JP2019180568A - Hollow fiber membrane for filtering ascitic fluid - Google Patents
Hollow fiber membrane for filtering ascitic fluid Download PDFInfo
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本発明は、腹水を多量に濾過するための中空糸膜に関する。 The present invention relates to a hollow fiber membrane for filtering a large amount of ascites.
従来、肝硬変などの腹水や胸水（以下、腹水と総称する）の溜まり易い患者に対して、腹水中のタンパク質を利用して患者の血中タンパク質濃度を上昇させるため、貯留部に針を刺し体外に排出した腹水を、中空糸膜などを用いた２種のフィルタにより濾過濃縮処理し、濃厚タンパク質溶液を得、これを患者に点滴する腹水濾過濃縮再静注法が行われている（例えば、特許文献１参照）。２種のフィルタの１つ目は腹水中に含まれるがん細胞、血球成分などの細胞成分を除くための濾過フィルタであり、細胞成分を通過させず、水分、タンパク質などの溶質成分は通過させるような孔径を有する膜が用いられる。一方、もうひとつのフィルタは希薄なタンパク質濃度である腹水から除水し、タンパク質を濃縮するための濃縮フィルタであり、タンパク質成分はほとんど通過せず、水分、電解質などは通過させる膜が用いられる。通常、利便性の観点から、濾過器で細胞成分を濾別した腹水を濃縮器で濃縮する方法が取られ、これらを連続して行う装置が用いられる。近年では、濾過器の洗浄を短時間で、かつ容易に行うことができることにより、大量の腹水を処理することが可能な腹水処理システムが開発されている(例えば、特許文献２参照)。 Conventionally, for patients who have a tendency to accumulate ascites or pleural effusion (hereinafter collectively referred to as ascites) such as cirrhosis, the protein in the ascites is used to increase the patient's blood protein concentration. Ascites drained into the ascites is filtered and concentrated with two types of filters using hollow fiber membranes, etc. to obtain a concentrated protein solution, and this is instilled into the patient ascites filtered concentrated re-injection method (for example, Patent Document 1). The first of the two types of filters is a filtration filter for removing cell components such as cancer cells and blood cell components contained in ascites, and does not allow cell components to pass through, but allows solute components such as moisture and protein to pass through. A membrane having such a pore size is used. On the other hand, the other filter is a concentration filter for removing water from ascites, which has a dilute protein concentration, and concentrating the protein. A membrane that hardly passes protein components and allows moisture, electrolyte, etc. to pass through is used. In general, from the viewpoint of convenience, a method of concentrating ascites obtained by filtering cell components with a filter with a concentrator is used, and a device that performs these continuously is used. In recent years, an ascites treatment system capable of treating a large amount of ascites by developing a filter in a short time and easily has been developed (see, for example, Patent Document 2).
がん細胞、血球成分などの細胞成分が含まれるがん性腹水を腹水濾過器で濾過する場合、肝性腹水の濾過と比較して、これら細胞成分が腹水濾過器内に貯留して目詰まりを起こし、濾過圧が上昇するまでの時間が短くなり、圧上昇するまでに処理できる腹水量が減る傾向にある。圧上昇した場合、濾過能力を回復するために腹水濾過器の出口を開放して腹水濾過器内部に溜まった細胞成分のフラッシングを行ったり、洗浄液を流して濾材を洗浄したりするという煩雑な操作が必要となり、またフラッシングや洗浄を行う操作により腹水を廃液するため、有用なタンパク質の回収率が低下する。そのため、場合によっては、腹水濾過器を新しいものと交換する必要がある。これらの操作は、施行者にとり、作業面で負担のかかるものである上、経済面の不利益もある。また、患者にとっては、処理時間が長くなるため、腹水から回収したタンパク質溶液が投与されるまでの拘束時間が長くなったり、腹水から回収したタンパク質の投与量が減少したりするという不利益がある。 When filtering cancerous ascites containing cell components such as cancer cells and blood cell components with an ascites filter, these cell components are stored in the ascites filter and clogged compared with filtration of hepatic ascites. The time until the filtration pressure rises is shortened, and the amount of ascites that can be treated before the pressure rises tends to decrease. When pressure rises, in order to recover the filtration capacity, the outlet of the ascites filter is opened to flush the cellular components accumulated inside the ascites filter, or the washing medium is flushed to wash the filter medium. In addition, ascites is drained by operations such as flushing and washing, and the recovery rate of useful proteins decreases. Therefore, in some cases, it is necessary to replace the ascites filter with a new one. These operations are burdensome in terms of work for the implementer and also have economic disadvantages. In addition, for the patient, the treatment time becomes longer, and there is a disadvantage that the restraint time until the protein solution recovered from the ascites is administered becomes longer or the dose of the protein recovered from the ascites decreases. .
これまで開発されてきた腹水濾過膜は、腹水の濾過過程で膜の表面にがん細胞や血球成分などの細胞成分が付着、堆積し、短時間で腹水濾過膜が目詰まりする。従って、例えば、１〜３Ｌ程度の腹水を処理しただけで目詰まりにより腹水濾過膜が使用不可になる場合があり、大量の腹水を継続的に処理することが困難であった。また腹水貯留バックが４Ｌであるため、腹水濾過膜の交換を必要とする場合がある。それゆえに、この発明の目的は多量の腹水を処理できる腹水濾過膜を提供することにある。 In the ascites filtration membrane that has been developed so far, cell components such as cancer cells and blood cell components adhere and accumulate on the surface of the membrane during the filtration of ascites, and the ascites filtration membrane is clogged in a short time. Therefore, for example, the ascites filtration membrane may become unusable due to clogging only by treating about 1 to 3 L of ascites, and it has been difficult to continuously treat a large amount of ascites. Moreover, since the ascites reservoir bag is 4L, the ascites filtration membrane may need to be replaced. Therefore, an object of the present invention is to provide an ascites filtration membrane capable of treating a large amount of ascites.
本発明者は、このような従来の欠点を改善するため、がん細胞、血球成分などの細胞成分の分画特性の向上と、これらの経時的劣化抑制について鋭意研究を重ねた結果、分離効率と経時的劣化は、中空糸膜の表面構造に大きく依存していることを見いだした。つまり、中空糸膜の内表面および外表面の細孔構造を制御することにより、膜内の目詰まりによる経時的劣化を減少させ大量の腹水を処理可能であることを見出して本発明を完成するに至った。すなわち、本発明は以下の構成を有する。
（１）体腔液を濾過することにより有用タンパク成分を回収するための中空糸膜であって、総タンパク濃度６．０ｇ／ｄｌ、白血球１０００／μｌ、赤血球６０００／μｌの擬似腹水溶液を全量濾過した際に、溶血が発生せず、膜間圧力差が３００ｍｍＨｇまで上昇するまでに得られる濾液量が４Ｌ／ｍ２以上であり、最大孔径が０．２μｍ以下である、腹水濾過用の中空糸膜。
（２）前記中空糸膜の内表面の孔の深さは５μｍ以上、孔の大きさは５μｍ以上３０μｍ以下である、（１）に記載の中空糸膜。
（３）前記中空糸膜は疎水性高分子と親水性高分子からなる、（１）または（２）に記載の中空糸膜。
（４）前記疎水性高分子はポリスルホン系樹脂であり、前記親水性高分子はポリビニルピロリドンである、（３）に記載の中空糸膜。
（５）（１）〜（４）のいずれかに記載の中空糸膜を収納した腹水濾過器であって、中空糸膜の内腔に連通する２以上のヘッダーおよび中空糸膜の外腔に連通する２以上のポートを有する、腹水濾過器。
（６）（５）に記載の腹水濾過器と、前記腹水濾過器で濾過された濾過液を濃縮する腹水濃縮器と、を少なくとも備え、前記腹水濾過器において内圧濾過によって腹水が処理される腹水処理システム。
In order to improve such conventional defects, the present inventor has conducted extensive research on improvement of fractionation characteristics of cell components such as cancer cells and blood cell components, and suppression of deterioration over time, and results in separation efficiency. It was found that the deterioration with time greatly depends on the surface structure of the hollow fiber membrane. In other words, by controlling the pore structure of the inner surface and outer surface of the hollow fiber membrane, it is found that it is possible to treat a large amount of ascites by reducing deterioration over time due to clogging in the membrane and completing the present invention. It came to. That is, the present invention has the following configuration.
(1) A hollow fiber membrane for recovering useful protein components by filtering body cavity fluid, and filtering the total amount of simulated ascites solution with a total protein concentration of 6.0 g / dl, leukocytes 1000 / μl, and erythrocytes 6000 / μl Ascites filtration hollow fiber in which no hemolysis occurs, the amount of filtrate obtained before the transmembrane pressure rises to 300 mmHg is 4 L / m 2 or more, and the maximum pore size is 0.2 μm or less film.
(2) The hollow fiber membrane according to (1), wherein the depth of the hole on the inner surface of the hollow fiber membrane is 5 μm or more and the size of the hole is 5 μm or more and 30 μm or less.
(3) The hollow fiber membrane according to (1) or (2), wherein the hollow fiber membrane is composed of a hydrophobic polymer and a hydrophilic polymer.
(4) The hollow fiber membrane according to (3), wherein the hydrophobic polymer is a polysulfone-based resin and the hydrophilic polymer is polyvinylpyrrolidone.
(5) An ascites filter containing the hollow fiber membrane according to any one of (1) to (4), wherein two or more headers communicating with the lumen of the hollow fiber membrane and the outer cavity of the hollow fiber membrane An ascites filter having two or more ports in communication.
(6) Ascites comprising at least ascites filter according to (5) and an ascites concentrator for concentrating the filtrate filtered by the ascites filter, wherein the ascites is treated by internal pressure filtration in the ascites filter Processing system.
本発明の中空糸膜は、がん細胞や血球細胞などの細胞成分を含むがん性腹水を処理する際に、膜の目詰まりが少なく、多量の腹水が処理できるため、洗浄液を流して濾過膜を洗浄したりするという煩雑な操作を必要としない。また、目詰まりによる中空糸膜の交換も少なくなる。よって、施行者の手技を容易にでき、経済面の負担も少なくなる。また、処理時間が短くなるため、患者の拘束時間も短くなる。 The hollow fiber membrane of the present invention is less clogged when treating cancerous ascites containing cell components such as cancer cells and blood cells, so that a large amount of ascites can be treated. The complicated operation of washing the membrane is not necessary. Moreover, the replacement of the hollow fiber membrane due to clogging is also reduced. Therefore, the procedure of the enforcer can be facilitated, and the economic burden is reduced. Further, since the processing time is shortened, the patient's restraint time is also shortened.
以下、本発明を詳細に説明する。 Hereinafter, the present invention will be described in detail.
本発明において、中空糸膜は、総タンパク濃度６．０ｇ／ｄｌ、白血球１０００／μｌ、赤血球６０００／μｌの擬似腹水溶液を全量濾過した際に、膜間圧力差が３００ｍｍＨｇに上昇するまでに得られる濾液量が４Ｌ／ｍ２以上である。現処理システムにおいて、腹水貯留バックの容量は４Ｌであり、濾液量が前記を下回ると膜面積の大きな濾過フィルタを必要とするとか、処理途中に濾過フィルタを交換する必要が生じる。 In the present invention, the hollow fiber membrane is obtained until the transmembrane pressure difference rises to 300 mmHg when all the simulated ascites solution having a total protein concentration of 6.0 g / dl, leukocytes 1000 / μl, and erythrocytes 6000 / μl is filtered. The amount of filtrate obtained is 4 L / m 2 or more. In the current processing system, the capacity of the ascites reservoir bag is 4L, and if the amount of filtrate falls below the above, a filtration filter having a large membrane area is required or the filtration filter needs to be replaced during the processing.
本発明において、中空糸膜の最大孔径は０．２μｍ以下である。最大孔径は、後述するバブルポイント法により測定された孔径を示し、最大孔径が０．２μｍ以下であれば、腹水に含まれる細菌やバクテリア等を９９％以上除去することが可能である。また、最大孔径が小さすぎると、有用成分であるアルブミン等の透過性が低下するため、最大孔径は０．０１μｍ以上であるのが好ましい。 In the present invention, the maximum pore diameter of the hollow fiber membrane is 0.2 μm or less. The maximum pore diameter indicates a pore diameter measured by a bubble point method to be described later. If the maximum pore diameter is 0.2 μm or less, 99% or more of bacteria and bacteria contained in ascites can be removed. In addition, if the maximum pore size is too small, the permeability of albumin or the like, which is a useful component, is reduced. Therefore, the maximum pore size is preferably 0.01 μm or more.
本発明の中空糸膜は、中空糸膜の内側から外側に向かって濾過を行う、いわゆる内圧濾過で用いてもよいし、中空糸膜の外側から内側に向かって濾過を行う外圧濾過で用いてもよいが、内圧濾過において好ましく用いられる。そのため、中空糸膜内表面の孔の平均深さは３μｍ以上であるのが好ましい。本発明において、中空糸膜内表面の孔の平均深さは、後述するようにレーザー顕微鏡を用いて測定したものである。中空糸膜内表面の孔の平均深さが浅すぎると、すなわち内表面の比表面積が小さくなるためか、経時的な処理速度の低下や処理量の低下が大きくなる。一方、内表面の孔の平均深さが深すぎると、逆洗等による洗浄性が低下する。したがって、中空糸膜内表面の孔の平均深さは、４μｍ以上１０μｍ以下がより好ましい。 The hollow fiber membrane of the present invention may be used in so-called internal pressure filtration that performs filtration from the inside to the outside of the hollow fiber membrane, or may be used in external pressure filtration that performs filtration from the outside to the inside of the hollow fiber membrane. However, it is preferably used in internal pressure filtration. Therefore, the average depth of the holes on the inner surface of the hollow fiber membrane is preferably 3 μm or more. In the present invention, the average depth of the holes on the inner surface of the hollow fiber membrane is measured using a laser microscope as described later. If the average depth of the pores on the inner surface of the hollow fiber membrane is too shallow, that is, the specific surface area of the inner surface is decreased, the processing speed and the processing amount are decreased with time. On the other hand, if the average depth of the holes on the inner surface is too deep, the washability due to backwashing or the like deteriorates. Therefore, the average depth of the holes on the inner surface of the hollow fiber membrane is more preferably 4 μm or more and 10 μm or less.
本発明において、中空糸膜内表面の平均孔径は、５μｍ以上３０μｍ以下が好ましく、より好ましくは１０μｍ以上２５μｍ以下である。本発明において、中空糸膜内表面の平均孔径は、後述するようにレーザー顕微鏡を用いて測定したものである。平均孔径が小さすぎる場合には、満足する腹水処理性能が確保できず、また平均孔径が大きすぎる場合には血球成分にダメージが加わり、溶血等の問題が発生する。 In the present invention, the average pore diameter of the inner surface of the hollow fiber membrane is preferably 5 μm or more and 30 μm or less, more preferably 10 μm or more and 25 μm or less. In the present invention, the average pore diameter on the inner surface of the hollow fiber membrane is measured using a laser microscope as described later. When the average pore diameter is too small, satisfactory ascites treatment performance cannot be ensured, and when the average pore diameter is too large, the blood cell component is damaged and problems such as hemolysis occur.
本発明において、中空糸膜は、疎水性高分子と親水性高分子から構成されるのが好ましい。疎水性高分子としては、ポリスルホン系樹脂が好ましく、下記一般式（１）で示される繰り返し単位を有するポリスルホン樹脂（以下、ＰＳｆと略記する）や下記一般式（２）で示されるポリエーテルスルホン樹脂（以下、ＰＥＳと略記する）がポリスルホン系樹脂として広く市販されており、入手も容易なため好ましい。
本発明において、親水性高分子としては、ポリスルホン系樹脂とミクロな相分離構造を形成するものが好ましく用いられる。ポリエチレングリコール、ポリビニルアルコール、カルボキシメチルセルロース、ポリビニルピロリドン等を挙げる事ができるが、安全性や経済性の面よりポリビニルピロリドンを用いるのが好ましい実施態様である。該ポリビニルピロリドンは、Ｎ−ビニルピロリドンをビニル重合させた水溶性の高分子化合物であり、ＢＡＳＦ社より「コリドン」、ＩＳＰ社より「プラスドン」、第一工業製薬社より「ピッツコール」の商品名で市販されており、それぞれ各種の分子量の製品がある。一般には、親水性の付与効率では低分子量のもの（重量平均分子量３０万以下）が、一方、溶出量を低くする点では高分子量のもの（重量平均分子量３０万超）を用いるのが好適であるが、最終製品の中空糸膜束の要求特性に合わせて適宜選択される。単一の分子量のものを用いても良いし、分子量の異なる製品を２種以上混合して用いても良い。また、市販の製品を精製し、例えば分子量分布をシャープにしたものを用いても良い。 In the present invention, as the hydrophilic polymer, those that form a micro phase separation structure with a polysulfone resin are preferably used. Polyethylene glycol, polyvinyl alcohol, carboxymethyl cellulose, polyvinyl pyrrolidone and the like can be mentioned, but it is a preferred embodiment that polyvinyl pyrrolidone is used from the viewpoint of safety and economy. The polyvinyl pyrrolidone is a water-soluble polymer compound obtained by vinyl polymerization of N-vinyl pyrrolidone. There are products of various molecular weights. In general, it is preferable to use a low molecular weight (weight average molecular weight of 300,000 or less) in terms of hydrophilic imparting efficiency, and a high molecular weight (weight average molecular weight greater than 300,000) in terms of lowering the elution amount. However, it is appropriately selected according to the required characteristics of the hollow fiber membrane bundle of the final product. Those having a single molecular weight may be used, or two or more products having different molecular weights may be mixed and used. Moreover, you may use what refine | purified a commercial product and sharpened molecular weight distribution, for example.
本発明において、中空糸膜は、内径が２００μｍ以上５００μｍ以下であることが好ましい。内径が２００μｍよりも小さいと、中空糸膜の中空部を流れる濾液の流動圧損が大きくなるため流量を大きくできないことがある。また、内径が５００μｍよりも大きいと、中空糸膜製造時の収率が低下することがある。 In the present invention, the hollow fiber membrane preferably has an inner diameter of 200 μm or more and 500 μm or less. If the inner diameter is smaller than 200 μm, the flow pressure loss of the filtrate flowing through the hollow portion of the hollow fiber membrane increases, and the flow rate may not be increased. Moreover, when an internal diameter is larger than 500 micrometers, the yield at the time of hollow fiber membrane manufacture may fall.
本発明において、中空糸膜は、膜厚が５０μｍ以上１００μｍ以下であることが好ましい。膜厚が５０μｍよりも小さいと、濾液中に細胞等が漏れることがある。また、膜厚が１００μｍよりも大きいと、膜抵抗が大きくなるため膜間圧力差（ＴＭＰ、Ｔｒａｎｓ Ｍｅｍｂｒａｎｅ Ｐｒｅｓｓｕｒｅ）が上昇しやすくなる問題がある。 In the present invention, the hollow fiber membrane preferably has a thickness of 50 μm or more and 100 μm or less. When the film thickness is smaller than 50 μm, cells or the like may leak into the filtrate. On the other hand, if the film thickness is larger than 100 μm, the film resistance increases, and therefore there is a problem that the pressure difference between films (TMP, Trans Membrane Pressure) tends to increase.
以下、中空糸膜の製造について、詳細に説明する。
本発明の中空糸膜の製造方法は、公知の手段を用いることができるが、乾湿式紡糸法を用いるのが好ましい。具体的には、ポリスルホン系樹脂、ＰＶＰ、ポリスルホン系樹脂およびＰＶＰの共通溶媒、必要に応じてポリスルホン系樹脂の非溶媒を混練、溶解した製膜溶液を二重管ノズルのスリット部から吐出し、中心部から芯液を同時に吐出し、エアギャップを経て外部凝固液に浸漬することで中空糸膜を得ることができる。
Hereinafter, the production of the hollow fiber membrane will be described in detail.
The hollow fiber membrane production method of the present invention can employ known means, but preferably uses a dry and wet spinning method. Specifically, polysulfone-based resin, PVP, polysulfone-based resin and PVP common solvent, if necessary, a non-solvent of polysulfone-based resin is kneaded and discharged from the slit portion of the double tube nozzle, A hollow fiber membrane can be obtained by simultaneously discharging the core liquid from the center and immersing it in an external coagulation liquid through an air gap.
本発明において、前記溶媒は、Ｎ−メチル−２−ピロリドン（以下、ＮＭＰと略記する）、Ｎ，Ｎ−ジメチルホルムアミド（以下、ＤＭＦと略記する）、Ｎ，Ｎ−ジメチルアセトアミド（以下、ＤＭＡｃと略記する）、ジメチルスルホキシド（以下、ＤＭＳＯと略記する）、ε−カプロラクタムなどを使用することができるが、ＮＭＰ、ＤＭＦ、ＤＭＡｃなどが好ましく、ＮＭＰがより好ましい。 In the present invention, the solvent is N-methyl-2-pyrrolidone (hereinafter abbreviated as NMP), N, N-dimethylformamide (hereinafter abbreviated as DMF), N, N-dimethylacetamide (hereinafter referred to as DMAc). (Abbreviated), dimethyl sulfoxide (hereinafter abbreviated as DMSO), ε-caprolactam and the like can be used, but NMP, DMF, DMAc and the like are preferable, and NMP is more preferable.
また、製膜溶液には、ポリスルホン系樹脂に対する非溶媒を添加するのが好ましい。例えば、エチレングリコール（以下、ＥＧと略記する）、プロピレングリコール（以下、ＰＧと略記する）、ジエチレングリコール（以下、ＤＥＧと略記する）、トリエチレングリコール（以下、ＴＥＧと略記する）、ポリエチレングリコール（以下、ＰＥＧと略記する）、グリセリン、水などが例示されるが、ＤＥＧ、ＴＥＧ、ＰＥＧなどが好ましく、ＴＥＧがより好ましい。 In addition, it is preferable to add a non-solvent for the polysulfone resin to the membrane forming solution. For example, ethylene glycol (hereinafter abbreviated as EG), propylene glycol (hereinafter abbreviated as PG), diethylene glycol (hereinafter abbreviated as DEG), triethylene glycol (hereinafter abbreviated as TEG), polyethylene glycol (hereinafter abbreviated as “EG”). , Abbreviated as PEG), glycerin, water and the like are exemplified, but DEG, TEG, PEG and the like are preferable, and TEG is more preferable.
製膜溶液、芯液および外部凝固液における溶媒／非溶媒の比は、中空糸膜構造の制御に重要な要因となる。溶媒に対して非溶媒が同量かやや過剰気味であることが好ましく、具体的には、溶媒／非溶媒比が重量比で３５／６５〜５５／４５であることが好ましく、４０／６０〜５０／５０がより好ましい。溶媒の含有量が少なすぎると膜表面の凝固が進行しやすくなるため、膜断面に欠点が生じやすくなり溶血などの不具合が発生しやすくなる。また、溶媒含有量が多すぎると、相分離の進行が過度に抑制され、大孔径の空孔が生じやすくなり、最大孔径の維持が出来なくなる。 The ratio of solvent / non-solvent in the membrane-forming solution, core solution and external coagulation solution is an important factor for controlling the hollow fiber membrane structure. It is preferable that the non-solvent is the same amount as the solvent, or is slightly excessive, and specifically, the solvent / non-solvent ratio is preferably 35/65 to 55/45 by weight, and 40/60 to 50/50 is more preferable. When the content of the solvent is too small, the film surface is likely to be coagulated, so that the cross section of the film is liable to cause defects and problems such as hemolysis are liable to occur. Moreover, when there is too much solvent content, the progress of phase separation will be suppressed too much, and it will become easy to produce a void | hole with a large pore diameter, and it will become impossible to maintain a maximum pore diameter.
製膜溶液における疎水性高分子の濃度は、製膜が可能であれば特に制限されないが、１０〜２５重量％程度が好ましく、１５〜２０重量％がより好ましい。高い透過性を得るには疎水性高分子の濃度は低いほうが好ましいが、過度に低いと強度の低下や、分離特性の悪化を招く可能性がある。 The concentration of the hydrophobic polymer in the film forming solution is not particularly limited as long as film formation is possible, but is preferably about 10 to 25% by weight, and more preferably 15 to 20% by weight. In order to obtain high permeability, it is preferable that the concentration of the hydrophobic polymer is low. However, if the concentration is too low, strength may be lowered and separation characteristics may be deteriorated.
親水性高分子の添加量は、製膜に支障をきたすことなく、中空糸膜に親水性を付与し、被処理液濾過時の非特異吸着を抑制するのに十分な量であれば特に制限されないが、製膜溶液における親水性高分子の濃度として８〜１２重量％程度が好ましい。親水性高分子の添加量が少ないと、膜への親水性付与が不十分となり、膜特性の保持性が低下する可能性がある。逆に、多いと、親水性付与効果が飽和してしまい効率が良くなく、また、製膜溶液の相分離（凝固）が過度に進行しやすくなり、操業性が悪化するのに加え、本発明の好ましい膜構造を形成するのに不利となる。 The amount of the hydrophilic polymer added is not particularly limited as long as it is sufficient to impart hydrophilicity to the hollow fiber membrane and prevent non-specific adsorption during filtration of the liquid to be processed without affecting the membrane formation. However, the concentration of the hydrophilic polymer in the film forming solution is preferably about 8 to 12% by weight. If the amount of the hydrophilic polymer added is small, hydrophilicity imparting to the film becomes insufficient, and the retention of film characteristics may be reduced. On the other hand, if the amount is too large, the hydrophilicity-imparting effect is saturated and the efficiency is not good, and the phase separation (coagulation) of the film-forming solution is likely to proceed excessively, and the operability is deteriorated. It is disadvantageous to form a preferable film structure.
中空糸膜の製膜時に使用される芯液の組成は、製膜溶液に含まれる溶媒および／または非溶媒を主成分とした液体を使用するのが好ましい。ただし、製膜溶液に含まれる溶媒のみでは、中空部（内腔）壁面での凝固が過度に抑制されるため好ましい表面構造を得ることができない。従って、溶媒と非溶媒の混合液、溶媒と水の混合液、溶媒と非溶媒と水の混合液のいずれかを使用するのが好ましい。芯液に含まれる溶媒（溶媒＋非溶媒）の量を８２〜８６重量％程度とするのが好ましい。また、溶媒の量が少ないと凝固が進行しやすくなり、膜構造が緻密になり過ぎてしまう。このため、濾過性能の低下を招く可能性が大きくなる。また、溶媒の量が大きすぎると製膜原液の凝固が不十分となり中空糸膜をノズルより引き出せなくなる。 As the composition of the core liquid used for forming the hollow fiber membrane, it is preferable to use a liquid mainly composed of a solvent and / or a non-solvent contained in the membrane forming solution. However, a preferable surface structure cannot be obtained with only the solvent contained in the film-forming solution because coagulation on the wall surface of the hollow portion (lumen) is excessively suppressed. Therefore, it is preferable to use any one of a mixed solution of a solvent and a non-solvent, a mixed solution of a solvent and water, and a mixed solution of a solvent, non-solvent, and water. The amount of the solvent (solvent + non-solvent) contained in the core liquid is preferably about 82 to 86% by weight. Further, when the amount of the solvent is small, solidification tends to proceed, and the film structure becomes too dense. For this reason, possibility that the fall of filtration performance will be increased. On the other hand, if the amount of the solvent is too large, the membrane-forming stock solution is not sufficiently solidified and the hollow fiber membrane cannot be pulled out from the nozzle.
外部凝固液は、溶媒、非溶媒、および水との混合液を使用するのが好ましい。この際、外部凝固液中に含まれる溶媒と非溶媒の重量比率は、製膜溶液の溶媒／非溶媒比率と同一であることが好ましい。製膜溶液に使用されるのと同一の溶媒および非溶媒を、製膜溶液中の比率と同一にして混合し、これに水を添加して希釈したものが好ましく用いられる。製膜溶液、芯液、外部凝固液の溶媒／非溶媒比率を同一とすることにより、外部凝固液の組成変化を抑制することができ、製造コスト、管理の面より好ましい。 As the external coagulation liquid, a mixed liquid of a solvent, a non-solvent, and water is preferably used. At this time, the weight ratio of the solvent and the non-solvent contained in the external coagulation liquid is preferably the same as the solvent / non-solvent ratio of the film forming solution. The same solvent and non-solvent that are used for the film-forming solution are mixed in the same ratio as in the film-forming solution, and diluted by adding water to this is preferably used. By making the solvent / non-solvent ratio of the film forming solution, the core solution, and the external coagulating liquid the same, it is possible to suppress the composition change of the external coagulating liquid, which is preferable from the viewpoint of manufacturing cost and management.
本発明において、内表面を特定の形状とするためには、外部凝固液中の水の含有率を４０〜６０重量％程度とするのが好ましい。水の含有率が多いと凝固が進行しやすくなり、膜構造が緻密化して濾過特性が低下してしまう。水の含有率が少ないと、外部凝固液中で製膜溶液の凝固が不十分となり、中空糸膜を凝固液中より引き出せなくなる。また、外部凝固液の温度は、好ましくは５５〜７０℃程度である。温度が高いと凝固が不十分になり最大孔径が大きくなる傾向がある。 In the present invention, in order to make the inner surface have a specific shape, the content of water in the external coagulation liquid is preferably about 40 to 60% by weight. If the water content is high, coagulation tends to proceed, the membrane structure becomes dense, and the filtration characteristics deteriorate. When the water content is low, the membrane-forming solution is insufficiently coagulated in the external coagulation liquid, and the hollow fiber membrane cannot be drawn out from the coagulation liquid. The temperature of the external coagulation liquid is preferably about 55 to 70 ° C. When the temperature is high, solidification becomes insufficient and the maximum pore size tends to increase.
本発明において、膜構造を制御する他の因子として、ノズル温度が挙げられる。ノズル温度が低いと、凝固が進行しやすくなり、膜構造が緻密化して透過性が低下してしまう。また、ノズル温度が高いと相分離の進行が過度に抑制され、大孔径の空孔が生じやすくなり、分離特性や強度の低下を招く可能性が大きくなってしまう。したがって、ノズル温度は、好ましくは６０〜７５℃程度である。 In the present invention, nozzle temperature is another factor that controls the film structure. If the nozzle temperature is low, solidification tends to proceed, the membrane structure becomes dense, and the permeability is lowered. Moreover, when the nozzle temperature is high, the progress of phase separation is excessively suppressed, and pores having a large pore diameter are likely to be generated, which increases the possibility of causing a decrease in separation characteristics and strength. Therefore, the nozzle temperature is preferably about 60 to 75 ° C.
紡糸速度については、欠陥のない中空糸膜が得られ、生産性が確保できれば特に制限されないが、好ましくは、５〜１００ｍ／ｍｉｎ程度である。紡速が低すぎると、生産性が低下することがある。紡速が高すぎると凝固を完了させるために外部凝固浴の大型化が必要になるとか、外部凝固浴からの外部凝固液の持ち出しが多くなるなど、コスト面で不利になることがある。 The spinning speed is not particularly limited as long as a hollow fiber membrane having no defect can be obtained and productivity can be secured, but it is preferably about 5 to 100 m / min. If the spinning speed is too low, the productivity may decrease. If the spinning speed is too high, it may be disadvantageous in terms of cost, for example, it is necessary to enlarge the size of the external coagulation bath in order to complete the coagulation, or the amount of external coagulation liquid taken out from the external coagulation bath is increased.
中空糸膜は、外部凝固浴を通過した後、引き続き洗浄工程に導かれ、３０〜８０℃程度の温水で洗浄される。 After passing through the external coagulation bath, the hollow fiber membrane is subsequently guided to a washing step and washed with warm water of about 30 to 80 ° C.
洗浄工程を経た中空糸膜は、カセ巻機によって束に巻き取った後、所定の長さに切断して中空糸膜束を得る。得られた中空糸膜の芯液を遠心機にて脱液する。 The hollow fiber membranes that have undergone the washing step are wound into a bundle by a casserole winder and then cut into a predetermined length to obtain a hollow fiber membrane bundle. The hollow fiber membrane core liquid obtained is drained with a centrifuge.
芯液を遠心脱液した中空糸膜の安全性を確保するため熱水洗浄する。熱水の温度は、好ましくは６０〜９５℃程度、処理時間は５〜１５分程度である。 Hot water cleaning is performed to ensure the safety of the hollow fiber membrane from which the core liquid is centrifuged and drained. The temperature of the hot water is preferably about 60 to 95 ° C., and the treatment time is about 5 to 15 minutes.
中空糸膜の乾燥方法は、風乾、減圧乾燥、熱風乾燥、マイクロ波乾燥など通常利用される乾燥方法が広く利用できる。乾燥に先立って、上記の加熱処理を施しておくことで、乾燥による膜特性の変化も抑制することができる。熱風乾燥時の熱風温度は、特に制限されないが、好ましくは２５〜１００℃、より好ましくは３０〜８０℃である。これより温度が低いと乾燥までに長時間を要し、これより温度が高いと熱風生成のためのエネルギーコストが高くなる。 As a method for drying the hollow fiber membrane, commonly used drying methods such as air drying, reduced pressure drying, hot air drying, and microwave drying can be widely used. By performing the above heat treatment prior to drying, changes in film properties due to drying can also be suppressed. Although the hot air temperature at the time of hot air drying is not specifically limited, Preferably it is 25-100 degreeC, More preferably, it is 30-80 degreeC. If the temperature is lower than this, it takes a long time to dry, and if the temperature is higher than this, the energy cost for generating hot air increases.
腹水濾過器は、中空糸膜束を筒状容器へ挿入し、両束端にポリウレタン等のポッティング剤を注入して両端をシールした後、ポッティング部を切断除去して中空糸膜端面を開口させ、ヘッダーを取り付けることにより作製することができる。 The ascites filter inserts a hollow fiber membrane bundle into a cylindrical container, injects a potting agent such as polyurethane at both ends of the bundle and seals both ends, then cuts and removes the potting portion to open the end surface of the hollow fiber membrane. It can be produced by attaching a header.
図１は、腹水濾過器１の構成の概略を示す図である。腹水濾過器１は、筒状容器２の内部にその長手方向に沿って複数の中空糸膜３が配置されている。筒状容器２は、中空糸膜内腔に連通するヘッダー６ａ、６ｂおよび中空糸膜外腔に連通するポート７ａ、７ｂを備えている。複数の中空糸膜３の両端部は、筒状容器２の両端部においてポッティング剤８により接着されている。かかる構成により、腹水がヘッダー６ａまたは６ｂから中空糸膜３の内腔に流入し、中空糸膜３を透過することにより腹水から病因物質が除去される。中空糸膜３の外腔に透過された濾過液は、ポート７ａまたは７ｂから排出される。 FIG. 1 is a diagram showing an outline of the configuration of the ascites filter 1. The ascites filter 1 has a plurality of hollow fiber membranes 3 arranged in a cylindrical container 2 along the longitudinal direction thereof. The cylindrical container 2 includes headers 6a and 6b communicating with the hollow fiber membrane lumen and ports 7a and 7b communicating with the hollow fiber membrane outer space. Both ends of the plurality of hollow fiber membranes 3 are bonded to each other at both ends of the cylindrical container 2 by a potting agent 8. With this configuration, ascites flows from the header 6a or 6b into the lumen of the hollow fiber membrane 3 and permeates through the hollow fiber membrane 3, whereby the pathogenic substance is removed from the ascites. The filtrate that has permeated into the outer space of the hollow fiber membrane 3 is discharged from the port 7a or 7b.
図２は、腹水濾過器１を備えた腹水処理システムの構成の概略図である。腹水処理システム１１は、腹水バッグ１２と、腹水濾過器１と、腹水濃縮器１３と、濃縮腹水バッグ１４と、腹水バッグ１２と腹水濾過器１を接続する第１の流路１５と、腹水濾過器１と腹水濃縮器１３を接続する第２の流路１６と、腹水濃縮器１３と濃縮腹水バッグ１４を接続する第３の流路１７とを有している。 FIG. 2 is a schematic diagram of the configuration of the ascites treatment system including the ascites filter 1. Ascites treatment system 11 includes ascites bag 12, ascites filter 1, ascites concentrator 13, concentrated ascites bag 14, first flow path 15 connecting ascites bag 12 and ascites filter 1, and ascites filtration. The second flow path 16 that connects the container 1 and the ascites concentrator 13, and the third flow path 17 that connects the ascites concentrator 13 and the concentrated ascites bag 14.
第１の流路１５は、ポリ塩化ビニルなどの軟質性のチューブであり、腹水バッグ１２の出口から腹水濾過器１のヘッダー６ａに接続されている。第１の流路１５には、ローラーポンプ１８が設けられ、腹水バッグ１２の腹水を腹水濾過器１に送ることができる。なお、ローラーポンプ１８を設けずに、腹水バッグ１２の腹水を重力落下により腹水濾過器１に供給するようにしてもよい。 The first flow path 15 is a soft tube such as polyvinyl chloride, and is connected to the header 6 a of the ascites filter 1 from the outlet of the ascites bag 12. A roller pump 18 is provided in the first flow path 15, and the ascites in the ascites bag 12 can be sent to the ascites filter 1. In addition, you may make it supply the ascites of the ascites bag 12 to the ascites filter 1 by gravity fall, without providing the roller pump 18. FIG.
第２の流路１６は、ポリ塩化ビニルなどの軟質性チューブであり、腹水濾過器１のポート７ｂから腹水濃縮器１３の上部ヘッダーに接続されている。第２の流路１６には、ローラーポンプ１９が設けられ、腹水濾過器１で濾過された濾過液を腹水濃縮器１３に送ることができる。 The second flow path 16 is a soft tube such as polyvinyl chloride, and is connected from the port 7 b of the ascites filter 1 to the upper header of the ascites concentrator 13. A roller pump 19 is provided in the second flow path 16, and the filtrate filtered by the ascites filter 1 can be sent to the ascites concentrator 13.
第３の流路１７は、ポリ塩化ビニルなどの軟質性チューブであり、腹水濃縮器１３の下部ヘッダーから濃縮腹水バッグ１４に接続されている。 The third flow path 17 is a soft tube such as polyvinyl chloride, and is connected from the lower header of the ascites concentrator 13 to the concentrated ascites bag 14.
濃縮腹水バッグ１４は、ポリ塩化ビニルなどの軟質性の樹脂からなる容器であり、腹水濃縮器１３で濃縮された有用物質を含む濃縮液を収容できる。 The concentrated ascites bag 14 is a container made of a soft resin such as polyvinyl chloride, and can contain a concentrated liquid containing useful substances concentrated by the ascites concentrator 13.
以下、本発明の有効性について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。なお、以下の実施例における評価方法は以下の通りである。 Hereinafter, the effectiveness of the present invention will be described with reference to examples, but the present invention is not limited thereto. In addition, the evaluation methods in the following examples are as follows.
（腹水濾過器の作製）
中空糸膜を約３０ｃｍの長さに切断し、ポリエチレンフィルムで巻いて中空糸膜束とした。この中空糸膜束を円筒型のポリカーボネート製筒状容器に挿入し、両末端をウレタンポッティング剤で固めた。端部を切断して、両末端が開口した腹水濾過器を得た。中空糸膜の本数は、適宜設定した。なお、円筒状の筒状容器は円筒面２箇所にポートを設け、中空糸膜の外面を流体が灌流できるようにし、両末端にはヘッダーを装着して、中空糸膜の内面を流体が灌流できるようにした。
(Production of ascites filter)
The hollow fiber membrane was cut into a length of about 30 cm and wound with a polyethylene film to form a hollow fiber membrane bundle. This hollow fiber membrane bundle was inserted into a cylindrical polycarbonate cylindrical container, and both ends were hardened with a urethane potting agent. The ascites filter with both ends opened was obtained by cutting the ends. The number of hollow fiber membranes was set as appropriate. The cylindrical cylindrical container is provided with ports at two locations on the cylindrical surface so that fluid can be perfused on the outer surface of the hollow fiber membrane, headers are attached to both ends, and fluid is perfused on the inner surface of the hollow fiber membrane. I was able to do it.
（ループ型ミニモジュールの作製）
中空糸膜を約４０ｃｍの長さに切断し、ループ型に束ね、端部をパラフィンフィルムで固定した。このループ型中空糸膜束の端部をパイプ（スリーブ）に挿入し、ウレタンポッティング剤で固めた。端部を切断して、端部がスリーブで固定されたループ型ミニモジュールを得た。中空糸膜の本数は、適宜設定した。
(Production of loop type mini module)
The hollow fiber membrane was cut into a length of about 40 cm, bundled in a loop shape, and the end was fixed with a paraffin film. The end of this loop type hollow fiber membrane bundle was inserted into a pipe (sleeve) and hardened with a urethane potting agent. The end portion was cut to obtain a loop type mini module having the end portion fixed by a sleeve. The number of hollow fiber membranes was set as appropriate.
（膜面積の計算）
腹水濾過器の膜面積は中空糸膜の内径を基準として求めた。次式［１］によって腹水濾過器の膜面積が計算できる。
Ａ＝ｎ×π×ｄ×Ｌ ［１］
ここで、ｎは中空糸膜の本数、πは円周率、ｄは中空糸膜の内径［ｍ］、Ｌは腹水濾過器における中空糸膜の有効長［ｍ］である。
(Calculation of membrane area)
The membrane area of the ascites filter was determined based on the inner diameter of the hollow fiber membrane. The membrane area of the ascites filter can be calculated by the following equation [1].
A = n × π × d × L [1]
Here, n is the number of hollow fiber membranes, π is the circumference, d is the inner diameter [m] of the hollow fiber membrane, and L is the effective length [m] of the hollow fiber membrane in the ascites filter.
（最大孔径の測定）
ループ型ミニモジュール全体を十分な量の２−プロパノール（以下ｉＰＡと略記する）に３分間浸漬して、内腔、膜壁部分にｉＰＡを行き渡らせた。ループ型モジュールの中空糸膜部分全体がｉＰＡに浸った状態で、スリーブを圧力計を装着して加圧圧力がモニターできるようにした窒素ラインに接続し、加圧した。中空糸膜の膜壁部分からコンスタントに気泡が出始めたポイントをバブルポイントＰ［Ｐａ］として記録した。１サンプルにつき３回の測定を実施し、バブルポイントの測定値の平均値をそのサンプルのバブルポイントとした。さらに、次式［２］により、ｉＰＡで測定したバブルポイント（Ｐ［ｂａｒ］）から算出される最大孔径を得た。
最大孔径［μｍ］＝４γＣＯＳθ／Ｐ ［２］
γは、溶媒の表面張力（Ｎ／ｍ）を示す。また、θは、膜素材と溶媒との接触角（°）を示す。Ｐは、バブルポイント圧力（Ｐａ）を示す。ｉＰＡの表面張力γ＝２０．８、接触角０°よりＣＯＳθ=１で計算される。
(Maximum pore size measurement)
The entire loop type mini-module was immersed in a sufficient amount of 2-propanol (hereinafter abbreviated as iPA) for 3 minutes to spread iPA over the lumen and the membrane wall. With the entire hollow fiber membrane portion of the loop type module immersed in iPA, the sleeve was connected to a nitrogen line equipped with a pressure gauge so that the pressurized pressure could be monitored and pressurized. The point at which bubbles started to constantly emerge from the membrane wall portion of the hollow fiber membrane was recorded as the bubble point P [Pa]. Three measurements were performed per sample, and the average value of the measured values of bubble points was taken as the bubble point of the sample. Furthermore, the maximum pore diameter calculated from the bubble point (P [bar]) measured by iPA was obtained by the following equation [2].
Maximum pore diameter [μm] = 4γCOSθ / P [2]
γ represents the surface tension (N / m) of the solvent. Θ represents a contact angle (°) between the film material and the solvent. P represents bubble point pressure (Pa). iPA surface tension γ = 20.8, contact angle 0 °, COSθ = 1.
（擬似腹水処理性能の測定）
総タンパク質濃度を６．０±０．５ｇ／ｄｌに調整した牛血漿に、牛全血を遠心分離した際に得られるバフィー層を添加し、多項目血球分析装置(ｓｙｓｍｅｘ ｐｏｃｈ−１００ｉＶ Ｄｉｆｆ)により白血球１０００／μｌ、赤血球６０００／μｌに調整した。これを擬似腹水とした。調整した擬似腹水をローラーポンプにより５０ｍｌ／ｍｉｎの定速で腹水濾過器に送液した。このとき、腹水濾過器の中空糸膜内側出口は閉鎖状態で、濾液排出口は開放状態とした。中空糸膜内外にかかる圧力差(以下、ＴＭＰと略記する)が３００ｍｍＨｇに上昇するまでに得られる濾液量を測定した。
(Measurement of simulated ascites treatment performance)
A buffy layer obtained by centrifuging bovine whole blood was added to bovine plasma whose total protein concentration was adjusted to 6.0 ± 0.5 g / dl, and a multi-item blood cell analyzer (sysmex poch-100iV Diff) was used. White blood cells were adjusted to 1000 / μl and red blood cells to 6000 / μl. This was designated as simulated ascites. The adjusted simulated ascites was fed to the ascites filter at a constant speed of 50 ml / min by a roller pump. At this time, the hollow fiber membrane inner outlet of the ascites filter was closed, and the filtrate outlet was opened. The amount of filtrate obtained until the pressure difference (hereinafter abbreviated as TMP) applied to the inside and outside of the hollow fiber membrane increased to 300 mmHg was measured.
（溶血率測定）
総タンパク質濃度を６．０±０．５ｇ／ｄｌ、ヘマトクリット３２±２％に調整した牛全血を使用し、腹水濾過器の中空糸膜内側に２００ｍｌ／ｍｉｎ×３．５分送液した。その時に濾液側に出てきた液をサンプリングした(０分値)。サンプリング後、濾液側から濾過をかけ、濾液流量が１００ｍｌ／ｍｉｎになるように調整し、３０分循環後の濾液をサンプリングした(３０分値)。牛全血原液、０分値、３０分値のヘモグロビン濃度を多項目血球分析装置(ｓｙｓｍｅｘ ｐｏｃｈ−１００ｉＶ Ｄｉｆｆ)を用いて分析した。各分析値より溶血率を次式［３］により算出した。溶血率が０．２％以下であれば、溶血がないと判定する。
溶血率＝(３０分値−０分値)/元の牛全血 ［３］
(Measurement of hemolysis rate)
Using whole bovine blood whose total protein concentration was adjusted to 6.0 ± 0.5 g / dl and hematocrit 32 ± 2%, the solution was fed into the inside of the hollow fiber membrane of the ascites filter at 200 ml / min × 3.5 minutes. The liquid that came out to the filtrate side at that time was sampled (0 minute value). After sampling, filtration was performed from the filtrate side, the filtrate flow rate was adjusted to 100 ml / min, and the filtrate after circulation for 30 minutes was sampled (30 minute value). Bovine whole blood undiluted solution, 0 minute value and 30 minute hemoglobin concentration were analyzed using a multi-item blood cell analyzer (sysmex poch-100iV Diff). The hemolysis rate was calculated by the following equation [3] from each analysis value. If the hemolysis rate is 0.2% or less, it is determined that there is no hemolysis.
Hemolysis rate = (30 minute value-0 minute value) / original bovine whole blood [3]
（中空糸膜内表面の孔の大きさおよび深さの測定）
中空糸膜内表面の孔の平均深さと平均孔径は、中空糸膜を剃刀で割腹し、レーザー顕微鏡（ＫＥＹＥＮＣＥ、ＶＫ−８５００）によって倍率１５０倍で観察し、ＫＥＹＥＮＣＥ、ＶＫ ＡＮＡＬＹＺＥＲによって測定した。
(Measurement of pore size and depth on the inner surface of the hollow fiber membrane)
The average depth and average pore diameter of the inner surface of the hollow fiber membrane were measured with a KEYENCE and VK ANALYZER by observing the hollow fiber membrane with a razor and observing it with a laser microscope (KEYENCE, VK-8500) at a magnification of 150 times.
［実施例１］
ＰＥＳ（ＢＡＳＦ社製、６０２０Ｐ）１７．０重量％、ＰＶＰ（ＢＡＳＦ社製、コリドン（登録商標）Ｋ３０）１０．０重量％、ＮＭＰ（三菱化学社製）３２．８５重量％、ＴＥＧ（三菱化学社製）４０．１５重量％を混合、溶解し製膜溶液を得た。一方、ＮＭＰ３７．８重量％、ＴＥＧ４６．２重量％、ＲＯ水１６．０重量％の混合液を調製し、この溶液を芯液とした。二重管ノズルの環状部から前記製膜溶液を、中心部から前記芯液を吐出し、エアギャップを通過させた後、ＮＭＰ２６．１重量％、ＴＥＧ３１．９重量％、ＲＯ水４２．０重量％の混合液からなる外部凝固液に導いた。この際、ノズル温度は６７℃、外部凝固液温度は６３℃に設定した。さらに、外部凝固液から中空糸膜を引き出し、６０℃の水洗工程を通過させ、２５ｍ／ｍｉｎの紡速で綛に捲き上げた。得られた中空糸膜６７２０本の束を長さ４３ｃｍに切断し、ガーゼを巻いた後、８０℃のＲＯ水で水洗し、熱風乾燥機にて６０℃で乾燥させた。得られた乾燥中空糸膜の内径は２５０μｍ、膜厚は７５μｍであった。
[Example 1]
PES (BASF, 6020P) 17.0 wt%, PVP (BASF, Kollidon (registered trademark) K30) 10.0 wt%, NMP (Mitsubishi Chemical Corporation) 32.85 wt%, TEG (Mitsubishi Chemical) 40.15 wt% was mixed and dissolved to obtain a film forming solution. On the other hand, a mixed liquid of NMP 37.8 wt%, TEG 46.2 wt%, and RO water 16.0 wt% was prepared, and this solution was used as a core liquid. After discharging the film-forming solution from the annular part of the double tube nozzle and the core liquid from the center part and passing through the air gap, NMP 26.1% by weight, TEG 31.9% by weight, RO water 42.0% by weight % To an external coagulation liquid consisting of a mixed solution. At this time, the nozzle temperature was set to 67 ° C., and the external coagulating liquid temperature was set to 63 ° C. Further, the hollow fiber membrane was drawn out from the external coagulation liquid, passed through a water washing step at 60 ° C., and wound up into a kite at a spinning speed of 25 m / min. The resulting bundle of 6720 hollow fiber membranes was cut to a length of 43 cm, wound with gauze, washed with 80 ° C. RO water, and dried at 60 ° C. with a hot air dryer. The obtained dry hollow fiber membrane had an inner diameter of 250 μm and a film thickness of 75 μm.
得られた中空糸膜を４０ｃｍの長さに切断し、ループ型に束ね、端部をパラフィンフィルムで固定した。このループ型中空糸膜束の端部をパイプ（スリーブ）に挿入し、ウレタンポッティング剤で固めた。端部を切断して、端部がスリーブで固定されたループ型ミニモジュールを作製した。得られたループ型ミニモジュールを用い、最大孔径を測定した結果を表１に示す。 The obtained hollow fiber membrane was cut into a length of 40 cm, bundled in a loop shape, and the end was fixed with a paraffin film. The end of this loop type hollow fiber membrane bundle was inserted into a pipe (sleeve) and hardened with a urethane potting agent. The end portion was cut, and a loop type mini-module having the end portion fixed with a sleeve was produced. Table 1 shows the results of measuring the maximum pore size using the obtained loop type mini-module.
得られた中空糸膜束を筒状容器に挿入後、ポリウレタン樹脂で中空糸膜束端部と容器端部を液密に接着した。ポリウレタン樹脂が硬化した後、中空部が開口するように接着部の一部を切断し、ヘッダーを取り付けることにより腹水濾過器を作製した。得られた腹水濾過器を用い、擬似腹水処理性能と溶血率を測定した結果を表１に示す。 After the obtained hollow fiber membrane bundle was inserted into a cylindrical container, the end portion of the hollow fiber membrane bundle and the end portion of the container were liquid-tightly bonded with a polyurethane resin. After the polyurethane resin was cured, an ascites filter was prepared by cutting a part of the adhesive part so that the hollow part opened and attaching a header. Table 1 shows the results of measuring simulated ascites treatment performance and hemolysis rate using the obtained ascites filter.
［実施例２］
ＰＥＳ（ＢＡＳＦ社製、６０２０Ｐ）１７．３重量％、ＰＶＰ（ＢＡＳＦ社製、コリドン（登録商標）Ｋ３０）１０．０重量％、ＮＭＰ（三菱化学社製）３２．７１５重量％、ＴＥＧ（三菱化学社製）３９．９８５重量％を混合、溶解し製膜溶液を得た。得られた製膜溶液を用いて実施例１と同様にして中空糸膜を作製した。得られた乾燥中空糸膜の内径は２５０μｍ、膜厚は７５μｍであった。
[Example 2]
17.3% by weight of PES (manufactured by BASF, 6020P), 10.0% by weight of PVP (manufactured by BASF, Kollidon (registered trademark) K30), 32.715% by weight of NMP (manufactured by Mitsubishi Chemical), TEG (Mitsubishi Chemical) 39.985 wt% was mixed and dissolved to obtain a film forming solution. A hollow fiber membrane was produced in the same manner as in Example 1 using the obtained membrane-forming solution. The obtained dry hollow fiber membrane had an inner diameter of 250 μm and a film thickness of 75 μm.
得られた中空糸膜を用いて評価用モジュールおよび腹水濾過器を作製し、実施例と同様の実験を行った。 Using the obtained hollow fiber membrane, an evaluation module and an ascites filter were prepared, and an experiment similar to the example was performed.
［実施例３］
ＰＥＳ（ＢＡＳＦ社製、６０２０Ｐ）１６．７重量％、ＰＶＰ（ＢＡＳＦ社製、コリドン（登録商標）Ｋ３０）１０．０重量％、ＮＭＰ（三菱化学社製）３２．９８５重量％、ＴＥＧ（三菱化学社製）４０．３１５重量％を混合、溶解し製膜溶液を得た。得られた製膜溶液を用いて実施例１と同様にして中空糸膜を作製した。得られた乾燥中空糸膜の内径は２５０μｍ、膜厚は７５μｍであった。
[Example 3]
16.7% by weight of PES (manufactured by BASF, 6020P), 10.0% by weight of PVP (manufactured by BASF, Kollidon (registered trademark) K30), 32.985% by weight of NMP (manufactured by Mitsubishi Chemical), TEG (Mitsubishi Chemical) 40.315% by weight was mixed and dissolved to obtain a film forming solution. A hollow fiber membrane was produced in the same manner as in Example 1 using the obtained membrane-forming solution. The obtained dry hollow fiber membrane had an inner diameter of 250 μm and a film thickness of 75 μm.
得られた中空糸膜を用いて評価用モジュールおよび腹水濾過器を作製し、実施例と同様の実験を行った。 Using the obtained hollow fiber membrane, an evaluation module and an ascites filter were prepared, and an experiment similar to the example was performed.
［実施例４］
ＮＭＰ３６．９重量％、ＴＥＧ４５．１重量％、ＲＯ水１８．０重量％の混合液を芯液として用いた以外は実施例１と同様にして中空糸膜を作製した。得られた乾燥中空糸膜の内径は２５０μｍ、膜厚は７５μｍであった。
[Example 4]
A hollow fiber membrane was produced in the same manner as in Example 1 except that a mixed solution of 36.9% by weight of NMP, 45.1% by weight of TEG, and 18.0% by weight of RO water was used as the core solution. The obtained dry hollow fiber membrane had an inner diameter of 250 μm and a film thickness of 75 μm.
得られた中空糸膜を用いて評価用モジュールおよび腹水濾過器を作製し、実施例と同様の実験を行った。 Using the obtained hollow fiber membrane, an evaluation module and an ascites filter were prepared, and an experiment similar to the example was performed.
［実施例５］
ＮＭＰ３８．７重量％、ＴＥＧ４７．３重量％、ＲＯ水１４．０重量％の混合液を芯液として用いた以外は実施例１と同様にして中空糸膜を作製した。得られた乾燥中空糸膜の内径は２５０μｍ、膜厚は７５μｍであった。
[Example 5]
A hollow fiber membrane was prepared in the same manner as in Example 1 except that a mixed solution of NMP 38.7% by weight, TEG 47.3% by weight, and RO water 14.0% by weight was used as the core solution. The obtained dry hollow fiber membrane had an inner diameter of 250 μm and a film thickness of 75 μm.
得られた中空糸膜を用いて評価用モジュールおよび腹水濾過器を作製し、実施例と同様の実験を行った。 Using the obtained hollow fiber membrane, an evaluation module and an ascites filter were prepared, and an experiment similar to the example was performed.
［実施例６］
ノズル温度を６２℃とした以外は実施例１と同様にして中空糸膜を作製した。得られた乾燥中空糸膜の内径は２５０μｍ、膜厚は７５μｍであった。
[Example 6]
A hollow fiber membrane was produced in the same manner as in Example 1 except that the nozzle temperature was 62 ° C. The obtained dry hollow fiber membrane had an inner diameter of 250 μm and a film thickness of 75 μm.
得られた中空糸膜を用いて評価用モジュールおよび腹水濾過器を作製し、実施例と同様の実験を行った。 Using the obtained hollow fiber membrane, an evaluation module and an ascites filter were prepared, and an experiment similar to the example was performed.
［実施例７］
ノズル温度を７２℃とした以外は実施例１と同様にして中空糸膜を作製した。得られた乾燥中空糸膜の内径は２５０μｍ、膜厚は７５μｍであった。
[Example 7]
A hollow fiber membrane was produced in the same manner as in Example 1 except that the nozzle temperature was 72 ° C. The obtained dry hollow fiber membrane had an inner diameter of 250 μm and a film thickness of 75 μm.
得られた中空糸膜を用いて評価用モジュールおよび腹水濾過器を作製し、実施例と同様の実験を行った。 Using the obtained hollow fiber membrane, an evaluation module and an ascites filter were prepared, and an experiment similar to the example was performed.
［比較例１］
ノズル温度を７５℃とした以外は実施例３と同様にして中空糸膜を作製した。得られた乾燥中空糸膜の内径は２５０μｍ、膜厚は７５μｍであった。
[Comparative Example 1]
A hollow fiber membrane was produced in the same manner as in Example 3 except that the nozzle temperature was 75 ° C. The obtained dry hollow fiber membrane had an inner diameter of 250 μm and a film thickness of 75 μm.
得られた中空糸膜を用いて評価用モジュールおよび腹水濾過器を作製し、実施例と同様の実験を行った。 Using the obtained hollow fiber membrane, an evaluation module and an ascites filter were prepared, and an experiment similar to the example was performed.
［比較例２］
ノズル温度を５７℃とした以外は実施例２と同様にして中空糸膜を作製した。得られた乾燥中空糸膜の内径は２５０μｍ、膜厚は７５μｍであった。
[Comparative Example 2]
A hollow fiber membrane was produced in the same manner as in Example 2 except that the nozzle temperature was 57 ° C. The obtained dry hollow fiber membrane had an inner diameter of 250 μm and a film thickness of 75 μm.
得られた中空糸膜を用いて評価用モジュールおよび腹水濾過器を作製し、実施例と同様の実験を行った。 Using the obtained hollow fiber membrane, an evaluation module and an ascites filter were prepared, and an experiment similar to the example was performed.
［比較例３］
ポリエチレンおよびエチレンビニルアルコール共重合体からなる中空糸膜を内挿した腹水濾過器（ＡＨＦ（登録商標）−ＭＯＷ、旭化成メディカル社）を用いて実施例１と同様の実験を行った。
[Comparative Example 3]
The same experiment as in Example 1 was performed using an ascites filter (AHF (registered trademark) -MOW, Asahi Kasei Medical Co., Ltd.) in which a hollow fiber membrane made of polyethylene and an ethylene vinyl alcohol copolymer was inserted.
本発明の中空糸膜は、がん細胞や血球細胞などの細胞成分を含むがん性腹水を処理する際に、膜の目詰まりが少なく、多量の腹水が処理できるため、施行者の手技を容易にでき、経済面の負担も少なくなる。また、処理時間が短くなるため、患者の拘束時間も短くなる。また、これら腹水濾過濃縮再静注法として利用されるだけでなく、血漿分離膜への応用も期待できる。 The hollow fiber membrane of the present invention has less membrane clogging and can treat a large amount of ascites when treating cancerous ascites containing cell components such as cancer cells and blood cells. This is easy and the economic burden is reduced. Further, since the processing time is shortened, the patient's restraint time is also shortened. Moreover, it can be used not only as an ascites filtration concentration reinfusion method but also as a plasma separation membrane.
１ 腹水濾過器
２ 筒状容器
３ 中空糸膜
６ａ、６ｂ ヘッダー
７ａ、７ｂ ポート
８ ポッティング剤
１１ 腹水処理システム
１２ 腹水バッグ
１３ 腹水濃縮器
１４ 濃縮腹水バッグ
１５ 第１の流路
１６ 第２の流路
１７ 第３の流路
１８、１９ ローラーポンプ
DESCRIPTION OF SYMBOLS 1 Ascites filter 2 Cylindrical container 3 Hollow fiber membrane 6a, 6b Header 7a, 7b Port 8 Potting agent 11 Ascites treatment system 12 Ascites bag 13 Ascites concentrator 14 Concentrated ascites bag 15 1st flow path 16 2nd flow path 17 Third flow path 18, 19 Roller pump
Claims (6)
An ascites treatment system comprising at least the ascites filter according to claim 5 and an ascites concentrator for concentrating the filtrate filtered by the ascites filter, wherein ascites is treated by internal pressure filtration in the ascites filter. .
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