JP2015202232A - Carrier for blood purification column as well as blood purification column and blood purification method using the carrier - Google Patents
Carrier for blood purification column as well as blood purification column and blood purification method using the carrier Download PDFInfo
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- JP2015202232A JP2015202232A JP2014083529A JP2014083529A JP2015202232A JP 2015202232 A JP2015202232 A JP 2015202232A JP 2014083529 A JP2014083529 A JP 2014083529A JP 2014083529 A JP2014083529 A JP 2014083529A JP 2015202232 A JP2015202232 A JP 2015202232A
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- Prior art keywords
- blood purification
- carrier
- purification column
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- mass
- Prior art date
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- 210000004369 blood Anatomy 0.000 title claims abstract description 110
- 239000008280 blood Substances 0.000 title claims abstract description 110
- 238000000746 purification Methods 0.000 title claims abstract description 85
- 238000000034 method Methods 0.000 title claims description 21
- 239000003446 ligand Substances 0.000 claims abstract description 52
- 239000002158 endotoxin Substances 0.000 claims abstract description 43
- 239000000178 monomer Substances 0.000 claims abstract description 42
- 239000007790 solid phase Substances 0.000 claims abstract description 35
- MYRTYDVEIRVNKP-UHFFFAOYSA-N 1,2-Divinylbenzene Chemical compound C=CC1=CC=CC=C1C=C MYRTYDVEIRVNKP-UHFFFAOYSA-N 0.000 claims abstract description 28
- PPBRXRYQALVLMV-UHFFFAOYSA-N Styrene Chemical group C=CC1=CC=CC=C1 PPBRXRYQALVLMV-UHFFFAOYSA-N 0.000 claims abstract description 27
- 239000000126 substance Substances 0.000 claims abstract description 21
- 229920000642 polymer Polymers 0.000 claims abstract description 19
- 238000006243 chemical reaction Methods 0.000 claims abstract description 10
- 239000002245 particle Substances 0.000 claims description 54
- 125000000217 alkyl group Chemical group 0.000 claims description 27
- 125000004432 carbon atom Chemical group C* 0.000 claims description 19
- 150000004292 cyclic ethers Chemical group 0.000 claims description 17
- 108010040201 Polymyxins Proteins 0.000 claims description 15
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 13
- 125000002947 alkylene group Chemical group 0.000 claims description 11
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 8
- 239000007787 solid Substances 0.000 claims description 7
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- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 3
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- 230000003115 biocidal effect Effects 0.000 claims description 2
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- 239000012085 test solution Substances 0.000 description 8
- GWCJNVUIVCCXER-UHFFFAOYSA-N 2-(1-phenylprop-2-enoxymethyl)oxirane Chemical compound C=1C=CC=CC=1C(C=C)OCC1CO1 GWCJNVUIVCCXER-UHFFFAOYSA-N 0.000 description 7
- 125000000962 organic group Chemical group 0.000 description 7
- 238000004062 sedimentation Methods 0.000 description 7
- VZSRBBMJRBPUNF-UHFFFAOYSA-N 2-(2,3-dihydro-1H-inden-2-ylamino)-N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]pyrimidine-5-carboxamide Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C(=O)NCCC(N1CC2=C(CC1)NN=N2)=O VZSRBBMJRBPUNF-UHFFFAOYSA-N 0.000 description 6
- PTTPXKJBFFKCEK-UHFFFAOYSA-N 2-Methyl-4-heptanone Chemical compound CC(C)CC(=O)CC(C)C PTTPXKJBFFKCEK-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- 108010093965 Polymyxin B Proteins 0.000 description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 6
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- 125000000816 ethylene group Chemical group [H]C([H])([*:1])C([H])([H])[*:2] 0.000 description 4
- ZSIAUFGUXNUGDI-UHFFFAOYSA-N hexan-1-ol Chemical compound CCCCCCO ZSIAUFGUXNUGDI-UHFFFAOYSA-N 0.000 description 4
- 239000003999 initiator Substances 0.000 description 4
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- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 4
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 4
- 229910052938 sodium sulfate Inorganic materials 0.000 description 4
- 235000011152 sodium sulphate Nutrition 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 238000002560 therapeutic procedure Methods 0.000 description 4
- 238000011282 treatment Methods 0.000 description 4
- 241000894006 Bacteria Species 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 206010040047 Sepsis Diseases 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 229940088710 antibiotic agent Drugs 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 230000000052 comparative effect Effects 0.000 description 3
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- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- KNIWPHSUTGNZST-UHFFFAOYSA-N polymyxin E2 Natural products CC(C)CCCCC(=O)NC(CCN)C(=O)NC(C(C)O)C(=O)NC(CCN)C(=O)NC1CCNC(=O)C(C(C)O)NC(=O)C(CCN)NC(=O)C(CCN)NC(=O)C(CC(C)C)NC(=O)C(CC(C)C)NC(=O)C(CCN)NC1=O KNIWPHSUTGNZST-UHFFFAOYSA-N 0.000 description 3
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- 235000002639 sodium chloride Nutrition 0.000 description 3
- 239000001488 sodium phosphate Substances 0.000 description 3
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- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 3
- QPFMBZIOSGYJDE-UHFFFAOYSA-N 1,1,2,2-tetrachloroethane Chemical compound ClC(Cl)C(Cl)Cl QPFMBZIOSGYJDE-UHFFFAOYSA-N 0.000 description 2
- BBMCTIGTTCKYKF-UHFFFAOYSA-N 1-heptanol Chemical compound CCCCCCCO BBMCTIGTTCKYKF-UHFFFAOYSA-N 0.000 description 2
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- SZNYYWIUQFZLLT-UHFFFAOYSA-N 2-methyl-1-(2-methylpropoxy)propane Chemical compound CC(C)COCC(C)C SZNYYWIUQFZLLT-UHFFFAOYSA-N 0.000 description 2
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- 108091003079 Bovine Serum Albumin Proteins 0.000 description 2
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Abstract
Description
本発明は、血液浄化カラム用担体並びに当該担体を用いた血液浄化カラムおよび血液浄化方法に関する。 The present invention relates to a blood purification column carrier, a blood purification column using the carrier, and a blood purification method.
エンドトキシンはグラム陰性細菌の細胞壁由来のリポ多糖類（ＬＰＳ）であり、細菌性毒素を代表する物質である。エンドトキシンが血液中に流入すると、極微量であっても、発熱や、致死性ショック、血圧低下、血管内凝固、白血球の活性化などが引き起こされる。
また、エンドトキシンが血液中に流入すると、敗血症の原因となる細菌に患者が感染していなくても、敗血症が引き起こされる。敗血症ショックが長期にわたると臓器にダメージを与えることになり、多臓器不全などの致死的な症状をもたらすことが知られている。敗血症の治療には、強力な抗菌薬の投与とともに、昇圧剤、補液、酸素投与、人工呼吸管理などの様々な支持療法が用いられるが、治療成績は決して良好ではない。
Endotoxin is a lipopolysaccharide (LPS) derived from the cell wall of Gram-negative bacteria, and is a substance representing bacterial toxins. When endotoxin flows into the blood, it causes fever, lethal shock, blood pressure reduction, intravascular coagulation, leukocyte activation, and the like, even in trace amounts.
In addition, when endotoxin flows into the blood, sepsis is caused even if the patient is not infected with bacteria that cause sepsis. It is known that when septic shock lasts for a long time, the organ is damaged, and fatal symptoms such as multi-organ failure occur. For the treatment of sepsis, various supportive therapies such as pressor, fluid replacement, oxygen administration, and artificial respiration management are used together with administration of powerful antibacterial drugs, but the treatment results are never good.
一方、血液中に原因物質がある疾患が薬剤では十分に改善されない場合には、体外循環による血液浄化療法（アフェレーシス療法）が利用されている。この治療方法は、血液を体外に取り出し、疾患の原因物質を血液中から除去し、血液を患者に戻すことで、血液を浄化するものである。
上記血液浄化療法は、処理する血液の成分分離の有無などにより、血漿交換（ｐｌａｓｍａ ｅｘｃｈａｎｇｅ、ＰＥ）、二重濾過法（ｄｏｕｂｌｅ ｆｉｌｔｒａｔｉｏｎ ｐｌａｓｍａｐｈｅｒｅｓｉｓ、ＤＦＰＰ）、血漿吸着療法（ｐｌａｓｍａ ａｄｓｏｒｐｔｉｏｎ、ＰＡ）、直接血液潅流法（ｄｉｒｅｃｔ ｈｅｍｏｐｅｒｆｕｓｉｏｎ、ＤＨＰ）、白血球除去療法などに分類される。簡便に浄化を行うことができるため、上記の中でも直接血液潅流法への注目が高まっており、斯様な方法で血液中に流入したエンドトキシンを除去するのに使用される血液浄化器の開発も行われている。
On the other hand, when a disease having a causative substance in the blood is not sufficiently improved by a drug, blood purification therapy (apheresis therapy) by extracorporeal circulation is used. This treatment method purifies the blood by taking the blood out of the body, removing the causative agent of the disease from the blood, and returning the blood to the patient.
The above blood purification therapy is based on plasma exchange (PE), double filtration plasmapheresis (DFPP), plasma adsorption (PA), direct blood depending on the presence or absence of separation of blood components to be treated. It is classified into perfusion method (direct hemoperfusion, DHP), leukocyte removal therapy, and the like. Among the above, the direct blood perfusion method has attracted attention because it can be easily purified, and the development of a blood purifier used to remove endotoxin that has flowed into the blood by such a method has also been developed. Has been done.
上記血液浄化器に利用されるエンドトキシン吸着物質として、ポリミキシン類、ポリリジン、ポリエチレンイミン、オリゴペプチドなどが知られている（非特許文献１および２、特許文献１）。特に、ポリミキシン類はバシルス属細菌の一種であるＢａｃｉｌｌｕｓ Ｐｏｌｙｍａｘが産生するポリペプチド抗生物質であり、抗生物質として長きにわたり使用された実績もあるため、ポリミキシン類をエンドトキシン吸着物質として用いた血液浄化器が種々提案されている。 Polymyxins, polylysine, polyethyleneimine, oligopeptides and the like are known as endotoxin adsorbing substances used in the blood purifier (Non-patent Documents 1 and 2, Patent Document 1). In particular, polymyxins are polypeptide antibiotics produced by Bacillus Polymax, a kind of bacteria belonging to the genus Bacillus, and since they have been used for a long time as antibiotics, blood purifiers using polymyxins as endotoxin adsorbents Various proposals have been made.
例えば、クロロアセトアミドメチル化ポリスチレン繊維にポリミキシンＢを共有結合させたエンドトキシン吸着体が知られており（特許文献２〜５）、医療現場でも使用されている。また、特許文献６には、クロロアセトアミドメチル化ポリスルホン膜にポリミキシンＢを結合させたエンドトキシン除去膜が記載されている。
しかしながら、特許文献２〜５に記載のクロロアセトアミドメチル化ポリスチレン繊維や特許文献６に記載のクロロアセトアミドメチル化ポリスルホン膜を固相担体としたエンドトキシン吸着体は、血液の通液性が不十分となる場合がある、通液速度を大きくした際にエンドトキシンが十分には吸着されない場合があるなどという問題がある。
For example, an endotoxin adsorbent in which polymyxin B is covalently bonded to a chloroacetamidomethylated polystyrene fiber is known (Patent Documents 2 to 5), and is also used in the medical field. Patent Document 6 describes an endotoxin removal membrane in which polymyxin B is bound to a chloroacetamidomethylated polysulfone membrane.
However, the endotoxin adsorbent using the chloroacetamidomethylated polystyrene fiber described in Patent Documents 2 to 5 and the chloroacetamidomethylated polysulfone membrane described in Patent Document 6 as a solid phase carrier has insufficient blood permeability. In some cases, there is a problem that endotoxin may not be sufficiently adsorbed when the flow rate is increased.
また、多孔質粒子にポリミキシン類が固定されたエンドトキシン吸着体も提案されており、血液浄化カラム用担体として利用されている。
斯様な多孔質粒子を固相担体としたエンドトキシン吸着体として、多孔質セルロース粒子にポリミキシンＢを結合させた吸着体（非特許文献３）、多孔質セルロース粒子にエポキシ基を導入しポリミキシンＥを結合させた吸着体（特許文献７および８）、アガロース由来多孔質粒子（セファロース）にシアノブロミド基を導入しポリミキシンＢを結合させた吸着体（特許文献９および非特許文献４）、特定のエピクロロヒドリン架橋アガロース粒子にジビニルスルホンを反応させポリミキシンＢを結合させた吸着体（特許文献１０）、メタクリレート系共重合体粒子にスペーサーを導入しポリミキシンＢを結合させた吸着体（特許文献１１）が報告されている。
しかしながら、上記多孔質粒子を固相担体としたエンドトキシン吸着体はいずれも、ポリミキシン類の結合に先立って、粒子に反応性の官能基を導入しておく活性化を必須として製造されるものであり、簡便に製造することができないものであった。また、強塩基などの過酷な反応条件で活性化させた場合には粒子の強度の低下が懸念される。さらに、シアノブロミド基の導入やジビニルスルホンの使用により活性化して得たものは、ポリミキシン類の結合部がアルカリ等の条件に対して不安定であり、ポリミキシン類が漏出する懸念がある。
An endotoxin adsorbent in which polymyxins are immobilized on porous particles has also been proposed and is used as a carrier for blood purification columns.
As an endotoxin adsorbent using such porous particles as a solid support, an adsorbent obtained by binding polymyxin B to porous cellulose particles (Non-patent Document 3), an epoxy group is introduced into the porous cellulose particles, and polymyxin E is introduced. Bonded adsorbents (Patent Documents 7 and 8), adsorbents in which cyanobromide groups are introduced into agarose-derived porous particles (Sepharose) and polymyxin B is bound (Patent Documents 9 and 4), specific epithelium Adsorbents obtained by reacting chlorohydrin-crosslinked agarose particles with divinyl sulfone and binding polymyxin B (Patent Document 10), Adsorbents obtained by introducing spacers into methacrylate copolymer particles and binding polymyxin B (Patent Document 11) Has been reported.
However, any endotoxin adsorbent using the above porous particles as a solid phase carrier is produced by activating the introduction of reactive functional groups into the particles prior to the binding of polymyxins. It cannot be easily manufactured. Further, when activated under severe reaction conditions such as a strong base, there is a concern that the strength of the particles may be reduced. Furthermore, those obtained by activation by introduction of a cyanobromide group or use of divinylsulfone have a fear that polymyxins may leak out because the bonding part of polymyxins is unstable with respect to conditions such as alkali.
また、近年では、スチレン−ジビニルベンゼン共重合体の担体表面上にポリミキシン類を疎水的相互作用によって固定したエンドトキシン吸着体も報告されているが（特許文献１２）、疎水的相互作用による固定は強固なものではなく、製造過程や使用する際にポリミキシン類が漏出することが懸念される。 In recent years, an endotoxin adsorbent in which polymyxins are immobilized on a carrier surface of a styrene-divinylbenzene copolymer by hydrophobic interaction has also been reported (Patent Document 12), but the fixation by hydrophobic interaction is strong. However, there is a concern that polymyxins leak out during the production process and use.
以上のような背景の下、製造が簡便であり、エンドトキシンを効率よく除去することができる血液浄化カラム用担体が求められている。また、リガンド漏出等のリスクが低く安全性の高い血液浄化カラム用担体の開発も同時に強く望まれている。
したがって、本発明が解決しようとする課題は、製造が簡便であり、エンドトキシンを効率よく除去することができ、安全性が高い血液浄化カラム用担体を提供することにある。
Under the background as described above, there is a demand for a blood purification column carrier that is easy to manufacture and can efficiently remove endotoxin. In addition, the development of a carrier for a blood purification column that has a low risk of leakage of the ligand and a high safety is strongly desired at the same time.
Therefore, the problem to be solved by the present invention is to provide a blood purification column carrier that is easy to manufacture, can efficiently remove endotoxin, and has high safety.
そこで、本発明者らは、鋭意研究を行った結果、架橋成分としてのジビニルベンゼン系モノマーに由来する繰り返し単位と、リガンド結合部としての３員環または４員環の環状エーテル基を有するスチレン系モノマーに由来する繰り返し単位と、他のスチレン系モノマーに由来する繰り返し単位とを、特定量で有するポリマーを含む固相担体に、エンドトキシンに対する吸着能を有するリガンドを固定することによって、製造が簡便であり、エンドトキシンを効率よく除去することができ、安全性が高い血液浄化カラム用担体が得られることを見出し、本発明を完成するに至った。 Therefore, as a result of intensive studies, the present inventors have found that a styrene type having a repeating unit derived from a divinylbenzene monomer as a crosslinking component and a 3-membered or 4-membered cyclic ether group as a ligand binding portion. By immobilizing a ligand capable of adsorbing endotoxin on a solid phase carrier containing a polymer having a specific amount of a repeating unit derived from a monomer and a repeating unit derived from another styrenic monomer, the production is simple. The present inventors have found that endotoxin can be efficiently removed and a highly safe carrier for blood purification column can be obtained, and the present invention has been completed.
すなわち、本発明は、〔１〕ポリマーを含む固相担体に、エンドトキシンに対する吸着能を有するリガンドを固定してなる血液浄化カラム用担体であって、前記ポリマーが、ジビニルベンゼン系モノマーに由来する構造単位（Ａ）：１０〜３０質量％およびスチレン系モノマーに由来する構造単位（Ｂ）：７０〜９０質量％を有し、且つ前記スチレン系モノマーに由来する構造単位（Ｂ）のうち３０〜７０質量％が、３員環または４員環の環状エーテル基を有するスチレン系モノマーに由来する構造単位（ｂ−１）であるポリマーであり、前記リガンドが、前記３員環または４員環の環状エーテル基と前記リガンドの１級アミノ基との反応により形成された化学結合によって前記固相担体に固定されていることを特徴とする、血液浄化カラム用担体を提供するものである。 That is, the present invention provides [1] a blood purification column carrier comprising a solid phase carrier containing a polymer and a ligand capable of adsorbing endotoxin immobilized thereon, wherein the polymer is derived from a divinylbenzene monomer. Unit (A): 10 to 30% by mass and structural unit (B) derived from styrene monomer: 70 to 90% by mass, and 30 to 70 of structural unit (B) derived from styrene monomer A polymer whose mass% is a structural unit (b-1) derived from a styrenic monomer having a 3-membered ring or a 4-membered cyclic ether group, wherein the ligand is a 3-membered or 4-membered cyclic ring A blood purification column fixed to the solid phase carrier by a chemical bond formed by a reaction between an ether group and a primary amino group of the ligand There is provided a carrier.
また、本発明は、〔２〕上記〔１〕の血液浄化カラム用担体がカラム容器に充填されたことを特徴とする、血液浄化カラムを提供するものである。 The present invention also provides [2] a blood purification column, wherein the blood purification column carrier of [1] above is packed in a column container.
さらに、本発明は、〔３〕上記〔２〕の血液浄化カラムに血液を通液することを特徴とする、血液浄化方法を提供するものである。 Furthermore, the present invention provides [3] a blood purification method, wherein blood is passed through the blood purification column of [2].
本発明の血液浄化カラム用担体は、エンドトキシンを効率よく除去することができ、また、リガンド漏出等のリスクが低く安全性が高い。さらに、製造が簡便である。
本発明の血液浄化カラムを用いることにより、血液中に含まれるエンドトキシンを安全かつ効率的に除去することができる。
The carrier for blood purification column of the present invention can efficiently remove endotoxin, and has low risk of ligand leakage and the like and high safety. Furthermore, the manufacture is simple.
By using the blood purification column of the present invention, endotoxin contained in blood can be removed safely and efficiently.
〔血液浄化カラム用担体〕
本発明の血液浄化カラム用担体は、ポリマーを含む固相担体に、エンドトキシンに対する吸着能を有するリガンドを固定してなる血液浄化カラム用担体であって、
前記ポリマーが、ジビニルベンゼン系モノマーに由来する構造単位（Ａ）：１０〜３０質量％およびスチレン系モノマーに由来する構造単位（Ｂ）：７０〜９０質量％を有し、且つ前記スチレン系モノマーに由来する構造単位（Ｂ）のうち３０〜７０質量％が、３員環または４員環の環状エーテル基を有するスチレン系モノマーに由来する構造単位（ｂ−１）であるポリマーであり、
前記リガンドが、前記３員環または４員環の環状エーテル基と前記リガンドの１級アミノ基との反応により形成された化学結合によって前記固相担体に固定されていることを特徴とするものである。
まず、本発明の血液浄化カラム用担体に使用される固相担体について説明する。
[Carrier for blood purification column]
The blood purification column carrier of the present invention is a blood purification column carrier comprising a solid phase carrier containing a polymer and a ligand capable of adsorbing endotoxin immobilized thereon,
The polymer has a structural unit (A) derived from a divinylbenzene monomer: 10 to 30% by mass and a structural unit (B) derived from a styrene monomer: 70 to 90% by mass, and the styrene monomer 30 to 70% by mass of the derived structural unit (B) is a polymer that is a structural unit (b-1) derived from a styrenic monomer having a 3-membered or 4-membered cyclic ether group,
The ligand is fixed to the solid phase carrier by a chemical bond formed by a reaction between the 3-membered or 4-membered cyclic ether group and a primary amino group of the ligand. is there.
First, the solid phase carrier used for the blood purification column carrier of the present invention will be described.
＜固相担体＞
（構造単位（Ａ））
構造単位（Ａ）は、ジビニルベンゼン系モノマーに由来するものであればよいが、固相担体の機械的強度、特に耐圧力性能の観点から、下記式（１）で表されるものが好ましい。
<Solid phase carrier>
(Structural unit (A))
The structural unit (A) may be derived from a divinylbenzene monomer, but is preferably represented by the following formula (1) from the viewpoint of mechanical strength of the solid support, particularly pressure resistance.
〔式（１）中、
Ｒ1およびＲ2は、それぞれ独立して、水素原子または炭素数１〜４のアルキル基を示し、
Ｒ3は、炭素数１〜１０の有機基を示し、
環Ｑは、ベンゼン環またはナフタレン環を示し、
ｐは、０〜４の整数を示す。〕
[In Formula (1),
R 1 and R 2 each independently represent a hydrogen atom or an alkyl group having 1 to 4 carbon atoms,
R 3 represents an organic group having 1 to 10 carbon atoms,
Ring Q represents a benzene ring or a naphthalene ring,
p shows the integer of 0-4. ]
式（１）中、Ｒ1およびＲ2で示されるアルキル基の炭素数としては、１または２が好ましい。また、当該アルキル基は、直鎖状でも分岐鎖状でもよい。アルキル基としては、メチル基、エチル基、ｎ−プロピル基、イソプロピル基、ｎ−ブチル基等が挙げられる。
また、Ｒ1およびＲ2としては、水素原子が好ましい。
In the formula (1), as the carbon number of the alkyl group represented by R 1 and R 2, 1 or 2 are preferred. The alkyl group may be linear or branched. Examples of the alkyl group include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, and an n-butyl group.
R 1 and R 2 are preferably hydrogen atoms.
Ｒ3で示される有機基の炭素数は、固相担体の疎水性を抑える観点およびエンドトキシン除去効率の観点から、好ましくは１〜６であり、より好ましくは１〜３であり、さらに好ましくは１または２である。
また、上記有機基としては、アルキル基が好ましい。当該アルキル基は、直鎖状でも分岐鎖状でもよい。アルキル基としては、例えば、上記Ｒ1で示されるアルキル基と同様のものが挙げられる。
The number of carbon atoms of the organic group represented by R 3 is preferably 1 to 6, more preferably 1 to 3, and still more preferably 1 from the viewpoint of suppressing the hydrophobicity of the solid support and the endotoxin removal efficiency. Or 2.
The organic group is preferably an alkyl group. The alkyl group may be linear or branched. As an alkyl group, the same thing as the alkyl group shown by said R < 1 > is mentioned, for example.
環Ｑとしては、固相担体の機械的強度およびエンドトキシン除去効率の観点から、ベンゼン環が好ましい。
ｐは０〜４の整数を示すが、固相担体の疎水性を抑える観点およびエンドトキシン除去効率の観点から、０または１が好ましい。なお、ｐが２〜４の整数の場合、ｐ個のＲ3は同一であっても異なっていてもよい。
The ring Q is preferably a benzene ring from the viewpoint of the mechanical strength of the solid support and the endotoxin removal efficiency.
p represents an integer of 0 to 4, and is preferably 0 or 1 from the viewpoint of suppressing the hydrophobicity of the solid phase carrier and the endotoxin removal efficiency. In addition, when p is an integer of 2 to 4, p R 3 may be the same or different.
上記式（１）で表される構造単位としては、固相担体の疎水性を抑える観点およびエンドトキシン除去効率の観点から、下記式（２）で表されるものが特に好ましい。 As the structural unit represented by the above formula (1), those represented by the following formula (2) are particularly preferred from the viewpoint of suppressing the hydrophobicity of the solid phase carrier and from the viewpoint of endotoxin removal efficiency.
〔式（２）中、各記号は前記と同義であり、Ｒ3は、炭素数１〜１０の有機基を示し、ｐは、０〜４の整数を示す。〕 [In formula (2), each symbol is as defined above, R 3 represents an organic group having 1 to 10 carbon atoms, and p represents an integer of 0 to 4. ]
構造単位（Ａ）を誘導するモノマーとしては、例えば、ジビニルベンゼン、ジビニルトルエン、ジビニルキシレン、ジビニルナフタレン等が挙げられる。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。
これらの中でも、重合反応の反応性の観点やエンドトキシン除去効率の観点から、ジビニルベンゼンが特に好ましい。
Examples of the monomer for deriving the structural unit (A) include divinylbenzene, divinyltoluene, divinylxylene, divinylnaphthalene and the like. These can be used alone or in combination of two or more.
Among these, divinylbenzene is particularly preferable from the viewpoint of the reactivity of the polymerization reaction and the viewpoint of endotoxin removal efficiency.
構造単位（Ａ）の含有量は、ポリマー全量中、１０〜３０質量％であるが、機械的強度の観点および脆性を抑える観点から、１２．５〜２７．５質量％が好ましく、１５〜２５質量％が特に好ましい。当該含有量が１０質量％未満である場合は、カラムに血液を通液した際にかかる圧力に耐えるために血液浄化カラム用担体に要求される機械的強度が充分には得られない。また、上記含有量が３０質量％を超える場合は、血液浄化カラム用担体の脆性が高くなる。
なお、本明細書におけるポリマー中の各構造単位の含有量は、13Ｃ−ＮＭＲ等により測定可能である。
The content of the structural unit (A) is 10 to 30% by mass in the total amount of the polymer, but is preferably 12.5 to 27.5% by mass from the viewpoint of mechanical strength and suppressing brittleness. Mass% is particularly preferred. When the content is less than 10% by mass, the mechanical strength required for the blood purification column carrier cannot be obtained sufficiently to withstand the pressure applied when blood is passed through the column. Moreover, when the said content exceeds 30 mass%, the brittleness of the support | carrier for blood purification columns will become high.
In addition, content of each structural unit in the polymer in this specification can be measured by 13 C-NMR or the like.
（構造単位（Ｂ））
スチレン系モノマーに由来する構造単位（Ｂ）は、その構造単位（Ｂ）全量中に、３員環または４員環の環状エーテル基を有するスチレン系モノマーに由来する構造単位（ｂ−１）を３０〜７０質量％含有するものである。なお、本明細書において、「スチレン系モノマー」とは、ジビニルベンゼン系モノマー以外のスチレン系モノマーのことをいうものとする。
上記構造単位（ｂ−１）を誘導する３員環または４員環の環状エーテル基を有するスチレン系モノマーとしては、下記式（３）で表される環状エーテル基を有するものが好ましく、下記式（４）で表されるものがより好ましい。
(Structural unit (B))
The structural unit (B) derived from the styrenic monomer includes the structural unit (b-1) derived from the styrenic monomer having a 3-membered or 4-membered cyclic ether group in the total amount of the structural unit (B). 30-70 mass% is contained. In the present specification, the “styrene monomer” refers to a styrene monomer other than the divinylbenzene monomer.
As the styrenic monomer having a 3-membered or 4-membered cyclic ether group for deriving the structural unit (b-1), those having a cyclic ether group represented by the following formula (3) are preferable. What is represented by (4) is more preferable.
〔式（３）中、Ｒ4は、置換または非置換の炭素数１または２のアルキレン基を示す。〕 [In Formula (3), R 4 represents a substituted or unsubstituted alkylene group having 1 or 2 carbon atoms. ]
〔式（４）中、
Ｒ5は、水素原子または炭素数１〜４のアルキル基を示し、
Ｒ6は、炭素数２または３のアルキレン基を示し、
Ｒ7は、炭素数１〜１０のアルキル基を示し、
ｍおよびｎは、それぞれ独立して、０〜６の整数を示し、
ｑは、０〜４の整数を示し、
Ｒ4は前記と同義であり、置換または非置換の炭素数１または２のアルキレン基を示す。〕
[In Formula (4),
R 5 represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms,
R 6 represents an alkylene group having 2 or 3 carbon atoms,
R 7 represents an alkyl group having 1 to 10 carbon atoms,
m and n each independently represents an integer of 0 to 6,
q represents an integer of 0 to 4,
R 4 has the same meaning as described above, and represents a substituted or unsubstituted alkylene group having 1 or 2 carbon atoms. ]
式（３）および（４）中、Ｒ4で示されるアルキレン基としては、メチレン基、エチレン基等が挙げられるが、リガンドの１級アミノ基との反応性を向上させる観点から、メチレン基が好ましい。なお、アルキレン基が有していてもよい置換基としては、メチル基、エチル基等が挙げられる。 In formulas (3) and (4), examples of the alkylene group represented by R 4 include a methylene group and an ethylene group. From the viewpoint of improving the reactivity with the primary amino group of the ligand, preferable. Examples of the substituent that the alkylene group may have include a methyl group and an ethyl group.
式（４）中、Ｒ5は、水素原子または炭素数１〜４のアルキル基を示す。Ｒ5で示されるアルキル基の炭素数としては、１または２が好ましい。また、当該アルキル基は、直鎖状でも分岐鎖状でもよい。アルキル基としては、メチル基、エチル基、ｎ−プロピル基、イソプロピル基、ｎ−ブチル基等が挙げられる。
これらの中でも、Ｒ5としては、重合反応の反応性の観点から、水素原子が好ましい。
In formula (4), R 5 represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms. The carbon number of the alkyl group represented by R 5 is preferably 1 or 2. The alkyl group may be linear or branched. Examples of the alkyl group include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, and an n-butyl group.
Among these, R 5 is preferably a hydrogen atom from the viewpoint of the reactivity of the polymerization reaction.
また、Ｒ6で示されるアルキレン基としては、エチレン基、トリメチレン基、プロピレン基等が挙げられるが、エチレン基が好ましい。 Examples of the alkylene group represented by R 6 include an ethylene group, a trimethylene group, and a propylene group, with an ethylene group being preferred.
また、Ｒ7で示されるアルキル基の炭素数は、固相担体の疎水性を抑える観点およびエンドトキシン除去効率の観点から、好ましくは１〜６であり、より好ましくは１〜３であり、さらに好ましくは１または２である。
また、上記アルキル基は、直鎖状でも分岐鎖状でもよい。アルキル基としては、例えば、上記Ｒ5で示されるアルキル基と同様のものが挙げられる。
In addition, the number of carbon atoms of the alkyl group represented by R 7 is preferably 1 to 6, more preferably 1 to 3, and still more preferably from the viewpoint of suppressing the hydrophobicity of the solid support and the endotoxin removal efficiency. Is 1 or 2.
The alkyl group may be linear or branched. As an alkyl group, the same thing as the alkyl group shown by said R < 5 > is mentioned, for example.
ｍおよびｎは、それぞれ独立して、０〜６の整数を示すが、ｍとしては、０〜３の整数が好ましい。また、ｎとしては、０〜３の整数が好ましく、０または１がより好ましい。なお、ｎが２〜６の整数の場合、ｎ個のＲ6は同一であっても異なっていてもよい。
また、ｑは、０〜４の整数を示すが、固相担体の疎水性を抑える観点およびエンドトキシン除去効率の観点から、０または１が好ましい。なお、ｑが２〜４の整数の場合、ｑ個のＲ7は同一であっても異なっていてもよい。
m and n each independently represents an integer of 0 to 6, and m is preferably an integer of 0 to 3. Moreover, as n, the integer of 0-3 is preferable and 0 or 1 is more preferable. When n is an integer of 2 to 6, n R 6 s may be the same or different.
Q represents an integer of 0 to 4, and is preferably 0 or 1 from the viewpoint of suppressing the hydrophobicity of the solid phase carrier and the endotoxin removal efficiency. In addition, when q is an integer of 2-4, q R < 7 > may be the same or different.
３員環または４員環の環状エーテル基を有するスチレン系モノマーとしては、例えば、ビニルベンジルグリシジルエーテル、イソプロペニルベンジルグリシジルエーテル、ビニルフェニルブチルグリシジルエーテル、ビニルベンジルオキシエチルグリシジルエーテル等が挙げられる。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。
これらの中でも、重合反応の反応性やエンドトキシン除去効率の観点から、ビニルベンジルグリシジルエーテルが好ましい。
Examples of the styrenic monomer having a 3-membered or 4-membered cyclic ether group include vinyl benzyl glycidyl ether, isopropenyl benzyl glycidyl ether, vinyl phenyl butyl glycidyl ether, vinyl benzyloxyethyl glycidyl ether, and the like. These can be used alone or in combination of two or more.
Among these, vinylbenzyl glycidyl ether is preferable from the viewpoint of the reactivity of the polymerization reaction and endotoxin removal efficiency.
構造単位（ｂ−１）の含有量は、スチレン系モノマーに由来する構造単位（Ｂ）の全質量中、３０〜７０質量％であるが、エンドトキシン除去効率の観点およびリガンドの漏出を抑制する観点から、３５〜６５質量％が好ましく、４０〜６０質量％がより好ましい。当該含有量が３０質量％未満の場合は、カラムを血液浄化に用いた際のリガンド漏出量が増大し、安全性が不十分となる。また、上記含有量が７０質量％を超える場合は、エンドトキシン除去効率が不十分となる。 The content of the structural unit (b-1) is 30 to 70% by mass in the total mass of the structural unit (B) derived from the styrenic monomer, but the viewpoint of endotoxin removal efficiency and the viewpoint of suppressing the leakage of the ligand. From 35 to 65 mass% is preferable, and 40 to 60 mass% is more preferable. When the content is less than 30% by mass, the amount of leakage of the ligand when the column is used for blood purification increases, resulting in insufficient safety. Moreover, when the said content exceeds 70 mass%, endotoxin removal efficiency becomes inadequate.
また、本発明で用いる固相担体に含まれるポリマーとしては、エンドトキシン除去効率の観点から、スチレン系モノマーに由来する構造単位として、上記構造単位（ｂ−１）に加えて、下記式（５）で表される構造単位（ｂ−２）をさらに含むものが好ましい。 Moreover, as a polymer contained in the solid phase carrier used in the present invention, from the viewpoint of endotoxin removal efficiency, as a structural unit derived from a styrenic monomer, in addition to the structural unit (b-1), the following formula (5) What further contains the structural unit (b-2) represented by these is preferable.
〔式（５）中、
Ｒ8は、水素原子または炭素数１〜４のアルキル基を示し、
Ｒ9は、炭素数１〜１０の有機基を示し、
ｔは、０〜５の整数を示す。〕
[In Formula (5),
R 8 represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms,
R 9 represents an organic group having 1 to 10 carbon atoms,
t shows the integer of 0-5. ]
式（５）中、Ｒ8で示されるアルキル基の炭素数としては、１または２が好ましい。また、当該アルキル基は、直鎖状でも分岐鎖状でもよい。アルキル基としては、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、ｔｅｒｔ−ブチル基等が挙げられる。
また、Ｒ8としては、水素原子が好ましい。
In the formula (5), the number of carbon atoms of the alkyl group represented by R 8 is preferably 1 or 2. The alkyl group may be linear or branched. Examples of the alkyl group include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, and a tert-butyl group.
R 8 is preferably a hydrogen atom.
Ｒ9で示される有機基の炭素数は、固相担体の疎水性を抑える観点およびエンドトキシン除去効率の観点から、好ましくは１〜６であり、より好ましくは１〜３であり、さらに好ましくは１または２である。
また、上記有機基としては、アルキル基が好ましい。当該アルキル基は、直鎖状でも分岐鎖状でもよい。アルキル基としては、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、ｔｅｒｔ−ブチル基等が挙げられる。
The number of carbon atoms of the organic group represented by R 9 is preferably 1 to 6, more preferably 1 to 3, and still more preferably 1 from the viewpoint of suppressing the hydrophobicity of the solid phase carrier and the endotoxin removal efficiency. Or 2.
The organic group is preferably an alkyl group. The alkyl group may be linear or branched. Examples of the alkyl group include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, and a tert-butyl group.
また、ｔは、０〜５の整数を示すが、固相担体の疎水性を抑える観点およびエンドトキシン除去効率の観点から、０〜３が好ましく、０または１がより好ましい。なお、ｔが２〜５の整数の場合、ｔ個のＲ9は同一であっても異なっていてもよい。 T represents an integer of 0 to 5, but 0 to 3 is preferable and 0 or 1 is more preferable from the viewpoint of suppressing the hydrophobicity of the solid phase carrier and the endotoxin removal efficiency. Incidentally, when t is integer of 2 to 5, t number of R 9 may be different even in the same.
構造単位（ｂ−２）を誘導するスチレン系モノマーとしては、例えば、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−ブチルスチレン等が挙げられる。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。 Examples of the styrenic monomer for deriving the structural unit (b-2) include styrene, 4-methylstyrene, 2,4-dimethylstyrene, 2,4,6-trimethylstyrene, 4-ethylstyrene, and 4-isopropylstyrene. , 4-tert-butylstyrene and the like. These can be used alone or in combination of two or more.
構造単位（ｂ−２）の含有量としては、エンドトキシン除去効率の観点およびリガンドの漏出を抑制する観点から、スチレン系モノマーに由来する構造単位（Ｂ）の全質量中、３０〜７０質量％が好ましく、３５〜６５質量％がより好ましく、４０〜６０質量％が特に好ましい。
構造単位（ｂ−１）と構造単位（ｂ−２）との含有量の比率〔（ｂ−１）：（ｂ−２）〕としては、エンドトキシン除去効率の観点およびリガンドの漏出を抑制する観点から、質量比で、３０：７０〜７０：３０が好ましく、３５：６５〜６５：３５がより好ましく、４０：６０〜６０：４０が特に好ましい。
The content of the structural unit (b-2) is 30 to 70% by mass in the total mass of the structural unit (B) derived from the styrene monomer from the viewpoint of endotoxin removal efficiency and the suppression of ligand leakage. Preferably, 35 to 65% by mass is more preferable, and 40 to 60% by mass is particularly preferable.
As the ratio of the content of the structural unit (b-1) and the structural unit (b-2) [(b-1) :( b-2)], a viewpoint of endotoxin removal efficiency and a viewpoint of suppressing leakage of the ligand From a mass ratio, 30:70 to 70:30 are preferable, 35:65 to 65:35 are more preferable, and 40:60 to 60:40 are particularly preferable.
構造単位（Ｂ）の含有量は、ポリマー全量中、７０〜９０質量％であるが、機械的強度の観点および脆性を抑える観点から、７２．５〜８７．５質量％が好ましく、７５〜８５質量％が特に好ましい。当該含有量が７０質量％未満である場合は、血液浄化カラム用担体の脆性が高くなる。また、上記含有量が９０質量％を超える場合は、カラムに血液を通液した際にかかる圧力に耐えるために血液浄化カラム用担体に要求される機械的強度が充分には得られない。 The content of the structural unit (B) is 70 to 90% by mass in the total amount of the polymer, but 72.5 to 87.5% by mass is preferable from the viewpoint of mechanical strength and brittleness, and 75 to 85 Mass% is particularly preferred. When the content is less than 70% by mass, the blood purification column carrier becomes brittle. Further, when the content exceeds 90% by mass, the mechanical strength required for the blood purification column carrier cannot be sufficiently obtained to withstand the pressure applied when blood is passed through the column.
また、構造単位（Ａ）および（Ｂ）の合計含有量としては、固相担体に含まれるポリマー中、８０〜１００質量％が好ましく、９０〜１００質量％がより好ましく、９５〜１００質量％がさらに好ましい。 The total content of the structural units (A) and (B) is preferably 80 to 100% by mass, more preferably 90 to 100% by mass, and 95 to 100% by mass in the polymer contained in the solid phase carrier. Further preferred.
また、本発明で用いる固相担体の形状は特に限定されず、例えば、粒子状、板状、繊維状、中空糸状、不織布状、膜状、モノリス等が挙げられる。
このような形状の固相担体の中でも、血液を通液しやすくする観点から、粒子状の固相担体が好ましく、多孔質粒子がより好ましい。また、本発明の血液浄化カラム用担体は、固相担体が粒子状である場合であっても、エンドトキシンを効率よく除去することができる。
Moreover, the shape of the solid phase carrier used in the present invention is not particularly limited, and examples thereof include particles, plates, fibers, hollow fibers, nonwoven fabrics, membranes, and monoliths.
Among the solid-phase carriers having such a shape, a particulate solid-phase carrier is preferable and porous particles are more preferable from the viewpoint of facilitating blood passage. In addition, the blood purification column carrier of the present invention can efficiently remove endotoxin even when the solid phase carrier is in the form of particles.
また、本発明で用いる固相担体の比表面積としては、３０〜５００ｍ2／ｇが好ましく、４０〜２５０ｍ2／ｇがより好ましく、５０〜２００ｍ2／ｇがさらに好ましく、６０〜１５０ｍ2／ｇがさらに好ましく、７０〜１００ｍ2／ｇが特に好ましい。本発明の血液浄化カラム用担体は、固相担体の比表面積が上記のような範囲であっても、エンドトキシンを効率よく除去することができる。 Moreover, as a specific surface area of the solid-phase carrier used by this invention, 30-500 m < 2 > / g is preferable, 40-250 m < 2 > / g is more preferable, 50-200 m < 2 > / g is more preferable, 60-150 m < 2 > / g. Is more preferable, and 70 to 100 m 2 / g is particularly preferable. The carrier for blood purification column of the present invention can efficiently remove endotoxin even when the specific surface area of the solid phase carrier is in the above range.
また、本発明で用いる固相担体の体積平均粒径としては、血液の通液性およびエンドトキシン除去効率の観点から、８０〜２０００μｍが好ましく、１５０〜８００μｍがより好ましく、３００〜６００μｍが特に好ましい。また、体積平均粒径の変動係数は、好ましくは４０％以下であり、より好ましくは３０％以下である。 The volume average particle size of the solid phase carrier used in the present invention is preferably 80 to 2000 μm, more preferably 150 to 800 μm, and particularly preferably 300 to 600 μm from the viewpoint of blood permeability and endotoxin removal efficiency. The coefficient of variation of the volume average particle diameter is preferably 40% or less, more preferably 30% or less.
また、本発明で用いる固相担体の体積平均細孔径としては、エンドトキシン除去効率の観点から、１０〜３００ｎｍが好ましく、２０〜２００ｎｍがより好ましく、３０〜１００ｎｍが特に好ましい。 The volume average pore diameter of the solid phase carrier used in the present invention is preferably 10 to 300 nm, more preferably 20 to 200 nm, and particularly preferably 30 to 100 nm from the viewpoint of endotoxin removal efficiency.
上記比表面積、体積平均粒径、変動係数および体積平均細孔径は、後述する実施例に記載の方法で測定した値をいう。 The specific surface area, volume average particle diameter, coefficient of variation, and volume average pore diameter refer to values measured by the methods described in Examples described later.
＜リガンド＞
本発明の血液浄化カラム用担体は、エンドトキシンに対する吸着能を有するリガンドが、構造単位（ｂ−１）の３員環または４員環の環状エーテル基とリガンドの１級アミノ基との反応により形成された化学結合によって、上記固相担体に固定されたものである。
<Ligand>
In the blood purification column carrier of the present invention, a ligand capable of adsorbing endotoxin is formed by a reaction between a 3-membered or 4-membered cyclic ether group of the structural unit (b-1) and a primary amino group of the ligand. It is fixed to the solid phase carrier by the formed chemical bond.
リガンドは、エンドトキシンに対する吸着能を有し、且つ１級アミノ基を有するものであれば特に限定されないが、例えば、抗生物質や、ポリリジンまたはポリエチレンイミン等のカチオン性高分子等が挙げられる。中でも、抗生物質が好ましい。
上記抗生物質としては、ポリミキシン類やヒスタチンなどのペプチド化合物が好ましく、低分子ペプチドがより好ましく、エンドトキシン除去効率の観点から、ポリミキシン類が特に好ましい。
ポリミキシン類としては、ポリミキシンＡ、ポリミキシンＢ１、ポリミキシンＢ２、ポリミキシンＤ１、ポリミキシンＥ１、ポリミキシンＥ２（ポリミキシンＥ類はコリスチンとも呼ばれる）等が挙げられる。また、硫酸塩、塩酸塩等の塩も同様にリガンドとして用いることができる。
上記リガンドは、１種を単独でまたは２種以上を組み合わせて用いてもよい。
The ligand is not particularly limited as long as it has an ability to adsorb endotoxin and has a primary amino group, and examples thereof include antibiotics and cationic polymers such as polylysine or polyethyleneimine. Of these, antibiotics are preferred.
As the antibiotic, peptide compounds such as polymyxins and histatin are preferable, low molecular peptides are more preferable, and polymyxins are particularly preferable from the viewpoint of endotoxin removal efficiency.
Examples of polymyxins include polymyxin A, polymyxin B1, polymyxin B2, polymyxin D1, polymyxin E1, and polymyxin E2 (polymyxin E is also called colistin). Similarly, salts such as sulfates and hydrochlorides can be used as ligands.
The above ligands may be used alone or in combination of two or more.
本発明の血液浄化カラム用担体のリガンド結合量としては、エンドトキシン除去効率の観点およびリガンドの漏出を抑制する観点から、本発明の血液浄化カラム用担体の乾燥重量１ｇあたり１０〜５０ｍｇが好ましい。
また、本発明の血液浄化カラム用担体において、固定されたリガンド分子内の全ての１級アミノ基のうち固相担体への結合に用いられた１級アミノ基の割合（以下、この割合を単に「結合割合」とも記載する）としては、エンドトキシン除去効率の観点およびリガンドの漏出を抑制する観点から、５〜８０％が好ましく、１０〜６０％がさらに好ましく、２０〜４０％がさらに好ましく、２０〜３０％がさらに好ましく、２０〜２７．５％が特に好ましい。
上記リガンド結合量および結合割合は、後述する実施例に記載の方法で測定した値をいう。
The ligand binding amount of the blood purification column carrier of the present invention is preferably 10 to 50 mg per 1 g of the dry weight of the blood purification column carrier of the present invention from the viewpoint of endotoxin removal efficiency and the suppression of ligand leakage.
In the blood purification column carrier of the present invention, the ratio of primary amino groups used for binding to the solid phase carrier out of all the primary amino groups in the immobilized ligand molecule (hereinafter, this ratio is simply referred to as the ratio). From the viewpoint of endotoxin removal efficiency and the suppression of ligand leakage, it is preferably 5 to 80%, more preferably 10 to 60%, still more preferably 20 to 40%. -30% is more preferable, and 20-27.5% is particularly preferable.
The ligand binding amount and the binding ratio refer to values measured by the method described in Examples described later.
また、本発明の血液浄化カラム用担体としては、ヒドロキシ基を含む基を担体の表面に有するものが好ましい。斯かる血液浄化カラム用担体は、例えば、リガンド固定後に残存した構造単位（ｂ−１）の３員環または４員環の環状エーテル基を開環させることで得ることができる。斯様な血液浄化カラム用担体とすることにより、血液中に含まれるタンパク質や脂質等の非特異的吸着が抑制され、上記残存した環状エーテル基と固定されたリガンドの１級アミノ基との余分な反応を抑制することができる。ヒドロキシ基を含む基としては、構造単位（ｂ−１）の３員環または４員環の環状エーテル基が開環したものが好ましく、下記式（６）で表される基がより好ましく、１，２−ジヒドロキシエチル基が特に好ましい。 In addition, the carrier for blood purification column of the present invention preferably has a group containing a hydroxy group on the surface of the carrier. Such a carrier for a blood purification column can be obtained, for example, by opening a 3-membered or 4-membered cyclic ether group of the structural unit (b-1) remaining after ligand fixation. By using such a blood purification column carrier, nonspecific adsorption of proteins and lipids contained in blood is suppressed, and the remaining cyclic ether group and the primary amino group of the immobilized ligand are extraneous. Reaction can be suppressed. The group containing a hydroxy group is preferably a group in which the 3- or 4-membered cyclic ether group of the structural unit (b-1) is opened, more preferably a group represented by the following formula (6). A 2-dihydroxyethyl group is particularly preferred.
〔式（６）中、Ｒ4は前記と同義であり、置換または非置換の炭素数１または２のアルキレン基を示す。〕 [In Formula (6), R < 4 > is synonymous with the above-mentioned and shows a substituted or unsubstituted C1-C2 alkylene group. ]
Ｒ4で示されるアルキレン基としては、メチレン基、エチレン基等が挙げられるが、リガンドの１級アミノ基との反応性を向上させる観点から、メチレン基が好ましい。なお、アルキレン基が有していてもよい置換基としては、メチル基、エチル基等が挙げられる。 Examples of the alkylene group represented by R 4 include a methylene group and an ethylene group, and a methylene group is preferred from the viewpoint of improving the reactivity with the primary amino group of the ligand. Examples of the substituent that the alkylene group may have include a methyl group and an ethyl group.
本発明の血液浄化カラム用担体は、リガンドの漏出を抑制して安全性を高める観点から、担体の沈降体積に対して３０倍の水に懸濁し、１２１℃、１時間のオートクレーブ処理を施すことで得られる抽出液１０ｍＬに対する０．０１規定過マンガン酸カリウム消費量が１．０ｍＬ以下であるのが好ましい。 The carrier for the blood purification column of the present invention is suspended in water 30 times the sedimentation volume of the carrier and subjected to autoclaving at 121 ° C. for 1 hour from the viewpoint of enhancing the safety by suppressing leakage of the ligand. It is preferable that the consumption amount of 0.01 N potassium permanganate with respect to 10 mL of the extract obtained in 1 is 1.0 mL or less.
本発明の血液浄化カラム用担体は、（工程１）本発明で用いる固相担体を懸濁重合等により得て、（工程２）得られた固相担体に、エンドトキシンに対する吸着能を有するリガンドを固定し、（工程３）必要に応じて、残存する３員環または４員環の環状エーテル基を開環させることにより得ることができる。 The carrier for a blood purification column of the present invention is obtained by (step 1) obtaining the solid phase carrier used in the present invention by suspension polymerization or the like, and (step 2) adding a ligand capable of adsorbing endotoxin to the obtained solid phase carrier. (Step 3) If necessary, it can be obtained by opening the remaining 3-membered or 4-membered cyclic ether group.
（工程１）
工程１は、本発明のポリマーを誘導する各モノマーを使用し、常法に従い水系媒体中で懸濁重合を行えばよい。
懸濁重合は、ラジカル重合開始剤を用いて行うのが好ましく、ラジカル重合開始剤としては、例えば、アゾビスイソブチロニトリル、アゾビスイソ酪酸メチル、アゾビス−２，４−ジメチルバレロニトリル等のアゾ系開始剤が挙げられる。重合開始剤の使用量は、通常、モノマー総量１００質量部に対して０．０１〜１０質量部程度である。
(Process 1)
In Step 1, each monomer for deriving the polymer of the present invention is used, and suspension polymerization may be performed in an aqueous medium according to a conventional method.
The suspension polymerization is preferably performed using a radical polymerization initiator. Examples of the radical polymerization initiator include azo series such as azobisisobutyronitrile, azobisisobutyric acid methyl, azobis-2,4-dimethylvaleronitrile, and the like. Initiators are mentioned. The usage-amount of a polymerization initiator is about 0.01-10 mass parts normally with respect to 100 mass parts of monomer total amounts.
また、工程１は、多孔質粒子として固相担体を得る観点から、多孔化剤存在下で行うのが好ましい。多孔化剤としては、例えば、ヘキサン、ヘプタン、オクタン、ノナン、デカン、ウンデカン等の脂肪族炭化水素類；シクロヘキサン、シクロペンタン等の脂環式炭化水素類；ベンゼン、トルエン、キシレン、ナフタレン、エチルベンゼン等の芳香族炭化水素類、四塩化炭素、テトラクロロエタン等のハロゲン化炭化水素類；ブタノール、ペンタノール、ヘキサノール、ヘプタノール、ヘキサノール、４−メチル−２−ペンタノール、２−エチル−１−ヘキサノール等の脂肪族アルコール類；シクロヘキサノール等の脂環式アルコール類；２−フェニルエチルアルコール、ベンジルアルコール等の芳香族アルコール類；ジエチルケトン、メチルイソブチルケトン、ジイソブチルケトン、アセトフェノン、２−オクタノン、シクロヘキサノン等のケトン類；ジブチルエーテル、ジイソブチルエーテル、アニソール、エトキシベンゼン等のエーテル類；酢酸イソペンチル、酢酸ブチル、酢酸−３−メトキシブチル、マロン酸ジエチル等のエステル類が挙げられる。
多孔化剤の使用量は、通常、モノマー総量１００質量部に対して７０〜３５０質量部程度である。
Step 1 is preferably performed in the presence of a porosifying agent from the viewpoint of obtaining a solid phase carrier as porous particles. Examples of the porosifying agent include aliphatic hydrocarbons such as hexane, heptane, octane, nonane, decane, and undecane; alicyclic hydrocarbons such as cyclohexane and cyclopentane; benzene, toluene, xylene, naphthalene, ethylbenzene, and the like. Aromatic hydrocarbons, halogenated hydrocarbons such as carbon tetrachloride, tetrachloroethane; butanol, pentanol, hexanol, heptanol, hexanol, 4-methyl-2-pentanol, 2-ethyl-1-hexanol, etc. Aliphatic alcohols; cycloaliphatic alcohols such as cyclohexanol; aromatic alcohols such as 2-phenylethyl alcohol and benzyl alcohol; diethyl ketone, methyl isobutyl ketone, diisobutyl ketone, acetophenone, 2-octanone, cyclohexanone, etc. Ton class; dibutyl ether, diisobutyl ether, anisole, ethers such as ethoxy benzene; isopentyl acetate, butyl acetate, 3-methoxybutyl, esters such as diethyl malonate.
The amount of the porous agent used is usually about 70 to 350 parts by mass with respect to 100 parts by mass of the total amount of monomers.
また、工程１は、水系媒体中で行うのが好ましい。また、上記水系媒体は、水溶性高分子、無機塩等の分散安定剤；アニオン性界面活性剤、ノニオン界面活性剤、両性界面活性剤等の界面活性剤；無機系重合禁止剤、有機系重合禁止剤等の重合禁止剤が添加されていてもよい。
水系媒体の使用量は、モノマー総量１００質量部に対して、６００〜６０００質量部が好ましい。
Step 1 is preferably performed in an aqueous medium. The aqueous medium is a dispersion stabilizer such as a water-soluble polymer or an inorganic salt; a surfactant such as an anionic surfactant, a nonionic surfactant or an amphoteric surfactant; an inorganic polymerization inhibitor or an organic polymerization. A polymerization inhibitor such as an inhibitor may be added.
The amount of the aqueous medium used is preferably 600 to 6000 parts by mass with respect to 100 parts by mass of the total amount of monomers.
重合反応の温度は、１０時間半減期温度＋２０℃を中心に、上下２０℃以内が好ましく、より好ましくは上下１５℃以内である。また重合時間は通常５分〜４８時間、好ましくは１０分〜２４時間である。 The temperature of the polymerization reaction is preferably within 20 ° C. above and below, more preferably within 15 ° C. above and below, centering on the 10-hour half-life temperature + 20 ° C. The polymerization time is usually 5 minutes to 48 hours, preferably 10 minutes to 24 hours.
（工程２）
工程２は、３員環または４員環の環状エーテル基に対する１級アミノ基の求核置換反応が進行する条件で行えばよい。例えば、リン酸バッファー、ホウ酸バッファー、炭酸バッファー等の水系バッファー中で、固相担体とリガンドとを接触させる方法が挙げられる。また、上記の求核置換反応を促進するため、硫酸ナトリウム、硫酸カリウム、塩化ナトリウム、塩化カリウム、クエン酸三ナトリウム等の塩を共存させてもよい。
(Process 2)
Step 2 may be performed under the condition that the nucleophilic substitution reaction of the primary amino group with respect to the 3-membered or 4-membered cyclic ether group proceeds. For example, a method of bringing a solid phase carrier into contact with a ligand in an aqueous buffer such as a phosphate buffer, a borate buffer, or a carbonate buffer can be mentioned. Moreover, in order to accelerate | stimulate said nucleophilic substitution reaction, you may coexist salts, such as sodium sulfate, potassium sulfate, sodium chloride, potassium chloride, and trisodium citrate.
工程２の反応温度は特に限定されないが、４〜９０℃が好ましく、１０〜８０℃がより好ましく、３０〜６０℃が特に好ましい。また、反応時間は特に限定されないが、１〜７２時間が好ましく、４〜４８時間がより好ましく、１２〜３６時間が特に好ましい。 Although the reaction temperature of the process 2 is not specifically limited, 4-90 degreeC is preferable, 10-80 degreeC is more preferable, and 30-60 degreeC is especially preferable. The reaction time is not particularly limited, but is preferably 1 to 72 hours, more preferably 4 to 48 hours, and particularly preferably 12 to 36 hours.
（工程３）
工程３の開環反応は、例えば、酸性水溶液または塩基性水溶液中で行うことができる。
酸性水溶液としては、硫酸水溶液、塩酸水溶液、硝酸水溶液等が挙げられ、塩基性水溶液としては、水酸化ナトリウム水溶液、水酸化カリウム水溶液、水酸化カルシウム水溶液等が挙げられる。
開環反応の反応温度は、通常、４〜９０℃であり、が好ましく、１０℃〜８０℃がさらに好ましく、２０〜６０℃が特に好ましい。
(Process 3)
The ring-opening reaction in step 3 can be performed, for example, in an acidic aqueous solution or a basic aqueous solution.
Examples of the acidic aqueous solution include a sulfuric acid aqueous solution, a hydrochloric acid aqueous solution, and a nitric acid aqueous solution. Examples of the basic aqueous solution include a sodium hydroxide aqueous solution, a potassium hydroxide aqueous solution, and a calcium hydroxide aqueous solution.
The reaction temperature of the ring-opening reaction is usually from 4 to 90 ° C, preferably from 10 to 80 ° C, particularly preferably from 20 to 60 ° C.
本発明の血液浄化カラム用担体は、エンドトキシンを効率よく除去することができ、また、リガンド漏出等のリスクが低く安全性が高い。また、製造が簡便である。特に、カラム容器に充填することで、全血潅流型体外循環用カラムとして用いることができ、敗血症の治療やエンドトキシンの体内への混入に伴う多臓器不全、免疫系の活性化に伴う諸症状の治療に好適に用いることができる。 The carrier for blood purification column of the present invention can efficiently remove endotoxin, and has low risk of ligand leakage and the like and high safety. Moreover, manufacture is simple. In particular, by filling the column container, it can be used as a whole blood perfusion type extracorporeal circulation column. It can be suitably used for treatment.
〔血液浄化カラム〕
本発明の血液浄化カラムは、本発明の血液浄化カラム用担体がカラム容器に充填されたことを特徴とするものである。
[Blood purification column]
The blood purification column of the present invention is characterized in that the carrier for blood purification column of the present invention is packed in a column container.
〔血液浄化方法〕
本発明の血液浄化方法は、血液浄化カラムに血液を通液することを特徴とするものである。斯かる血液浄化方法は、血液浄化カラムに通液された血液を体内に戻す工程を含むものでもよく、斯様な体内に血液を戻す工程を含まないものでもよい。
[Blood purification method]
The blood purification method of the present invention is characterized by passing blood through a blood purification column. Such a blood purification method may include a step of returning blood passed through the blood purification column into the body, or may not include such a step of returning blood to the body.
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を以下に示す。
（体積平均粒径および変動係数）
多孔質粒子の体積平均粒径および変動係数は、濃度が１０質量％となるように多孔質粒子を純水中に懸濁させ、この懸濁液を用いてレーザー回折散乱式粒度分布測定装置（ベックマン・コールター社製 ＬＳ１３３２０）にて測定した。
Each analysis condition in the examples is shown below.
(Volume average particle size and coefficient of variation)
The volume average particle size and coefficient of variation of the porous particles are obtained by suspending the porous particles in pure water so that the concentration is 10% by mass, and using this suspension, a laser diffraction scattering type particle size distribution measuring device ( It was measured by Beckman Coulter LS13320).
（体積平均細孔径および比表面積）
多孔質粒子の体積平均細孔径および比表面積は、多孔質粒子を４０℃で２４時間真空乾燥させた乾燥粒子について、水銀ポロシメーター（島津製作所社製 オートポアＩＶ９５２０）を用いて、細孔径の測定範囲を１０−５０００ｎｍとして測定した。
(Volume average pore diameter and specific surface area)
The volume average pore diameter and specific surface area of the porous particles are determined by measuring the pore diameter measurement range using a mercury porosimeter (Autopore IV9520 manufactured by Shimadzu Corporation) for the dried particles obtained by vacuum drying the porous particles at 40 ° C. for 24 hours. Measured as 10-5000 nm.
（リガンド結合量）
沈降体積１ｍＬ相当の血液浄化カラム用担体を乾燥して、これを６Ｎ塩酸（和光純薬工業社製）と懸濁して圧力封入管に加え、凍結脱気のうえ１４５℃で５時間加熱した。得られた上澄み５０μＬをサンプル管に加え、減圧下で乾固したのち、エタノール／純水／トリエチルアミン／イソチオシアン酸フェニルの体積比７／１／１／１混合液２００μＬを加え、遮光し室温下で２０分間撹拌振とうした。この溶液を減圧下で２時間乾燥させたのち、アセトニトリル（和光純薬工業社製）１ｍＬで溶解し、さらにこのアセトニトリル溶液５００μＬと６０ｍＭ酢酸ナトリウム（和光純薬工業社製）溶液（ｐＨ６．６）５００μＬとを混和してＨＰＬＣ用試料を調製した。同様に調製した各アミノ酸の分析値を外部標準として、ＨＰＬＣ分析で得られる各ラベル化アミノ酸のピーク面積から各アミノ酸の含量を求め、リガンドの分子量（コリスチンの場合、２．５硫酸塩と仮定して分子量１４０８とした）とアミノ酸組成比から、血液浄化カラム用担体のリガンド結合量を算出した。
また、結合割合に関しても、上述のアミノ酸組成比から下記式にして算出した。
結合割合 ＝（固相担体への結合に用いられた１級アミノ基）／（リガンド分子内の全ての１級アミノ基）
(Ligand binding amount)
A blood purification column carrier having a sedimentation volume of 1 mL was dried, suspended in 6N hydrochloric acid (manufactured by Wako Pure Chemical Industries, Ltd.), added to a pressure sealed tube, freeze-degassed, and heated at 145 ° C. for 5 hours. Add 50 μL of the obtained supernatant to a sample tube and dry under reduced pressure. Then add 200 μL of ethanol / pure water / triethylamine / phenyl isothiocyanate volume ratio 7/1/1/1, and shield from light at room temperature. Shake and shake for 20 minutes. This solution was dried under reduced pressure for 2 hours, and then dissolved in 1 mL of acetonitrile (manufactured by Wako Pure Chemical Industries). Further, 500 μL of this acetonitrile solution and 60 mM sodium acetate (manufactured by Wako Pure Chemical Industries) solution (pH 6.6) A sample for HPLC was prepared by mixing with 500 μL. Similarly, using the analytical value of each amino acid prepared as an external standard, the content of each amino acid is determined from the peak area of each labeled amino acid obtained by HPLC analysis, and the molecular weight of the ligand (in the case of colistin, 2.5 sulfate is assumed). The amount of ligand binding of the carrier for blood purification column was calculated from the amino acid composition ratio.
The binding ratio was also calculated from the above amino acid composition ratio according to the following formula.
Binding ratio = (primary amino group used for binding to the solid support) / (all primary amino groups in the ligand molecule)
製造例１−１
純水４３１３ｇに、ポリビニルアルコール（日本合成化学社製、ＧＨ−２３）２５．８８ｇおよびドデシル硫酸ナトリウム（花王社製、エマール１０Ｇ）０．４３１３ｇを添加し、一晩撹拌して分散媒を調製した。また、得られた分散媒から１００ｇを分取し、これを５０ｇずつに分け、それぞれに２，２’−アゾイソブチロニトリル（和光純薬工業社製）４．２ｇを添加して分散し、開始剤分散液とした。
次に、ビニルベンジルグリシジルエーテル（東レ・ファインケミカル社製）９１．０ｇ（単量体の全質量に対して４０質量％）、スチレン（日本オキシラン社製）９１．０ｇ（単量体の全質量に対して４０質量％）およびジビニルベンゼン（新日鉄住金化学社製）４５．５ｇ（単量体の全質量に対して２０質量％）を、ジイソブチルケトン（三井化学社製）２２８．７ｇに溶解させ、単量体溶液を調製した。
上記分散媒４２３９．３ｇおよび単量体溶液４５６．２ｇを、温度計、攪拌翼および冷却管を備えた７Ｌセパラブルフラスコに投入し、窒素雰囲気下、１３８ｒｐｍで撹拌を開始した。続いてセパラブルフラスコを加温し、内温が７０℃に到達したところで開始剤分散液５０ｇを添加し、温度を７０℃に維持したまま５時間攪拌した。次いで開始剤分散液５０ｇを追添し、７０℃で２時間撹拌したのち、内温を８５℃に加温してさらに１時間撹拌した。反応液を冷却したのち、ヌッチェでろ過し、純水とエタノールで洗浄したのち、目開き３５５μｍ〜７１０μｍで篩分級して、多孔質粒子１−１を沈降体積４００ｍＬで得た。
得られた多孔質粒子１−１の体積平均粒径は５５２μｍ（変動係数２５％）、体積平均細孔径は６３ｎｍ、比表面積は８６ｍ2／ｇであった。得られた多孔質粒子１−１のＳＥＭ写真を図１−１〜１−３に示す。
Production Example 1-1
To 4313 g of pure water, 25.88 g of polyvinyl alcohol (manufactured by Nippon Synthetic Chemical Co., Ltd., GH-23) and 0.4313 g of sodium dodecyl sulfate (manufactured by Kao Corporation, Emar 10G) were added and stirred overnight to prepare a dispersion medium. . Further, 100 g was taken from the obtained dispersion medium, divided into 50 g portions, and 4.2 g of 2,2′-azoisobutyronitrile (manufactured by Wako Pure Chemical Industries, Ltd.) was added and dispersed in each. An initiator dispersion was obtained.
Next, 91.0 g of vinylbenzyl glycidyl ether (Toray Fine Chemical Co., Ltd.) (40% by mass with respect to the total mass of the monomer), 91.0 g of styrene (Nihon Oxirane Co., Ltd.) (to the total mass of the monomer) 40 mass%) and 45.5 g of divinylbenzene (manufactured by Nippon Steel & Sumikin Chemical Co., Ltd.) (20 mass% with respect to the total mass of the monomer) are dissolved in 228.7 g of diisobutylketone (manufactured by Mitsui Chemicals). A monomer solution was prepared.
The dispersion medium 4239.3 g and the monomer solution 456.2 g were put into a 7 L separable flask equipped with a thermometer, a stirring blade and a cooling tube, and stirring was started at 138 rpm in a nitrogen atmosphere. Subsequently, the separable flask was heated, and when the internal temperature reached 70 ° C, 50 g of the initiator dispersion was added, and the mixture was stirred for 5 hours while maintaining the temperature at 70 ° C. Next, 50 g of the initiator dispersion was added, and the mixture was stirred at 70 ° C. for 2 hours, and then the internal temperature was raised to 85 ° C. and further stirred for 1 hour. After cooling the reaction solution, it was filtered with Nutsche, washed with pure water and ethanol, and then sieved with an opening of 355 μm to 710 μm to obtain porous particles 1-1 with a sedimentation volume of 400 mL.
The obtained porous particles 1-1 had a volume average particle size of 552 μm (coefficient of variation 25%), a volume average pore size of 63 nm, and a specific surface area of 86 m 2 / g. SEM photographs of the obtained porous particles 1-1 are shown in FIGS. 1-1 to 1-3.
実施例１
製造例１−１で得られた多孔質粒子１−１を２５０ｍＬ分取し、これを、０．１Ｍリン酸ナトリウム／０．５Ｍ硫酸ナトリウム水溶液（ｐＨ７．７）５００ｍＬで３回濾過洗浄したのち、１Ｌ滅菌ボトルに投入した。
次いで、コリスチン硫酸塩（Ｘｅｌｌｉａ社製）２．５６ｇを、０．１Ｍリン酸ナトリウム／０．５Ｍ硫酸ナトリウム水溶液（ｐＨ７．７）９０ｍＬに溶解し、この溶液全量を前記１Ｌ滅菌ボトルに加えたのち、懸濁液量を０．１Ｍリン酸ナトリウム／０．５Ｍ硫酸ナトリウム水溶液（ｐＨ７．７）で７５０ｍＬにメスアップしてボトルを密閉し、４０℃で２４時間振とうした。懸濁液から担体を濾別し、０．１Ｍ硫酸水溶液（和光純薬工業社製）５００ｍＬで３回濾過洗浄したのち、１Ｌ滅菌ボトルに投入して密閉し、４０℃で２４時間振とうした。懸濁液から担体を濾別し、０．１Ｍ硫酸水溶液、純水、１６ｖｏｌ％エタノール水溶液を用いて各々５００ｍＬで３回ずつ濾過洗浄して、血液浄化カラム用担体１を得た。
血液浄化カラム用担体１のリガンド結合量は、担体の乾燥重量１ｇあたり２６ｍｇであった（結合割合：２１．６％）。
Example 1
After 250 mL of the porous particles 1-1 obtained in Production Example 1-1 were collected, this was filtered and washed three times with 500 mL of 0.1 M sodium phosphate / 0.5 M sodium sulfate aqueous solution (pH 7.7). It was put into a 1 L sterilization bottle.
Next, 2.56 g of colistin sulfate (manufactured by Xellia) was dissolved in 90 mL of 0.1 M sodium phosphate / 0.5 M sodium sulfate aqueous solution (pH 7.7), and the total amount of this solution was added to the 1 L sterilized bottle. The suspension volume was made up to 750 mL with 0.1 M sodium phosphate / 0.5 M aqueous sodium sulfate solution (pH 7.7), the bottle was sealed, and shaken at 40 ° C. for 24 hours. The carrier was separated from the suspension by filtration, washed with 500 mL of 0.1 M sulfuric acid aqueous solution (manufactured by Wako Pure Chemical Industries, Ltd.) three times, placed in a 1 L sterilized bottle, sealed, and shaken at 40 ° C. for 24 hours. . The carrier was separated from the suspension by filtration, washed with 500 mL each three times using 0.1 M sulfuric acid aqueous solution, pure water, and 16 vol% ethanol aqueous solution to obtain carrier 1 for blood purification column.
The ligand binding amount of the carrier 1 for blood purification column was 26 mg per 1 g of the dry weight of the carrier (binding ratio: 21.6%).
製造例１−２
単量体溶液を、ビニルベンジルグリシジルエーテル（東レ・ファインケミカル社製）７７．１ｇ（単量体の全質量に対して４０質量％）、スチレン（日本オキシラン社製）７７．１ｇ（単量体の全質量に対して４０質量％）、ジビニルベンゼン（新日鉄住金化学社製）３８．６ｇ（単量体の全質量に対して２０質量％）をジイソブチルケトン（三井化学社製）２５８．３ｇに溶解させて調製した以外は製造例１−１と同様の操作を行い、多孔質粒子１−２を沈降体積４００ｍＬで得た。
得られた多孔質粒子１−２の体積平均粒径は５２１μｍ（変動係数１７％）、体積平均細孔径は７２ｎｍ、比表面積は９６ｍ2／ｇであった。
Production Example 1-2
The monomer solution was prepared by using 77.1 g of vinylbenzyl glycidyl ether (Toray Fine Chemical Co., Ltd.) (40% by mass based on the total mass of the monomer), 77.1 g of styrene (Nihon Oxirane Co., Ltd.) 40% by mass with respect to the total mass) and 38.6 g of divinylbenzene (manufactured by Nippon Steel & Sumikin Chemical Co., Ltd.) (20% by mass with respect to the total mass of the monomer) are dissolved in 258.3 g of diisobutyl ketone (manufactured by Mitsui Chemicals). Except having prepared, it carried out similarly to manufacture example 1-1, and obtained the porous particle 1-2 by 400 mL of sedimentation volume.
The obtained porous particles 1-2 had a volume average particle diameter of 521 μm (coefficient of variation: 17%), a volume average pore diameter of 72 nm, and a specific surface area of 96 m 2 / g.
実施例２
多孔質粒子１−１を多孔質粒子１−２に変更した以外は実施例１と同様の操作を行い、血液浄化カラム用担体２を得た。
血液浄化カラム用担体２のリガンド結合量は、担体の乾燥重量１ｇあたり２５ｍｇであった（結合割合：２０．８％）。
Example 2
A blood purification column carrier 2 was obtained by performing the same operation as in Example 1 except that the porous particle 1-1 was changed to the porous particle 1-2.
The ligand binding amount of the carrier 2 for blood purification column was 25 mg per 1 g of the dry weight of the carrier (binding ratio: 20.8%).
製造例２−１
単量体溶液を、ビニルベンジルグリシジルエーテル（東レ・ファインケミカル社製）１４１．０ｇ（単量体の全質量に対して６０質量％）、スチレン（日本オキシラン社製）４７．０ｇ（単量体の全質量に対して２０質量％）、ジビニルベンゼン（新日鉄住金化学社製）４７．０ｇ（単量体の全質量に対して２０質量％）をジイソブチルケトン（三井化学社製）２２８．３ｇに溶解させて調製した以外は製造例１−１と同様の操作を行い、多孔質粒子２−１を沈降体積４００ｍＬで得た。
得られた多孔質粒子２−１の体積平均粒径は４８４μｍ（変動係数２３％）、体積平均細孔径は７３ｎｍ、比表面積は８３ｍ2／ｇであった。
Production Example 2-1
The monomer solution was prepared by adding 141.0 g of vinylbenzyl glycidyl ether (Toray Fine Chemical Co., Ltd.) (60% by mass with respect to the total mass of the monomer) and 47.0 g of styrene (Nihon Oxirane Co., Ltd.) 20 wt% with respect to the total mass), 47.0 g of divinylbenzene (manufactured by Nippon Steel & Sumikin Chemical Co., Ltd.) (20 wt% with respect to the total mass of the monomer) are dissolved in 228.3 g of diisobutyl ketone (manufactured by Mitsui Chemicals). Except having prepared, it carried out similarly to manufacture example 1-1, and obtained the porous particle 2-1 by 400 mL of sedimentation volume.
The obtained porous particles 2-1 had a volume average particle diameter of 484 μm (coefficient of variation 23%), a volume average pore diameter of 73 nm, and a specific surface area of 83 m 2 / g.
比較例１
多孔質粒子１−１を多孔質粒子２−１に変更した以外は実施例１と同様の操作を行い、血液浄化カラム用担体３を得た。
血液浄化カラム用担体３のリガンド結合量は、担体の乾燥重量１ｇあたり２５ｍｇであった（結合割合：３３．２％）。
Comparative Example 1
A blood purification column carrier 3 was obtained in the same manner as in Example 1 except that the porous particles 1-1 were changed to the porous particles 2-1.
The ligand binding amount of the carrier 3 for blood purification column was 25 mg per 1 g of the dry weight of the carrier (binding ratio: 33.2%).
製造例２−２
単量体溶液を、ビニルベンジルグリシジルエーテル（東レ・ファインケミカル社製）１１９．５ｇ（単量体の全質量に対して６０質量％）、スチレン（日本オキシラン社製）３９．８ｇ（単量体の全質量に対して２０質量％）、ジビニルベンゼン（新日鉄住金化学社製）３９．８ｇ（単量体の全質量に対して２０質量％）をジイソブチルケトン（三井化学社製）２５８．０ｇに溶解させて調製した以外は製造例１−１と同様の操作を行い、多孔質粒子２−２を沈降体積４００ｍＬで得た。
得られた多孔質粒子２−２の体積平均粒径は５３８μｍ（変動係数２５％）、体積平均細孔径は１３１ｎｍ、比表面積は９４ｍ2／ｇであった。
Production Example 2-2
The monomer solution was composed of 119.5 g of vinyl benzyl glycidyl ether (manufactured by Toray Fine Chemical Co., Ltd.) (60% by mass with respect to the total mass of the monomer), 39.8 g of styrene (manufactured by Nippon Oxirane Co., Ltd.) 20% by mass with respect to the total mass) and 39.8 g of divinylbenzene (manufactured by Nippon Steel & Sumikin Chemical Co., Ltd.) (20% by mass with respect to the total mass of the monomer) are dissolved in 258.0 g of diisobutyl ketone (manufactured by Mitsui Chemicals). Except having prepared, it carried out similarly to manufacture example 1-1, and obtained the porous particle 2-2 by 400 mL of sedimentation volume.
The obtained porous particles 2-2 had a volume average particle size of 538 μm (variation coefficient 25%), a volume average pore size of 131 nm, and a specific surface area of 94 m 2 / g.
比較例２
多孔質粒子１−１を多孔質粒子２−２に変更した以外は実施例１と同様の操作を行い、血液浄化カラム用担体４を得た。
血液浄化カラム用担体４のリガンド結合量は、担体の乾燥重量１ｇあたり３３ｍｇであった（結合割合：３０．０％）。
Comparative Example 2
A blood purification column carrier 4 was obtained in the same manner as in Example 1 except that the porous particles 1-1 were changed to the porous particles 2-2.
The ligand binding amount of the carrier 4 for blood purification column was 33 mg per 1 g of the dry weight of the carrier (binding ratio: 30.0%).
製造例２−３
単量体溶液を、ビニルベンジルグリシジルエーテル（東レ・ファインケミカル社製）４４．１ｇ（単量体の全質量に対して２０質量％）、スチレン（日本オキシラン社製）１３２．４ｇ（単量体の全質量に対して６０質量％）、ジビニルベンゼン（新日鉄住金化学社製）４４．１ｇ（単量体の全質量に対して２０質量％）をジイソブチルケトン（三井化学社製）２２９．０ｇに溶解させて調製した以外は製造例１−１と同様の操作を行い、多孔質粒子２−３を沈降体積４００ｍＬで得た。
得られた多孔質粒子２−３の体積平均粒径は５５２μｍ（変動係数２５％）、体積平均細孔径は４９ｎｍ、比表面積は８８ｍ2／ｇであった。
Production Example 2-3
The monomer solution was charged with 44.1 g of vinylbenzyl glycidyl ether (Toray Fine Chemical Co., Ltd.) (20% by mass with respect to the total mass of the monomer), 132.4 g of styrene (Nihon Oxirane Co., Ltd.) 60 mass% with respect to the total mass), 44.1 g of divinylbenzene (manufactured by Nippon Steel & Sumikin Chemical Co., Ltd.) (20 mass% with respect to the total mass of the monomer) are dissolved in 229.0 g of diisobutyl ketone (manufactured by Mitsui Chemicals). Except having prepared, it carried out similarly to manufacture example 1-1, and obtained the porous particle 2-3 with the sedimentation volume of 400 mL.
The obtained porous particles 2-3 had a volume average particle diameter of 552 μm (coefficient of variation 25%), a volume average pore diameter of 49 nm, and a specific surface area of 88 m 2 / g.
比較例３
多孔質粒子１−１を多孔質粒子２−３に変更した以外は実施例１と同様の操作を行い、血液浄化カラム用担体５を得た。
血液浄化カラム用担体５のリガンド結合量は、担体の乾燥重量１ｇあたり１８ｍｇであった（結合割合：１２．４％）。
Comparative Example 3
A blood purification column carrier 5 was obtained in the same manner as in Example 1 except that the porous particles 1-1 were changed to porous particles 2-3.
The ligand binding amount of the carrier 5 for blood purification column was 18 mg per 1 g of dry weight of the carrier (binding rate: 12.4%).
試験例１ 過マンガン酸カリウム消費量
吸着型血液浄化器品質基準の溶出物試験法を参照して、以下の手順で血液浄化カラム用担体１〜５を用いた場合の溶出物量（過マンガン酸カリウム消費量）を評価した。
純水で濾過洗浄した血液浄化カラム用担体１．５ｍＬに対して４５ｍＬの純水を加えて得られた懸濁液をスクリュー管に加え、１２１℃、１時間の条件で高圧蒸気滅菌処理したうえで、熱時濾過して試験液を得た。また、試験液の調製に用いた純水を試験液と同一条件で加熱・濾過して空試験液を得た。
５０ｍＬ三角フラスコに、試験液または空試験液１０ｍＬと、０．０１Ｎ過マンガン酸カリウム水溶液（和光純薬工業社製）２０ｍＬと、１０％硫酸水溶液（和光純薬工業社製）１ｍＬとを加え、沸騰水浴で２０分間加熱した。氷浴冷却ののち、ヨウ化カリウム（和光純薬工業社製）０．１ｇを加え、撹拌後１０分間静置した。次いで、でんぷん溶液５滴を加えて０．０１Ｎチオ硫酸ナトリウム水溶液で滴定し、溶出物量（過マンガン酸カリウム消費量）を下式により算出した。結果を表１に示した。
溶出物量（過マンガン酸カリウム消費量（ｍＬ））＝空試験液の滴定量（ｍＬ）−試験液の滴定量（ｍＬ）
Test Example 1 Potassium permanganate consumption With reference to the eluate test method of the adsorption blood purifier quality standard, the eluate amount (potassium permanganate) when blood purification column carriers 1 to 5 are used in the following procedure Consumption).
A suspension obtained by adding 45 mL of pure water to 1.5 mL of a blood purification column carrier filtered and washed with pure water is added to a screw tube, and then subjected to high-pressure steam sterilization at 121 ° C. for 1 hour. Then, it was filtered while hot to obtain a test solution. Moreover, the pure water used for the preparation of the test solution was heated and filtered under the same conditions as the test solution to obtain a blank test solution.
To a 50 mL Erlenmeyer flask, add 10 mL of test solution or blank test solution, 20 mL of 0.01N potassium permanganate aqueous solution (manufactured by Wako Pure Chemical Industries, Ltd.), and 1 mL of 10% sulfuric acid aqueous solution (manufactured by Wako Pure Chemical Industries, Ltd.), Heated in a boiling water bath for 20 minutes. After cooling in an ice bath, 0.1 g of potassium iodide (manufactured by Wako Pure Chemical Industries, Ltd.) was added, and the mixture was allowed to stand for 10 minutes after stirring. Subsequently, 5 drops of starch solution were added and titrated with 0.01N sodium thiosulfate aqueous solution, and the amount of eluate (potassium permanganate consumption) was calculated by the following formula. The results are shown in Table 1.
Eluate volume (potassium permanganate consumption (mL)) = titration of blank test solution (mL)-titration of test solution (mL)
試験例２ エンドトキシン除去率
以下の手順で、血液浄化カラム用担体１〜５のエンドトキシン除去率を評価した。
ＬＰＳ（Ｓｉｇｍａ−Ａｌｄｒｉｃｈ社製、Ｌｉｐｏｐｏｌｙｓａｃｃｈａｒｉｄｅｓ ｆｒｏｍ Ｅｓｃｈｅｒｉｃｈｉａ ｃｏｌｉ ０５５：Ｂ５）１μｇ／ｍＬ水溶液を非動化したウシ胎児血清（ＥＱＵＩＴＥＣＨ／ＢＩＯ社製）の上清で希釈し、１０ｎｇ／ｍＬのＬＰＳ含有ウシ胎児血清溶液を得た。
５０ｍＬコニカルチューブに血液浄化カラム用担体０．５ｍＬを加え、蒸留水を加えて撹拌後に抜き取る操作を数回繰り返して担体を洗浄した後、前記のＬＰＳ含有ウシ胎児血清溶液３ｍＬを加えた。３７℃の水浴中で振とうし、１５分後および１２０分後に上清１００μＬをサンプリングし、直ちに氷上に静置した０．０１％ ＴｒｉｔｏｎＸ−１００（Ｓｉｇｍａ−Ａｌｄｒｉｃｈ社製）９００μＬに加え、撹拌後に氷上に静置した。この溶液を７０℃で１０分間加熱処理したのち、直ちに氷上で冷却し、蒸留水で１００倍に希釈して測定サンプルを得た。
得られた測定サンプル中のＬＰＳ量をエンドスペシー法で評価し、下記式にてエンドトキシン（ＬＰＳ）除去率を算出した。結果を表１に示した。
エンドトキシン（ＬＰＳ）除去率（％）＝１００×（初期ＬＰＳ濃度−試験サンプル中のＬＰＳ濃度）／初期濃度
Test Example 2 Endotoxin Removal Rate The endotoxin removal rate of blood purification column carriers 1 to 5 was evaluated by the following procedure.
LPS (manufactured by Sigma-Aldrich, Lipopolysaccharides from Escherichia coli 055: B5) diluted with 1 μg / mL aqueous solution of fetal bovine serum (EQUITECH / BIO), diluted with supernatant of 10 ng / mL LPS A serum solution was obtained.
After adding 0.5 mL of a carrier for blood purification column to a 50 mL conical tube, washing the carrier by adding distilled water and removing it after stirring several times, 3 mL of the LPS-containing fetal calf serum solution was added. Shake in a 37 ° C. water bath, sample 100 μL of the supernatant after 15 and 120 minutes, and immediately add to 900 μL of 0.01% Triton X-100 (manufactured by Sigma-Aldrich) left on ice. Placed on ice. This solution was heat-treated at 70 ° C. for 10 minutes, immediately cooled on ice, and diluted 100 times with distilled water to obtain a measurement sample.
The amount of LPS in the obtained measurement sample was evaluated by the end specie method, and the endotoxin (LPS) removal rate was calculated by the following formula. The results are shown in Table 1.
Endotoxin (LPS) removal rate (%) = 100 × (initial LPS concentration−LPS concentration in test sample) / initial concentration
表１に示すとおり、血液浄化カラム用担体１〜２は、過マンガン酸カリウム消費量が小さくリガンドが溶出しにくいものであり、かつエンドトキシン除去効率が良好であった。一方で、血液浄化カラム担体３〜４は、過マンガン酸カリウム消費量は小さいものの、エンドトキシン除去効率が不良であった。また、血液浄化カラム担体５は、エンドトキシン除去効率は良好であるものの、過マンガン酸カリウム消費量が大きかった。 As shown in Table 1, the blood purification column carriers 1 and 2 had low potassium permanganate consumption and were difficult to elute the ligand, and had good endotoxin removal efficiency. On the other hand, the blood purification column carriers 3 to 4 had poor endotoxin removal efficiency although the consumption of potassium permanganate was small. Moreover, although the blood purification column carrier 5 had good endotoxin removal efficiency, consumption of potassium permanganate was large.
Claims (10)
前記ポリマーが、ジビニルベンゼン系モノマーに由来する構造単位（Ａ）：１０〜３０質量％およびスチレン系モノマーに由来する構造単位（Ｂ）：７０〜９０質量％を有し、且つ前記スチレン系モノマーに由来する構造単位（Ｂ）のうち３０〜７０質量％が、３員環または４員環の環状エーテル基を有するスチレン系モノマーに由来する構造単位（ｂ−１）であるポリマーであり、
前記リガンドが、前記３員環または４員環の環状エーテル基と前記リガンドの１級アミノ基との反応により形成された化学結合によって前記固相担体に固定されていることを特徴とする、
血液浄化カラム用担体。 A blood purification column carrier comprising a solid phase carrier containing a polymer and a ligand capable of adsorbing endotoxin immobilized thereon,
The polymer has a structural unit (A) derived from a divinylbenzene monomer: 10 to 30% by mass and a structural unit (B) derived from a styrene monomer: 70 to 90% by mass, and the styrene monomer 30 to 70% by mass of the derived structural unit (B) is a polymer that is a structural unit (b-1) derived from a styrenic monomer having a 3-membered or 4-membered cyclic ether group,
The ligand is fixed to the solid support by a chemical bond formed by a reaction between the 3-membered or 4-membered cyclic ether group and a primary amino group of the ligand,
Carrier for blood purification column.
Ｒ4は、置換または非置換の炭素数１または２のアルキレン基を示し、
Ｒ5は、水素原子または炭素数１〜４のアルキル基を示し、
Ｒ6は、炭素数２または３のアルキレン基を示し、
Ｒ7は、炭素数１〜１０のアルキル基を示し、
ｍおよびｎは、それぞれ独立して、０〜６の整数を示し、
ｑは、０〜４の整数を示す。〕 The blood purification column carrier according to any one of claims 1 to 6, wherein the styrene monomer having a 3-membered ring or a 4-membered cyclic ether group is a monomer represented by the following formula (4). .
R 4 represents a substituted or unsubstituted alkylene group having 1 or 2 carbon atoms,
R 5 represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms,
R 6 represents an alkylene group having 2 or 3 carbon atoms,
R 7 represents an alkyl group having 1 to 10 carbon atoms,
m and n each independently represents an integer of 0 to 6,
q shows the integer of 0-4. ]
血液浄化カラム。 A carrier for a blood purification column according to any one of claims 1 to 8 is packed in a column container,
Blood purification column.
血液浄化方法。 Blood is passed through the blood purification column according to claim 9,
Blood purification method.
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| CN114225919B (en) * | 2021-11-26 | 2023-07-04 | 江苏贝美医疗科技有限公司 | Endotoxin adsorbent and preparation method and application thereof |
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