JP4381058B2 - Hollow fiber blood purifier with excellent blood compatibility - Google Patents
Hollow fiber blood purifier with excellent blood compatibility Download PDFInfo
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Description
本発明は血液適合性に優れた中空糸型血液浄化器に関する。特に疎水性高分子と親水性高分子からなる中空糸膜を用いた医療用中空糸型血液浄化器に関するものである。 The present invention relates to a hollow fiber blood purifier excellent in blood compatibility. In particular, the present invention relates to a medical hollow fiber blood purifier using a hollow fiber membrane composed of a hydrophobic polymer and a hydrophilic polymer.
血液浄化などを目的とした医療用中空糸型血液浄化器に用いられる中空糸膜素材には、天然素材であるセルロース、またその誘導体であるセルロースジアセテート、セルローストリアセテート、合成高分子としてはポリスルホン、ポリメチルメタクリレート、ポリアクリロニトリルなどが広く用いられている。特に最近では合成高分子、中でもポリスルホン系のポリマーを主原料とした中空糸膜が注目されている。ポリスルホンなどの疎水性高分子は単独ではタンパクが吸着し易いなど血液適合性に問題があり、親水性高分子をブレンドし膜の親水性を向上させる方法が開発されている。親水性高分子をブレンドすることにより、膜の親水性が向上して血液中の蛋白が吸着しにくくなり、膜特性の経時的変化は少なく、分画特性に優れた膜となる。 The hollow fiber membrane material used for medical hollow fiber blood purifiers for blood purification and the like includes cellulose, which is a natural material, and cellulose diacetate, cellulose triacetate, which are derivatives thereof, polysulfone as a synthetic polymer, Polymethyl methacrylate, polyacrylonitrile and the like are widely used. In recent years, hollow fiber membranes mainly made of synthetic polymers, especially polysulfone polymers, have attracted attention. Hydrophobic polymers such as polysulfone have a problem in blood compatibility because they tend to adsorb proteins by themselves, and a method for improving hydrophilicity of the membrane by blending hydrophilic polymers has been developed. By blending the hydrophilic polymer, the hydrophilicity of the membrane is improved and it becomes difficult for proteins in the blood to be adsorbed, so that the membrane properties change little with time and the membrane has excellent fractionation properties.
ポリスルホン系の高分子を主成分とした中空糸膜の製造技術は開示されており、その分画分子量は３０００〜４００００（例えば、特許文献１参照）である。さらに分画特性に優れた膜、特に、高分子量の血液蛋白質を除去する目的で、外表面の開孔率を規定した発明がある（例えば、特許文献２参照）。血液浄化を目的とした中空糸膜において、最近では、より大きな分子量の除去対象成分をいかに効率よく除去できるかが評価され、その指標はアルブミンやβ−２ミクログロブリンなどの除去率などが用いられるが、たとえばサイトカインのようなメディエーターを用いた性能特性の規定は上記文献ではなされていない。
本発明は、主として疎水性高分子と親水性高分子とからなる中空糸膜を用いて構成した中空糸型血液浄化器において、血液適合性を向上させた中空糸型血液浄化器を得ることを課題とするものである。 The present invention relates to a hollow fiber blood purifier constructed by using a hollow fiber membrane mainly composed of a hydrophobic polymer and a hydrophilic polymer, to obtain a hollow fiber blood purifier with improved blood compatibility. It is to be an issue.
本発明は以下のものである。
（１）ポリエーテルスルホン３５〜４５質量部とポリビニルピロリドン２〜８質量部とからなる紡糸原液および内液として流動パラフィンをノズルから吐出し、１０〜５０ｍｍの空中走行部を経て５〜７０質量％のN-メチル-2-ピロリドン水溶液からなる凝固浴内に導き凝固させ、引き続き洗浄、乾燥して中空糸膜を得る際に、中空糸膜の製造に比抵抗が０．３〜２MΩcmのRO水を用い、ドラフト比を１５〜３０とし、凝固浴内で２５〜４５％の延伸を行うことによって、中空糸膜の内表面に存在するポリビニルピロリドンの割合を１０〜２８重量％、中空糸膜へのメチレンブルーの吸着率を３０％以上８０％以下、溶出物UV値を０．０２２以下とした中空糸膜を含む中空糸型血液浄化器において、
（ａ）インターロイキン６の吸着率が、血液循環試験の循環１時間後において５０％以上８５％以下である
（ｂ）補体活性化産物Ｃ３ａの変化率が、血液循環試験の循環１０分後において７０％以上１１０％以下である
（ｃ）ブラジキニンの変化率が、血液循環試験の循環３０分後において１００％以上１２０％以下である
これらのすべての性能を併せ持つことを特徴とする中空糸型血液浄化器。
（２）該中空糸膜の血液接触部である内表面は孔径の均一性が高い微細構造からなり、一方、膜表面には緻密層の形成が抑制されていることを特徴とする（１）に記載の中空糸型血液浄化器。
The present invention is as follows.
(1) Liquid paraffin is discharged from a nozzle as a spinning dope consisting of 35 to 45 parts by mass of polyethersulfone and 2 to 8 parts by mass of polyvinyl pyrrolidone and an internal solution, and passes through an aerial traveling part of 10 to 50 mm and 5 to 70% by mass. RO water with a specific resistance of 0.3 to 2 MΩcm when producing a hollow fiber membrane when it is introduced into a coagulation bath consisting of an aqueous solution of N-methyl-2-pyrrolidone and solidified, followed by washing and drying to obtain a hollow fiber membrane. And a draft ratio of 15 to 30 and stretching to 25 to 45% in the coagulation bath, the proportion of polyvinyl pyrrolidone present on the inner surface of the hollow fiber membrane is 10 to 28% by weight to the hollow fiber membrane. In a hollow fiber type blood purifier comprising a hollow fiber membrane having a methylene blue adsorption rate of 30% to 80% and an eluate UV value of 0.022 or less ,
(A) Adsorption rate of interleukin 6 is 50% or more and 85% or less after 1 hour of circulation in blood circulation test (b) Change rate of complement activation product C3a is 10 minutes after circulation in blood circulation test in at most 110% 70% (c) bradykinin rate of change, hollow fiber, characterized in that both all of these performances is not more than 120% to 100% or more in the circulation after 30 minutes circulation of blood test Blood purifier.
(2) The inner surface, which is the blood contact portion of the hollow fiber membrane, has a fine structure with a highly uniform pore size, while the formation of a dense layer is suppressed on the membrane surface (1) hollow fiber blood purifier according to.
疎水性高分子と親水性高分子とからなる中空糸を含む中空糸型血液浄化器において、サイトカインの吸着除去性能および補体活性抑制性能およびブラジキニン産生抑制性能を有する血液適合性に優れた中空糸型血液浄化器が得られる。 A hollow fiber type blood purifier comprising a hollow fiber composed of a hydrophobic polymer and a hydrophilic polymer, and having excellent blood compatibility with cytokine adsorption removal performance, complement activity inhibition performance, and bradykinin production inhibition performance A type blood purifier is obtained.
本発明の中空糸型血液浄化器に用いる中空糸膜の素材は、主として疎水性高分子と親水性高分子である。疎水性高分子には、ポリアクリロニトリル、ポリスルホン系樹脂、ポリメチルメタクリレート、ポリアミドなどが挙げられる。一般的に、ポリアクリロニトリルやポリメチルメタクリレートから作製された膜にはインターロイキンが吸着し易いことや、ポリアクリロニトリル製の膜は陰性荷電が強く、ブラジキニンが産生されやすいことが知られているが、本発明においては、物理的特性の優れたポリスルホン系樹脂が好ましい。ポリスルホン系樹脂は陰性荷電を有するため単独ではキニン産生能を発現する可能性があるが、後述する親水性高分子とブレンドしポリマーアロイ化することにより親疎水バランスを調整しやすく、また補体を活性化しやすいOH基を含まず、さらに親水性高分子との混合状態でも細孔の制御がし易いため好ましい。ポリスルホン系樹脂とは、スルホン結合を有する高分子化合物の総称であり、特に規定はしないが、化１式または化２式で示す化学構造を持つポリスルホンが入手容易なため好ましく、中でも化２式のポリエーテルスルホン（ＰＥＳ）がガラス転移温度が高く加工性に優れており好ましい。 The material of the hollow fiber membrane used in the hollow fiber blood purifier of the present invention is mainly a hydrophobic polymer and a hydrophilic polymer. Examples of the hydrophobic polymer include polyacrylonitrile, polysulfone resin, polymethyl methacrylate, and polyamide. In general, it is known that interleukin is easily adsorbed on a film made of polyacrylonitrile or polymethyl methacrylate, and that a film made of polyacrylonitrile has a strong negative charge and is likely to produce bradykinin. In the present invention, a polysulfone resin having excellent physical properties is preferable. Polysulfone resins have a negative charge and may exhibit kinin-producing ability alone. However, blending with the hydrophilic polymer described later to polymer alloy makes it easy to adjust the hydrophilic / hydrophobic balance, and complements are also available. It is preferable because it does not contain an OH group that is easily activated and is easy to control pores even in a mixed state with a hydrophilic polymer. The polysulfone-based resin is a general term for polymer compounds having a sulfone bond, and is not particularly defined. However, a polysulfone having a chemical structure represented by Chemical Formula 1 or Chemical Formula 2 is preferable because it is easily available. Polyethersulfone (PES) is preferable because of its high glass transition temperature and excellent workability.
親水性高分子にはポリビニルピロリドン、ポリビニルアルコール、ポリエチレングリコール、カルボキシメチルセルロース、デンプン、酢酸セルロースなどが使用できる。特にポリビニルピロリドン（ＰＶＰ）がポリスルホン系樹脂と相溶性が良く血液接触面の親水性−疎水性のバランスをコントロールし易く好ましい。 As the hydrophilic polymer, polyvinyl pyrrolidone, polyvinyl alcohol, polyethylene glycol, carboxymethyl cellulose, starch, cellulose acetate and the like can be used. In particular, polyvinylpyrrolidone (PVP) is preferable because it has good compatibility with the polysulfone-based resin and can easily control the hydrophilic-hydrophobic balance of the blood contact surface.
親水性高分子の重量平均分子量は、中空糸膜の孔径や、架橋反応に影響するので、その目的に応じて任意に選定しなければならないが、通常は500〜1,200,000程度のものが使用できる。親水性高分子の選択は、第一に、使用する疎水性高分子との相溶性が良いもの、第二に、製膜後の膜表面への親水性ポリマーの存在率、すなわち、膜表面へどれだけ留まる性質をもつか、簡単に溶出してしまわないかなどを検討した上で判断する。これらの検討項目は親水性高分子の分子量に依存している場合が多いが、条件が許す範囲内で、より高分子量のものを使用する方が、紡糸工程中の熱履歴による低分子量化の心配がなく好ましい。ポリエチレングリコールとしては、重量平均分子量300〜100,000程度のものが好適に使用できる。例えば、疎水性高分子がポリエーテルスルホンである場合、親水性高分子は相溶性のよいポリビニルピロリドンが好ましく、さらにその分子量については、前記したように、高分子量のものが好ましく、例えば、ＢＡＳＦ社製の分子量10,000（Ｋ−１５）から分子量1,200,000（Ｋ−９０）が好ましい。より好ましくは100,000〜1,200,000、さらに好ましくは250,000〜1,200,000である。特にポリビニルピロリドンは適切な条件下で、蛋白質との水素結合が予測され、本発明のサイトカイン吸着除去効果に有利に作用すると考えられるので好ましい。このような高分子量の親水性高分子を用いると、製膜後の親水性高分子の膜表面への固定化のコントロールが容易であり、親水性高分子の溶出を抑制することができる。本発明の中空糸膜を構成する疎水性高分子は、親水性高分子により親水化されており、特に膜表面は１５〜２８質量％程度の親水性高分子が存在するのが好ましい。 The weight-average molecular weight of the hydrophilic polymer affects the pore size of the hollow fiber membrane and the crosslinking reaction, and must be arbitrarily selected according to the purpose, but usually about 500 to 1,200,000 can be used. The selection of the hydrophilic polymer is, firstly, one having good compatibility with the hydrophobic polymer to be used, and secondly, the abundance of the hydrophilic polymer on the membrane surface after film formation, that is, to the membrane surface. Judgment will be made after considering how long it will remain and whether it will be eluted easily. These considerations often depend on the molecular weight of the hydrophilic polymer, but within the range allowed by the conditions, using a higher molecular weight will lower the molecular weight due to thermal history during the spinning process. There is no worry. As the polyethylene glycol, those having a weight average molecular weight of about 300 to 100,000 can be suitably used. For example, when the hydrophobic polymer is polyethersulfone, the hydrophilic polymer is preferably compatible polyvinyl pyrrolidone, and the molecular weight is preferably a high molecular weight as described above. For example, BASF The molecular weight is preferably 10,000 (K-15) to 1,200,000 (K-90). More preferably, it is 100,000-1,200,000, More preferably, it is 250,000-1,200,000. In particular, polyvinylpyrrolidone is preferable because hydrogen bonding with a protein is predicted under appropriate conditions, and it is considered that it advantageously acts on the cytokine adsorption removal effect of the present invention. When such a high molecular weight hydrophilic polymer is used, it is easy to control the immobilization of the hydrophilic polymer on the membrane surface after film formation, and the elution of the hydrophilic polymer can be suppressed. The hydrophobic polymer constituting the hollow fiber membrane of the present invention is hydrophilized with a hydrophilic polymer, and it is particularly preferred that the membrane surface has a hydrophilic polymer of about 15 to 28% by mass.
本発明における中空糸膜としては、内径が100〜300μm、膜厚が10〜70μmであることが好ましい。内径が100〜300μmであれば、通常の血液透析での血液流量100〜300mL/minにおいて血液剪断速度が適切であり、タンパク吸着や血液に与えるダメージを最小限に抑えることができるため好ましい。より好ましい内径は130〜280μm、さらに好ましくは150〜250μmである。また、膜厚が薄すぎると血液処理に必要な耐圧性が損なわれる可能性がある。また膜厚が厚すぎると溶質透過性が低下することがある。したがって、膜厚は12〜60μmがより好ましく、13〜50μmがさらに好ましい。 The hollow fiber membrane in the present invention preferably has an inner diameter of 100 to 300 μm and a film thickness of 10 to 70 μm. An inner diameter of 100 to 300 μm is preferable because the blood shear rate is appropriate at a blood flow rate of 100 to 300 mL / min in normal hemodialysis, and protein adsorption and damage to blood can be minimized. The inner diameter is more preferably 130 to 280 μm, still more preferably 150 to 250 μm. If the film thickness is too thin, the pressure resistance required for blood treatment may be impaired. If the film thickness is too thick, the solute permeability may decrease. Therefore, the film thickness is more preferably 12 to 60 μm, and further preferably 13 to 50 μm.
サイトカインには炎症反応に関係したものがあり、これらは透析療法を受けることで増加し患者への悪影響（炎症、発熱など）が予測されるため、血液中から除去することが望まれる物質である。特に透析と関係するサイトカインとしては、インターロイキン1、2、6、TNF（腫瘍壊死因子）が挙げられる。サイトカイン吸着性能は、血液を用いた循環試験にて炎症性サイトカインであるＩＬ−６の量について、循環前後の割合で評価する。具体的には循環１時間後の吸着率が５０％以上１００％以下であるのが好ましい。さらには６０％以上が好ましい。サイトカインは透析療法中でも、膜の種類によっては産生されるものである。よってin vitroでの循環試験で吸着率５０％以上である場合には、吸着除去率が産生量を上まわり、血液中のＩＬ−６量が増加しないため好ましい。in vitroでの循環試験では、試験血液中でのサイトカインの濃度は増加しない、また、炎症性サイトカインＩＬ−６は全てを除去しても生体に影響ないものであるため、全てのサイトカインを吸着できた場合には吸着率１００％となる。
本発明において、サイトカインを効率よく膜に吸着させるための手段としては、中空糸膜の血液接触面である内表面の親水性高分子と疎水性高分子のバランスをコントロールすることである。親水性と疎水性のバランスは、紡糸原液中の親水性高分子と疎水性高分子の割合、また、紡糸工程では、ドープを二重紡糸口金の外側から、内液を二重紡糸口金の内側から吐出する際の、エアーギャップ長、そして凝固条件（組成、濃度、温度）でコントロールするのが好ましい。
例えば、疎水性高分子がＰＥＳ、親水性高分子がＰＶＰの場合、ドープの各々の組成は、ＰＥＳが３０質量部から５０質量部の範囲、ＰＶＰが１質量部から１０質量部の範囲、溶媒はＮ−メチル−２−ピロリドン（ＮＭＰ）、非溶媒にトリエチレングリコール（ＴＥＧ）とし、それぞれを混合し加熱して均一状態とする。PESとPVPを前記範囲にすることが、中空糸膜内表面の親疎水バランスを適正化する第一のポイントとなる。ＰＥＳのより好ましい範囲は３３〜４８質量部、さらに好ましい範囲は３５〜４５質量部である。ＰＶＰのより好ましい範囲は２〜９質量部、さらに好ましい範囲は２〜８質量部である。疎水性高分子に対して親水性高分子が多すぎると、製膜後の洗浄においても過剰の親水性高分子を洗い落とすことが困難となることがある。また、親水性高分子の添加量が少なすぎると疎水性の強い膜になり、サイトカインの吸着量を増大することはできるが、他の有用なタンパクの吸着が多くなったり、吸着タンパクの影響により溶質透過性が低下することがある。したがって、紡糸原液中の疎水性高分子に対する親水性高分子の質量割合は、４〜２７質量％が好ましい。４〜２３質量％がより好ましい。この範囲であれば、中空糸膜の親疎水バランスをコントロールしやすいため好ましい。
エアーギャップ長は１０〜５０ｍｍが好ましく、１５〜４５ｍｍがより好ましい。エアギャップ長が長すぎると、糸切れ、糸揺れに融着が発生しやすくなり紡糸安定性が低下することがある。また、エアギャップ長が短すぎると、相分離の進行が不十分になるため均一な細孔径が得られなくなることがある。またドラフト比は１０〜５０が好ましい。より好ましくは１５〜４５、さらに好ましくは２０〜４０である。ドラフト比が１０より小さいと孔径の制御が難しくなったり、またドラフト比が５０以上になると糸切れが発生しやすく紡糸安定性が低下することがある。凝固浴での凝固反応の前のエアギャップ部分での凝固や物理的強度の負荷は、膜の孔形状に大きく影響を及ぼすので過度に負荷をかけない上記範囲の条件が望ましい。凝固浴の組成は５〜７０質量％のＮＭＰ水溶液が好ましい。７〜６５質量％がより好ましい。また、凝固浴中で、１〜８０％の延伸を行うことが好ましい。２〜６０％の延伸を行うことがより好ましい。３〜５０％がさらに好ましい。ここで言う延伸とは、第二凝固浴入口ローラー速度と第二凝固浴出口ローラー速度との比である。延伸は一般に細孔形状の変形や配向をもたらす。極端な延伸は細孔の変形、つぶれ、過度の配向につながり、このような内表面を持つ中空糸膜は血液と接触した際に血小板粘着および血中蛋白の吸着、積層化により、膜性能が経時的に低下することがある。一方、ＰＥＳのような結晶化しにくいポリマーを非凝固性の内液を用いて紡糸する場合は、凝固反応がゆるやかであり、凝固浴中における延伸効果はマイルドである。したがって、このような条件の延伸工程を経た中空糸膜は膜のスポンジ構造の変形が微視的であり、また血液接触部である内表面の状態は、細孔形状の変形が大きくなりすぎず、孔の分布が均一な状態となる。このような凝固条件を使用することで膜表面の緻密化が抑制され、余剰の親水性高分子が洗い流され易くなり、使用時の溶出物量を低減できる。また、凝固液の温度は室温以下であることが好ましい。具体的には０〜３０℃、さらに好ましくは５〜２５℃である。この条件にすることにより膜表面の緻密化を抑制できるので好ましい。
また、紡糸工程で親水性、疎水性バランスをある程度整えた後、洗浄工程で中空糸膜の親水性、疎水性バランスを最適化するのが好ましい。さらに、乾燥条件を適正化することにより中空糸膜中の親水性高分子を固定化することが好ましい。洗浄工程では、凝固工程で固定化しきれなかった過剰の親水性高分子を洗い落とすとともに、膜表面に存在する親水性高分子の表面への局在化と膨潤を促す。一方、乾燥工程では、疎水性高分子と親水性高分子の物理的な相互作用、すなわち疎水性高分子鎖と親水性高分子鎖の絡み合いの程度を強くし、親疎水バランスを整えることができる。
洗浄方法としては、凝固浴から引き上げた中空糸膜を、ＲＯ水からなる水洗槽に導き３０℃以上で６０秒以上かけて通過させるのが好ましい。温度が低すぎると、過剰の親水性高分子を洗浄しきれず、水洗槽を長くしたり、紡糸速度を遅くしたりする必要があるなどコストアップに繋がることがある。また、温度が高すぎると水が沸騰してしまい中空糸膜が安定して走行しなくなることがある。水洗槽の温度は９０℃以下が好ましい。
また、乾燥時に絶乾しないことが好ましい。具体的には、疎水性高分子の平衡水分率以上の含水率で乾燥を止めることが好ましい。例えば、ポリエーテルスルホンでは２．１質量％以上の含水率であることが好ましい。含水率が2.1質量％以上であれば、前述したように、疎水性高分子と親水性高分子の絡み合いの程度が適切となり血液浄化使用時の親水性高分子の溶出が少なくなるため好ましい。含水率が多すぎると、中空糸膜保存中に雑菌が増殖したりすることがあるので、含水率は１５質量％以下が好ましい。より好ましくは１２質量％以下である。さらに好ましくは１０質量％以下である。乾燥温度は５０℃〜１００℃が好ましく、さらには６０℃〜９０℃が好ましい。乾燥温度が高すぎると親水性高分子が熱劣化・分解し、溶出物量が増える可能性がある。また乾燥温度が低すぎると、乾燥時間が延びるため中空糸膜の製造コストが上がることがある。また、過乾燥防止対策として、後述するようなグリセリン水溶液に浸漬してもよい。
サイトカインを効率よく膜に吸着させるための第二の手段としては、孔の均一性、整列性の適正化が挙げられる。本発明のサイトカインの血液浄化器への吸着機構は明らかではないが、以下のように考えられる。本発明の血液浄化器の中空糸膜は膜内表面が孔径の均一性が高い微細構造からなるのが特徴である。すなわち、膜内表面には多数の孔が存在する。一方で、サイトカイン、例えば、ＩＬ−６は分子量約２６，０００のアミノ酸からなる糖蛋白質である。この糖蛋白質は、マクロに解釈して、血液中では親水性基を外側に向けた球状構造をとっていると予測され、その球のサイズは常に一定であると考えられる。本発明の血液浄化器の中空糸内面に存在する孔は一定のサイズであることが特徴であり、ここに、ＩＬ−６がフィットすると考えられる。膜表面に存在する孔内の表面にも親水性高分子は適度なバランスで保持されており、そこに存在する親水性高分子とＩＬ−６が相互作用して膜内表面および膜内部の孔に吸着すると考えられる。ここで、親水性高分子がポリビニルピロリドンである場合には、糖蛋白質と水素結合することができるので、より強固な結合となる。膜内表面の孔の均一性、整列性を達成する手段としては、上記したようにエアギャップ長を最適化すること、および凝固条件と延伸条件の組合せの最適化が効果的である。詳細な理由は不明だが、エアギャップ長を前記範囲に設定することで相分離における核を多数発生させ、つぎに前記範囲に設定された凝固浴中で適正な延伸をかけることにより発生した核がバラツキ無く成長し、結果として均一な径の細孔が整列した状態となりやすくなるものと考える。
Some cytokines are related to inflammatory reactions, and these are substances that should be removed from the blood because they are expected to increase after receiving dialysis therapy and adversely affect patients (inflammation, fever, etc.) . In particular, cytokines related to dialysis include interleukins 1, 2, 6, and TNF (tumor necrosis factor). Cytokine adsorption performance is evaluated by the ratio before and after circulation for the amount of IL-6, which is an inflammatory cytokine, in a circulation test using blood. Specifically, the adsorption rate after 1 hour of circulation is preferably 50% or more and 100% or less. Furthermore, 60% or more is preferable. Cytokines are produced during dialysis therapy, depending on the type of membrane. Therefore, when the adsorption rate is 50% or more in an in vitro circulation test, the adsorption removal rate exceeds the production amount, and the amount of IL-6 in the blood does not increase, which is preferable. In an in vitro circulation test, the cytokine concentration in the test blood does not increase, and even if all of the inflammatory cytokine IL-6 is removed, it does not affect the living body, so that all cytokines can be adsorbed. In this case, the adsorption rate is 100%.
In the present invention, a means for efficiently adsorbing the cytokine to the membrane is to control the balance between the hydrophilic polymer and the hydrophobic polymer on the inner surface which is the blood contact surface of the hollow fiber membrane. The balance between hydrophilicity and hydrophobicity is the ratio of hydrophilic polymer to hydrophobic polymer in the spinning dope, and in the spinning process, the dope is from the outside of the double spinneret and the inner solution is inside of the double spinneret. It is preferable to control by the air gap length and the coagulation conditions (composition, concentration, temperature) at the time of discharging from the air.
For example, when the hydrophobic polymer is PES and the hydrophilic polymer is PVP, the composition of each dope is such that PES is in the range of 30 to 50 parts by mass, PVP is in the range of 1 to 10 parts by mass, solvent Is N-methyl-2-pyrrolidone (NMP), triethylene glycol (TEG) is used as a non-solvent, and each is mixed and heated to a uniform state. Setting PES and PVP in the above ranges is the first point for optimizing the hydrophilic / hydrophobic balance on the inner surface of the hollow fiber membrane. A more preferable range of PES is 33 to 48 parts by mass, and a more preferable range is 35 to 45 parts by mass. A more preferable range of PVP is 2 to 9 parts by mass, and a more preferable range is 2 to 8 parts by mass. If there are too many hydrophilic polymers relative to the hydrophobic polymer, it may be difficult to wash off excess hydrophilic polymer even after washing after film formation. In addition, if the amount of hydrophilic polymer added is too small, a strong hydrophobic membrane can be formed and the amount of cytokine adsorbed can be increased, but the adsorption of other useful proteins increases or the effect of adsorbed proteins. Solute permeability may be reduced. Therefore, the mass ratio of the hydrophilic polymer to the hydrophobic polymer in the spinning dope is preferably 4 to 27% by mass. 4-23 mass% is more preferable. If it is this range, since it is easy to control the hydrophilic-hydrophobic balance of a hollow fiber membrane, it is preferable.
The air gap length is preferably 10 to 50 mm, more preferably 15 to 45 mm. If the air gap length is too long, fusion is likely to occur in yarn breakage and yarn swinging, and spinning stability may be lowered. On the other hand, if the air gap length is too short, the progress of phase separation becomes insufficient, and a uniform pore diameter may not be obtained. The draft ratio is preferably 10-50. More preferably, it is 15-45, More preferably, it is 20-40. If the draft ratio is less than 10, it is difficult to control the hole diameter, and if the draft ratio is 50 or more, yarn breakage is likely to occur and the spinning stability may be lowered. The coagulation and physical strength load at the air gap before the coagulation reaction in the coagulation bath greatly affects the pore shape of the membrane. The composition of the coagulation bath is preferably a 5 to 70% by mass NMP aqueous solution. 7-65 mass% is more preferable. Moreover, it is preferable to extend | stretch 1 to 80% in a coagulation bath. It is more preferable to perform 2 to 60% stretching. 3 to 50% is more preferable. The term “stretching” as used herein refers to the ratio between the second coagulation bath inlet roller speed and the second coagulation bath outlet roller speed. Stretching generally causes pore shape deformation and orientation. Extreme stretching leads to deformation, crushing, and excessive orientation of the pores, and hollow fiber membranes with such an inner surface have improved membrane performance due to platelet adhesion and blood protein adsorption and lamination when in contact with blood. May decrease over time. On the other hand, when spinning a polymer that is difficult to crystallize, such as PES, using a non-coagulable internal solution, the coagulation reaction is gentle and the stretching effect in the coagulation bath is mild. Therefore, the hollow fiber membrane that has undergone the stretching process under such conditions has microscopic deformation of the sponge structure of the membrane, and the state of the inner surface, which is the blood contact portion, does not cause excessive deformation of the pore shape. The pore distribution is uniform. By using such coagulation conditions, densification of the film surface is suppressed, excess hydrophilic polymer is easily washed away, and the amount of eluate during use can be reduced. Moreover, it is preferable that the temperature of coagulation liquid is below room temperature. Specifically, it is 0-30 degreeC, More preferably, it is 5-25 degreeC. This condition is preferable because densification of the film surface can be suppressed.
Further, it is preferable to optimize the hydrophilicity / hydrophobicity balance of the hollow fiber membrane in the washing step after adjusting the hydrophilicity / hydrophobicity balance to some extent in the spinning step. Furthermore, it is preferable to fix the hydrophilic polymer in the hollow fiber membrane by optimizing the drying conditions. In the washing step, excess hydrophilic polymer that could not be fixed in the coagulation step is washed off, and the hydrophilic polymer existing on the membrane surface is localized and swelled. On the other hand, in the drying process, the physical interaction between the hydrophobic polymer and the hydrophilic polymer, that is, the degree of entanglement between the hydrophobic polymer chain and the hydrophilic polymer chain can be strengthened, and the hydrophilic / hydrophobic balance can be adjusted. .
As a washing method, it is preferable that the hollow fiber membrane pulled up from the coagulation bath is guided to a water washing tank made of RO water and passed at 30 ° C. or more over 60 seconds or more. If the temperature is too low, excess hydrophilic polymer cannot be washed out, which may lead to an increase in cost, for example, it is necessary to lengthen the washing tank or slow down the spinning speed. If the temperature is too high, water may boil and the hollow fiber membrane may not run stably. The temperature of the washing tank is preferably 90 ° C. or lower.
Moreover, it is preferable not to dry completely at the time of drying. Specifically, it is preferable to stop drying at a moisture content equal to or higher than the equilibrium moisture content of the hydrophobic polymer. For example, in the case of polyethersulfone, the water content is preferably 2.1% by mass or more. A water content of 2.1% by mass or more is preferable because, as described above, the degree of entanglement between the hydrophobic polymer and the hydrophilic polymer is appropriate, and the elution of the hydrophilic polymer during blood purification is reduced. If the water content is too high, miscellaneous bacteria may grow during storage of the hollow fiber membrane, so the water content is preferably 15% by mass or less. More preferably, it is 12 mass% or less. More preferably, it is 10 mass% or less. The drying temperature is preferably 50 ° C to 100 ° C, more preferably 60 ° C to 90 ° C. If the drying temperature is too high, the hydrophilic polymer may be thermally deteriorated and decomposed, resulting in an increase in the amount of eluate. On the other hand, if the drying temperature is too low, the drying time may be extended, which may increase the manufacturing cost of the hollow fiber membrane. Moreover, you may immerse in the glycerol aqueous solution which is mentioned later as a measure against overdrying.
As a second means for efficiently adsorbing cytokine to the membrane, pore uniformity and alignment are optimized. Although the mechanism of adsorption of the cytokine of the present invention to the blood purifier is not clear, it is considered as follows. The hollow fiber membrane of the blood purifier of the present invention is characterized in that the inner surface of the membrane has a fine structure with high uniformity of pore diameter. That is, a large number of pores exist on the inner surface of the film. On the other hand, cytokines such as IL-6 are glycoproteins composed of amino acids having a molecular weight of about 26,000. This glycoprotein is interpreted macroscopically and is predicted to have a spherical structure with the hydrophilic group facing outward in blood, and the size of the sphere is considered to be always constant. The hole existing in the inner surface of the hollow fiber of the blood purifier of the present invention is characterized by a certain size, and it is considered that IL-6 fits therein. The hydrophilic polymer is also maintained in an appropriate balance on the surface in the pores existing on the membrane surface, and the hydrophilic polymer and IL-6 existing there interact with each other so that the pores inside the membrane and inside the membrane It is thought to be adsorbed on Here, when the hydrophilic polymer is polyvinylpyrrolidone, it can be hydrogen-bonded to the glycoprotein, so that the bond is stronger. As means for achieving the uniformity and alignment of the pores on the inner surface of the membrane, it is effective to optimize the air gap length as described above and to optimize the combination of solidification conditions and stretching conditions. Although the detailed reason is unknown, a large number of nuclei in phase separation are generated by setting the air gap length in the above range, and then the nuclei generated by applying appropriate stretching in the coagulation bath set in the above range It is thought that it grows without variation, and as a result, pores with uniform diameters are easily aligned.
補体は親水性高分子と接触することで活性化されるといわれている。補体活性化により一過性の白血球減少や低酸素血症をきたす。疎水性高分子と親水性高分子をブレンドした血液浄化膜においても、血液と接触する親水性高分子の割合で補体活性化がみられることがある。このようなブレンド膜においては、補体活性化を抑制させるために、血液接触面の親水性高分子の量をコントロールすることや親水性高分子の溶出量を抑制することが重要である。補体活性化の指標は、血液を用いた循環試験にて、補体活性化産物Ｃ３ａの量を測定し、循環前後の割合で評価する。具体的には循環初期を１００％とした場合、循環１０分後のＣ３ａ値が７０％以上１２０％以下であるのが好ましく、さらには１１０％以下が好ましい。１２０％以上の値を示す場合は、測定値の誤差範囲を考慮しても有意に上昇したと解釈でき、値が上昇することはすなわち血液浄化膜により免疫系が活性化したことを意味する。補体活性化産物Ｃ３ａ値は循環試験中に減少しないものであり、測定誤差を考慮しても７０％以下である場合には、適切な評価が行われていない可能性がある。
補体活性を抑制する最も有効な方法は、補体活性を抑制するといわれている水酸基を持つ素材を使用しないことである。その他、有効であると思われる方法して、免疫系を活性化させないために、膜からの溶出物量を減らすことである。膜からの溶出物量を抑制する手段としては、先に記したような分子量範囲の親水性高分子を使用することや、膜表面の緻密層形成の抑制がある。特定の分子量の親水性高分子を使用することは、ポリマーの分解によるオリゴマー溶出の問題を軽減させるし、膜表面の緻密層形成が抑制されていることは、製膜後の洗浄効率が良いということである。
Complement is said to be activated by contact with a hydrophilic polymer. Complement activation causes transient leukopenia and hypoxemia. Even in a blood purification membrane in which a hydrophobic polymer and a hydrophilic polymer are blended, complement activation may be observed at a ratio of the hydrophilic polymer in contact with blood. In such a blend membrane, in order to suppress complement activation, it is important to control the amount of the hydrophilic polymer on the blood contact surface and to suppress the elution amount of the hydrophilic polymer. As an indicator of complement activation, the amount of complement activation product C3a is measured in a circulation test using blood, and evaluated by the ratio before and after the circulation. Specifically, assuming that the initial stage of circulation is 100%, the C3a value after 10 minutes of circulation is preferably 70% or more and 120% or less, and more preferably 110% or less. When a value of 120% or more is indicated, it can be interpreted that the value has increased significantly even when the error range of the measurement value is taken into account, and an increase in value means that the immune system has been activated by the blood purification membrane. Complement activation product C3a value does not decrease during the circulation test, and if it is 70% or less even if measurement error is taken into consideration, there is a possibility that appropriate evaluation has not been performed.
The most effective method of suppressing complement activity is not to use a material having a hydroxyl group that is said to suppress complement activity. Another method that seems to be effective is to reduce the amount of eluate from the membrane so as not to activate the immune system. Means for suppressing the amount of eluate from the membrane include the use of a hydrophilic polymer having a molecular weight range as described above, and suppression of the formation of a dense layer on the membrane surface. The use of a hydrophilic polymer having a specific molecular weight reduces the problem of oligomer elution due to polymer degradation, and the fact that the formation of a dense layer on the film surface is suppressed means that the cleaning efficiency after film formation is good. That is.
ブラジキニンは陰性荷電を持つ血液透析膜にて血液透析した際に産生される。血液透析膜の陰性荷電の定量は一般にはゼータ電位を測定することで評価する。例えば、ポリアクリロニトリルでは−１００ｍＶであり、またポリスルホンでは−２０ｍＶである。本発明の中空糸型血液浄化器に用いる疎水性高分子は単体では陰性荷電を示すものであり、単体で膜に加工した場合には、血液と接触した際の血液への影響は無視できなくなる。 Bradykinin is produced when hemodialysis is performed on a hemodialysis membrane having a negative charge. Quantification of the negative charge of the hemodialysis membrane is generally evaluated by measuring the zeta potential. For example, it is −100 mV for polyacrylonitrile and −20 mV for polysulfone. The hydrophobic polymer used in the hollow fiber blood purifier of the present invention is negatively charged as a single substance, and when processed into a membrane as a single substance, the effect on blood when contacted with blood cannot be ignored. .
メチレンブルーはプラスの荷電を持つ染料で、例えばマイナス荷電を持つ中空糸膜に、水溶液を循環させた場合、イオン結合により染料が膜に吸着するので、膜のマイナス荷電を評価するのに用いることができる。血液浄化器に用いる中空糸膜は、生体適合性や薬剤の吸着などの観点から、極端に荷電を持つことは望ましくない。そのため、メチレンブルーの吸着率は３０％以上８０％以下が好ましい。３０％以下である場合は、陽性荷電を持つ傾向にあり抗凝血剤であるヘパリンを吸着することがある。また８０％以上である場合は陰性荷電が強く抗凝血剤であるメシル酸ナファモスタットを吸着することがある。 Methylene blue is a positively charged dye. For example, when an aqueous solution is circulated through a negatively charged hollow fiber membrane, the dye is adsorbed on the membrane by ionic bonding, so it can be used to evaluate the negative charge of the membrane. it can. It is not desirable that the hollow fiber membrane used for the blood purifier is extremely charged from the viewpoint of biocompatibility and drug adsorption. Therefore, the methylene blue adsorption rate is preferably 30% or more and 80% or less. If it is 30% or less, heparin that tends to have a positive charge and an anticoagulant may be adsorbed. On the other hand, if it is 80% or more, nafamostat mesylate, which has a strong negative charge and is an anticoagulant, may be adsorbed.
本発明の中空糸型血液浄化器に用いる中空糸膜は疎水性高分子と親水性高分子をブレンドすることが特徴であり、さらに、親水性高分子を血液接触面に一定濃度局在化させることが特徴であり、疎水性高分子の荷電の影響を少なくできる。ブラジキニン産生量は、血液を用いた循環試験にて、ブラジキニンの濃度を測定し、循環前後の割合で評価する。具体的には循環初期を１００％とした場合、循環３０分後のブラジキニン値が７０％以上、１２０％以下であるのが好ましく、１１５％以下がより好ましく、１１０％以下がさらに好ましい。１２０％以上の値を示す場合は、測定値の誤差範囲を考慮しても有意に上昇したと解釈でき、血液浄化膜によりブラジキニンの産生反応が起こったことを意味する。ブラジキニンは循環試験中に減少しないものであり、測定誤差を考慮しても７０％以下である場合には、適切な評価が行われていない可能性がある。 The hollow fiber membrane used in the hollow fiber blood purifier of the present invention is characterized by blending a hydrophobic polymer and a hydrophilic polymer, and further localizes the hydrophilic polymer at a constant concentration on the blood contact surface. It is characteristic that the influence of the charge of the hydrophobic polymer can be reduced. The amount of bradykinin production is evaluated by measuring the concentration of bradykinin in a circulation test using blood and the ratio before and after circulation. Specifically, assuming that the initial stage of circulation is 100%, the bradykinin value after 30 minutes of circulation is preferably 70% or more and 120% or less, more preferably 115% or less, and even more preferably 110% or less. When a value of 120% or more is indicated, it can be interpreted that it has increased significantly even when the error range of the measurement value is taken into account, and means that a production reaction of bradykinin has occurred by the blood purification membrane. Bradykinin does not decrease during the circulation test, and if the measurement error is 70% or less even when considering the measurement error, there is a possibility that appropriate evaluation has not been performed.
ブラジキニン産生を抑制するための、陰性荷電除去対策としては、紡糸工程全てにおいてＲＯ水を用いることが効果的である。例えば、中空糸膜の洗浄工程において、ＲＯ水を使用することで、膜に付着している帯電性物質を効率よく除去することができるし、膜そのものの荷電を弱めることができる。当然のことながら、ＲＯ水にはイオン性物質は含有されていないので、イオンが膜に吸着することもない。使用するＲＯ水は比抵抗が０．３〜２ＭΩｃｍのものが好ましく、さらには０．４〜１．９ＭΩｃｍのものが好ましい。 As a negative charge removal measure for suppressing bradykinin production, it is effective to use RO water in all spinning processes. For example, by using RO water in the washing process of the hollow fiber membrane, the chargeable substance adhering to the membrane can be efficiently removed, and the charge of the membrane itself can be weakened. As a matter of course, since ionic substances are not contained in the RO water, ions are not adsorbed on the membrane. The RO water used preferably has a specific resistance of 0.3 to 2 MΩcm, more preferably 0.4 to 1.9 MΩcm.
膜表面の荷電を除去する第二の手段としては、静電気を抑えることである。静電気は主に乾燥や摩擦により発生する。中空糸膜の乾燥を防ぐ方法として、前記したように、乾燥工程で絶乾しないことやグリセリン処理をすることが挙げられる。グリセリン処理に用いるグリセリン水溶液の濃度は１５〜７０質量％が好ましく、さらには２０〜６０質量％が好ましい。また、別の手段として、乾燥時のエアーを除電することが有効である。除電処理はプラスとマイナスを発生する除電機器を用いて、膜の帯電量に応じた中空糸膜の耐電極性とは反対極性のイオンを与えることによって膜の静電気を中和することによって行われる。帯電量に応じた反対極性のイオンを供給する方法としては、Ion Current Control方式を取り入れた除電機器を用いた方法を用いて中空糸膜を直接除電することができる。Ion Current Control方式とは、帯電物と除電機器のアース電極との電位差によって生じるイオン電流をセンシングすることで、帯電物の帯電状況を把握し、その帯電量に応じた反対極性のイオンを供給するように、プラス、マイナスそれぞれの電極針に高電圧をかける時間（パルス幅）を制御するものである。 The second means for removing the charge on the film surface is to suppress static electricity. Static electricity is mainly generated by drying and friction. As described above, as a method for preventing the hollow fiber membrane from being dried, it is possible to prevent the hollow fiber membrane from being completely dried in the drying step or to perform glycerin treatment. The concentration of the glycerin aqueous solution used for the glycerin treatment is preferably 15 to 70% by mass, and more preferably 20 to 60% by mass. As another means, it is effective to neutralize the air during drying. The neutralization treatment is performed by neutralizing the static electricity of the membrane by using a static elimination device that generates plus and minus and giving ions of the opposite polarity to the electrode resistance of the hollow fiber membrane according to the charge amount of the membrane. . As a method of supplying ions of opposite polarity according to the amount of charge, the hollow fiber membrane can be directly discharged by using a method using a discharging device incorporating the Ion Current Control method. The Ion Current Control method senses the ionic current generated by the potential difference between the charged object and the ground electrode of the static eliminator, and grasps the charged state of the charged object, and supplies ions of the opposite polarity according to the charge amount. Thus, the time (pulse width) for applying a high voltage to the positive and negative electrode needles is controlled.
さらに摩擦を防ぐ方法として、紡糸機のローラーやガイドの素材を適正化することも効果的である。ローラーやガイドの素材としては、テフロン（Ｒ）、ベークライト、ステンレス、プラスチックなどがあるが、中空糸膜との摩擦を最小限にするステンレスが適している。またそれらの形状は中空糸との摩擦を最小限にするために、接触部が滑らかな曲線になっていることが好ましい。また、アースをつけることも好ましい。 Furthermore, as a method for preventing friction, it is also effective to optimize the materials of the rollers and guides of the spinning machine. As materials for rollers and guides, there are Teflon (R), bakelite, stainless steel, plastic, and the like. Stainless steel that minimizes friction with the hollow fiber membrane is suitable. Further, in order to minimize the friction with the hollow fiber, it is preferable that the contact portion has a smooth curve. It is also preferable to attach a ground.
また、膜表面の親水性高分子と疎水性高分子とのバランスもブラジキニンの産生に影響する。親水性高分子と疎水性高分子とのバランスを調製する手段は前記した通りであるが、ブラジキニンの産生については、膜表面に存在する親水性高分子量を限定することが好ましい。中空糸膜の内表面に存在する親水性高分子の割合を１０質量％以上２８質量％以下、さらには１５質量％以上２７質量％以下にすることが好ましい。１０質量％未満では親水性に乏しく蛋白や血小板の吸着、粘着が顕著であるとともに、疎水性高分子の影響を受けてブラジキニンの産生が加速されることがある。また２８質量％以上では、中空糸膜からの親水性高分子の溶出抑制のコントロールが困難である上に、膜表面の親水性が強すぎて補体の活性化が著しくなることがある。内表面近傍の親水性高分子の存在比をこのように１０質量％以上２８質量％以下の存在比にコントロールすることで、血液浄化膜として適切な性能を発揮できるとともに、ブラジキニンの産生を抑制できる。 The balance between the hydrophilic polymer and the hydrophobic polymer on the membrane surface also affects the production of bradykinin. The means for adjusting the balance between the hydrophilic polymer and the hydrophobic polymer is as described above, but for the production of bradykinin, it is preferable to limit the amount of hydrophilic polymer present on the membrane surface. The ratio of the hydrophilic polymer present on the inner surface of the hollow fiber membrane is preferably 10% by mass to 28% by mass, more preferably 15% by mass to 27% by mass. If it is less than 10% by mass, hydrophilicity is poor and protein and platelet adsorption and adhesion are remarkable, and the production of bradykinin may be accelerated by the influence of the hydrophobic polymer. If it is 28% by mass or more, it is difficult to control the elution suppression of the hydrophilic polymer from the hollow fiber membrane, and the hydrophilicity of the membrane surface is too strong, and the activation of complement may be remarkable. By controlling the abundance ratio of the hydrophilic polymer in the vicinity of the inner surface to an abundance ratio of 10% by mass or more and 28% by mass or less in this way, it is possible to exhibit appropriate performance as a blood purification membrane and to suppress the production of bradykinin. .
本発明の中空糸膜を製造する典型的な方法の一つは、後述する実施例などにおいてみるとおり、疎水性高分子と親水性高分子、共通溶媒、非溶媒などからなる紡糸原液を、ノズルから内液とともに吐出し空中走行部を経て凝固浴内に導き、凝固浴内で高倍率の延伸を掛けながら中空糸膜を凝固させる手法により入手することができるものである。この延伸速度、延伸倍率を適度に制御しないと、延伸方向に配向することによるフィブリル化のような、いわゆる孔が繊維方向につぶれるという現象が発生する。孔のつぶれは、血中ダンパク質のリークや、タンパク質の過剰吸着の原因になることがある。本発明ではこのような障害を克服している。 One of the typical methods for producing the hollow fiber membrane of the present invention is that, as seen in Examples described later, a spinning stock solution composed of a hydrophobic polymer and a hydrophilic polymer, a common solvent, a non-solvent, etc. It can be obtained by a method in which it is discharged together with the internal liquid, led into the coagulation bath through the aerial traveling section, and the hollow fiber membrane is coagulated while being stretched at a high magnification in the coagulation bath. If the stretching speed and the stretching ratio are not controlled appropriately, a phenomenon that so-called pores collapse in the fiber direction, such as fibrillation by orientation in the stretching direction, occurs. The crushing of pores may cause blood protein leaks and excessive protein adsorption. The present invention overcomes such obstacles.
本発明の内表面の細孔形状が均一が高い微細構造であるということは、スポンジ構造の変形がないということであり、このような変形を防止する為に、延伸倍率、延伸速度などの延伸条件を微妙に制御することにより達成できる。さらに、孔径の均一性が高いということは、孔径のばらつきが少なく、ボイドのような孔も少ないということである。そして、本発明の中空糸膜の孔は不均一に形成されているわけではなく、多くの孔が整然と整列されたように配置されているということである。 The fact that the pore shape of the inner surface of the present invention is a highly uniform microstructure means that there is no deformation of the sponge structure, and in order to prevent such deformation, stretching such as stretching ratio, stretching speed, etc. This can be achieved by finely controlling the conditions. Furthermore, the high uniformity of the hole diameter means that there is little variation in the hole diameter and there are few holes such as voids. And the hole of the hollow fiber membrane of this invention is not necessarily formed unevenly, but it is arrange | positioning so that many holes may be arranged orderly.
このような構造の中空糸膜を製造する場合に、疎水性高分子、親水性高分子の種類、紡糸原液の仕様、凝固条件などの違いが構造にも微妙に影響するが、本発明は、従来公知の凝固条件からは予想できない、制御された製造条件と工程、特に中空糸膜の凝固速度にあわせて延伸を付与することによって達成できたものである。 When producing a hollow fiber membrane having such a structure, the difference in hydrophobic polymer, type of hydrophilic polymer, specifications of the spinning stock solution, coagulation conditions, etc., subtly affects the structure. This can be achieved by controlling the production conditions and processes, which cannot be predicted from conventionally known coagulation conditions, particularly by applying stretching in accordance with the coagulation rate of the hollow fiber membrane.
以下、本発明の有効性を実施例を挙げて説明するが、本発明はこれらに限定されるものではない。
（溶出物（ＵＶ値）の測定）
中空糸膜１．０ｇを水１００ｍｌに浸漬し７０℃水浴中１時間加温し試験液を調整する。試験液の吸光度を波長２２０〜３５０ｎｍの範囲で測定する。なお人工腎臓装置承認基準では、本条件での規格を０．１以下としている。
（中空糸膜内表面の親水性高分子量の測定）
中空糸膜を両面テープの上に並べた後、カッターで繊維軸方向に切開し、中空糸膜の内側が表になるように押し広げたものを試料とし、Ｘ線光電子分光（ＥＳＣＡ）光電子脱出角度４５度にて測定する。ポリビニルピロリドンの場合、Ｃ１ｓ、Ｏ１ｓ、Ｎ１ｓ、Ｓ２ｐスペクトルの面積強度より、装置付属の相対感度係数を用いて窒素の表面濃度（Ｎ）と硫黄の表面濃度（Ｓ）を求め、
表面ＰＶＰ濃度＝Ｎ×１００／（Ｎ×１１１＋Ｓ×４４２）
より表面ＰＶＰ濃度を算出する。
（血液循環試験 インターロイキン−６の吸着評価）
膜面積１．５ｍ２のモジュールの透析液側を生理食塩水で満たし、人ヘパリン加血２００ｍｌを血液バッグに詰め、血液バッグとモジュールをチューブで連結し、３７℃で血液流速１００ｍｌ／ｍｉｎ、１時間循環する。循環開始前と循環６０分との血液をサンプリングし、ＩＬ−６濃度を測定する。測定した値はヘマトクリットの値で補正する。
補正値＝測定値（60分）×（（Ht(0)×100／Ht(60)）−Ht(0)）／（100− Ht(0)）
Ht(0)：ヘマトクリット（０分）
Ht(60)：ヘマトクリット（６０分）
補正値から吸着率を算出する。
吸着率（％）＝１００−補正値（60分）／循環開始前値×100
（血液循環試験 補体活性化産物Ｃ３ａの変化率）
膜面積１．５ｍ２のモジュールの透析液側を生理食塩水で満たし、人ヘパリン加血２００ｍｌを血液バッグに詰め、血液バッグとモジュールをチューブで連結し、３７℃で血液流速１００ｍｌ／ｍｉｎ、１０分間循環する。循環開始前と循環１０分後との血液をサンプリングし、Ｃ３ａ濃度を測定する。測定した値はヘマトクリットの値で補正する。
補正値＝測定値（10分）×（（Ht(0)×100／Ht(10)）−Ht(0)）／（100−Ht(0)）
Ht(0)：ヘマトクリット（０分）
Ht(10)：ヘマトクリット（１０分）
補正値から変化率を算出する。
変化率（％）＝補正値（10分）／循環開始前値×100
（血液循環試験 ブラジキニンの変化率）
膜面積１．５ｍ２のモジュールの透析液側を生理食塩水で満たし、人ヘパリン加血２００ｍｌを血液バッグに詰め、血液バッグとモジュールをチューブで連結し、３７℃で血液流速１００ｍｌ／ｍｉｎ、３０分間循環する。循環開始前と循環３０分との血液をサンプリングし、ブラジキニン濃度を測定する。測定した値はヘマトクリットの値で補正する。
補正値＝測定値（30分）×（（Ht(0)×100／Ht(30)）−Ht(0)）／（100−Ht(0)）
Ht(0)：ヘマトクリット（０分）
Ht(30)：ヘマトクリット（３０分）
補正値から変化率を算出する。
変化率（％）＝補正値（30分）／循環開始前値×100
（中空糸膜内面の荷電評価）
膜面積１．５ｍ２のモジュールの透析液側を生理食塩水で満たし、血液側に５ｐｐｍに調製したメチレンブルーを１００ｍｌ／ｍｉｎの流速で１時間循環し、循環前後のメチレンブルーの濃度を吸光度４９０ｎｍから算出し、膜へのメチレンブルーの吸着率を測定する。吸着率が大きいほど、陰性荷電が強いことを意味する。
吸着率（％）＝（循環前の濃度−循環後の濃度）／循環前の濃度×１００
Hereinafter, the effectiveness of the present invention will be described with reference to examples, but the present invention is not limited thereto.
(Measurement of eluate (UV value))
A hollow fiber membrane (1.0 g) is immersed in 100 ml of water and heated in a 70 ° C. water bath for 1 hour to prepare a test solution. The absorbance of the test solution is measured in the wavelength range of 220 to 350 nm. In the artificial kidney device approval criteria, the standard under this condition is 0.1 or less.
(Measurement of hydrophilic high molecular weight on the inner surface of the hollow fiber membrane)
After arranging the hollow fiber membranes on the double-sided tape, the sample was cut in the fiber axis direction with a cutter and spread so that the inside of the hollow fiber membranes would be the front, and X-ray photoelectron spectroscopy (ESCA) photoemission Measure at an angle of 45 degrees. In the case of polyvinylpyrrolidone, the surface concentration of nitrogen (N) and the surface concentration of sulfur (S) are obtained from the area intensity of the C1s, O1s, N1s, and S2p spectra using the relative sensitivity coefficient attached to the device.
Surface PVP concentration = N × 100 / (N × 111 + S × 442)
Further, the surface PVP concentration is calculated.
(Adsorption evaluation of interleukin-6 in blood circulation test)
The dialysate side of a module with a membrane area of 1.5 m 2 is filled with physiological saline, 200 ml of human heparinized blood is filled in a blood bag, the blood bag and the module are connected by a tube, and a blood flow rate of 100 ml / min, Circulate time. Blood samples before the start of circulation and 60 minutes after circulation are sampled, and the IL-6 concentration is measured. The measured value is corrected with the value of hematocrit.
Correction value = measured value (60 minutes) x ((Ht (0) x 100 / Ht (60))-Ht (0)) / (100-Ht (0))
Ht (0): Hematocrit (0 minutes)
Ht (60): Hematocrit (60 minutes)
The adsorption rate is calculated from the correction value.
Adsorption rate (%) = 100−correction value (60 minutes) / value before starting circulation × 100
(Change in blood circulation test complement activation product C3a)
The dialysate side of the module with a membrane area of 1.5 m 2 is filled with physiological saline, 200 ml of human heparinized blood is filled in a blood bag, the blood bag and the module are connected with a tube, and the blood flow rate is 100 ml / min at 37 ° C., 10 Circulate for a minute. Sampling blood before the start of circulation and 10 minutes after the circulation, and measuring the C3a concentration. The measured value is corrected with the value of hematocrit.
Correction value = measured value (10 minutes) x ((Ht (0) x 100 / Ht (10))-Ht (0)) / (100-Ht (0))
Ht (0): Hematocrit (0 minutes)
Ht (10): Hematocrit (10 minutes)
The rate of change is calculated from the correction value.
Rate of change (%) = Correction value (10 minutes) / Before circulation start value x 100
(Change rate of blood circulation test bradykinin)
The dialysate side of a module with a membrane area of 1.5 m 2 is filled with physiological saline, 200 ml of human heparinized blood is filled in a blood bag, the blood bag and the module are connected with a tube, and a blood flow rate of 100 ml / min at 30 ° C., 30 Circulate for a minute. Blood samples before the start of circulation and 30 minutes after circulation are sampled and the bradykinin concentration is measured. The measured value is corrected with the value of hematocrit.
Correction value = measured value (30 minutes) x ((Ht (0) x 100 / Ht (30))-Ht (0)) / (100-Ht (0))
Ht (0): Hematocrit (0 minutes)
Ht (30): Hematocrit (30 minutes)
The rate of change is calculated from the correction value.
Rate of change (%) = Correction value (30 minutes) / Before circulation start value x 100
(Evaluation of charge inside hollow fiber membrane)
Fill the dialysate side of the module with a membrane area of 1.5 m 2 with physiological saline, circulate methylene blue prepared at 5 ppm on the blood side for 1 hour at a flow rate of 100 ml / min, and calculate the concentration of methylene blue before and after circulation from the absorbance at 490 nm. Then, the adsorption rate of methylene blue to the membrane is measured. The larger the adsorption rate, the stronger the negative charge.
Adsorption rate (%) = (concentration before circulation−concentration after circulation) / concentration before circulation × 100
実施例１（血液浄化器の製造と評価）
ＰＥＳ（住化ケムテックス社4800P）およびＢＡＳＦ社製ＰＶＰ（Ｋ−９０）をＮＭＰとＴＥＧの混合液（重量比でＮＭＰ：ＴＥＧ＝８：２）にそれぞれ４２質量％、５質量％になるよう混合し１５０℃で１０時間撹拌し溶解、均一な溶液とした。紡糸原液中の疎水性高分子に対する親水性高分子の質量割合は11.9質量％であった。この溶液を十分減圧脱泡した後、孔径４０μｍの焼結フィルターで濾過し、不純物を除いて紡糸原液とし１２０℃でキープした。この紡糸原液を１２０℃に加熱した二重環状スリット口金から吐出すると同時に、紡糸原液に対して非凝固性である流動パラフィンを内液として吐出した。口金から凝固層までの４０ｍｍの乾式部分を経て２５℃にコントロールした凝固層内に紡糸原液／内液を落とし込み凝固させた。このときのドラフト比は２５であった。凝固浴は１５質量％ＮＭＰ水溶液を用いた。凝固浴中で４５％延伸をかけて中空糸膜として成形した。凝固浴へは、ステンレス製のガイドとローラーによって液面方向に進路を整えた。さらに凝固液中もステンレス製のガイドによって中空糸膜の進路を整えた。凝固浴から引き上げた中空糸膜は、５０℃のＲＯ水からなる水洗浴に導き９０秒間浸漬通過させ、過剰のＰＶＰと溶媒を除去した。３０質量％のグリセリン水溶液浴を経ることで表面へのグリセリン塗布を行った後、７０℃の熱風乾燥機中に導き乾燥処理を行った。乾燥後の中空糸膜は、除電ブロワー（キーエンス社製 梗塞除電ブロワーＳＪ−Ｆ０２０）により静電気を除去しながらワインダーにて７５ｍ／ｍｉｎの速度でボビン芯に巻取った。実施例1の紡糸工程で用いた水は全てＲＯ水であり、比抵抗は１．１ＭΩｃｍであった。得られた中空糸膜の内径は200.5μm、膜厚は14.8μm、含水率は２．１質量％であった。
Example 1 (Production and evaluation of blood purifier)
PES (Sumika Chemtex Corp. 4800P) and BASF PVP (K-90) were mixed in a mixed solution of NMP and TEG (NMP: TEG = 8: 2 by weight ratio) to 42 mass% and 5 mass%, respectively. Then, the mixture was stirred at 150 ° C. for 10 hours to obtain a homogeneous solution. The mass ratio of the hydrophilic polymer to the hydrophobic polymer in the spinning dope was 11.9% by mass. This solution was sufficiently degassed under reduced pressure, and then filtered through a sintered filter having a pore diameter of 40 μm to remove impurities, and a spinning stock solution was kept at 120 ° C. The spinning stock solution was discharged from a double annular slit die heated to 120 ° C., and at the same time, liquid paraffin that was non-solidifying with respect to the spinning stock solution was discharged as an internal solution. The spinning solution / inner solution was dropped into a coagulation layer controlled at 25 ° C. through a 40 mm dry part from the die to the coagulation layer, and coagulated. The draft ratio at this time was 25. A 15 mass% NMP aqueous solution was used for the coagulation bath. A hollow fiber membrane was formed by stretching 45% in a coagulation bath. To the coagulation bath, the course was adjusted in the liquid surface direction by a stainless guide and roller. Furthermore, the course of the hollow fiber membrane was adjusted with a stainless steel guide in the coagulation liquid. The hollow fiber membrane pulled up from the coagulation bath was introduced into a washing bath composed of 50 ° C. RO water and immersed for 90 seconds to remove excess PVP and solvent. The glycerin was applied to the surface by passing through a 30% by mass glycerin aqueous solution bath, and then was guided into a hot air dryer at 70 ° C. for drying treatment. The dried hollow fiber membrane was wound around a bobbin core at a speed of 75 m / min with a winder while removing static electricity with a static elimination blower (Infarct static elimination blower SJ-F020 manufactured by Keyence Corporation). All of the water used in the spinning process of Example 1 was RO water, and the specific resistance was 1.1 MΩcm. The resulting hollow fiber membrane had an inner diameter of 200.5 μm, a film thickness of 14.8 μm, and a moisture content of 2.1% by mass.
これらの中空糸膜１００９８本をポリエチレン製パイプに挿入し、３０ｃｍの長さに切断しバンドルとした。 10098 of these hollow fiber membranes were inserted into a polyethylene pipe and cut into a length of 30 cm to form a bundle.
バンドルを充填率６０vol％でケースに充填し、端部をウレタン樹脂で接着し、樹脂を切り出し中空糸膜端部が開口したモジュールとした。このモジュールを２０ｋＧｙでガンマ線照射して滅菌済み完成品とした。 The bundle was filled in the case at a filling rate of 60 vol%, the end part was bonded with urethane resin, the resin was cut out, and the hollow fiber membrane end part was opened. This module was irradiated with gamma rays at 20 kGy to obtain a sterilized finished product.
完成したモジュールの中空糸膜について溶出物（ＵＶ値）の測定、膜内表面のＰＶＰの量を測定した。結果を表１に示した。 For the hollow fiber membrane of the completed module, the eluate (UV value) was measured, and the amount of PVP on the inner surface of the membrane was measured. The results are shown in Table 1.
完成したモジュールについて、血液循環試験を行い、ＩＬ−６の吸着率、Ｃ３ａ変化率、ブラジキニン変化率、メチレンブルー吸着率を求めた。結果を表１に示した。
実施例２（血液浄化器の製造と評価）
ＰＥＳ（住化ケムテックス社4800P）およびＢＡＳＦ社製ＰＶＰ（Ｋ−９０）をＮＭＰとＴＥＧの混合液（重量比でＮＭＰ：ＴＥＧ＝８：２）にそれぞれ４１質量％、７質量％になるよう混合し１５０℃で１０時間撹拌し溶解、均一な溶液とした。紡糸原液中の疎水性高分子に対する親水性高分子の質量割合は17.1質量％であった。この溶液を十分減圧脱泡した後、孔径４０μｍの焼結フィルターで濾過し、不純物を除いて紡糸原液とし１２０℃でキープした。この紡糸原液を１２０℃に加熱した二重環状スリット口金から吐出すると同時に、紡糸原液に対して非凝固性である流動パラフィンを内液として吐出した。口金から凝固層までの２０ｍｍの乾式部分を経て２５℃にコントロールした凝固層内に紡糸原液／内液を落とし込み凝固させた。このときのドラフト比は30であった。凝固浴は１５％ＮＭＰ水溶液を用いた。凝固浴中での２５％延伸工程を経て中空糸膜として成形した。凝固浴へは、ステンレス製のガイドとローラによって液面方向に進路を整えた。さらに凝固液中もステンレス製のガイドによって進路を整えた。凝固浴から引き上げた中空糸膜は、４０℃のＲＯ水からなる水洗浴に導き９０秒間浸漬通過させ、過剰のＰＶＰと溶媒を除去した。３０質量％のグリセリン水溶液浴を経ることで表面へのグリセリン塗布を行った後、７０℃の熱風乾燥機中に導き乾燥処理を行った。乾燥後の中空糸膜は、除電ブロワー（キーエンス社製 梗塞除電ブロワーＳＪ−Ｆ０２０）により静電気を除去しながらワインダーにて７５ｍ／ｍｉｎの速度でボビン芯に巻取った。実施例2の紡糸工程で用いた水は全てＲＯ水であり、比抵抗は１．０ＭΩｃｍであった。得られた中空糸膜の内径は199.6μm、膜厚は14.7μm、含水率は２．２質量％であった。
The completed module was subjected to a blood circulation test to determine IL-6 adsorption rate, C3a change rate, bradykinin change rate, and methylene blue adsorption rate. The results are shown in Table 1.
Example 2 (Production and evaluation of blood purifier)
PES (Sumika Chemtex Corp. 4800P) and BASF PVP (K-90) were mixed in a mixture of NMP and TEG (NMP: TEG = 8: 2 in weight ratio) to 41 mass% and 7 mass%, respectively. Then, the mixture was stirred at 150 ° C. for 10 hours to obtain a homogeneous solution. The mass ratio of the hydrophilic polymer to the hydrophobic polymer in the spinning dope was 17.1% by mass. This solution was sufficiently degassed under reduced pressure, and then filtered through a sintered filter having a pore diameter of 40 μm to remove impurities, and a spinning stock solution was kept at 120 ° C. The spinning stock solution was discharged from a double annular slit die heated to 120 ° C., and at the same time, liquid paraffin that was non-solidifying with respect to the spinning stock solution was discharged as an internal solution. The spinning solution / inner solution was dropped into a coagulation layer controlled at 25 ° C. through a 20 mm dry part from the die to the coagulation layer, and coagulated. The draft ratio at this time was 30. A 15% NMP aqueous solution was used for the coagulation bath. A hollow fiber membrane was formed through a 25% stretching step in a coagulation bath. To the coagulation bath, the course was adjusted in the liquid surface direction by a stainless guide and roller. Furthermore, the course of the coagulation liquid was adjusted with a stainless steel guide. The hollow fiber membrane pulled up from the coagulation bath was introduced into a washing bath composed of 40 ° C. RO water and immersed for 90 seconds to remove excess PVP and solvent. The glycerin was applied to the surface by passing through a 30% by mass glycerin aqueous solution bath, and then was guided into a hot air dryer at 70 ° C. for drying treatment. The dried hollow fiber membrane was wound around a bobbin core at a speed of 75 m / min with a winder while removing static electricity with a static elimination blower (Infarct static elimination blower SJ-F020 manufactured by Keyence Corporation). All of the water used in the spinning process of Example 2 was RO water, and the specific resistance was 1.0 MΩcm. The obtained hollow fiber membrane had an inner diameter of 199.6 μm, a film thickness of 14.7 μm, and a moisture content of 2.2% by mass.
モジュール化および評価は実施例１と同様に行い、結果を表１に示した。
比較例１（血液浄化器の製造と評価）
実施例1と同様の紡糸原液を調製した。この溶液を十分減圧脱泡した後、孔径４０μｍの焼結フィルターで濾過し、不純物を除いて紡糸原液とし１２０℃でキープした。この紡糸原液を１２０℃に加熱した二重環状スリット口金から吐出すると同時に、紡糸原液に対して非凝固性である流動パラフィンを内液として吐出した。口金から凝固層までの５ｍｍの乾式部分を経て２５℃にコントロールした凝固層内に紡糸原液／内液を落とし込み凝固させた。このときのドラフト比は８であった。凝固浴は１５％ＮＭＰ水溶液を用いた。凝固浴中での延伸は実施せず、中空糸膜として成形した。凝固浴へは、テフロン（Ｒ）製のガイドとローラによって液面方向に進路を整えた。さらに凝固液中もテフロン（Ｒ）製のガイドによって進路を整えた。中空糸膜巻き取りの過程において、３０℃の水道水水洗浴を経た後、７０℃熱風乾燥にて絶乾した。その後３０質量％のグリセリン水溶液浴を経て、表面へのグリセリン塗布を行い、７５ｍ／ｍｉｎの速度でボビン芯に巻取った。比較例1の紡糸工程で用いた水は全て水道水であった。得られた中空糸膜の内径は199.8μm、膜厚は20.1μm、含水率は1.2質量％であった。
Modularization and evaluation were performed in the same manner as in Example 1, and the results are shown in Table 1.
Comparative Example 1 (Production and evaluation of blood purifier)
A spinning dope similar to that in Example 1 was prepared. This solution was sufficiently degassed under reduced pressure, and then filtered through a sintered filter having a pore diameter of 40 μm to remove impurities, and a spinning stock solution was kept at 120 ° C. The spinning stock solution was discharged from a double annular slit die heated to 120 ° C., and at the same time, liquid paraffin that was non-solidifying with respect to the spinning stock solution was discharged as an internal solution. The spinning solution / inner solution was dropped into a coagulation layer controlled at 25 ° C. through a 5 mm dry part from the die to the coagulation layer, and coagulated. The draft ratio at this time was 8. A 15% NMP aqueous solution was used for the coagulation bath. Stretching in a coagulation bath was not performed, and a hollow fiber membrane was formed. To the coagulation bath, the course was adjusted in the liquid surface direction with a Teflon (R) guide and a roller. Further, the course of the coagulation liquid was adjusted with a guide made of Teflon (R). In the process of winding the hollow fiber membrane, after passing through a 30 ° C. tap water washing bath, it was completely dried by hot air drying at 70 ° C. Thereafter, a glycerin coating was applied to the surface through a 30% by mass glycerin aqueous solution bath and wound around a bobbin core at a speed of 75 m / min. All the water used in the spinning process of Comparative Example 1 was tap water. The resulting hollow fiber membrane had an inner diameter of 199.8 μm, a film thickness of 20.1 μm, and a moisture content of 1.2% by mass.
モジュール化および評価は実施例１と同様に行い、結果を表１に示した。 Modularization and evaluation were performed in the same manner as in Example 1, and the results are shown in Table 1.
ＩＬ−６の吸着がほとんどみられなかったことから、孔径の制御が十分に行われていないことが予想される。このことは、ドラフト比が小さいことと、延伸を実施しなかったことによると考えられる。補体活性が高かったのは、乾燥工程で絶乾したため、中空糸膜の内表面にＰＶＰが多量に局在化し、溶出物量が増え、循環試験中にも溶出物として抽出されていたためと考えられる。ブラジキニンの変化率が高く、メチレンブルーの吸着率も高かったことから、荷電の影響が考えられた。紡糸工程におけるローラーやガイドの素材、また水道水による洗浄により陰性荷電の影響が顕著になったと予測される。また静電気の影響でボビン芯への巻取性が大きく低下し、工業的に実施することは困難と思われた。
比較例２（血液浄化器の製造と評価）
実施例1と同様の紡糸原液を調製した。この溶液を十分減圧脱泡した後、孔径４０μｍの焼結フィルターで濾過し、不純物を除いて紡糸原液とし１２０℃でキープした。この紡糸原液を１２０℃に加熱した二重環状スリット口金から吐出すると同時に、紡糸原液に対して非凝固性である流動パラフィンを内液として吐出した。口金から凝固層までの２００ｍｍの乾式部分を経て２５℃にコントロールした凝固層内に紡糸原液／内液を落とし込み凝固させた。このときのドラフト比は18であった。凝固浴は１５％ＮＭＰである。凝固浴中での１５０％延伸工程を経て、中空糸膜として成形した。凝固浴へは、テフロン（Ｒ）製のガイドとローラーによって液面方向に進路を整えた。さらに凝固液中もテフロン（Ｒ）製のガイドによって進路を整えた。中空糸膜巻き取りの過程において、３０℃の水道水水洗浴を経ることで洗浄、さらに７０℃熱風乾燥し、７５ｍ／ｍｉｎの速度でボビン芯に巻取った。比較例２の紡糸工程で用いた水は全て水道水であった。得られた中空糸膜の内径は199.8μm、膜厚は15.1μm、含水率は1.1質量％であった。
Since almost no adsorption of IL-6 was observed, it is expected that the pore diameter was not sufficiently controlled. This is considered to be due to the fact that the draft ratio is small and the stretching was not performed. Complement activity was high because it was completely dried in the drying process, and PVP was localized in a large amount on the inner surface of the hollow fiber membrane, resulting in an increase in the amount of eluate and extraction as an eluate during the circulation test. It is done. Since the rate of change of bradykinin was high and the adsorption rate of methylene blue was also high, the effect of charge was considered. The negative charge is expected to be noticeable due to the roller and guide materials used in the spinning process and the cleaning with tap water. In addition, the windability on the bobbin core was greatly reduced due to the influence of static electricity, and it seemed difficult to implement industrially.
Comparative Example 2 (Production and evaluation of blood purifier)
A spinning dope similar to that in Example 1 was prepared. This solution was sufficiently degassed under reduced pressure, and then filtered through a sintered filter having a pore diameter of 40 μm to remove impurities, and a spinning stock solution was kept at 120 ° C. The spinning stock solution was discharged from a double annular slit die heated to 120 ° C., and at the same time, liquid paraffin that was non-solidifying with respect to the spinning stock solution was discharged as an internal solution. The spinning solution / inner solution was dropped into a coagulation layer controlled at 25 ° C. through a 200 mm dry part from the die to the coagulation layer, and coagulated. The draft ratio at this time was 18. The coagulation bath is 15% NMP. A hollow fiber membrane was formed through a 150% stretching step in a coagulation bath. To the coagulation bath, the course was adjusted in the liquid surface direction with a Teflon (R) guide and a roller. Further, the course of the coagulation liquid was adjusted with a guide made of Teflon (R). In the process of winding the hollow fiber membrane, it was washed by passing through a 30 ° C. tap water washing bath, further dried by hot air at 70 ° C., and wound around a bobbin core at a speed of 75 m / min. All the water used in the spinning process of Comparative Example 2 was tap water. The resulting hollow fiber membrane had an inner diameter of 199.8 μm, a film thickness of 15.1 μm, and a moisture content of 1.1% by mass.
モジュール化および評価は実施例１と同様に行い、結果を表１に示した。 Modularization and evaluation were performed in the same manner as in Example 1, and the results are shown in Table 1.
ＩＬ−６の吸着がほとんどみられなかったことから、孔径の制御が十分に行われていないことが予想される。このことは、エアーギャップ長が長いことと、極端な延伸を実施したため、孔径を均一にすることが出来なかったと考えられる。その半面、中空糸膜の洗浄性は向上し、親水性高分子の大半が洗浄工程で洗い流されたと考えられ、表面のＰＶＰ量は少なく、溶出物試験結果も基準値以下であり、補体活性も比較的低かった。ブラジキニンの変化率が高く、メチレンブルーの吸着率も高かったことから、荷電の影響が考えられた。紡糸工程におけるローラーやガイドの素材、また水道水による洗浄により陰性荷電の影響が顕著になったと予測される。またグリセリン処理を行わなかったことから、静電気が発生しボビン芯への巻取性が大きく低下し、工業的に実施することは困難と思われた。
参考例１（血液浄化器の評価）
市販のポリスルホン膜血液透析器について血液循環試験およびメチレンブルー循環試験を実施した。測定したインターロイキン−６の吸着率、Ｃ３ａ変化率、ブラジキニン変化率、メチレンブルー吸着率を表１に示した。
参考例２（血液浄化器の評価）
市販のポリアクリロニトリル膜血液透析器について血液循環試験およびメチレンブルー循環試験を実施した。測定したＩＬ−６の吸着率、Ｃ３ａ変化率、ブラジキニン変化率、メチレンブルー吸着率を表１に示した。
参考例３（血液浄化器の評価）
市販のヘモファン膜（再生セルロース膜の水酸基をジエチルアミノエチル基でマスキングした膜（陽性荷電を持つ））血液透析器についてメチレンブルー循環試験を実施した。測定したメチレンブルー吸着率を表１に示した。
Since almost no adsorption of IL-6 was observed, it is expected that the pore diameter was not sufficiently controlled. This is considered to be because the air gap length was long and extreme stretching was performed, so that the hole diameter could not be made uniform. On the other hand, the detergency of the hollow fiber membrane has been improved, most of the hydrophilic polymer is thought to have been washed away in the washing process, the amount of PVP on the surface is small, and the eluate test results are below the standard value, complement activity. Was also relatively low. Since the rate of change of bradykinin was high and the adsorption rate of methylene blue was also high, the effect of charge was considered. The negative charge is expected to be noticeable due to the roller and guide materials used in the spinning process and the cleaning with tap water. In addition, since glycerin treatment was not performed, static electricity was generated and the winding property onto the bobbin core was greatly reduced, and it seemed difficult to implement industrially.
Reference Example 1 (Evaluation of blood purifier)
Blood circulation tests and methylene blue circulation tests were performed on commercially available polysulfone membrane hemodialyzers. Table 1 shows the measured interleukin-6 adsorption rate, C3a change rate, bradykinin change rate, and methylene blue adsorption rate.
Reference Example 2 (Evaluation of blood purifier)
A blood circulation test and a methylene blue circulation test were performed on a commercially available polyacrylonitrile membrane hemodialyzer. Table 1 shows the measured IL-6 adsorption rate, C3a change rate, bradykinin change rate, and methylene blue adsorption rate.
Reference Example 3 (Evaluation of blood purifier)
A methylene blue circulation test was performed on a commercially available hemophane membrane (a membrane in which the hydroxyl group of a regenerated cellulose membrane was masked with a diethylaminoethyl group (having a positive charge)) hemodialyzer. The measured methylene blue adsorption rate is shown in Table 1.
実施例１、２ではＩＬ−６の吸着率が大きく吸着除去性能が発現された。また、Ｃ３ａ変化率も小さく補体活性化が起こりにくいことが示された。さらにブラジキニン変化率も小さく、メチレンブルーの吸着率が高くないことから陰性荷電の影響も小さいことがわかる。比較例１、２では延伸工程の違いによりインターロイキンの吸着サイトのサイズが微妙に変化したためか、ＩＬ−６吸着率が低くなった。比較例１、２、参考例１は一般的なポリスルホン系の膜の特徴を示した。参考例２のＩＬ−６吸着が報告されているポリアクリロニトリル膜ではＩＬ−６の高い吸着率が示されたが、陰性荷電の影響がブラジキニン変化率で顕著となり、報告通りの結果が得られ、血液循環試験における評価系の正当性を証明している。一方陽性荷電膜である参考例３ではメチレンブルーの吸着率が顕著に低く、陰性荷電評価についても正当性を証明している。 In Examples 1 and 2, the adsorption rate of IL-6 was large and the adsorption removal performance was expressed. In addition, the C3a change rate was small, indicating that complement activation is unlikely to occur. Furthermore, the rate of change of bradykinin is small, and since the methylene blue adsorption rate is not high, it can be seen that the influence of negative charge is small. In Comparative Examples 1 and 2, the IL-6 adsorption rate decreased because the size of the adsorption site of the interleukin slightly changed due to the difference in the stretching process. Comparative Examples 1 and 2 and Reference Example 1 showed the characteristics of a general polysulfone-based membrane. In the polyacrylonitrile membrane in which IL-6 adsorption was reported in Reference Example 2, a high adsorption rate of IL-6 was shown, but the influence of negative charge became significant in the bradykinin change rate, and the results as reported were obtained. It proves the validity of the evaluation system in the blood circulation test. On the other hand, in Reference Example 3, which is a positively charged membrane, the adsorption rate of methylene blue is remarkably low, and the validity of negative charge evaluation is proved.
疎水性高分子と親水性高分子とからなる中空糸を含む中空糸型血液浄化器において、サイトカインの吸着除去性能および補体活性抑制性能およびブラジキニン産生抑制性能を有する血液適合性に優れた中空糸型血液浄化器が得られる。この中空糸型血液浄化器慢性の腎臓疾患の治療法である定期的な短時間の血液浄化療法および急性疾患や重症疾患に対する持続的血液浄化療法に適応できる。 A hollow fiber type blood purifier comprising a hollow fiber composed of a hydrophobic polymer and a hydrophilic polymer, and having excellent blood compatibility with cytokine adsorption removal performance, complement activity inhibition performance, and bradykinin production inhibition performance A type blood purifier is obtained. This hollow fiber blood purifier can be applied to regular short-term blood purification therapy for chronic kidney disease and continuous blood purification therapy for acute and severe diseases.
Claims (2)
（ａ）インターロイキン６の吸着率が、血液循環試験の循環１時間後において５０％以上８５％以下である
（ｂ）補体活性化産物Ｃ３ａの変化率が、血液循環試験の循環１０分後において７０％以上１１０％以下である
（ｃ）ブラジキニンの変化率が、血液循環試験の循環３０分後において１００％以上１２０％以下である
これらのすべての性能を併せ持つことを特徴とする中空糸型血液浄化器。 Liquid paraffin is discharged from a nozzle as a spinning dope consisting of 35 to 45 parts by mass of polyethersulfone and 2 to 8 parts by mass of polyvinyl pyrrolidone and an internal solution, and is passed through an aerial traveling part of 10 to 50 mm and 5 to 70% by mass of N- When a hollow fiber membrane is obtained by coagulating into a coagulation bath consisting of an aqueous methyl-2-pyrrolidone solution, followed by washing and drying, RO water having a specific resistance of 0.3-2 MΩcm is used for the production of the hollow fiber membrane, By setting the draft ratio to 15 to 30 and stretching 25 to 45% in the coagulation bath, the proportion of polyvinylpyrrolidone present on the inner surface of the hollow fiber membrane is 10 to 28% by weight, and methylene blue is added to the hollow fiber membrane. In a hollow fiber blood purifier including a hollow fiber membrane having an adsorption rate of 30% to 80% and an eluate UV value of 0.022 or less ,
(A) Adsorption rate of interleukin 6 is 50% or more and 85% or less after 1 hour of circulation in blood circulation test (b) Change rate of complement activation product C3a is 10 minutes after circulation in blood circulation test in at most 110% 70% (c) bradykinin rate of change, hollow fiber, characterized in that both all of these performances is not more than 120% to 100% or more in the circulation after 30 minutes circulation of blood test Blood purifier.
Inner surface is a blood-contacting portion of the hollow fiber membrane is made of highly uniform microstructure of the hole diameter, whereas, according to claim 1, characterized in that formation of the dense layer is suppressed on the membrane surface Hollow fiber blood purifier.
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