JPH0749052B2 - エンドトキシン中和剤 - Google Patents

エンドトキシン中和剤

Info

Publication number
JPH0749052B2
JPH0749052B2 JP5002625A JP262593A JPH0749052B2 JP H0749052 B2 JPH0749052 B2 JP H0749052B2 JP 5002625 A JP5002625 A JP 5002625A JP 262593 A JP262593 A JP 262593A JP H0749052 B2 JPH0749052 B2 JP H0749052B2
Authority
JP
Japan
Prior art keywords
polymyxin
fiber
endotoxin
neutralizing agent
fibers
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
JP5002625A
Other languages
English (en)
Other versions
JPH05329207A (ja
Inventor
正智 小玉
徹 谷
一芳 花沢
太郎 岡藤
和雄 寺本
四郎 西海
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Toray Industries Inc
Original Assignee
Toray Industries Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to JP58112695A priority Critical patent/JPH0738880B2/ja
Priority to EP84106810A priority patent/EP0129786B1/en
Priority to US06/833,421 priority patent/US4661260A/en
Priority to US07/022,960 priority patent/US4771104A/en
Application filed by Toray Industries Inc filed Critical Toray Industries Inc
Priority to JP5002625A priority patent/JPH0749052B2/ja
Publication of JPH05329207A publication Critical patent/JPH05329207A/ja
Publication of JPH0749052B2 publication Critical patent/JPH0749052B2/ja
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Classifications

    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
    • B01J20/28—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof characterised by their form or physical properties
    • B01J20/28014—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof characterised by their form or physical properties characterised by their form
    • B01J20/28033—Membrane, sheet, cloth, pad, lamellar or mat
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D15/00—Separating processes involving the treatment of liquids with solid sorbents; Apparatus therefor
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
    • B01J20/28—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof characterised by their form or physical properties
    • B01J20/28014—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof characterised by their form or physical properties characterised by their form
    • B01J20/28023—Fibres or filaments
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
    • B01J20/28—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof characterised by their form or physical properties
    • B01J20/28014—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof characterised by their form or physical properties characterised by their form
    • B01J20/28028—Particles immobilised within fibres or filaments
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
    • B01J20/28—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof characterised by their form or physical properties
    • B01J20/28014—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof characterised by their form or physical properties characterised by their form
    • B01J20/28033—Membrane, sheet, cloth, pad, lamellar or mat
    • B01J20/28038—Membranes or mats made from fibers or filaments
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
    • B01J20/28—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof characterised by their form or physical properties
    • B01J20/28054—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof characterised by their form or physical properties characterised by their surface properties or porosity
    • B01J20/28057—Surface area, e.g. B.E.T specific surface area
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
    • B01J20/30—Processes for preparing, regenerating, or reactivating
    • B01J20/32—Impregnating or coating ; Solid sorbent compositions obtained from processes involving impregnating or coating
    • B01J20/3231—Impregnating or coating ; Solid sorbent compositions obtained from processes involving impregnating or coating characterised by the coating or impregnating layer
    • B01J20/3242—Layers with a functional group, e.g. an affinity material, a ligand, a reactant or a complexing group
    • B01J20/3244—Non-macromolecular compounds
    • B01J20/3246—Non-macromolecular compounds having a well defined chemical structure
    • B01J20/3248—Non-macromolecular compounds having a well defined chemical structure the functional group or the linking, spacer or anchoring group as a whole comprising at least one type of heteroatom selected from a nitrogen, oxygen or sulfur, these atoms not being part of the carrier as such
    • B01J20/3251—Non-macromolecular compounds having a well defined chemical structure the functional group or the linking, spacer or anchoring group as a whole comprising at least one type of heteroatom selected from a nitrogen, oxygen or sulfur, these atoms not being part of the carrier as such comprising at least two different types of heteroatoms selected from nitrogen, oxygen or sulphur
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
    • B01J20/30—Processes for preparing, regenerating, or reactivating
    • B01J20/32—Impregnating or coating ; Solid sorbent compositions obtained from processes involving impregnating or coating
    • B01J20/3231—Impregnating or coating ; Solid sorbent compositions obtained from processes involving impregnating or coating characterised by the coating or impregnating layer
    • B01J20/3242—Layers with a functional group, e.g. an affinity material, a ligand, a reactant or a complexing group
    • B01J20/3244—Non-macromolecular compounds
    • B01J20/3246—Non-macromolecular compounds having a well defined chemical structure
    • B01J20/3248—Non-macromolecular compounds having a well defined chemical structure the functional group or the linking, spacer or anchoring group as a whole comprising at least one type of heteroatom selected from a nitrogen, oxygen or sulfur, these atoms not being part of the carrier as such
    • B01J20/3253—Non-macromolecular compounds having a well defined chemical structure the functional group or the linking, spacer or anchoring group as a whole comprising at least one type of heteroatom selected from a nitrogen, oxygen or sulfur, these atoms not being part of the carrier as such comprising a cyclic structure not containing any of the heteroatoms nitrogen, oxygen or sulfur, e.g. aromatic structures
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
    • B01J20/30—Processes for preparing, regenerating, or reactivating
    • B01J20/32—Impregnating or coating ; Solid sorbent compositions obtained from processes involving impregnating or coating
    • B01J20/3231—Impregnating or coating ; Solid sorbent compositions obtained from processes involving impregnating or coating characterised by the coating or impregnating layer
    • B01J20/3242—Layers with a functional group, e.g. an affinity material, a ligand, a reactant or a complexing group
    • B01J20/3244—Non-macromolecular compounds
    • B01J20/3246—Non-macromolecular compounds having a well defined chemical structure
    • B01J20/3248—Non-macromolecular compounds having a well defined chemical structure the functional group or the linking, spacer or anchoring group as a whole comprising at least one type of heteroatom selected from a nitrogen, oxygen or sulfur, these atoms not being part of the carrier as such
    • B01J20/3255—Non-macromolecular compounds having a well defined chemical structure the functional group or the linking, spacer or anchoring group as a whole comprising at least one type of heteroatom selected from a nitrogen, oxygen or sulfur, these atoms not being part of the carrier as such comprising a cyclic structure containing at least one of the heteroatoms nitrogen, oxygen or sulfur, e.g. heterocyclic or heteroaromatic structures

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  • Chemical & Material Sciences (AREA)
  • Analytical Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • External Artificial Organs (AREA)
  • Medicinal Preparation (AREA)

Description

【発明の詳細な説明】
【０００１】
【産業上の利用分野】本発明は、エンドトキシンの毒性
を減弱させる中和剤に関する。
【０００２】
【従来の技術】エンドトキシンは、哺乳動物の血中に入
ると発熱を起こす物質であり、その量が多いときには致
死作用すら示す。このエンドトキシンが血中に入る機会
は、肝膿傷、胆のう炎などの重度の細菌感染症、胃穿孔
や外科手術後の感染症のときであるが、そのほか細菌で
は人工透析や輸液の際にも、器具等のエンドトキシン汚
染によって起こりうる。ポリミキシンはエンドトキシン
の中和作用を有する抗生物質であるが、血中に入ると腎
毒性が強いのでその使用は経口投与あるいは局所投与に
限られ、その使用量にも制限がある。
【０００３】
【発明が解決しようとする課題】本発明の課題は、ポリ
ミキシンのエンドトキシン中和作用を生かしつつ、副作
用を減弱することにある。
【０００４】
【課題を解決するための手段】本発明は、上記目的を達
成するために下記の構成を有する。
【０００５】「α−ハロゲン化アシル基、ハロゲン化ベ
ンジル基およびイソシアン酸基から選ばれた置換基を有
する繊維状担体にポリミキシンを固定化してなるエンド
トキシン中和剤。」本発明でいうポリミキシンとは、Ｂ
ａｃｉｌｌｕｓ ｐｏｌｙｍａｘにより産生される抗生
物質であり、ポリミキシンＡ、ポリミキシンＢ1 、ポリ
ミキシンＢ2 、ポリキシンＤ1 、ポリミキシンＥ1 およ
びポリミキシンＥ2 等の、グラム陰性菌に対する抗菌作
用を有するものを意味する。
【０００６】本発明で言う繊維状担体とは、０．１〜１
００ｍ2 ／ｇの表面積を有する繊維状成型物であり、使
用条件下において、化学的および物理的に安定であると
ともに、ポリミキシンを化学的に固定しうる官能基を有
するものを意味する。本発明においては、これらの繊維
状担体として、α−ハロン化アシル基、ハロゲン化ベン
ジル基およびイソシアン酸基から選ばれる置換基を有す
る繊維状担体が用いられ、さらには、これらの置換基を
有する、ポリスチレン繊維または架橋ポリスチレン繊
維、アクリル酸・アクリロニトリル共重合体繊維、カル
ボキシル基を有するポリビニルアルコール繊維が好まし
く用いられる。本発明中和剤に固定化されているポリミ
キシンの量は、少なすぎるとエンドトキシンの中和がで
きなくなるので、１０mg/g担体以上、より好ましくは５
０mg/g担体以上であることが好ましい。
【０００７】本発明中和剤の調製は、繊維状担体とポリ
ミキシンを混合することにより、あるいは、さらにペプ
チド縮合剤｛ジシクロヘキシルカルボジイミド，１−エ
チル−３−（３−ジメチルアミノプロピル）−カルボジ
イミド｝などを添加することにより容易に達成できる。
【０００８】本発明中和剤の用途は、輸液および透析液
中のエンドトキシン除去のほか、エンドトキシン血症患
者の治療などがあり、その使用方法の代表例として、該
中和剤を充填したカラムに輸液、透析液または血液を循
環させる方法がある。
【０００９】本発明のエンドトキシン中和剤の作用機構
は明確ではないが、エンドトキシンの吸着作用よりも分
解作用に基づくと考えられる。
【００１０】
【実施例】
実施例１ ポリプロピレン（三井“ノーブレン”Ｊ３ＨＧ）５０重
量部を島成分とし、ポリスチレン（“スタイロン”６６
６）４６重量部、ポリプロピレン（住友“ノーブレン”
ＷＦ−７２７−Ｆ）４重量部の混合物を海成分とする海
島型複合繊維（島数１６、単糸繊度２．６デニール、引
張強度２．９g/d 、伸度５０％ねフィラメント数４２）
５０ｇを、Ｎ−メチロール−α−クロルアセトアミド５
０ｇ、ニトロベンゼン４００ｇ、９８％硫酸４００ｇお
よびパラホルムアルデヒド０．８５ｇからなる混合溶液
中に浸し、２０℃で１時間反応させた。繊維を反応液か
ら取り出し、０℃の氷水５ｌ中に投じて反応停止させた
のち、水で洗浄し、次に、繊維に付着しているニトロベ
ンゼンをメタノールで抽出除去した。この繊維を５０℃
で真空乾燥して、クロルアセトアミドメチル化繊維（繊
維Ａ）７１ｇを得た。
【００１１】ポリミキシンＢファイザー（台糖ファイザ
ー株式会社）４．８ｇ（５０万単位のもの８０本）を４
００ｍｌの水にとかし、この中に繊維Ａ１１ｇを加え、
５時間振とう後、酸化マグネシウム１．５ｇを添加し、
室温で６０時間振とうした。つぎに、この反応母液から
とり出し、クロマトカラムにつめて、０．１Ｎ−塩酸４
８００mlで洗浄した。この洗浄液と反応母液を混合した
溶液について、ミクロビュレット法で溶液中のポリミキ
シン量を算出した。一方、反応した繊維は、さらに水２
５ｌおよび生理食塩水６ｌで洗って、ポリミキシンＢ固
定化繊維（繊維Ｂ）を得た。固定化量は残存法から１１
０ｍｇ／ｇであった。
【００１２】実施例２ Ｅｓｃｈｅｒｉｃｈｉａ Ｃｏｌｉ ０１１１：Ｂ４の
リボ多糖体（ディフコ・ラボラトリーズ社製、フェノー
ル抽出法）の０．５mg/ml の水溶液２０mlに繊維Ｂ２ｇ
を加え、３７℃で６０分振とう後、上澄を１mlずつ、Ｂ
ＡＬＢ／Ｃマウスに尾静脈から投与して、４８時間後の
死亡率を調べたところ、１３匹中４匹（３１％）が死亡
した。繊維Ｂの代わりに繊維Ａを用いて同様な実験を行
ったところ、マウス１１匹中１１匹（１００％）が死亡
した。この実験からポリミキシン固定化繊維がリボ多糖
体を無毒化していることがわかる。
【００１３】実施例３ Ｅｓｃｈｅｒｉｃｉａ Ｃｏｌｉ ０２６：Ｂ６（ディ
フコ・ラボラトリーズ社製、フェノール抽出法）の０．
５mg/ml の水溶液に繊維Ｂ２ｇを加え、３７℃で６０分
間振とう後、上澄を１mlずつ、ＢＡＬＢ／Ｃマウスに尾
静脈から投与して、４８時間後の死亡率を調べたとこ
ろ、８匹中１匹（１２．５％）が死亡した。対照とし
て、繊維Ｂで処理しなかった水溶液について同様の投与
を行ったところ、１３匹中１２匹（９２％）が死亡し
た。この実験からポリミキシン固定化繊維がリボ多糖体
を無毒化していることがわかる。
【００１４】実施例４ Ｅｓｃｈｅｒｉｃｈｉａ Ｃｏｌｉ ０１１１：Ｂ４の
リボ多糖体の０．５mg/ml 水溶液、０．２５mg/ml 水溶
液および０．１２５mg/ml 水溶液２０mlに、繊維Ｂ２ｇ
を加え、３７℃で６０分間振とうしたのち、上澄をＢＡ
ＬＢ／Ｃマウスに尾静脈から１mlずつ投与して、４８時
間後の死亡率を調べたところ、０．５mg/ml では１５匹
中１５匹、０．２５mg/ml では１３匹中１匹、０．１２
５mg/mlでは１３匹中０匹の死亡率であった。
【００１５】
【発明の効果】本発明のエンドトキシン中和剤は、ポリ
ミキシンを高い密度で固定化しているため、溶液中のエ
ンドトキシンを分解・無毒化することともに、ポリミキ
シンが溶液液中に溶出しないため、該中和剤で処理され
た溶液が毒性を示さないとに特徴を有する。
───────────────────────────────────────────────────── フロントページの続き 審査官 多喜 鉄雄

Claims (2)

    【特許請求の範囲】
  1. 【請求項１】α−ハロゲン化アシル基、ハロゲン化ベン
    ジル基およびイソシアン酸基から選ばれた置換基を有す
    る繊維状担体にポリミキシンを固定化してなるエンドト
    キシン中和剤。
  2. 【請求項２】繊維状担体が、ポリスチレン繊維または架
    橋ポリスチレン繊維、アクリル酸・アクリロニトリル共
    重合体繊維およびカルボキシル基を有するポリビニルア
    ルコール繊維から選ばれることを特徴とする請求項１記
    載のエンドトキシン中和剤。
JP5002625A 1983-06-24 1993-01-11 エンドトキシン中和剤 Expired - Lifetime JPH0749052B2 (ja)

Priority Applications (5)

Application Number Priority Date Filing Date Title
JP58112695A JPH0738880B2 (ja) 1983-06-24 1983-06-24 エンドトキシン血症治療剤
EP84106810A EP0129786B1 (en) 1983-06-24 1984-06-14 Endotoxin detoxifying material
US06/833,421 US4661260A (en) 1983-06-24 1986-02-21 Endotoxin detoxifying process
US07/022,960 US4771104A (en) 1983-06-24 1987-03-06 Endotoxin detoxifying material
JP5002625A JPH0749052B2 (ja) 1983-06-24 1993-01-11 エンドトキシン中和剤

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP58112695A JPH0738880B2 (ja) 1983-06-24 1983-06-24 エンドトキシン血症治療剤
JP5002625A JPH0749052B2 (ja) 1983-06-24 1993-01-11 エンドトキシン中和剤

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
JP58112695A Division JPH0738880B2 (ja) 1983-06-24 1983-06-24 エンドトキシン血症治療剤

Publications (2)

Publication Number Publication Date
JPH05329207A JPH05329207A (ja) 1993-12-14
JPH0749052B2 true JPH0749052B2 (ja) 1995-05-31

Family

ID=26336059

Family Applications (2)

Application Number Title Priority Date Filing Date
JP58112695A Expired - Lifetime JPH0738880B2 (ja) 1983-06-24 1983-06-24 エンドトキシン血症治療剤
JP5002625A Expired - Lifetime JPH0749052B2 (ja) 1983-06-24 1993-01-11 エンドトキシン中和剤

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Also Published As

Publication number Publication date
EP0129786A2 (en) 1985-01-02
EP0129786A3 (en) 1986-01-22
JPH0738880B2 (ja) 1995-05-01
US4771104A (en) 1988-09-13
EP0129786B1 (en) 1990-02-07
JPH05329207A (ja) 1993-12-14
US4661260A (en) 1987-04-28
JPS605166A (ja) 1985-01-11

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