glycidyl methacrylate and 113 g of styrene, 6.8 g of 2,2′-azobis (isobutyronitrile) as a polymerization initiator, and 475 g of N, N-dimethylformamide were mixed and placed in a flask. Nitrogen was blown into this, the temperature was raised to 70 ° C., polymerized for 6 hours, and then cooled to room temperature. This solution was purified by reprecipitation with methanol and dried under reduced pressure to obtain a copolymer (S-1-1).
In the obtained copolymer (S-1-1), the content of repeating units derived from glycidyl methacrylate was 48 mol%, and the content of repeating units derived from styrene was 52 mol%. These contents were measured by 13 C-NMR.
次いで、得られた共重合体(S−1−1)10gおよびチオグリセロール32.1gと、N,N−ジメチルホルムアミド95gとを混合してフラスコに入れた。これに窒素を吹き込みながら60℃まで昇温し、触媒としてトリエチルアミン120gを添加した後4時間反応させ、その後室温に冷却した。この溶液を水による再沈殿で精製し、凍結乾燥することで共重合体(G−1−1)を得た。
次いで、得られた共重合体(G−1−1)10gを85.5gの水に分散させ、フラスコへ入れた。これに、30%過酸化水素水溶液を4.5g添加し、室温で18時間反応させた。得られた水溶液を透析することで、共重合体(N−1−1)を得た(収率:13%)。この共重合体(N−1−1)と水を混合し、濃度を1質量%に調整したところ、共重合体(N−1−1)は水に溶解していた。
また、得られた共重合体(N−1−1)の数平均分子量は19000であり、重量平均分子量は30000であり、分子量分布は1.59であった。
共重合体(N−1−1)の構造は13C−NMRで確認した。
Next, 10 g of the obtained copolymer (S-1-1), 32.1 g of thioglycerol, and 95 g of N, N-dimethylformamide were mixed and placed in a flask. The temperature was raised to 60 ° C. while blowing nitrogen, and 120 g of triethylamine was added as a catalyst, followed by reaction for 4 hours, and then cooled to room temperature. This solution was purified by reprecipitation with water and freeze-dried to obtain a copolymer (G-1-1).
Next, 10 g of the obtained copolymer (G-1-1) was dispersed in 85.5 g of water and put into a flask. To this, 4.5 g of 30% aqueous hydrogen peroxide solution was added and reacted at room temperature for 18 hours. The aqueous solution obtained was dialyzed to obtain a copolymer (N-1-1) (yield: 13%). When this copolymer (N-1-1) and water were mixed and the concentration was adjusted to 1% by mass, the copolymer (N-1-1) was dissolved in water.
Moreover, the number average molecular weight of the obtained copolymer (N-1-1) was 19000, the weight average molecular weight was 30000, and molecular weight distribution was 1.59.
The structure of the copolymer (N-1-1) was confirmed by 13 C-NMR.
実施例2 共重合体(N−1−2)の合成
上記実施例1と同様の合成経路で共重合体(N−1−2)を得た。
グリシジルメタクリレート170gおよびスチレン56.8gと、重合開始剤として2,2'−アゾビス(イソブチロニトリル)6.8gと、N,N−ジメチルホルムアミド475gとを混合しフラスコに入れた。これに窒素を吹き込み、70℃まで昇温し、6時間重合させ、その後室温に冷却した。この溶液をメタノールによる再沈殿で精製し、減圧乾燥することで共重合体(S−1−2)を得た。
得られた共重合体(S−1−2)において、グリシジルメタクリレートに由来する繰り返し単位の含有量は67モル%であり、スチレンに由来する繰り返し単位の含有量は33モル%であった。なお、これら含有量は実施例1と同様にして測定した。
Example 2 Synthesis of Copolymer (N-1-2) A copolymer (N-1-2) was obtained by the same synthesis route as in Example 1 above.
170 g of glycidyl methacrylate and 56.8 g of styrene, 6.8 g of 2,2′-azobis (isobutyronitrile) as a polymerization initiator, and 475 g of N, N-dimethylformamide were mixed and placed in a flask. Nitrogen was blown into this, the temperature was raised to 70 ° C., polymerized for 6 hours, and then cooled to room temperature. This solution was purified by reprecipitation with methanol and dried under reduced pressure to obtain a copolymer (S-1-2).
In the obtained copolymer (S-1-2), the content of repeating units derived from glycidyl methacrylate was 67 mol%, and the content of repeating units derived from styrene was 33 mol%. These contents were measured in the same manner as in Example 1.
次いで、得られた共重合体(S−1−2)10gおよびチオグリセロール44.7gと、N,N−ジメチルホルムアミド95gとを混合してフラスコに入れた。これに窒素を吹き込みながら60℃まで昇温し、触媒としてトリエチルアミン167gを添加した後4時間反応させ、その後室温に冷却した。この溶液を水による再沈殿で精製し、凍結乾燥することで共重合体(G−1−2)を得た。 Next, 10 g of the obtained copolymer (S-1-2) and 44.7 g of thioglycerol and 95 g of N, N-dimethylformamide were mixed and placed in a flask. The temperature was raised to 60 ° C. while blowing nitrogen, and 167 g of triethylamine was added as a catalyst, followed by reaction for 4 hours, and then cooled to room temperature. This solution was purified by reprecipitation with water and freeze-dried to obtain a copolymer (G-1-2).
次いで、得られた共重合体(G−1−2)10gを84.4gの水に分散させ、フラスコへ入れた。これに、30%過酸化水素水溶液を5.6g添加し、室温で18時間反応させた。得られた水溶液を透析することで、共重合体(N−1−2)を得た(収率:18%)。この共重合体(N−1−2)と水を混合し、濃度を1質量%に調整したところ、共重合体(N−1−2)は水に溶解していた。
また、得られた共重合体(N−1−2)の数平均分子量は31000であり、重量平均分子量は56000であり、分子量分布は1.81であった。
共重合体(N−1−2)の構造は13C−NMRで確認した。
Subsequently, 10 g of the obtained copolymer (G-1-2) was dispersed in 84.4 g of water and put into a flask. To this, 5.6 g of 30% aqueous hydrogen peroxide solution was added and reacted at room temperature for 18 hours. The aqueous solution obtained was dialyzed to obtain a copolymer (N-1-2) (yield: 18%). When the copolymer (N-1-2) and water were mixed and the concentration was adjusted to 1% by mass, the copolymer (N-1-2) was dissolved in water.
Moreover, the number average molecular weight of the obtained copolymer (N-1-2) was 31000, the weight average molecular weight was 56000, and molecular weight distribution was 1.81.
The structure of the copolymer (N-1-2) was confirmed by 13 C-NMR.
実施例3 共重合体(N−1−3)の合成
上記実施例1と同様の合成経路で共重合体(N−1−3)を得た。
グリシジルメタクリレート170gおよびスチレン56.8gと、重合開始剤として2,2'−アゾビス(イソブチロニトリル)2.27gと、酢酸エチル450gとを混合しフラスコに入れた。これに窒素を吹き込み、70℃まで昇温し、8時間重合させ、その後室温に冷却した。この溶液をメタノールによる再沈殿で精製し、減圧乾燥することで共重合体(S−1−3)を得た。
得られた共重合体(S−1−3)において、グリシジルメタクリレートに由来する繰り返し単位の含有量は67モル%であり、スチレンに由来する繰り返し単位の含有量は33モル%であった。なお、これら含有量は実施例1と同様にして測定した。
Example 3 Synthesis of Copolymer (N-1-3) A copolymer (N-1-3) was obtained by the same synthesis route as in Example 1.
170 g of glycidyl methacrylate and 56.8 g of styrene, 2.27 g of 2,2′-azobis (isobutyronitrile) as a polymerization initiator and 450 g of ethyl acetate were mixed and placed in a flask. Nitrogen was blown into this, the temperature was raised to 70 ° C., polymerized for 8 hours, and then cooled to room temperature. This solution was purified by reprecipitation with methanol and dried under reduced pressure to obtain a copolymer (S-1-3).
In the obtained copolymer (S-1-3), the content of repeating units derived from glycidyl methacrylate was 67 mol%, and the content of repeating units derived from styrene was 33 mol%. These contents were measured in the same manner as in Example 1.
次いで、得られた共重合体(S−1−3)10gおよびチオグリセロール44.7gと、N,N−ジメチルホルムアミド95gとを混合してフラスコに入れた。これに窒素を吹き込みながら60℃まで昇温し、触媒としてトリエチルアミン167gを添加した後4時間反応させ、その後室温に冷却した。この溶液を水による再沈殿で精製し、凍結乾燥することで共重合体(G−1−3)を得た。 Next, 10 g of the obtained copolymer (S-1-3) and 44.7 g of thioglycerol and 95 g of N, N-dimethylformamide were mixed and placed in a flask. The temperature was raised to 60 ° C. while blowing nitrogen, and 167 g of triethylamine was added as a catalyst, followed by reaction for 4 hours, and then cooled to room temperature. This solution was purified by reprecipitation with water and freeze-dried to obtain a copolymer (G-1-3).
次いで、得られた共重合体(G−1−3)10gを84.4gの水に分散させ、フラスコへ入れた。これに、30%過酸化水素水溶液を5.6g添加し、室温で18時間反応させた。得られた水溶液を透析することで、共重合体(N−1−3)を得た(収率:15%)。この共重合体(N−1−3)と水を混合し、濃度を1質量%に調整したところ、共重合体(N−1−3)は水に溶解していた。
また、得られた共重合体(N−1−3)の数平均分子量は33000であり、重量平均分子量は60000であり、分子量分布は1.82であった。
共重合体(N−1−3)の構造は13C−NMRで確認した。
Next, 10 g of the obtained copolymer (G-1-3) was dispersed in 84.4 g of water and put into a flask. To this, 5.6 g of 30% aqueous hydrogen peroxide solution was added and reacted at room temperature for 18 hours. The aqueous solution obtained was dialyzed to obtain a copolymer (N-1-3) (yield: 15%). When the copolymer (N-1-3) and water were mixed and the concentration was adjusted to 1% by mass, the copolymer (N-1-3) was dissolved in water.
Moreover, the number average molecular weight of the obtained copolymer (N-1-3) was 33000, the weight average molecular weight was 60000, and molecular weight distribution was 1.82.
The structure of the copolymer (N-1-3) was confirmed by 13 C-NMR.
上記実施例1〜3で得た共重合体(N−1−1)〜(N−1−3)のHLB値(小田式)を以下の表1に示す。なお、共重合体(N−1−1)〜(N−1−3)が有する繰り返し単位(A)からなるホモポリマーを合成し、1gを純水100gに添加したところ常温(25℃)で溶解した。また、共重合体(N−1−1)〜(N−1−3)が有する繰り返し単位(B)からなるホモポリマーを合成し、1gを純水100gに添加したところ常温(25℃)で溶解しきらなかった。 The HLB values (Oda formula) of the copolymers (N-1-1) to (N-1-3) obtained in Examples 1 to 3 are shown in Table 1 below. In addition, when the homopolymer which consists of the repeating unit (A) which a copolymer (N-1-1)-(N-1-3) has was synthesize | combined and 1 g was added to 100 g of pure waters, it was normal temperature (25 degreeC). Dissolved. Moreover, when the homopolymer which consists of the repeating unit (B) which a copolymer (N-1-1)-(N-1-3) has was synthesize | combined and 1 g was added to 100 g of pure waters, it was normal temperature (25 degreeC). It did not dissolve completely.
試験例
(1) 第1試薬の調製
0.1質量%牛血清アルブミン(BSA)含有10mM HEPES緩衝液(pH7.5)に、共重合体N−1−1、N−1−2またはN−1−3を、最終濃度が表2に示す濃度となるようにそれぞれ添加し、これを試験No.2〜7の「第1試薬」として供した。なお、試験No.1では、0.1質量%BSA含有10mM HEPES緩衝液(pH7.5)を「第1試薬」として供した。
(2) 第2試薬の調製
免疫診断用ラテックス粒子(品番:G0305(平均粒子径:0.31μm、表面COOH基の含有量:0.21mmol/g−LTx、JSR株式会社製))の10質量%水溶液1mLと、HEPES緩衝液(0.05M、pH7.5)9mLとを混合し(粒子の濃度=1質量%)、これに1−エチル−3−(3−ジメチルアミノプロピル)カルボジイミド塩酸塩(同仁化学社製)を、最終濃度が0.05質量%となるように添加した。更に、この粒子分散液に、抗CRP(C反応性蛋白)抗体(ウサギ)の10mg/mL水溶液を0.5mL加えて室温で3時間攪拌し、抗体を粒子の表面に固定化させた。
その後、この粒子分散液に1質量%BSA水溶液を0.5mL加え、室温で10時間回転攪拌し、これを15,000rpmにて15分間遠心分離し、粒子を沈殿として回収した。
次いで、HEPES緩衝液(0.05M、pH7.5)10mLに上記粒子を再懸濁させ、超音波で10分間分散させた。この再懸濁および分散の操作をもう一度繰り返した後、粒子分散液に0.02質量%BSA含有10mM HEPES緩衝液(pH7.5)を200mL加えて粒子固形分が0.05質量%となるように調整し、超音波で10分間分散させ、0.8μmディスクフィルターに通した。
これら一連の操作により、BSAがブロッキング剤としてコーティングされた抗体固定化ラテックス粒子の分散液を得た。この分散液を試験No.1〜7の「第2試薬」として供した。
(3) ラテックス凝集反応用凝集促進剤の評価
免疫ラテックス凝集測定においては、日立7180型自動分析装置を使用し、波長570nmおよび測定温度37℃にて、3μLの検体(標的物質(CRP抗原)の生理食塩水希釈液)と上記(1)で調製した第1試薬150μLとをセルに加えて均一攪拌した後、5分間保持した。
その後、上記(2)で調製した第2試薬150μLをセルに加えて均一攪拌した後、50秒経過時の吸光度と200秒経過時の吸光度との差を計測した。結果を表2に示す。
Test Example (1) Preparation of First Reagent Copolymer N-1-1, N-1-2 or N- in 0.1% bovine serum albumin (BSA) -containing 10 mM HEPES buffer (pH 7.5) 1-3 were added so that the final concentration would be the concentration shown in Table 2, respectively. It served as 2 to 7 “first reagents”. In addition, Test No. In No. 1, a 10 mM HEPES buffer solution (pH 7.5) containing 0.1% by mass BSA was used as the “first reagent”.
(2) Preparation of second reagent 10 mass of latex particle for immunodiagnostic (Product No .: G0305 (average particle size: 0.31 μm, content of surface COOH group: 0.21 mmol / g-LTx, manufactured by JSR Corporation)) 1 mL of a 1% aqueous solution and 9 mL of HEPES buffer (0.05 M, pH 7.5) were mixed (particle concentration = 1% by mass), and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride was added thereto. (Dojin Chemical Co., Ltd.) was added so that the final concentration was 0.05% by mass. Furthermore, 0.5 mL of a 10 mg / mL aqueous solution of an anti-CRP (C-reactive protein) antibody (rabbit) was added to this particle dispersion and stirred at room temperature for 3 hours to immobilize the antibody on the surface of the particles.
Thereafter, 0.5 mL of a 1% by mass BSA aqueous solution was added to the particle dispersion, and the mixture was rotated and stirred at room temperature for 10 hours, and centrifuged at 15,000 rpm for 15 minutes to collect particles as a precipitate.
The particles were then resuspended in 10 mL of HEPES buffer (0.05 M, pH 7.5) and dispersed with ultrasound for 10 minutes. After repeating this resuspension and dispersion operation once more, 200 mL of 10 mM HEPES buffer (pH 7.5) containing 0.02 mass% BSA is added to the particle dispersion so that the particle solid content becomes 0.05 mass%. And dispersed with an ultrasonic wave for 10 minutes, and passed through a 0.8 μm disk filter.
Through a series of these operations, a dispersion of antibody-immobilized latex particles coated with BSA as a blocking agent was obtained. This dispersion was designated as Test No. It was used as 1 to 7 “second reagents”.
(3) Evaluation of agglutination accelerator for latex agglutination reaction In the measurement of immune latex agglutination, Hitachi 7180 type automatic analyzer was used, and 3 μL of sample (target substance (CRP antigen) was analyzed at a wavelength of 570 nm and a measurement temperature of 37 ° C. (Diluted solution of physiological saline) and 150 μL of the first reagent prepared in (1) above were added to the cell and stirred uniformly for 5 minutes.
Thereafter, 150 μL of the second reagent prepared in (2) above was added to the cell and stirred uniformly, and then the difference between the absorbance after 50 seconds and the absorbance after 200 seconds was measured. The results are shown in Table 2.
以上の結果から、実施例1〜3で得られた共重合体を含有するラテックス凝集反応用凝集促進剤を用いれば、低い抗原濃度でも標的物質を検出できることがわかる。 From the above results, it is understood that the target substance can be detected even at a low antigen concentration by using the aggregation accelerator for latex aggregation reaction containing the copolymers obtained in Examples 1 to 3.
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