JPH059234A - Pyrogen-adsorbing substance - Google Patents
Pyrogen-adsorbing substanceInfo
- Publication number
- JPH059234A JPH059234A JP3254068A JP25406891A JPH059234A JP H059234 A JPH059234 A JP H059234A JP 3254068 A JP3254068 A JP 3254068A JP 25406891 A JP25406891 A JP 25406891A JP H059234 A JPH059234 A JP H059234A
- Authority
- JP
- Japan
- Prior art keywords
- substance
- pyrogen
- adsorbent
- heat
- exothermic
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Medicinal Preparation (AREA)
- Addition Polymer Or Copolymer, Post-Treatments, Or Chemical Modifications (AREA)
Abstract
Description
【産業上の利用分野】本発明は、注射等により生体内に
投与された場合に発熱を惹起する元凶となる物質、すな
わち、発熱物質（パイロジェン）の除去に有効な不溶性
発熱物質吸着体に関する。BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an insoluble heat-generating substance adsorbent which is effective in removing a substance that causes fever when administered into a living body by injection or the like, that is, a pyrogen.
【従来の技術】生体内に投与される医薬品の製造におい
ては、発熱物質を除去する技術の重要性は非常に高い。
ここで言う発熱物質は、ジフテリア菌や黄色ブドウ球菌
等が分泌する外毒素と大腸菌等のグラム陰性菌の細胞壁
の成分である内毒素に分類される。このうち、通常、問
題となるのは後者のグラム陰性菌の内毒素であり、その
正体は多糖類と結合した脂質の複合体、すなわち、リポ
ポリサッカライド（ＬＰＳ）中の活性中心にあたる糖脂
質であるリピッドＡであることが知られている。このよ
うな発熱物質が混入した注射剤等が生体内に投与された
場合、これらの発熱物質が視床下部等の温熱中枢に作用
して発熱を起こすと考えられており、その結果、重篤な
発熱現象や時にはショック死に至らせる場合もある。従
って注射剤等の医薬品製造においては、通常、安全性確
認の為ウサギを用いた発熱試験が実施されており、発熱
物質が混入していないことを確認することが義務づけら
れている。このような発熱物質を除く方法として、炭素
粉末やイオン交換樹脂等を用いて発熱物質を吸着除去す
る方法や酸あるいはアルカリを用いて発熱物質を分解し
て除去する方法、またウルトラメンブランフィルターを
用いてこれらを選択除去する方法等が知られている。さ
らには、ヒスタミン等の含イミダゾール化合物や核酸塩
基をデキストラン系のゲル担体に結合させ、これを発熱
物質の吸着除去に応用した例も報告されている（美濃部
等、Ｊｏｕｒｎａｌ ｏｆｃｈｒｏｍａｔｏｇｒａｐｈ
ｙ，２６２，ｐ．１９３−１９８（１９８３））。しか
しながら、医薬品製造における発熱物質の除去は、対象
となる製剤そのものが不安定であったり、生成する際の
目的物質の量に対して除去されるべき発熱物質の量が非
常に微量であること等の理由から、さらには工業的製造
レベルに前記の方法を適用させる際にはまだ技術的にも
多くの問題が残されており、これらの問題を解決できる
効果的でしかも簡便な方法の開発が切望されている。こ
のような状況のもとで、ポリアミノ酸球状粒子を担体と
し、これにイミダゾール誘導体を結合させることを特徴
とする新規な発熱物質吸着体が、発熱物質との親和性に
優れしかも担体の硬質性に基づく発熱物質吸着操作上の
利点を有していることが見いだされた（特開平０１−１
２７０３９）。しかしながら、発熱物質吸着体を調製す
る際には数段階の反応過程を要し多少の煩雑性を伴うこ
とは否めず、またリガンドとなるイミダゾール誘導体休
の導入量には限界があり、自ずと発熱物質の吸着能にも
限界があった。また、ポリスチレン等にアミノ基を担持
した吸着剤も知られているが、選択吸着性は充分ではな
い（特公平３−３１５１６）。2. Description of the Related Art In the production of drugs to be administered in vivo, the technology for removing pyrogens is very important.
The pyrogens mentioned here are classified into exotoxins secreted by diphtheria and staphylococcus aureus and endotoxins which are components of the cell wall of Gram-negative bacteria such as Escherichia coli. Of these, the problem is usually the latter endotoxin of Gram-negative bacteria, the true form of which is a lipid complex bound to a polysaccharide, that is, a glycolipid that is the active center in lipopolysaccharide (LPS). It is known to be a certain lipid A. It is considered that when an injection or the like mixed with such a pyrogen is administered into a living body, these pyrogens act on a heat center such as the hypothalamus to cause fever. It can lead to fever and sometimes shock death. Therefore, in the production of pharmaceuticals such as injections, a fever test using rabbits is usually carried out for safety confirmation, and it is obligatory to confirm that a pyrogen is not mixed. As a method of removing such a heat-generating substance, a method of adsorbing and removing the heat-generating substance by using carbon powder or an ion exchange resin, a method of decomposing and removing the heat-generating substance using an acid or an alkali, and an ultra membrane filter are used. There are known methods for selectively removing these. Furthermore, an example in which an imidazole-containing compound such as histamine or a nucleobase is bound to a dextran-based gel carrier and applied to the adsorption and removal of a pyrogen is also reported (Minobe et al., Journal of chromatograph.
y, 262, p. 193-198 (1983)). However, the removal of pyrogens in the manufacture of pharmaceutical products is such that the target drug product itself is unstable, or the amount of pyrogens to be removed is extremely small compared to the amount of the target substance at the time of production. For this reason, many technical problems still remain when the above method is applied to the industrial manufacturing level, and it is necessary to develop an effective and simple method that can solve these problems. Coveted. Under such circumstances, a novel exothermic substance adsorbent characterized by using polyamino acid spherical particles as a carrier and binding an imidazole derivative thereto has excellent affinity with the exothermic substance and also has a rigid carrier. It has been found that the method has an advantage in the operation of adsorbing a heat-generating substance based on
27039). However, preparation of a pyrogen adsorbent requires several steps of reaction process, and it is unavoidable that it involves some complications.In addition, there is a limit to the amount of imidazole derivative that serves as a ligand. There was a limit to the adsorption capacity of. Further, an adsorbent in which an amino group is supported on polystyrene or the like is also known, but its selective adsorption is not sufficient (Japanese Patent Publication No. 3-31516).
【発明が解決しようとする課題】本発明の課題は、選択
吸着性に優れ、工業的製造レベルにも適用できる発熱物
質吸着体を提供することである。SUMMARY OF THE INVENTION An object of the present invention is to provide a heat-generating substance adsorbent which is excellent in selective adsorption and can be applied to an industrial production level.
【課題を解決するための手段】これらの課題を解決すべ
く、本発明者は鋭意研究を重ねた結果、特定のポリアク
リルアミド誘導体が発熱物質に対して極めて高い親和性
を示し、目的物質から発熱物質を特異的に吸着除去で
き、同時にその製造も工業的に有利であることを見いだ
して本発明を完成するに至った。すなわち、本発明は、
Ｎ，Ｎ−ジメチルアクリルアミド及び／又はＮ，Ｎ−ジ
メチルアミノアルキルアクリルアミドと架橋型モノマー
との共重合体よりなる水不溶性の発熱物質吸着体に関す
る。[Means for Solving the Problems] As a result of intensive studies to solve these problems, the present inventor has found that a specific polyacrylamide derivative has an extremely high affinity for a heat-generating substance, and the target substance generates heat. The inventors have found that a substance can be specifically adsorbed and removed, and at the same time, its production is industrially advantageous, and the present invention has been completed. That is, the present invention is
The present invention relates to a water-insoluble exothermic substance adsorbent comprising a copolymer of N, N-dimethylacrylamide and / or N, N-dimethylaminoalkylacrylamide and a crosslinking monomer.
【化１】 一般式（２）においてｎ＝２〜６である。前述のごと
く、従来より発熱物質を除去する方法は種々試みられて
いるが、医薬品製造における発熱物質の除去操作におい
ては、処理するサンプル中の目的物質の濃度が比較的高
いのに対して、除去すべき発熱物質の量が非常に少ない
という問題があり、思うように発熱物質のみを吸着でき
ない場合が多く、発熱物質に対してより特異性の高い吸
着体やより効率の良い発熱物質の除去方法の開発が望ま
れている。また、医薬品の製造工程としての発熱物質除
去方法には、前記の特異性の点に加えて迅速に処理でき
る方法であることが要求される。本発明の発熱物質吸着
体は、従来の吸着技術で用いられていたアガロースゲル
やデキストラン系のセファロースゲルを用いずに、これ
に代わるアミド基を有する熱可塑性ポリマーを使用する
ことによって発熱物質のと親和性が大きく向上し、さら
に従来の多糖体ゲルに比較して優れた硬質性を有する特
性により、発熱物質を含有する、目的の最終的に精製す
べき物質から効率よくしかも迅速に該発熱物質を分離除
去することが可能となった。さらに、本発熱物質吸着体
は従来用いられていたポリマーと異なり熱可塑性をもつ
ポリマーであり、加工性や成形性に優れており工業的な
製造に有利になった。本発明の発熱物質吸着体に用いら
れるアクリルアミドの重合体（ポリアクリルアミド誘導
体）としては、Ｎ，Ｎ−ジメチルアクリルアミド（ＤＭ
ＡＡ、前記式（１）の化合物）やＮ，Ｎ−ジメチルアミ
ノエチルアクリルアミド（前記一般式（２）において、
ｎ＝２の化合物）、Ｎ，Ｎ−ジメチルアミノプロピルア
クリルアミド（ＤＭＡＰＡＡ、前記式（３）の化合物）
などをモノマーとする重合体である。これらのモノマー
を重合反応に付するに際しては、これらのモノマーのい
ずれかを単独使用してもよく、また併用してもよい。ま
た、これらのモノマーを重合反応に付するに際しては、
溶解性の理由より、下記（１１）〜（１５）で表される
ピペラジンジアクリルアミド（ＰＤＡ）、ブチレンビス
メタクリルアミド（ＢＢＭＡ）、Ｎ，Ｎ′ーメチルビス
アクリルアミド（ＭＢＡＡ）、アリルアクリルアミド
（ＡＡＡ）、Ｎ，Ｎ′−ヘキサンメチレンビスブチルア
クリルアミド（２Ｃ４ＤＤＡ）などの架橋型モノマーが
併用される。すなわち、本発明のアクリルアミド重合体
は、前記モノマーと架橋型モノマーとの共重合体であ
る。[Chemical 1] In the general formula (2), n = 2 to 6. As mentioned above, various methods for removing pyrogens have been attempted from the past, but in the process of removing pyrogens in pharmaceutical manufacturing, the concentration of the target substance in the sample to be processed is relatively high, but There is a problem that the amount of exothermic substances that should be used is very small, and it is often the case that only exothermic substances cannot be adsorbed as expected, so an adsorbent with higher specificity for exothermic substances and a more efficient exothermic substance removal method. Development is desired. In addition to the above-mentioned specificity, the method for removing a heat-generating substance as a manufacturing process of pharmaceuticals is required to be a method capable of rapid treatment. The exothermic substance adsorbent of the present invention does not use an agarose gel or a dextran-based sepharose gel used in a conventional adsorption technique, but uses a thermosetting polymer having an amide group instead of The affinity is greatly improved, and due to the property that it has excellent hardness as compared with the conventional polysaccharide gel, the pyrogen containing the pyrogen is efficiently and rapidly extracted from the target substance to be finally purified. It has become possible to separate and remove. Further, the present exothermic substance adsorbent is a polymer having thermoplasticity, which is different from the conventionally used polymers, and has excellent processability and moldability, which is advantageous for industrial production. Examples of the acrylamide polymer (polyacrylamide derivative) used for the exothermic substance adsorbent of the present invention include N, N-dimethylacrylamide (DM).
AA, the compound of the formula (1) and N, N-dimethylaminoethylacrylamide (in the general formula (2),
n = 2 compound), N, N-dimethylaminopropyl acrylamide (DMAPAA, compound of the above formula (3))
It is a polymer having as a monomer. When subjecting these monomers to the polymerization reaction, any of these monomers may be used alone or in combination. When subjecting these monomers to a polymerization reaction,
Due to solubility, piperazine diacrylamide (PDA), butylene bismethacrylamide (BBMA), N, N'-methylbisacrylamide (MBAA), allyl acrylamide (AAA) represented by the following (11) to (15). , N, N′-hexanemethylenebisbutylacrylamide (2C4DDA) and the like are used together. That is, the acrylamide polymer of the present invention is a copolymer of the above-mentioned monomer and a crosslinking monomer.
【化２】 本発明のアクリルアミド重合体を製造するための重合反
応それ自体には特別の制限はなく、常法通り、光重合や
ラジカル重合により容易に行なわれ得る。このようにし
て製造される種々のポリアクリルアミド誘導体は、水不
溶性であり、発熱物質吸着体として使用する場合はこれ
らのうちのいずれかを単独使用することもできるし、い
くつかを混合して使用することもできる。本発明の発熱
物質吸着体の形状は特に制限されることはなく、例えば
球状粒子、繊維、フィルムや粉末等いずれでも良い。球
状粒子は軽質パラフィンオイル中での懸濁重合により製
造することができる。粒子のサイズは、操作性及び吸着
性の観点から粒径１〜３００μｍとするとよい。繊維は
溶融紡糸により製造することができる。その横断面のサ
イズは、強度及び吸着性の観点から３０〜６０μｍとす
るとよい。フィルム状発熱物質吸着体の製造も常法によ
り容易に行うことができる。すなわち、ポリアクリルア
ミド誘導体のフィムは溶融押出し法により製造される。
膜厚は、強度及び吸着性の観点から１０〜５０μｍとす
るとよい。粉末状の発熱物質吸着体の製造は、光重合に
より容易に行うことができる。そのサイズは、操作性及
び吸着性の観点から１〜３００μｍとするとよい。シリ
カやアミルナ等の多孔質担体にポリアクリルアミド誘導
体を表面処理して用いることも可能である。さらには、
セルロース、ポリエステル、ポリアクリロニトリル、ポ
リオレフィン等、他の素材からなる繊維状の担体の表面
をポリアクリルアミド誘導体でコーティング処理して用
いることが可能である。用いられる繊維に特に制限はな
いが、比表面積の大きい繊維が有利に用いられる。この
ように発熱物質吸着性のあるポリアクリルアミド誘導体
を担体に担持せしめて使用する態様ももちろん本発明の
範囲内にある。このようなポリアクリルアミド誘導体で
表面処理した多孔質担体や繊維の特徴は、従来より使用
されている多糖類系の球状粒子に比較して硬質な点や比
表面積が大きい点にあり、発熱物質を目的の最終精製物
から効率よくしかも迅速に分離除去することが可能であ
る。加えて前記球状粒子形態に比ベポリマーの使用量が
少なくて済み、経済的にも有利である。本発明の発熱物
質吸着体を用いて発熱物質を除去する操作には特別の制
限はなく、例えば、カラムを用いたクロマトグラフィー
またはバッチ処理法のいずれの方法でも実施することが
できる。カラム法の場合には、本発明の発熱物質吸着体
をカラムに充填し、適当な緩衝液で洗浄した後に発熱物
質を含有する目的物質の溶液を通液し、素通り画分を回
収することによって発熱物質が除去された目的物質の溶
液を得ることができる。また、バッチ法においては発熱
物質を含有する目的物質の溶液に本発明の発熱物質吸着
体を添加し攪拌した後、吸着体のみを液体から分離除去
することにより発熱物質を含まない目的物質の溶液を得
ることができる。本発明の発熱物質吸着体は、従来のア
ガロースやデキストラン系の発熱物質吸着体粒子と比較
すると、膨潤性をほとんど示さず、カラムクロマトグラ
フィー等を極めて短時間のうちに行うことができ、発熱
物質の高速分離剤として工業的に使用される場合に最適
である。本発明の発熱物質吸着体は、発熱物質との親和
性に優れており、これに加えて、従来用いられていたア
ガロースやデキストラン系の物質を素材とした粒子に比
べて、吸着体が非常に硬質性に富み安定しているため、
膨潤度も極めて小さく発熱物質の除去操作を短時間のう
ちに実施することが可能である。また、本発明の発熱物
質吸着体は、特別な反応経路を経ることなくきわめて簡
便に製造される。さらにまた、その熱可塑性のために工
業的な成形加工が容易である点は従来の発熱物質吸着体
に無い特筆すべき特徴である。さらに、本発明の発熱物
質吸着体は、目的物質とは親和性が小さいために、目的
物質の回収率を低下させる事なく、発熱物質のみを極め
て選択的に除去することが可能である。[Chemical 2] The polymerization reaction itself for producing the acrylamide polymer of the present invention is not particularly limited, and can be easily carried out by photopolymerization or radical polymerization according to a conventional method. The various polyacrylamide derivatives produced in this manner are water-insoluble, and when used as an exothermic substance adsorbent, any one of them can be used alone, or some of them can be mixed and used. You can also do it. The shape of the exothermic substance adsorbent of the present invention is not particularly limited, and may be, for example, any of spherical particles, fibers, films, powders and the like. Spherical particles can be produced by suspension polymerization in light paraffin oil. The size of the particles is preferably 1 to 300 μm in terms of operability and adsorptivity. The fibers can be manufactured by melt spinning. The size of the cross section is preferably 30 to 60 μm from the viewpoint of strength and adsorptivity. The film-shaped exothermic substance adsorbent can be easily produced by a conventional method. That is, the polyacrylamide derivative film is produced by a melt extrusion method.
The film thickness is preferably 10 to 50 μm from the viewpoint of strength and adsorptivity. The powdery exothermic substance adsorbent can be easily produced by photopolymerization. The size is preferably 1 to 300 μm from the viewpoint of operability and adsorptivity. It is also possible to surface-treat and use a polyacrylamide derivative on a porous carrier such as silica or amylna. Moreover,
It is possible to coat the surface of a fibrous carrier made of another material such as cellulose, polyester, polyacrylonitrile, or polyolefin with a polyacrylamide derivative before use. The fibers used are not particularly limited, but fibers having a large specific surface area are advantageously used. As described above, the embodiment in which the polyacrylamide derivative having the adsorbability of the exothermic substance is used by being supported on the carrier is also within the scope of the present invention. The characteristics of the porous carrier and fiber surface-treated with such a polyacrylamide derivative are that they are harder and have a larger specific surface area than the spherical particles of polysaccharides that have been conventionally used, and that they can be used as a heat-generating substance. It is possible to efficiently and rapidly separate and remove from the target final purified product. In addition, the amount of the polymer used is smaller than that of the spherical particles, which is economically advantageous. There is no particular limitation on the operation of removing the heat-generating substance using the heat-generating substance adsorbent of the present invention, and for example, either chromatography using a column or batch processing can be performed. In the case of the column method, the column is filled with the pyrogen adsorbent of the present invention, and after washing with an appropriate buffer, the solution of the target substance containing the pyrogen is passed through to collect the flow-through fraction. A solution of the target substance from which the heat-generating substance has been removed can be obtained. In the batch method, a solution of a target substance containing no heat generating substance is prepared by adding the heat generating substance adsorbent of the present invention to a solution of the target substance containing a heat generating substance and stirring and then separating and removing only the adsorbent from the liquid. Can be obtained. The pyrogen adsorbent of the present invention shows almost no swelling property as compared with conventional agarose or dextran-based pyrogen adsorbent particles, and column chromatography or the like can be performed in an extremely short time. It is most suitable when it is industrially used as a high speed separating agent. The exothermic substance adsorbent of the present invention has excellent affinity with the exothermic substance, and in addition to this, the adsorbent has a very high affinity as compared with particles made of conventionally used agarose or dextran type substances. Because it is rich in hardness and stable,
The degree of swelling is also extremely small, and the operation of removing the heat-generating substance can be carried out in a short time. Further, the exothermic substance adsorbent of the present invention can be produced very simply without passing through a special reaction route. Furthermore, the fact that it is industrially easy to mold due to its thermoplasticity is a remarkable feature not found in conventional exothermic substance adsorbents. Further, since the exothermic substance adsorbent of the present invention has a small affinity for the target substance, it is possible to extremely selectively remove only the heat generating substance without lowering the recovery rate of the target substance.
【実施例】以下、実施例により本発明を更に説明する。
実施例１〜６は発熱物質吸着体の製造に関するものであ
り、実施例７は発熱物質の吸着除去に関するものであ
る。 実施例１ Ｎ，Ｎ−ジメチルアクリルアミド（ＤＭＡＡ）１４ｇ及
びピペラジンジアクリルアミド（ＰＤＡ）１１ｇにアゾ
ビスイソブチロニトリル（ラジカル重合開始剤）をモノ
マーの１重量％を加え、５０℃で１０分間静置して重合
させた。重合反応完了後、塊状の重合物をミキサーで粉
砕して粉末２３ｇを得た。標準フルイで分別して１０６
〜１５１μｍ径の成分を採取した。これを吸着体Ａと称
する。 実施例２ 原料として、Ｎ，Ｎ−ジメチルアクリルアミド（ＤＭＡ
Ａ）１４ｇとＮ，Ｎ′−ブチレンビスメタクリルアミド
（ＢＢＭＡ）１４ｇを用いた以外は、実施例１と同様に
行なって吸着体Ｂを得た。 実施例３ 原料として、Ｎ，Ｎ−ジメチルアミノプロピルアクリル
アミド（ＤＭＡＰＡＡ）２２ｇとＮ，Ｎ′−メチレンビ
スアクリルアミド（ＭＢＡＡ）９ｇを用いた以外は、実
施例１と同様に行なって吸着体Ｃを得た。 実施例４ 原料として、Ｎ，Ｎ−ジメチルアミノプロピルアクリル
アミド（ＤＭＡＰＡＡ）２２ｇとアリルアクリルアミド
（ＡＡＡ）１１ｇを用いた以外は、実施例１と同様に行
なって吸着体Ｄを得た。 実施例５ 原料として、Ｎ，Ｎ−ジメチルアミノプロピルアクリル
アミド（ＤＭＡＰＡＡ）２２ｇとピペラジンジアクリル
アミド（ＰＤＡ）１１ｇを用いた以外は、実施例１と同
様に行なって吸着体Ｅを得た。 実施例６ 原料として、Ｎ，Ｎ−ジメチルアミノプロピルアクリル
アミド（ＤＭＡＰＡＡ）２２ｇとＮ，Ｎ′−ヘキサメチ
レンビスブチルアクリルアミド（２Ｃ４ＤＡＡ）２０ｇ
を用いた以外は、実施例１と同様に行なって吸着体Ｆを
得た。 実施例７ 実施例１〜６で調製した吸着体のそれぞれ０．５ｇ（乾
燥重量）を発熱物質を含まない１０ｍＭリン酸緩衝液ｐ
Ｈ７．５（１．０Ｍ ＮａＣｌ含有）、１０ｍＭリン酸
緩衝液ｐＨ７．５（０．０７Ｍ ＮａＣｌ）で順次洗浄
した。これらの吸着体に発熱物質単独の水溶液（濃度は
Ｅ．ｃｏｌｉ ＵＫＴ−Ｂ ２５０ｎｇ／ｍｌ）又は発
熱物質を含有する、目的物質の百日咳抗原（ＦＨＡ）を
溶解したリン酸緩衝液（ｐＨ７．２、濃度は、発熱物質
については百日咳菌培養上清由来エンドトキシン１３
０，０００ｎｇ／ｍｌ、ＦＨＡについては５，０００Ｅ
Ｕ。）２０ｍｌを接触させ（バッチ処理法）、上清につ
いて残存する発熱物質量及び目的物質量の測定を行っ
た。はじめに含有されていた発熱物質量より上清に残存
した発熱物質量を引き、その差をはじめに含有されてい
た発熱物質量で除し、１００倍して発熱物質除去率とし
て表した。目的物質（ＦＨＡ）の回収率は、はじめに含
有されていた目的物質量で上清に含有されていた目的物
質量を除し、１００倍して得たものである。結果を表１
に示す。EXAMPLES The present invention will be further described below with reference to examples.
Examples 1 to 6 relate to the production of the exothermic substance adsorbent, and Example 7 relates to the adsorption and removal of the exothermic substance. Example 1 To 14 g of N, N-dimethylacrylamide (DMAA) and 11 g of piperazine diacrylamide (PDA), 1% by weight of azobisisobutyronitrile (radical polymerization initiator) was added, and the mixture was allowed to stand at 50 ° C. for 10 minutes. And polymerized. After the completion of the polymerization reaction, the massive polymer was crushed with a mixer to obtain 23 g of powder. 106 sorted by standard sieve
A component having a diameter of ˜151 μm was collected. This is referred to as adsorbent A. Example 2 As a raw material, N, N-dimethylacrylamide (DMA
An adsorbent B was obtained in the same manner as in Example 1 except that 14 g of A) and 14 g of N, N'-butylenebismethacrylamide (BBMA) were used. Example 3 An adsorbent C was obtained in the same manner as in Example 1 except that 22 g of N, N-dimethylaminopropylacrylamide (DMAPAA) and 9 g of N, N′-methylenebisacrylamide (MBAA) were used as raw materials. It was Example 4 An adsorbent D was obtained in the same manner as in Example 1 except that 22 g of N, N-dimethylaminopropyl acrylamide (DMAPAA) and 11 g of allyl acrylamide (AAA) were used as raw materials. Example 5 An adsorbent E was obtained in the same manner as in Example 1 except that 22 g of N, N-dimethylaminopropyl acrylamide (DMAPAA) and 11 g of piperazine diacrylamide (PDA) were used as raw materials. Example 6 As raw materials, 22 g of N, N-dimethylaminopropylacrylamide (DMAPAA) and 20 g of N, N′-hexamethylenebisbutylacrylamide (2C4DAA) were used.
An adsorbent F was obtained in the same manner as in Example 1 except that was used. Example 7 0.5 g (dry weight) of each of the adsorbents prepared in Examples 1-6 was added to a pyrogen-free 10 mM phosphate buffer p.
The cells were sequentially washed with H7.5 (containing 1.0 M NaCl) and 10 mM phosphate buffer pH 7.5 (0.07 M NaCl). An aqueous solution containing a pyrogen alone (concentration: E. coli UKT-B 250 ng / ml) or a pyrogen-containing phosphate buffer solution (pH 7.2, containing pertussis antigen (FHA), which is a target substance, dissolved in these adsorbents. Regarding the concentration of pyrogens, endotoxin 13 from Bordetella pertussis culture supernatant was used.
10,000 ng / ml, 5,000E for FHA
U. ) 20 ml was contacted (batch processing method), and the amount of the pyrogen and the amount of the target substance remaining in the supernatant were measured. The amount of the pyrogen that remained in the supernatant was subtracted from the amount of the pyrogen that was initially contained, and the difference was divided by the amount of the pyrogen that was initially contained, multiplied by 100 and expressed as the pyrogen removal rate. The recovery rate of the target substance (FHA) was obtained by dividing the amount of the target substance contained in the supernatant by the amount of the target substance contained in the beginning, and multiplying by 100. The results are shown in Table 1.
Shown in.
【表１】 表１から明らかなように、種々の吸着体において、いず
れも優れた選択的発熱物質吸着活性が認められた。な
お、発熱物質の検出はトキシノメーター（和光純薬社
製）によって行った。[Table 1] As is clear from Table 1, all of the various adsorbents exhibited excellent selective heat generating substance adsorption activity. In addition, the detection of the exothermic substance was performed by a toxinometer (made by Wako Pure Chemical Industries, Ltd.).
【発明の効果】本発明の発熱物質吸着体によれば、目的
物質の回収率を低下させることなく発熱物質のみを極め
て選択的にしかも迅速に除去することができる。また、
その製造も非常に容易であり、医薬品の工業的製造にも
適用可能な優れた吸着体である。According to the heat-generating substance adsorbent of the present invention, only the heat-generating substance can be removed extremely selectively and quickly without lowering the recovery rate of the target substance. Also,
Its production is very easy, and it is an excellent adsorbent applicable to industrial production of pharmaceuticals.
───────────────────────────────────────────────────── フロントページの続き (72)発明者 平山 忠一 熊本県熊本市下南部町373−12 (72)発明者 伊原 博隆 熊本県熊本市高平３丁目21番９号 (72)発明者 坂田 真砂代 熊本県熊本市徳王町271の５ (72)発明者 角田 俊誠 熊本県熊本市清水町楡木2136−58 (72)発明者 相原 勝敏 熊本県鹿本郡植木町岩野970ー８ (72)発明者 大沼 健一 神奈川県川崎市川崎区鈴木町１番１号 味 の素株式会社中央研究所内 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Tadakazu Hirayama 373-12 Shimonanbu-cho, Kumamoto-shi, Kumamoto (72) Inventor Hirotaka Ihara 3-21-9 Takahira, Kumamoto-shi, Kumamoto (72) Inventor Sasada Masashiro Kumamoto 271 Tokuo-cho, Kumamoto-shi, Japan 5 (72) Inventor Toshinori Kakuda 2136-58 Masaki, Shimizu-cho, Kumamoto-shi, Kumamoto Inventor Katsutoshi Aihara 970-8 Iwano, Ueki, Kamoto-gun, Kumamoto Ken-ichi Onuma Central Research Laboratory, Ajinomoto Co., Inc. 1-1, Suzuki-cho, Kawasaki-ku, Kawasaki-shi, Kanagawa
Claims (1)
ジメチルアクリルアミド及び／又はＮ，Ｎ−ジメチルア
ミノアルキルアクリルアミドと架橋型モノマーとの共重
合体よりなる水不溶性の発熱物質吸着体。Claims: 1. N, N-, which may be carried on a carrier.
A water-insoluble exothermic substance adsorbent comprising a copolymer of dimethylacrylamide and / or N, N-dimethylaminoalkylacrylamide and a crosslinking monomer.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP3254068A JPH059234A (en) | 1991-06-28 | 1991-06-28 | Pyrogen-adsorbing substance |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP3254068A JPH059234A (en) | 1991-06-28 | 1991-06-28 | Pyrogen-adsorbing substance |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH059234A true JPH059234A (en) | 1993-01-19 |
Family
ID=17259776
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP3254068A Pending JPH059234A (en) | 1991-06-28 | 1991-06-28 | Pyrogen-adsorbing substance |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH059234A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0706399A1 (en) * | 1993-06-02 | 1996-04-17 | Geltex Pharmaceuticals, Inc. | Compositions and process for removing bile salts |
-
1991
- 1991-06-28 JP JP3254068A patent/JPH059234A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0706399A1 (en) * | 1993-06-02 | 1996-04-17 | Geltex Pharmaceuticals, Inc. | Compositions and process for removing bile salts |
| EP0706399A4 (en) * | 1993-06-02 | 1998-08-12 | Geltex Pharma Inc | Compositions and process for removing bile salts |
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