JP6469123B2 - Hollow fiber membrane type body fluid filtration device, operation method and filtration method of hollow fiber membrane type body fluid filtration device - Google Patents

Hollow fiber membrane type body fluid filtration device, operation method and filtration method of hollow fiber membrane type body fluid filtration device Download PDF

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JP6469123B2
JP6469123B2 JP2016554120A JP2016554120A JP6469123B2 JP 6469123 B2 JP6469123 B2 JP 6469123B2 JP 2016554120 A JP2016554120 A JP 2016554120A JP 2016554120 A JP2016554120 A JP 2016554120A JP 6469123 B2 JP6469123 B2 JP 6469123B2
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陽子 徳永
陽子 徳永
淳輔 末光
淳輔 末光
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Asahi Kasei Medical Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M1/00—Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
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Description

本発明は、腹水および／又は胸水の体液から不要な生体成分を除去する中空糸膜型体液濾過装置、及びタンパク質溶液の濾過方法に関する。   The present invention relates to a hollow fiber membrane-type body fluid filtration device for removing unnecessary biological components from body fluid of ascites and / or pleural effusion, and a method for filtering a protein solution.

現在、肝硬変などの腹水や胸水の溜まり易い患者に対して、腹水や胸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、貯留部位に針を刺し体外に排出した腹水や胸水を、中空糸膜などを用いた２種のフィルター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種のフィルターの１つ目は腹水や胸水中に含まれる細菌やがん細胞、血球成分などの細胞成分を除くための濾過器であり、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ーは希薄なタンパク質濃度である腹水や胸水を除水し、タンパク質を濃縮するための濃縮フィルターであり、栄養成分であるアルブミンを含む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。   Ascites fluid and pleural effusion discharged from the body by inserting a needle into the storage site to increase the blood protein concentration of the patient using ascites or pleural effusion protein for patients with ascites or pleural effusion, such as cirrhosis. Ascites filtration concentration re-injection method is performed in which a concentrated protein solution is obtained by instilling the solution into a patient by filtration and concentration treatment using two types of filters using a hollow fiber membrane or the like (see, for example, Patent Document 1). ). The first of the two types of filters is a filter for removing cell components such as bacteria, cancer cells and blood cell components contained in ascites and pleural effusions. A membrane having a pore size that allows the component to pass therethrough is used. On the other hand, the other filter is a concentration filter for decontaminating ascites and pleural effusion with dilute protein concentration and concentrating protein. Almost no protein components including albumin, which is a nutrient component, pass through, such as water, electrolyte, etc. A membrane to be passed is used.

一方、腹水が貯留する患者は、大別すると肝硬変などの疾患が元で貯留する肝性腹水患者と、胃癌、卵巣癌、大腸癌などのがんが元で貯留するがん性腹水患者に分けられる。従来、本治療は主に肝性腹水患者に対して施行されることがほとんどであったが、近年、がん性腹水患者に対して本治療を実施することの治療効果が認められつつあり、がん性腹水患者に対する施行機会が増加している。   On the other hand, patients with ascites can be broadly divided into patients with hepatic ascites that accumulates due to diseases such as cirrhosis and those with cancer ascites that accumulates with cancer such as stomach cancer, ovarian cancer, and colon cancer. It is done. Conventionally, this treatment was mostly performed mainly for patients with hepatic ascites, but in recent years, the therapeutic effect of carrying out this treatment for patients with cancerous ascites has been recognized, Opportunities for patients with cancerous ascites are increasing.

一般的に、肝性腹水の性状は淡黄色透明の漿液性である。これに対しがん性腹水の性状は、赤血球が含まれる血性、乳糜が含まれる乳糜性、黄色混濁の膿性、ゼリー状の粘液性、および黄褐色の胆汁性等、様々な性状があり、細胞成分や乳糜、フィブリン塊等が多く含まれるため、濾過器の負荷が比較的高い。   In general, hepatic ascites is light yellow and transparent serous. On the other hand, the properties of cancerous ascites have various properties, such as blood properties including red blood cells, milkiness including milk chyle, purulent yellow turbidity, jelly-like mucus, and tan bile properties, Since it contains a lot of cell components, milk cake, fibrin clot, etc., the load on the filter is relatively high.

国際公開第１３／１７６１４０パンフレットInternational Publication No. 13/176140 Brochure

細胞成分や乳糜、フィブリン塊等（以下、生体不要成分と総称する）が含まれるがん性腹水を濾過器で濾過する場合、肝性腹水の濾過と比較して、これら生体不要成分が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濾過器の出口を開放して濾過器内部に溜まった生体不要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。場合によっては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, milk folds, fibrin clots, etc. (hereinafter collectively referred to as biological unnecessary components) with a filter, these biological unnecessary components are filtered compared to the filtration of hepatic ascites. The amount of ascites that can be treated before the pressure rises is shortened because the time until the filtration pressure rises is shortened due to the clogging caused by clogging. When the pressure rises, in order to restore the filtration capacity, the outlet of the filter is opened to flush unnecessary biological components accumulated inside the filter, or the washing medium is flushed to wash the filter medium. In addition, since the ascites is drained by operations such as flushing and washing, the recovery rate of useful proteins decreases. In some cases, it is necessary to replace the 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 is long, so there is a disadvantage that the restraint time until the protein solution collected from the ascites is administered becomes long or the dose of the protein collected from the ascites is reduced. .

本発明は上記の従来技術の問題点に鑑み、濾過器が圧上昇するまでに処理できるタンパク質溶液の量を増やす、生体不要成分を含むタンパク質溶液から生体不要成分を濾過する中空糸膜型体液濾過装置、及びタンパク質溶液の濾過方法を提供することを目的とする。   In view of the above-mentioned problems of the prior art, the present invention increases the amount of a protein solution that can be processed before the pressure of the filter increases, and hollow fiber membrane type body fluid filtration that filters biological unnecessary components from protein solutions containing biological unnecessary components An object is to provide an apparatus and a method for filtering a protein solution.

本発明者らは、上記課題について生体不要成分を含むタンパク質溶液の濾過器中空糸膜内の流れに着目して鋭意検討した結果、中空糸膜型濾過器は入口が上側になるように縦に配置され、前記入口から流入した生体不要成分を含むタンパク質溶液が濾過器中空糸膜内を下方向へ通液することによって、濾過器が圧上昇するまでに処理できるタンパク質溶液の量が増えることを見出し、本発明を完成するに至った。
即ち、本発明の態様は以下を含む。
（１）腹水および／又は胸水を濾過するための入口と濾液出口を有する中空糸膜型濾過器を含む中空糸膜型体液濾過装置であって、前記中空糸膜型濾過器は入口が上側になるように縦に配置され、前記入口から流入した生体不要成分を含むタンパク質溶液が中空糸膜内を下方向に通液し、中空糸膜外に流出した前記タンパク質溶液の濾液が濾液出口から流出するように構成され、前記中空糸膜型濾過器における、中空糸膜型濾過器内に配置された中空糸膜の下端側接着材面と下蓋とが形成する空間容量が、中空糸膜内容積の０．０５倍以上、２．６０倍以下である、中空糸膜型体液濾過装置。
（２）前記中空糸膜内を通過した溶液を貯留する貯留部を有する、（１）に記載の中空糸膜型体液濾過装置。
（３）前記貯留部は、前記中空糸膜型濾過器の下端に接続された貯留部材を有する、（２）に記載の中空糸膜型体液濾過装置。
（４）前記貯留部材がチューブおよび／または容器を含む、（３）に記載の中空糸膜型体液濾過装置。
（５）前記貯留部材が容器及び前記容器と前記中空糸膜型濾過器の下端とを接続するチューブを含み、前記チューブが開閉手段により開閉することのできる、（３）に記載の中空糸膜型体液濾過装置。
（６）前記貯留部の容量が５ｍＬ以上である、（２）〜（５）のいずれか１項に記載の中空糸膜型体液濾過装置。
（７）前記中空糸膜型濾過器における、中空糸膜の下端側接着材面から下蓋の内面までの高さが２．０ｍｍ以上である、（１）〜（６）のいずれか１項に記載の中空糸膜型体液濾過装置。
（８）前記中空糸膜型濾過器における、中空糸膜型濾過器内に配置された中空糸膜の下端側接着材面と下蓋とが形成する空間容量を中空糸膜本数で割った値が、０．８８×１０-3ｍＬ／本以上である、（１）〜（７）のいずれか１項に記載の中空糸膜型体液濾過装置。
（９）前記入口が生体不要成分を含むタンパク質溶液を貯留する原液容器または患者に接続可能である、（１）〜（８）のいずれか１項に記載の中空糸膜型体液濾過装置。
（１０）前記濾液出口が生体不要成分を除去したタンパク質溶液を濃縮する濃縮器または回収容器に接続されている、（１）〜（９）のいずれか１項に記載の中空糸膜型体液濾過装置。
（１１）前記原液容器または患者と、前記中空糸膜型濾過器との間に流量の制御手段を備える、（９）に記載の中空糸膜型体液濾過装置。
（１２）（１）〜（１１）のいずれか１項に記載の中空糸膜型体液濾過装置を用いて、生体不要成分を含むタンパク質溶液から生体不要成分を除去する濾過方法を実現する際に、ポンプを作動させて、前記中空糸膜型濾過器の入口側に陽圧をかけて、前記タンパク質溶液を入口から通液させる、中空糸膜型体液濾過装置の作動方法。
（１３）前記中空糸膜型濾過器の下端に接続された貯留部材の入口側にある開閉手段を閉塞した状態で濾過を開始し、濾過中に前記開閉手段を開放する、（１２）に記載の中空糸膜型体液濾過装置の作動方法。
（１４）前記中空糸膜型濾過器の入口側の圧力及び／又は前記中空糸膜型濾過器の入口側の圧力から濾液出口側の圧力を減算した圧力に応じて、前記開閉手段を開放する、（１３）に記載の中空糸膜型体液濾過装置の作動方法。
（１５）腹水および／又は胸水を濾過するための中空糸膜型濾過器を入口が上側になるように縦に配置し、原液容器から送られ、前記入口から流入した生体不要成分を含むタンパク質溶液を中空糸膜内を下方向に通液し、中空糸膜外に流出した前記タンパク質溶液の濾液を濾液出口から流出させ、
前記中空糸膜型濾過器における中空糸膜型濾過器内に配置された中空糸膜の下端側接着材面と下蓋とが形成する空間容量が中空糸膜内容積の０．０５倍以上、２．６０倍以下である、濾過方法。
（１６）前記中空糸膜型濾過器を上下逆さまにして、前記生体不要成分を含むタンパク質溶液を下から上に向けて通液し、その後、前記中空糸膜型濾過器の上下を元に戻して、生体不要成分を含むタンパク質溶液を上から下に向けて通液する、（１５）に記載の濾過方法。 The inventors of the present invention have made extensive studies on the above-mentioned problem by paying attention to the flow of the protein solution containing a biological unnecessary component in the filter hollow fiber membrane, and as a result, the hollow fiber membrane filter is vertically arranged so that the inlet is on the upper side. The amount of protein solution that can be processed by the time the filter rises in pressure is increased by passing the protein solution containing the unnecessary biological components flowing in from the inlet through the filter hollow fiber membrane downward. The headline and the present invention were completed.
That is, the aspect of this invention contains the following.
(1) A hollow fiber membrane body fluid filtration device including a hollow fiber membrane filter having an inlet for filtering ascites and / or pleural effusion and a filtrate outlet, the inlet of the hollow fiber membrane filter being on the upper side The protein solution containing unnecessary biological components flowing in from the inlet passes through the hollow fiber membrane downward, and the filtrate of the protein solution flowing out of the hollow fiber membrane flows out from the filtrate outlet. In the hollow fiber membrane filter, the space capacity formed by the lower end side adhesive material surface and the lower lid of the hollow fiber membrane disposed in the hollow fiber membrane filter is the content of the hollow fiber membrane. A hollow-fiber membrane-type body fluid filtration device that is 0.05 times or more and 2.60 times or less of the product.
(2) The hollow fiber membrane-type body fluid filtration device according to (1), which has a reservoir that stores the solution that has passed through the hollow fiber membrane.
(3) The hollow fiber membrane type body fluid filtration device according to (2), wherein the storage unit includes a storage member connected to a lower end of the hollow fiber membrane filter.
(4) The hollow fiber membrane type body fluid filtration device according to (3), wherein the storage member includes a tube and / or a container.
(5) The hollow fiber membrane according to (3), wherein the storage member includes a container and a tube connecting the container and a lower end of the hollow fiber membrane filter, and the tube can be opened and closed by an opening / closing means. Mold body fluid filtration device.
(6) The hollow fiber membrane-type body fluid filtration device according to any one of (2) to (5), wherein the capacity of the reservoir is 5 mL or more.
(7) In the hollow fiber membrane filter, any one of (1) to (6), wherein a height from a lower end side adhesive material surface of the hollow fiber membrane to an inner surface of the lower lid is 2.0 mm or more. The hollow fiber membrane type body fluid filtration device described in 1.
(8) In the hollow fiber membrane filter, a value obtained by dividing the space capacity formed by the lower end side adhesive material surface and the lower lid of the hollow fiber membrane disposed in the hollow fiber membrane filter by the number of hollow fiber membranes. The hollow fiber membrane type body fluid filtration device according to any one of (1) to (7), wherein is at least 0.88 × 10 −3 mL / tube.
(9) The hollow fiber membrane type body fluid filtration device according to any one of (1) to (8), wherein the inlet is connectable to a stock solution container or a patient for storing a protein solution containing a biological unnecessary component.
(10) The hollow fiber membrane type body fluid filtration according to any one of (1) to (9), wherein the filtrate outlet is connected to a concentrator or a collection container for concentrating a protein solution from which biological unnecessary components have been removed. apparatus.
(11) The hollow fiber membrane body fluid filtration device according to (9), comprising a flow rate control means between the stock solution container or patient and the hollow fiber membrane filter.
(12) When realizing a filtration method for removing unwanted biological components from a protein solution containing unwanted biological components using the hollow fiber membrane-type body fluid filtration device according to any one of (1) to (11) , by operating the pump, over a period of positive pressure to the inlet side of the hollow fiber membrane type filter, the protein solution Ru is passing liquid from the inlet, a method of operating a hollow fiber membrane type body fluid filtration device.
(13) to start the filtration in a state where the opening and closing means is closed on the inlet side of the hollow fiber membrane type connected to the lower end of the filter has been storage member, opening the closing means during filtration according to (12) Method of the hollow fiber membrane type body fluid filtration apparatus .
(14) The opening / closing means is opened in accordance with the pressure on the inlet side of the hollow fiber membrane filter and / or the pressure obtained by subtracting the pressure on the filtrate outlet side from the pressure on the inlet side of the hollow fiber membrane filter. ( 13) The operation method of the hollow fiber membrane type body fluid filtration device according to ( 13) .
(15) A protein solution containing a biologically unnecessary component that is sent vertically from an undiluted solution container and flows into the inlet through a hollow fiber membrane type filter for filtering ascites and / or pleural effusion vertically so that the inlet is on the upper side. Is allowed to flow downward through the hollow fiber membrane, and the filtrate of the protein solution that has flowed out of the hollow fiber membrane is caused to flow out from the filtrate outlet,
The space capacity formed by the lower end side adhesive surface and the lower lid of the hollow fiber membrane disposed in the hollow fiber membrane filter in the hollow fiber membrane filter is 0.05 times or more the hollow fiber membrane internal volume, 2. The filtration method which is 60 times or less.
(16) The hollow fiber membrane filter is turned upside down, and the protein solution containing the biological unnecessary component is passed from the bottom to the top, and then the hollow fiber membrane filter is turned upside down. The filtration method according to (15) , wherein a protein solution containing a biological unnecessary component is passed from above to below.

本発明によれば、例えば、がん性腹水等のがん細胞、細菌、血球成分などの細胞成分や乳糜、フィブリン塊等が多く含まれるタンパク質溶液を濾過器で濾過し、それらを除去したタンパク質溶液を作製する方法において、圧上昇するまでに処理できるタンパク質溶液の量を増やすことができる。   According to the present invention, for example, a protein solution containing a large amount of cancer cells such as cancerous ascites, cell components such as bacteria, blood cell components, milk powder, fibrin clots, and the like is filtered with a filter, and the proteins are removed therefrom. In the method for preparing the solution, the amount of the protein solution that can be processed before the pressure is increased can be increased.

中空糸膜型濾過器の構成の概略を示す縦断面図である。It is a longitudinal cross-sectional view which shows the outline of a structure of a hollow fiber membrane type filter. 中空糸膜型体液濾過装置の構成の一例を示す説明図である。It is explanatory drawing which shows an example of a structure of a hollow fiber membrane type body fluid filtration apparatus. 貯留部を有する中空糸膜型体液濾過装置の構成の一例を示す説明図である。It is explanatory drawing which shows an example of a structure of the hollow fiber membrane type body fluid filtration apparatus which has a storage part. 貯留部を有する中空糸膜型体液濾過装置の他の構成の一例を示す説明図である。It is explanatory drawing which shows an example of the other structure of the hollow fiber membrane type body fluid filtration apparatus which has a storage part. 空間容量を説明するための中空糸膜型濾過器の部分拡大断面図である。It is a partial expanded sectional view of the hollow fiber membrane type filter for demonstrating space capacity. 濃縮器に接続される中空糸膜型体液濾過装置の構成の一例を示す説明図である。It is explanatory drawing which shows an example of a structure of the hollow fiber membrane type body fluid filtration apparatus connected to a concentrator. 濃縮器に接続される中空糸膜型体液濾過装置の他の構成の一例を示す説明図である。It is explanatory drawing which shows an example of the other structure of the hollow fiber membrane type body fluid filtration apparatus connected to a concentrator.

以下、本発明を詳細に説明する。なお、本発明は、以下の実施の形態に限定されるものではなく、その要旨の範囲内で種々変形して実施することができる。   Hereinafter, the present invention will be described in detail. In addition, this invention is not limited to the following embodiment, It can implement by changing variously within the range of the summary.

本実施態様の中空糸膜型体液濾過装置は、入口と濾液出口を有する中空糸膜型濾過器を含み、前記中空糸膜型濾過器は入口が上側になるように縦に配置され、前記入口から流入した生体不要成分を含むタンパク質溶液が中空糸膜内を下方向に通液し、前記タンパク質溶液の濾液が濾液出口から流出する。   The hollow fiber membrane type body fluid filtration device of the present embodiment includes a hollow fiber membrane type filter having an inlet and a filtrate outlet, and the hollow fiber membrane type filter is arranged vertically such that the inlet is on the upper side. The protein solution containing the unnecessary biological components flowing in from below passes through the hollow fiber membrane downward, and the filtrate of the protein solution flows out from the filtrate outlet.

本実施態様の中空糸膜型体液濾過装置は、生体不要成分を含むタンパク質溶液を濾過し、生体不要成分を除去したタンパク質溶液を作製する装置である。   The hollow fiber membrane type body fluid filtration device of this embodiment is a device for producing a protein solution by filtering a protein solution containing a biological unnecessary component and removing the biological unnecessary component.

本明細書中、生体不要成分を含むタンパク質溶液とは、細菌やがん細胞、血球成分などの細胞成分や乳糜、フィブリン塊等（以下、生体不要成分と総称する）が含まれる体液を意味する。特定のがん患者や、肝臓病患者等には、生体に必要なタンパク質とともに生体不要成分を含む腹水や胸水が溜まることが知られており、このような腹水や胸水をろ過して生体不要成分を除き、生体に必要な成分を患者に戻すために中空糸膜型体液濾過装置による処理は有用である。   In the present specification, a protein solution containing a biologically unnecessary component means a body fluid containing cell components such as bacteria, cancer cells, blood cell components, milky cake, fibrin clot, and the like (hereinafter collectively referred to as biologically unnecessary components). . It is known that certain ascites and pleural effusions containing biologically unnecessary components as well as proteins necessary for living bodies accumulate in certain cancer patients and liver disease patients. In order to return components necessary for the living body to the patient, treatment with a hollow fiber membrane type body fluid filtration device is useful.

本明細書中、体液とは、主として腹水、胸水及び腹水と胸水の混合物を意味する。「中空糸膜型体液濾過装置」は少なくとも中空糸膜型濾過器を含み、これに加えてタンパク質溶液を導入するための回路や、濾液を導出するための回路を含む機器を示す。中空糸膜型体液濾過装置による体液処理においては、一旦バッグ等の原液容器に貯留してから導入する態様が一般的であるが、患者から採取した体液を直接濾過器に導入する態様も採用しうる。前者の場合は、原液容器及び原液容器と濾過器をつなぐ回路が中空糸膜型体液濾過装置に含まれ、後者の場合は、体液の採取手段と、採取手段と濾過器をつなぐ回路が中空糸膜型体液濾過装置に含まれる。また、タンパク質溶液の濾液は濃縮してから患者に戻すのが一般的であるが、濾液を回収容器に一旦貯留してから濃縮してもよいし、濾過器と濃縮器とをつないで連続的に処理してもよい。各態様に含まれる濾液の回収容器や濃縮器、回路等も中空糸膜型体液濾過装置に含まれる。各態様については、追って図を参照して詳述する。   In the present specification, the body fluid mainly means ascites, pleural effusion and a mixture of ascites and pleural effusion. “Hollow fiber membrane type body fluid filtration device” indicates at least a hollow fiber membrane type filter, and in addition, a device including a circuit for introducing a protein solution and a circuit for deriving a filtrate. In the body fluid treatment by the hollow fiber membrane type body fluid filtration device, an aspect in which the body fluid is once stored in a stock container such as a bag and then introduced is common, but an aspect in which body fluid collected from a patient is directly introduced into a filter is also employed. sell. In the former case, the stock solution container and the circuit connecting the stock solution container and the filter are included in the hollow fiber membrane type body fluid filtration device. In the latter case, the body fluid collecting means and the circuit connecting the collection means and the filter are hollow fibers. It is included in a membrane type body fluid filtration device. In general, the filtrate of the protein solution is concentrated and then returned to the patient. However, the filtrate may be temporarily stored in a collection container and then concentrated, or it may be continuously connected by connecting a filter and a concentrator. You may process. Filtrate collection containers, concentrators, circuits and the like included in each embodiment are also included in the hollow fiber membrane type body fluid filtration device. Each aspect will be described in detail later with reference to the drawings.

図１は、中空糸膜型濾過器１の一例を示す。図１に示されるように、中空糸膜型濾過器１は、筒状容器３と、筒状容器３の長手方向に沿って装填され、両端部が筒状容器３の両端部に固定されている中空糸膜４の束５と、筒状容器３の両端部の内側で中空糸膜４の束５の両端部を包囲すると共に、中空糸膜４の束５の両端部が埋設されて固定された接着材７と、筒状容器３の両端部にそれぞれ設けられる、中空糸膜４の端面に連通する入口１１または通液口１２を有する蓋（上側を上蓋３ａ、下側を下蓋３ｂという）と、筒状容器３の側面部に設けられた中空糸膜外側と連通する濾液出口９とを備える。濾液出口９は１以上設けてよい。濾液出口９を２個設けた場合は２個用いてもよいし、１個を使用しても良い。   FIG. 1 shows an example of a hollow fiber membrane filter 1. As shown in FIG. 1, the hollow fiber membrane filter 1 is loaded with a cylindrical container 3 along the longitudinal direction of the cylindrical container 3, and both ends are fixed to both ends of the cylindrical container 3. The hollow fiber membrane 4 bundle 5 and both ends of the hollow fiber membrane 4 are enclosed inside the both ends of the cylindrical container 3, and both ends of the bundle 5 of the hollow fiber membrane 4 are embedded and fixed. And a lid having an inlet 11 or a fluid passage 12 provided on both ends of the tubular container 3 and communicating with the end face of the hollow fiber membrane 4 (the upper lid is the upper lid 3a and the lower lid is the lower lid 3b) And a filtrate outlet 9 that communicates with the outside of the hollow fiber membrane provided on the side surface of the cylindrical container 3. One or more filtrate outlets 9 may be provided. When two filtrate outlets 9 are provided, two may be used or one may be used.

中空糸膜４は生体不要成分と水分、及び電解質やタンパク質などの溶質成分を分離できる膜である。素材は特に限定はなく、製膜時に孔径制御がしやすく且つ化学的安定性に優れる理由から、ポリエチレンなどのポリオレフィン系高分子、ポリスルホン系高分子、再生セルロース系高分子、ポリビニルアルコール系高分子などが好ましい。これら例示した中空糸膜素材には他の材料が含有されていても良く、また化学的に修飾されていても良い。中空糸膜４の基材に疎水性高分子を使用する場合は、膜に親水性を付与する為に親水性高分子をブレンドして製膜することが一般的である。親水性高分子としては、例えば、ポリビニルピロリドン（ＰＶＰ）、ポリエチレングリコール、ポリビニルアルコール、ポリプロピレングリコールなどが挙げられる。あるいはこれら親水性高分子を中空糸膜４の基材にコーティングしてもよい。通常、孔径が０．２μｍ以下で、かつタンパク質の透過率が８０％以上である中空糸膜４が用いられる。中空糸膜４は、汎従来公知の技術により製造できる。   The hollow fiber membrane 4 is a membrane capable of separating a biological unnecessary component and moisture, and a solute component such as an electrolyte or protein. The material is not particularly limited. For reasons of easy pore size control during film formation and excellent chemical stability, polyolefin polymers such as polyethylene, polysulfone polymers, regenerated cellulose polymers, polyvinyl alcohol polymers, etc. Is preferred. These exemplified hollow fiber membrane materials may contain other materials or may be chemically modified. When a hydrophobic polymer is used for the base material of the hollow fiber membrane 4, it is common to form a film by blending a hydrophilic polymer in order to impart hydrophilicity to the membrane. Examples of the hydrophilic polymer include polyvinyl pyrrolidone (PVP), polyethylene glycol, polyvinyl alcohol, and polypropylene glycol. Alternatively, these hydrophilic polymers may be coated on the base material of the hollow fiber membrane 4. Usually, a hollow fiber membrane 4 having a pore size of 0.2 μm or less and a protein permeability of 80% or more is used. The hollow fiber membrane 4 can be manufactured by generally known techniques.

中空糸膜型濾過器１の製造方法に関しても公知の方法を利用すればよい。例えば、中空糸膜束５を筒状容器３へ挿入し、両束端にポリウレタン等の接着材を注入して両端をシールした後、硬化後の余分な接着材を切断除去し中空糸膜端面を開口させ、蓋（上蓋３ａおよび下蓋３ｂ）を取り付けることにより製造できる。この方法により中空糸膜４の束５が筒状容器３に充填され、中空糸膜内側室と中空糸膜外側室とが形成され、中空糸膜内側室に通じる流体出入口１１、１２および中空糸膜外側室に通じる濾液出口９を持つ中空糸膜型濾過器１が製造できる。   A known method may be used as a method for manufacturing the hollow fiber membrane filter 1. For example, after inserting the hollow fiber membrane bundle 5 into the cylindrical container 3, injecting an adhesive such as polyurethane into both ends of the bundle and sealing both ends, the excess adhesive after curing is removed by cutting to remove the hollow fiber membrane end face. Can be manufactured by opening and attaching lids (upper lid 3a and lower lid 3b). By this method, the bundle 5 of the hollow fiber membranes 4 is filled into the cylindrical container 3 to form the hollow fiber membrane inner chamber and the hollow fiber membrane outer chamber, and the fluid inlets and outlets 11 and 12 leading to the hollow fiber membrane inner chamber and the hollow fibers. A hollow fiber membrane filter 1 having a filtrate outlet 9 leading to the membrane outer chamber can be produced.

本実施態様における中空糸膜型体液濾過装置２０は、図２に示すように、入口１１が上側になるように縦に配置され、生体不要成分を含むタンパク質溶液を入口１１から通液し、生体不要成分を含むタンパク質溶液は中空糸膜内側流路を下向きに流れ、中空糸膜４を介して生体不要成分の濾過が行われ、濾液出口９からタンパク質溶液の濾液を得る。濾液は、濾液出口９に接続された回収容器３０に収容される。回収容器３０は、液体を貯留することができればどのようなものでもよいが、通常、取り扱い性の観点から、ポリ塩化ビニル製のバッグが用いられる。回収容器３０の大きさは回収される濾液の量などにより決定される。濾液が多く回収容器１個に収容できない場合、回収容器３０は２個以上用いてよく、１個目の回収容器３０が満杯になったら次の回収容器３０と交換する。中空糸膜型濾過器１と原液容器４０との流路、及び中空糸膜型濾過器１と回収容器３０との流路はチューブで接続されている。一般的に、ポリ塩化ビニルなどから製造される軟質チューブが用いられる。中空糸膜型濾過器１と原液容器４０との間のチューブには、ローラーポンプ４１が設けられている。中空糸膜型濾過器１と回収容器３０との間のチューブには、エアーベントフィルター４２とクランプ４３が接続されている。   As shown in FIG. 2, the hollow fiber membrane-type body fluid filtration device 20 in the present embodiment is arranged vertically so that the inlet 11 is on the upper side, and a protein solution containing a biological unnecessary component is passed through the inlet 11, The protein solution containing unnecessary components flows downward through the hollow fiber membrane inner channel, and the biological unnecessary components are filtered through the hollow fiber membrane 4 to obtain a filtrate of the protein solution from the filtrate outlet 9. The filtrate is accommodated in a collection container 30 connected to the filtrate outlet 9. The recovery container 30 may be anything as long as it can store a liquid, but a polyvinyl chloride bag is usually used from the viewpoint of handling. The size of the collection container 30 is determined by the amount of filtrate collected. When the filtrate is large and cannot be accommodated in one collection container, two or more collection containers 30 may be used, and when the first collection container 30 is full, the next collection container 30 is replaced. The flow path between the hollow fiber membrane filter 1 and the stock solution container 40 and the flow path between the hollow fiber membrane filter 1 and the collection container 30 are connected by a tube. Generally, a soft tube manufactured from polyvinyl chloride or the like is used. A roller pump 41 is provided in a tube between the hollow fiber membrane filter 1 and the stock solution container 40. An air vent filter 42 and a clamp 43 are connected to the tube between the hollow fiber membrane filter 1 and the collection container 30.

従来、腹水濾過濃縮再静注法における生体不要成分を含むタンパク質溶液の濾過は、中空糸膜型濾過器は、入口を下側になるように縦に配置され、入口から流入した生体不要成分を含むタンパク質溶液が中空糸膜内を上方向へ通液していた。中空糸膜型濾過器を用いた生体不要成分を含むタンパク質溶液の濾過において、本発明者らが検討を進めたところ、タンパク質溶液の濾過方向を下向きにすることで、生体不要成分が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長くなり、圧上昇するまでに処理できる生体不要成分を含むタンパク質溶液の量が増えることを見出し、本発明を完成するに至ったのである。   Conventionally, filtration of protein solutions containing biologically unnecessary components in the ascites filtration concentration re-infusion method, hollow fiber membrane type filters are arranged vertically with the inlet on the lower side, and the biologically unnecessary components flowing from the inlet are removed. The contained protein solution was passed through the hollow fiber membrane upward. In the filtration of a protein solution containing a biologically unnecessary component using a hollow fiber membrane type filter, the present inventors have studied and found that the biologically unnecessary component is contained in the filter by setting the filtration direction of the protein solution downward. It has been found that the time until the filtration pressure rises due to clogging and the filtration pressure rises is increased, and the amount of protein solution containing unnecessary biological components that can be processed before the pressure rises is increased, and the present invention has been completed. It is.

濾過方向を下向きにすることで、生体不要成分が中空糸膜４内の下部から順に充填されていくことにより、生体不要成分による目詰まりまでの時間が延長し、濾過量の増加に至ったと推測した。   By placing the filtration direction downward, the biologically unnecessary components are sequentially filled from the lower part of the hollow fiber membrane 4, thereby extending the time until clogging by the biologically unnecessary components and presuming that the amount of filtration has increased. did.

濾過の間、下蓋３ｂに設けられた通液口１２は閉鎖されている。通液口１２を直接閉じてもよいし、通液口１２に接続したチューブの通液口１２側をクランプや鉗子などの部品で閉鎖して用いてもよい。   During filtration, the liquid passage port 12 provided in the lower lid 3b is closed. The liquid passage port 12 may be directly closed, or the tube connected to the liquid passage port 12 may be closed with a part such as a clamp or forceps.

中空糸膜４内のタンパク質溶液の濾過は、初めから上から下に向かって通液してもよく、初め下から上に向かって通液して途中から方向を変えてもよい。途中から、方向を変える場合は、例えば、初めは中空糸膜型濾過器１を上下逆向き、すなわち入口１１を下にし、通液口１２を上にして、下から上に向けてタンパク質溶液を通液し、濾過器入口圧やＴＭＰ（膜間圧力差。濾過器の入口１１側の圧力から濾液出口９側の圧力を減算した圧力。）が、例えば、１ｋＰａから２０ｋＰａの範囲になったときに、中空糸膜型濾過器１の上下を元に戻し、タンパク質溶液を上から下に向けて通液して濾過を再開することができる。   The protein solution in the hollow fiber membrane 4 may be filtered from the top to the bottom from the beginning, or may be passed from the bottom to the top to change the direction from the middle. When changing the direction from the middle, for example, initially, the hollow fiber membrane filter 1 is turned upside down, that is, the inlet 11 is directed downward, the fluid inlet 12 is directed upward, and the protein solution is directed from the bottom upward. When the pressure is passed through the filter, and the pressure at the inlet of the filter or TMP (pressure difference between the membranes, the pressure obtained by subtracting the pressure at the filtrate outlet 9 side from the pressure at the inlet 11 side of the filter) is in the range of 1 kPa to 20 kPa, for example. In addition, the upper and lower sides of the hollow fiber membrane filter 1 can be returned to the original position, and the protein solution can be passed from the top to the bottom to resume the filtration.

なお、中空糸膜型濾過器１で濾過を行うとき、入口１１側の容器内部にエアが存在すると液体が通過できない体積が形成され、中空糸膜４内の片流れ（中空糸膜４の一部しか液体が通過せず、濾過面積を有効に利用できない現象）が生じる場合がある。したがって、入口１１側の容器内部にエアが混入することを防ぐことが重要である。ここで、濾過前に中空糸膜型濾過器１内の溶液や気体（エア）を生理食塩液等でプライミングする場合、中空糸膜型濾過器１を上下逆さまにして、中空糸膜４内を下から上に向けてプライミング液を通液すると、中空糸膜４内や上蓋３ａ、下蓋３ｂ内、中空糸膜外空間のエアが容易に排除される。その後、引き続きタンパク質溶液の濾過を開始する場合も、中空糸膜型濾過器１内がタンパク質溶液で置換されるまで、中空糸膜型濾過器１を上下逆さまにしたまま、中空糸膜４内を下から上に向けて通液することができる。また、濾過初期に中空糸膜型濾過器１を上下逆さまにしてエアが混入した場合も、下側に位置する上蓋３ａ内に入ったエアは中空糸膜４内を上に向かって移動するため、中空糸膜型濾過器１の上下を元に戻して濾過を続けることができる。というのも、上下逆さまの時に上蓋３ａ内に入ったエアは上に向かって下蓋３ｂに向かい、上下を元に戻せば、エアが中空糸膜型濾過器1の下蓋３ｂに存在するため、入口１１側の容器内部のエアが液体の流れを阻害し、中空糸膜４内の片流れを引き起こすことを防ぐことができるためである。また、例えば、溶液が充填されていない（ドライの）中空糸膜型濾過器１をプライミングせずにそのまま濾過に用いる場合、中空糸膜型濾過器１を上下逆さまにしたまま、上側の通液口１２にプライミング用回路を接続し、プライミング用回路を開けた状態でタンパク質溶液を下から上に向けて通液し、タンパク質溶液が通液口１２から出てくる前にプライミング用回路の通液口１２側を閉じることにより、中空糸膜４内や上蓋３ａ、下蓋３ｂ内のエアを効率よくプライミング用回路から排出できる。   When filtration is performed by the hollow fiber membrane filter 1, a volume is formed in which liquid cannot pass if air is present inside the container on the inlet 11 side, and a single flow in the hollow fiber membrane 4 (part of the hollow fiber membrane 4). However, there is a case in which only a liquid passes and a filtration area cannot be used effectively. Therefore, it is important to prevent air from entering the inside of the container on the inlet 11 side. Here, when priming the solution or gas (air) in the hollow fiber membrane type filter 1 with physiological saline before filtration, the hollow fiber membrane type filter 1 is turned upside down and the inside of the hollow fiber membrane 4 is passed through. When the priming solution is passed from the bottom to the top, air in the hollow fiber membrane 4, the upper lid 3a, the lower lid 3b, and the space outside the hollow fiber membrane is easily removed. Thereafter, when the filtration of the protein solution is continued, the inside of the hollow fiber membrane 4 is kept upside down until the inside of the hollow fiber membrane filter 1 is replaced with the protein solution. It can be passed from bottom to top. Further, even when air is mixed by turning the hollow fiber membrane filter 1 upside down at the initial stage of filtration, the air that has entered the lower lid 3a moves upward in the hollow fiber membrane 4. The filtration can be continued by returning the upper and lower sides of the hollow fiber membrane filter 1 to the original state. This is because the air that has entered the upper lid 3a when turned upside down is directed upward to the lower lid 3b, and if the upper and lower sides are restored, the air is present in the lower lid 3b of the hollow fiber membrane filter 1. This is because it is possible to prevent the air inside the container on the inlet 11 side from obstructing the flow of the liquid and causing a single flow in the hollow fiber membrane 4. For example, when the hollow fiber membrane filter 1 that is not filled with a solution is used as it is for filtration without being primed, the upper liquid flow is maintained while the hollow fiber membrane filter 1 is turned upside down. The priming circuit is connected to the mouth 12, and the protein solution is passed from the bottom to the top with the priming circuit opened, and the priming circuit is passed before the protein solution comes out of the fluid inlet 12. By closing the mouth 12 side, the air in the hollow fiber membrane 4, the upper lid 3a, and the lower lid 3b can be efficiently discharged from the priming circuit.

中空糸膜型体液濾過装置２０は、中空糸膜４内を通過した溶液を貯留する貯留部を有するようにしてもよい。この場合は、中空糸膜型濾過器１の下端に貯留部材を接続して貯留部を設けてもよく、あるいは中空糸膜型濾過器内に配置された中空糸膜の下端側接着材面と下蓋とが形成する空間に貯留部を設けてもよく、その両方であってもよい。   The hollow fiber membrane type body fluid filtration device 20 may include a storage unit that stores the solution that has passed through the hollow fiber membrane 4. In this case, a storage member may be provided by connecting a storage member to the lower end of the hollow fiber membrane filter 1, or a lower end side adhesive material surface of the hollow fiber membrane disposed in the hollow fiber membrane filter and A storage part may be provided in the space formed by the lower lid, or both.

図３は、本実施形態の中空糸膜型体液濾過装置２０の別の例を示す。図３に示す例においては、中空糸膜型濾過器１の下端に貯留部材５０が接続されている。貯留部材５０は、中空糸膜型濾過器１の下蓋３ｂに有する通液口１２に接続されており、中空糸膜型濾過器１内に体液が導入されると、体液に含まれる生体不要成分は濾過圧により下方向へ移動する。中空糸膜型濾過器１の下端に貯留部材５０を接続して貯留部を設けることにより、生体不要成分が貯留部へ貯留され、中空糸膜４内への生体不要成分の貯留と目詰まりの速度が遅くなり、濾過圧が上昇するまでの時間が長くなり、圧上昇するまでに処理できる生体不要成分を含むタンパク質溶液量が更に増える。   FIG. 3 shows another example of the hollow fiber membrane type body fluid filtration device 20 of the present embodiment. In the example shown in FIG. 3, a storage member 50 is connected to the lower end of the hollow fiber membrane filter 1. The storage member 50 is connected to a liquid passage port 12 provided in the lower lid 3b of the hollow fiber membrane filter 1, and when a body fluid is introduced into the hollow fiber membrane filter 1, a living body contained in the body fluid is unnecessary. The component moves downward due to the filtration pressure. By connecting the storage member 50 to the lower end of the hollow fiber membrane type filter 1 and providing a storage part, the biologically unnecessary component is stored in the storage part, and the storage and clogging of the biologically unnecessary component in the hollow fiber membrane 4 are prevented. The speed becomes slower and the time until the filtration pressure rises becomes longer, and the amount of the protein solution containing a biological unnecessary component that can be processed before the pressure rises further increases.

貯留部材５０の出口はクランプ５１によって閉じられており、中空糸膜型濾過器１の下端からクランプ５１の上端まで、すなわち貯留部材５０のうち貯留部として機能する部分の容量は、クランプ５１の位置を変更することによって増減可能である。   The outlet of the storage member 50 is closed by a clamp 51, and the capacity of the portion that functions as the storage portion of the storage member 50 from the lower end of the hollow fiber membrane filter 1 to the upper end of the clamp 51 is the position of the clamp 51. It can be increased or decreased by changing

中空糸膜型濾過器１の下端から貯留部材５０の最下部までの距離Ｆは、貯留部の容量を確保する観点で、１０ｃｍ以上であることが好ましい。更に好ましくは２０ｃｍ以上である。また、医療施設における施行者の作業性の観点から、好ましくは１００ｃｍ以下であり、更に好ましくは６０ｃｍ以下である。   The distance F from the lower end of the hollow fiber membrane filter 1 to the lowest part of the storage member 50 is preferably 10 cm or more from the viewpoint of securing the capacity of the storage part. More preferably, it is 20 cm or more. Moreover, from a viewpoint of workability | operativity of the enforcer in a medical facility, Preferably it is 100 cm or less, More preferably, it is 60 cm or less.

貯留部材５０を閉じているクランプ５１を開くことにより、貯留部材５０内にあるエアを排出することも可能である。貯留部材５０の開閉手段はクランプ５１の他に、鉗子などを用いることが出来る。開閉をクランプや鉗子などで行う場合、貯留部材５０のうち貯留部として機能する部分の容量は、予め設定した容量で不足した場合等には、濾過中これら開閉手段の移動により変更することもできる。濾過前に中空糸膜型濾過器１内を例えば生理食塩液等でプライミングする場合、貯留部材５０であるチューブの先にプライミング用回路を接続して用いても良いし、チューブをプライミング用回路として併用してもよい。また、中空糸膜型濾過器１下端に接続したチューブは分岐することもでき、例えば２本に分岐する場合、１本は貯留部材５０として用い、残りの１本はプライミング用回路として用いてもよい。チューブの寸法や材質は特に限定されないが、チューブの内径は生体不要成分を貯留する機能を保持する観点から３．０ｍｍ以上が好ましい。またポリ塩化ビニルなどから製造される軟質チューブが好ましい。   It is also possible to discharge the air in the storage member 50 by opening the clamp 51 that closes the storage member 50. In addition to the clamp 51, forceps or the like can be used as the opening / closing means of the storage member 50. When opening and closing with a clamp or forceps, the capacity of the portion that functions as the storage portion of the storage member 50 can be changed by moving these opening and closing means during filtration if the preset capacity is insufficient. . When priming the inside of the hollow fiber membrane filter 1 with, for example, physiological saline before filtration, a priming circuit may be connected to the tip of the tube as the storage member 50, or the tube may be used as a priming circuit. You may use together. The tube connected to the lower end of the hollow fiber membrane filter 1 can also be branched. For example, when the tube is branched into two, one can be used as the storage member 50 and the remaining one can be used as a priming circuit. Good. The dimensions and material of the tube are not particularly limited, but the inner diameter of the tube is preferably 3.0 mm or more from the viewpoint of maintaining the function of storing unnecessary biological components. A soft tube manufactured from polyvinyl chloride or the like is preferable.

図４は、本実施形態の中空糸膜型体液濾過装置２０のさらに別の例を示す。中空糸膜型濾過器１には、チューブ６０を介して容器６１が接続され、貯留部材を形成している。図４に示す例では、容器６１は、チューブ６０を介して接続されているが、中空糸膜型濾過器１に直接接続されていても良い。   FIG. 4 shows still another example of the hollow fiber membrane type body fluid filtration device 20 of the present embodiment. A container 61 is connected to the hollow fiber membrane filter 1 via a tube 60 to form a storage member. In the example shown in FIG. 4, the container 61 is connected via the tube 60, but may be directly connected to the hollow fiber membrane filter 1.

貯留部材に用いる容器６１は硬質材質から成る容器でも軟質材質から成る容器でもよい。硬質容器の場合、生体不要成分を含むタンパク質溶液が貯留できるように、容器６１と中空糸膜型濾過器１との接続部以外の部分にエアや液体を排出する開閉口を設けるのが好ましい。開閉口が設けられていると、容器６１内に生体不要成分を含むタンパク質溶液を貯留し始める際に、開閉口から容器６１内のエアを排出したり、濾過前に事前にプライミング液を満たすためにエアを排出したりすることができる。容器６１が軟質部材の場合、硬質部材の場合と同様にエアや液体を排出する開閉口を設けてもよいし、濾過開始時は容器６１内のエアまたはプライミング液を極力排出した状態で開始してもよい。また、硬質部材の容器と軟質材質の容器６１ともに、開閉口には例えば細菌の混入を防ぐために除菌用エアーベントフィルターを接続してもよいし、回路を接続してプライミング液の流路として用いてもよい。容器６１の寸法や材質は特に限定されない。材質は、例えば硬質容器の場合、ポリプロピレン樹脂、ポリスチレン樹脂、ポリアクリロニトリル樹脂、スチレン・ブタジエン共重合体樹脂などが用いられ、軟質容器の場合、ポリ塩化ビニル樹脂などが用いられる。   The container 61 used for the storage member may be a container made of a hard material or a container made of a soft material. In the case of a hard container, it is preferable to provide an opening / closing port for discharging air or liquid at a portion other than the connection part between the container 61 and the hollow fiber membrane filter 1 so that a protein solution containing a biological unnecessary component can be stored. When the opening / closing port is provided, when the protein solution containing the biological unnecessary component is started to be stored in the container 61, the air in the container 61 is discharged from the opening / closing port or the priming solution is filled in advance before the filtration. It is possible to exhaust air. When the container 61 is a soft member, an opening / closing port for discharging air or liquid may be provided as in the case of a hard member, and when the filtration starts, the air or priming liquid in the container 61 is started as much as possible. May be. In addition, both the hard member container and the soft material container 61 may be connected to the opening / closing port with, for example, a sterilizing air vent filter in order to prevent contamination of bacteria, or connected to a circuit as a flow path for the priming liquid. It may be used. The dimensions and material of the container 61 are not particularly limited. For example, polypropylene resin, polystyrene resin, polyacrylonitrile resin, styrene-butadiene copolymer resin or the like is used in the case of a hard container, and polyvinyl chloride resin or the like is used in the case of a soft container.

図４に示すように、貯留部材がチューブ６０と、チューブ６０に接続された容器６１とからなる場合、チューブ６０を入口側開閉手段により開閉自在にすることが好ましい。この場合、容器６１の材質に依らず、貯留部材に開閉手段を設けるのが容易であり、クランプや鉗子によりなされ、操作性も簡易である。チューブ６０と容器６１は、一体化されていてもよいし、チューブ６０と容器６１とに例えばルアーコネクタ６２などの接続部品を備え、接続可能な別の部材から構成されていてもよい。チューブ６０の接続部品に、プライミング時は容器６１の代わりにプライミング用回路を接続し、濾過時は容器６１に接続することもできる。また、生体不要成分を含むタンパク質溶液の濾過量が大量である場合であって、濾過器入口圧やＴＭＰが上昇した後も濾過を継続したい場合は、チューブ６０上の開閉手段を閉じ、容器６１を交換することもできる。   As shown in FIG. 4, when the storage member includes a tube 60 and a container 61 connected to the tube 60, it is preferable that the tube 60 can be opened and closed by the inlet side opening / closing means. In this case, regardless of the material of the container 61, it is easy to provide an opening / closing means on the storage member, and it is made by a clamp or forceps, and the operability is also simple. The tube 60 and the container 61 may be integrated, or the tube 60 and the container 61 may be provided with a connecting component such as a luer connector 62 and may be configured by another connectable member. The connecting part of the tube 60 can be connected to a priming circuit instead of the container 61 at the time of priming, and can be connected to the container 61 at the time of filtration. If the amount of filtration of the protein solution containing unnecessary biological components is large and it is desired to continue filtration even after the filter inlet pressure and TMP rise, the opening / closing means on the tube 60 is closed and the container 61 is closed. Can also be replaced.

入口側開閉手段は、中空糸膜型濾過器１との接続部に設けられてもよいし、貯留部材の中空糸膜型濾過器１側の末端に設けられてもよい。入口開閉手段はコックでもよいし、図４に示す例のように貯留部材がチューブ６０と容器６１からなる場合には、チューブ６０を挟持するクランプや鉗子でもよい。また容器を交換する場合、更に容器入口に開閉手段を設けておき容器を密閉して交換することもできる。   The inlet side opening / closing means may be provided at the connection portion with the hollow fiber membrane filter 1 or may be provided at the end of the storage member on the hollow fiber membrane filter 1 side. The inlet opening / closing means may be a cock, or may be a clamp or forceps for holding the tube 60 when the storage member is made of the tube 60 and the container 61 as in the example shown in FIG. When the container is exchanged, an opening / closing means is further provided at the container inlet so that the container is sealed and exchanged.

貯留部材の入口側開閉手段は始めから開けた状態で濾過を開始しても良いし、閉じた状態で濾過を開始し、濾過の途中で開けてもよい。例えば中空糸膜型濾過器１内にプライミング液が充填されている場合、濾過開始時は、タンパク質溶液が貯留部内に流入し始めるまでプライミング液量分時間がかかる。濾過の初期はプライミング液によって中空糸膜４内のタンパク質溶液は希釈されている。特に、貯留部材として容器６１を用い、かつ開始時に貯留部材内にプライミング液等の溶液が入っていない場合、中空糸膜型濾過器１内のタンパク質溶液の濃度が、流入するタンパク質溶液の濃度と同等以上になってから、貯留部を使用すると、濾過器１の圧上昇までの時間が延びる。   Filtration may be started when the inlet side opening / closing means of the storage member is opened from the beginning, or filtration may be started when the storage member is closed, and may be opened during filtration. For example, when the hollow fiber membrane filter 1 is filled with a priming solution, it takes time for the amount of the priming solution until the protein solution starts to flow into the reservoir at the start of filtration. At the beginning of filtration, the protein solution in the hollow fiber membrane 4 is diluted with the priming solution. In particular, when the container 61 is used as a storage member and no solution such as a priming solution is contained in the storage member at the start, the concentration of the protein solution in the hollow fiber membrane filter 1 is equal to the concentration of the inflowing protein solution. If it becomes equal or more and uses a storage part, the time until the pressure rise of the filter 1 will be extended.

貯留部材の入口側開閉手段を開放するタイミングは、中空糸膜型濾過器１の入口圧またはＴＭＰが一定圧以上になった時点、または生体不要成分を含むタンパク質溶液の濾過量が一定量以上になった時点とするのが好ましい。開放後は、貯留部材の入口側開閉手段を開けた状態のまま濾過を継続することができる。   The timing at which the inlet side opening / closing means of the storage member is opened is the time when the inlet pressure or TMP of the hollow fiber membrane filter 1 becomes equal to or higher than a certain pressure, or the filtration amount of the protein solution containing unnecessary biological components is equal to or larger than a certain amount. It is preferable to set the point in time. After opening, the filtration can be continued with the inlet side opening / closing means of the storage member being opened.

これらのタイミングは、生体不要成分を含むタンパク質溶液の流入速度や濾過開始からの圧の上昇速度、タンパク質溶液の濃度、生体不要成分の内容などから決めることができる。濾過器入口圧またはＴＭＰに応じて開ける場合、開閉手段を開ける圧は好ましくは２ｋＰａ以上、より好ましくは５ｋＰａ以上である。また、濾過器入口圧またはＴＭＰが上昇していくと中空糸膜４の目詰まりが進んでいることが考えられるため、開閉手段を開ける濾過器入口圧またはＴＭＰは、好ましくは２０ｋＰａ以下、より好ましくは１０ｋＰａ以下である。更に、貯留部材の入口側の開閉手段を濾過途中から開ける場合であって、かつ貯留部材内がプライミング液などの溶液で満たされていない場合、中空糸膜型濾過器１と貯留部との落差により中空糸膜４内の生体不要成分を含むタンパク質溶液が勢いよく貯留部内へ流入する。これにより貯留部材入口側の開閉手段を開けて生体不要成分を含むタンパク質溶液が貯留部内へ流入する速度が、濾過器入口から流入する生体不要成分を含むタンパク質溶液の流入速度よりも早い場合、中空糸膜４の外側にある濾過されたタンパク質溶液が中空糸膜４内へ流れ、中空糸膜４上での濾過方向が逆となり、すなわち逆濾過が一時的に発生する。この場合、中空糸膜４の目詰まりが逆濾過により洗浄され、目詰まり状態が緩和することから、より中空糸膜型濾過器１の圧上昇までの時間が延び、好ましい。   These timings can be determined based on the inflow rate of the protein solution containing the biological unnecessary component, the rate of increase in pressure from the start of filtration, the concentration of the protein solution, the content of the biological unnecessary component, and the like. When opening according to the filter inlet pressure or TMP, the pressure for opening the opening / closing means is preferably 2 kPa or more, more preferably 5 kPa or more. Further, since the clogging of the hollow fiber membrane 4 is considered to progress as the filter inlet pressure or TMP increases, the filter inlet pressure or TMP for opening the opening / closing means is preferably 20 kPa or less, more preferably Is 10 kPa or less. Furthermore, when the opening / closing means on the inlet side of the storage member is opened in the middle of filtration and the inside of the storage member is not filled with a solution such as a priming liquid, a drop between the hollow fiber membrane filter 1 and the storage part As a result, the protein solution containing the biologically unnecessary components in the hollow fiber membrane 4 flows into the reservoir portion vigorously. Accordingly, when the opening / closing means on the inlet side of the storage member is opened and the speed at which the protein solution containing the biological unnecessary component flows into the storage portion is faster than the inflow speed of the protein solution containing the biological unnecessary component flowing from the filter inlet, The filtered protein solution outside the yarn membrane 4 flows into the hollow fiber membrane 4 and the filtration direction on the hollow fiber membrane 4 is reversed, that is, reverse filtration occurs temporarily. In this case, since the clogging of the hollow fiber membrane 4 is washed by reverse filtration and the clogged state is eased, the time until the pressure of the hollow fiber membrane filter 1 is increased is more preferable.

図５は、中空糸膜型濾過器１の別の例を部分的に示す。図５に示す中空糸膜型濾過器１は、貯留部として、中空糸膜４の下端側接着材面７ａと下蓋３ｂとが形成する空間の容量（図５の斜線部Ａ）（以下、「空間容量Ａ」とする。）を十分備え、例えば一般的な中空糸膜型濾過器１と比較して大きく設計されていてもよい。空間容量Ａは、中空糸膜内容積の０．０５倍以上であることが好ましい。また、下蓋３ｂの空間容量Ａは、中空糸膜４の上端側接着材面と上蓋３ａとが形成する空間の容量（下蓋３ｂに対応する上蓋３ａ内の空間容量）より大きく形成されていてもよい。   FIG. 5 partially shows another example of the hollow fiber membrane filter 1. The hollow fiber membrane type filter 1 shown in FIG. 5 has a capacity of the space formed by the lower end side adhesive material surface 7a of the hollow fiber membrane 4 and the lower lid 3b (shaded portion A in FIG. 5) (hereinafter referred to as “reservoir”). “Space capacity A”) is sufficient, and may be designed larger than, for example, a general hollow fiber membrane filter 1. The space capacity A is preferably 0.05 times or more of the hollow fiber membrane inner volume. Further, the space capacity A of the lower lid 3b is formed larger than the capacity of the space formed by the upper end side adhesive material surface of the hollow fiber membrane 4 and the upper cover 3a (the space capacity in the upper cover 3a corresponding to the lower cover 3b). May be.

空間容量Ａは、以下の方法で求めることが出来る。中空糸膜４の下端側接着材面７ａと下蓋３ｂとの間の空間を、断面形状に基づく単純な形状に近似して求める方法である。例えば、筒状容器３の下端部に下蓋３ｂを装着した状態の断面図（筒状容器３の軸線Ｂに沿った縦断面図）において、中空糸膜の下端側接着材面７ａ、下蓋３ｂの内面Ｃ（タンパク質溶液接触面）、及び下蓋３ｂの先端（通液口１２の先端）で囲まれる断面積（図５の斜線部Ａの断面積）を下蓋３ｂの軸線Ｂを中心に３６０度回転させたときにできる空間の体積（ｍＬ）を、一般的な円柱、円錐台などの体積を求める式を用いて算出できる。中空糸膜型濾過器１内の寸法は、例えばＸ線ＣＴ装置で測定したり、中空糸膜型濾過器１を解体してノギス等で測定してもよい。   The space capacity A can be obtained by the following method. In this method, the space between the lower end side adhesive material surface 7a of the hollow fiber membrane 4 and the lower lid 3b is approximated to a simple shape based on the cross-sectional shape. For example, in a cross-sectional view (longitudinal cross-sectional view along the axis B of the cylindrical container 3) with the lower lid 3b attached to the lower end of the cylindrical container 3, the lower end side adhesive material surface 7a of the hollow fiber membrane, the lower lid The cross-sectional area (cross-sectional area of the hatched portion A in FIG. 5) surrounded by the inner surface C (protein solution contact surface) of 3b and the tip of the lower lid 3b (tip of the fluid passage 12) is centered on the axis B of the lower lid 3b. The volume (mL) of the space that can be generated when it is rotated 360 degrees can be calculated using an equation for determining the volume of a general cylinder, frustum, or the like. The dimensions in the hollow fiber membrane filter 1 may be measured by, for example, an X-ray CT apparatus, or may be measured by calipers after disassembling the hollow fiber membrane filter 1.

中空糸膜内容積は、中空糸膜４の内径をｄ、中空糸膜４の長さをＬ、中空糸膜４の本数をＮとすると、以下の式で算出される。
中空糸膜内容積＝（ｄ／２）２×π×Ｌ×ＮThe inner volume of the hollow fiber membrane is calculated by the following formula, where d is the inner diameter of the hollow fiber membrane 4, L is the length of the hollow fiber membrane 4, and N is the number of the hollow fiber membranes 4.
Hollow fiber membrane volume = (d / 2) 2 × π × L × N

空間容量Ａは、中空糸膜内容積のより好ましくは０．０７倍以上、より好ましくは０．１０倍以上、より好ましくは０．２０倍以上、更に好ましくは０．４０倍以上である。また、中空糸膜型濾過器１の取り扱い性の観点から、より好ましくは２．６０倍以下であり、より好ましくは１．３０倍以下である。   The space capacity A is more preferably 0.07 times or more, more preferably 0.10 times or more, more preferably 0.20 times or more, and still more preferably 0.40 times or more the hollow fiber membrane internal volume. Moreover, from a viewpoint of the handleability of the hollow fiber membrane type filter 1, it is more preferably 2.60 times or less, more preferably 1.30 times or less.

中空糸膜型濾過器１は、中空糸膜の下端側の接着材面７ａから下蓋３ｂの内面Ｃまでの高さ（高さＥ）が、２．０ｍｍ以上であることが好ましい。２．０ｍｍ以上であると、生体不要成分が凝集し下蓋内空間の一部に滞留して中空糸膜４の開孔部を塞ぐのを防止し易い。図５に示すように、下端側の接着材面７ａから下蓋３ｂの内面Ｃまでの高さとは、接着材面７ａのうち中空糸膜４の開口部が位置する部分から、接着材面７ａに対し垂直に伸ばして下蓋内面Ｃに接するまでの最短距離である。但し、内面Ｃの表面に貯留容量に影響を与えない程度の凸部がある場合、その凸部部分は除外した最短距離とする。高さＥはより好ましくは３．７ｍｍ以上、より好ましくは５．０ｍｍ以上、より好ましくは１０．０ｍｍ以上であり、更に好ましくは１５．０ｍｍ以上である。中空糸膜型濾過器１の取り扱い性から、１００．０ｍｍ以下がより好ましく、更に５０．０ｍｍ以下が好ましい。   In the hollow fiber membrane filter 1, the height (height E) from the adhesive material surface 7a on the lower end side of the hollow fiber membrane to the inner surface C of the lower lid 3b is preferably 2.0 mm or more. When it is 2.0 mm or more, it is easy to prevent unnecessary biological components from aggregating and staying in a part of the inner space of the lower lid to block the opening portion of the hollow fiber membrane 4. As shown in FIG. 5, the height from the adhesive material surface 7a on the lower end side to the inner surface C of the lower lid 3b refers to the adhesive material surface 7a from the portion of the adhesive material surface 7a where the opening of the hollow fiber membrane 4 is located. It is the shortest distance from extending vertically to touching the inner surface C of the lower lid. However, if there is a convex portion on the inner surface C that does not affect the storage capacity, the convex portion is the shortest distance excluded. The height E is more preferably 3.7 mm or more, more preferably 5.0 mm or more, more preferably 10.0 mm or more, and further preferably 15.0 mm or more. From the handleability of the hollow fiber membrane type filter 1, it is more preferably 100.0 mm or less, and further preferably 50.0 mm or less.

中空糸膜型濾過器１は、中空糸膜型濾過器１内に配置された中空糸膜４の下端側接着材面７ａと下蓋３ｂとが形成する空間容量Ａを中空糸膜４の本数で割った値が、０．８８×１０−３ｍＬ／本以上であることが好ましい。空間容量Ａを中空糸膜４の本数で割った値が０．８８×１０−３ｍＬ／本以上であると、中空糸膜本数に対する空間容量Ａが大きい程生体不要成分が下蓋空間内にスムーズに拡散し中空糸膜４の開孔部を塞ぐリスクを低減できる。より好ましくは１．２０×１０−３ｍＬ／本以上、より好ましくは１．５９×１０−３ｍＬ／本以上、より好ましくは３．９６×１０−３ｍＬ／本以上であり、更に好ましくは６．１４×１０−３ｍＬ／本以上である。中空糸膜型濾過器１の取り扱い性から、４４．０×１０−３ｍＬ／本以下がより好ましく、更に２２．０×１０−３ｍＬ／本以下が好ましい。The hollow fiber membrane type filter 1 has the space capacity A formed by the lower end side adhesive material surface 7a and the lower lid 3b of the hollow fiber membrane 4 disposed in the hollow fiber membrane type filter 1 as the number of the hollow fiber membranes 4. The value divided by is preferably 0.88 × 10 −3 mL / piece or more. When the value obtained by dividing the space capacity A by the number of the hollow fiber membranes 4 is 0.88 × 10 −3 mL / number or more, the larger the space capacity A with respect to the number of the hollow fiber membranes, the more unnecessary biological components are in the lower lid space. The risk of diffusing smoothly and closing the opening of the hollow fiber membrane 4 can be reduced. More preferably 1.20 × 10 −3 mL / tube or more, more preferably 1.59 × 10 −3 mL / tube or more, more preferably 3.96 × 10 −3 mL / tube or more, and still more preferably 6.14 × 10 −3 mL / tube or more. From the handleability of the hollow fiber membrane type filter 1, 44.0 * 10 < -3 > mL / piece or less is more preferable, and 22.0 * 10 < -3 > mL / piece or less is more preferable.

図５は中空糸膜型濾過器１の例示のみであるが、中空糸膜型体液濾過装置２０の一部として利用する場合、中空糸膜型濾過器１の下端に貯留部材を接続してもよいし、貯留部材を接続しないで使用してもよい。空間容量Ａの大きい中空糸膜型濾過器１は、貯留部材を接続しない態様においても、生体不要成分を接着材面７ａより下に貯留しやすく、膜の目詰まりを起こしにくい点で有利である。   FIG. 5 is only an example of the hollow fiber membrane filter 1, but when used as a part of the hollow fiber membrane body fluid filtration device 20, a storage member may be connected to the lower end of the hollow fiber membrane filter 1. Alternatively, the storage member may be used without being connected. The hollow fiber membrane type filter 1 having a large space capacity A is advantageous in that it is easy to store biologically unnecessary components below the adhesive surface 7a even in a mode in which no storage member is connected, and the membrane is not easily clogged. .

貯留部の容量は５ｍＬ以上が好ましく、より好ましくは１０ｍＬ以上であり、更に好ましくは１５ｍＬ以上、特に好ましくは５０ｍＬ以上である。貯留部の容量が増すほど生体不要成分を貯留できる容量が増し、圧上昇するまでに処理できる生体不要成分を含むタンパク質溶液量が増加する。また、タンパク質溶液の液量の回収率を確保するために、より好ましくは４０５ｍＬ以下であり、２０５ｍＬ以下であり、更に好ましくは１０５ｍＬ以下である。なお、本実施の形態において、「貯留部の容量」は、中空糸膜型濾過器１の下端に貯留部材が設けられていない場合には、空間容量Ａであり、中空糸膜型濾過器１の下端に貯留部材が設けられている場合には、空間容量Ａに貯留部材の容量を加えた容量となる。   The capacity of the reservoir is preferably 5 mL or more, more preferably 10 mL or more, still more preferably 15 mL or more, and particularly preferably 50 mL or more. As the capacity of the reservoir increases, the capacity for storing the biologically unnecessary component increases, and the amount of the protein solution containing the biologically unnecessary component that can be processed before the pressure increases. Moreover, in order to ensure the recovery rate of the amount of protein solution, it is more preferably 405 mL or less, 205 mL or less, and further preferably 105 mL or less. In the present embodiment, the “capacity of the storage portion” is the space capacity A when the storage member is not provided at the lower end of the hollow fiber membrane filter 1, and the hollow fiber membrane filter 1 In the case where a storage member is provided at the lower end of the storage space, a capacity obtained by adding the capacity of the storage member to the space capacity A is obtained.

図６に示す中空糸膜型体液濾過装置２０は、中空糸膜型濾過器１の入口が生体不要成分を含むタンパク質溶液を貯留する原液容器４０に接続され、濾液出口９は濃縮器に接続されている。原液容器４０は、患者から採取した体液を収容しており、体液はポンプ４１によって送られ、中空糸膜型濾過器１に導入される。ポンプ４１としては、ローラーポンプや輸液ポンプなどのポンプが一般的に用いられる。ポンプの駆動を制御する制御装置を設けても良い。制御装置は、例えばコンピュータであり、所望の制御に係る情報を施行者に入力させる入力端末を兼ねてもよい。入口圧またはＴＭＰが一定圧以上に上昇したら、流量を下げたり流量を停止するなどの流量制御を行ってもよい。   In the hollow fiber membrane-type body fluid filtration device 20 shown in FIG. 6, the inlet of the hollow fiber membrane-type filter 1 is connected to a stock solution container 40 that stores a protein solution containing a biologically unnecessary component, and the filtrate outlet 9 is connected to a concentrator. ing. The stock solution container 40 contains body fluid collected from a patient, and the body fluid is sent by a pump 41 and introduced into the hollow fiber membrane filter 1. As the pump 41, a pump such as a roller pump or an infusion pump is generally used. You may provide the control apparatus which controls the drive of a pump. The control device is, for example, a computer, and may also serve as an input terminal that allows an enforcer to input information related to desired control. When the inlet pressure or TMP rises above a certain pressure, flow control such as decreasing the flow rate or stopping the flow rate may be performed.

本実施形態の中空糸膜型体液濾過装置２０において、中空糸膜型濾過器１の入口１１から流入する生体不要成分を含むタンパク質溶液の流量は、中空糸膜型濾過器１の中空糸膜単一面積あたり、好ましくは３ｍＬ／ｍｉｎ／ｍ２以上であり、好ましくは５ｍＬ／ｍｉｎ／ｍ２以上であり、さらに好ましくは１０ｍＬ／ｍｉｎ／ｍ２以上である。流量が増えるほどより濾過時間が短縮され効率がよい。また、好ましくは３００ｍＬ／ｍｉｎ／ｍ２以下であり、好ましくは２００ｍＬ／ｍｉｎ／ｍ２以下であり、更に好ましくは１００ｍＬ／ｍｉｎ／ｍ２以下である。生体不要成分の量にもよるが、３００ｍＬ／ｍｉｎ／ｍ２以下では中空糸膜４への生体不要成分の目詰まりがより起こりにくい。中空糸膜型濾過器１の中空糸膜面積は、中空糸膜の長さと本数、中空糸膜の径から求めることができる。径は、中空糸膜４の内側から外側へ濾過する場合は内径、中空糸膜４の外側から内側へ濾過する場合は外径を用いる。In the hollow fiber membrane-type body fluid filtration device 20 of the present embodiment, the flow rate of the protein solution containing a biological unnecessary component flowing in from the inlet 11 of the hollow fiber membrane-type filter 1 It is preferably 3 mL / min / m 2 or more per area, preferably 5 mL / min / m 2 or more, and more preferably 10 mL / min / m 2 or more. As the flow rate increases, the filtration time is shortened and the efficiency is improved. Moreover, it is preferably 300 mL / min / m 2 or less, preferably 200 mL / min / m 2 or less, and more preferably 100 mL / min / m 2 or less. Although it depends on the amount of the biologically unnecessary component, clogging of the biologically unnecessary component into the hollow fiber membrane 4 is less likely to occur at 300 mL / min / m 2 or less. The hollow fiber membrane area of the hollow fiber membrane filter 1 can be determined from the length and number of the hollow fiber membranes and the diameter of the hollow fiber membranes. The diameter is the inside diameter when filtering from the inside to the outside of the hollow fiber membrane 4 and the outside diameter when filtering from the outside to the inside of the hollow fiber membrane 4.

原液容器４０は、液体を貯留することができればどのようなものでもよいが、通常、取り扱い性の観点から、ポリ塩化ビニル製のバッグが用いられる。原液容器４０の大きさは貯留される体液の量などにより決定される。患者から採取する体液が多く原液容器１個に収容できない場合、原液容器４０は２個以上用いてよく、原液容器１個分の濾過が終了したら次の原液容器４０と交換する。また、体液を採取するにあたり、混在する血球成分の活性化を抑制するために、タンパク質溶液に抗凝固剤を添加してもよい。抗凝固剤の種類は、クエン酸又はその塩からなる群の他、フサン、ヘパリン、エチレンジアミン四酢酸（ＥＤＴＡ）などを使用することができるが、ヘパリンを好適に使用することができる。   The stock solution container 40 may be anything as long as it can store a liquid, but a polyvinyl chloride bag is usually used from the viewpoint of handleability. The size of the stock solution container 40 is determined by the amount of body fluid stored. When a large amount of body fluid is collected from a patient and cannot be accommodated in one stock solution container, two or more stock solution containers 40 may be used. When filtration of one stock solution container is completed, the next stock solution container 40 is replaced. Further, when collecting body fluid, an anticoagulant may be added to the protein solution in order to suppress the activation of mixed blood cell components. In addition to the group consisting of citric acid or a salt thereof, fusan, heparin, ethylenediaminetetraacetic acid (EDTA), and the like can be used as the type of anticoagulant, but heparin can be preferably used.

図６に示す例では、原液容器４０が回路に接続されているが、原液容器４０を使用せず、患者から採取した体液を直接又はポンプを介して中空糸膜型濾過器１に導入してもよい。患者から採取した体液を直接濾過器１に導入する場合、その採取速度の確認や逆流防止のために、点滴筒を用い、また採取速度を調整するためにローラークランプなどを備えることが好ましい。下蓋３ｂに接続されるチューブ６０には、開閉手段としてのクランプ６３が設けられている。   In the example shown in FIG. 6, the stock solution container 40 is connected to the circuit, but the stock solution container 40 is not used, and body fluid collected from the patient is introduced into the hollow fiber membrane filter 1 directly or via a pump. Also good. When the body fluid collected from the patient is directly introduced into the filter 1, it is preferable to use a drip tube for confirming the collection speed and preventing backflow, and to include a roller clamp or the like for adjusting the collection speed. The tube 60 connected to the lower lid 3b is provided with a clamp 63 as an opening / closing means.

濾液出口９の先に濃縮器（図示せず）が接続されており、濃縮器に濾液が導入される。中空糸膜型濾過器１により得たタンパク質溶液から、水分や電解質などを除去し、栄養成分であるアルブミンを含むタンパク質成分は濃縮する。また、濃縮器の濃縮液出口は、回収容器に接続されていてもよい。   A concentrator (not shown) is connected to the end of the filtrate outlet 9, and the filtrate is introduced into the concentrator. Water and electrolytes are removed from the protein solution obtained by the hollow fiber membrane filter 1, and the protein component containing albumin, which is a nutrient component, is concentrated. Moreover, the concentrate outlet of the concentrator may be connected to a collection container.

図７に示す中空糸膜型体液濾過装置２０は、原液容器４０が中空糸膜型濾過器１にポンプ等の送液手段を介さずに接続されている以外、図６に示す例とほぼ同じであるので、相違点のみ説明する。   The hollow fiber membrane-type body fluid filtration device 20 shown in FIG. 7 is substantially the same as the example shown in FIG. 6 except that the stock solution container 40 is connected to the hollow fiber membrane-type filter 1 without a liquid feeding means such as a pump. Therefore, only the differences will be described.

原液容器４０は中空糸膜型濾過器１より高い位置に設けられており、原液は重力によって中空糸膜型濾過器１に導入されるようになっている。原液容器を使用せず、患者から採取した体液をそのまま濾過する場合は、穿刺位置を中空糸膜型濾過器１より高くする必要がある。   The stock solution container 40 is provided at a position higher than the hollow fiber membrane filter 1, and the stock solution is introduced into the hollow fiber membrane filter 1 by gravity. When the body fluid collected from the patient is filtered as it is without using the stock solution container, it is necessary to make the puncture position higher than the hollow fiber membrane filter 1.

流量の制御手段（図示せず）を設ける場合は、原液容器４０または患者と、中空糸膜型濾過器１との間に備えることが好ましい。   When a flow rate control means (not shown) is provided, it is preferably provided between the stock solution container 40 or the patient and the hollow fiber membrane filter 1.

図７に示す例では、濾液出口９の先に濃縮器が接続されており、落差圧を駆動力として濃縮しているが、中空糸膜型濾過器１と濃縮器との駆動方法の組み合わせは特に限定されず、図６に示すように濃縮器はローラーポンプ４１によって駆動してもよく、原液の性状やシステムの設置場所等に応じて任意に設定可能である。ローラーポンプの代わりに吸引装置を使用してもよい。   In the example shown in FIG. 7, a concentrator is connected to the end of the filtrate outlet 9, and concentration is performed using the drop pressure as a driving force. However, a combination of driving methods of the hollow fiber membrane filter 1 and the concentrator is as follows. The concentrator may be driven by a roller pump 41 as shown in FIG. 6 and can be arbitrarily set according to the properties of the stock solution, the installation location of the system, and the like. A suction device may be used instead of the roller pump.

流量の制御手段を、中空糸膜型濾過器１の濾液出口９側に設けてもよい。また、濾過中は、流量の制御手段を原液容器４０（または患者）と中空糸膜型濾過器１との間に設けておき、濾過終了後に制御手段を中空糸膜型濾過器１と濃縮器または回収容器との間に付け替えてもよい。これにより濾過終了時、中空糸膜４の外側と濾液出口９との間の空間内にあるタンパク質溶液を送出することにも用いることができる。濾過終了時、エアが中空糸膜型濾過器１の入口１１まで達した時、例えば中空糸膜型濾過器１の濾液出口９側の回路上のクランプ４３を開け除菌用エアーベントフィルター４２を介してエアを取り入れ、タンパク質溶液を回収する。回収に制御手段を使わない場合は、濾液出口９の高さをタンパク質溶液の最終出口（中空糸膜型濾過器１の濾液出口９側に接続する濃縮器または回収容器３０の入口の位置）の高さよりも高い位置に配置し、落差を用いて回収することもできる。   The flow rate control means may be provided on the filtrate outlet 9 side of the hollow fiber membrane filter 1. Further, during filtration, a flow rate control means is provided between the stock solution container 40 (or patient) and the hollow fiber membrane filter 1, and after the filtration is completed, the control means is the hollow fiber membrane filter 1 and the concentrator. Or you may replace | exchange between collection containers. Thereby, at the time of completion | finish of filtration, it can use also for sending out the protein solution in the space between the outer side of the hollow fiber membrane 4, and the filtrate outlet 9. FIG. At the end of filtration, when the air reaches the inlet 11 of the hollow fiber membrane filter 1, for example, the clamp 43 on the circuit on the filtrate outlet 9 side of the hollow fiber membrane filter 1 is opened to disinfect the air vent filter 42 for sterilization. Intake air through and collect the protein solution. When the control means is not used for recovery, the height of the filtrate outlet 9 is the final outlet of the protein solution (the position of the inlet of the concentrator or the recovery container 30 connected to the filtrate outlet 9 side of the hollow fiber membrane filter 1). It can be arranged at a position higher than the height and recovered using a drop.

タンパク質溶液を入口から通液するにあたり、前記中空糸膜型濾過器１の入口１１側に陽圧をかけて通液することが好ましい。陽圧をかけることにより、中空糸膜型体液濾過装置２０の圧上昇までの時間延長効果が大きくなる。   In passing the protein solution from the inlet, it is preferable to pass a positive pressure on the inlet 11 side of the hollow fiber membrane filter 1. By applying a positive pressure, the effect of extending the time until the pressure of the hollow fiber membrane type body fluid filtration device 20 increases is increased.

以上の実施の形態では、中空糸膜の内側から外側に濾過する例であったが、上記すべての態様において、中空糸膜の外側から内側へ濾過してもよい。この場合、中空糸膜型体液濾過装置２０は、中空糸膜型濾過器１は入口が上側になるように縦に配置され、当該入口から流入した生体不要成分を含むタンパク質溶液が中空糸膜の外側を下方向に通液し、中空糸膜の内側に流出した前記タンパク質溶液の濾液が濾液出口から流出するように構成される。すなわち、生体不要成分を含むタンパク質溶液を、図１の中空糸膜型濾過器１における上側の入口（上記実施の形態における上側の濾液出口）９から流入させ、当該入口９から流入した生体不要成分を含むタンパク質溶液が中空糸膜４の外側を下方向に通液し、中空糸膜４の内側に流出したタンパク質溶液の濾液が濾液出口（上記実施の形態における通液口）１２から流出する。   In the above embodiment, the example of filtering from the inside to the outside of the hollow fiber membrane has been described. However, in all the above embodiments, the filtration may be performed from the outside to the inside of the hollow fiber membrane. In this case, in the hollow fiber membrane type body fluid filtration device 20, the hollow fiber membrane type filter 1 is arranged vertically so that the inlet is on the upper side, and the protein solution containing the biological unnecessary components flowing in from the inlet is the hollow fiber membrane. It is configured such that the filtrate of the protein solution that has flowed downward on the outside and flowed out to the inside of the hollow fiber membrane flows out from the filtrate outlet. That is, a protein solution containing a biologically unnecessary component is allowed to flow from the upper inlet (upper filtrate outlet in the above embodiment) 9 in the hollow fiber membrane filter 1 of FIG. The protein solution containing is allowed to flow down the outside of the hollow fiber membrane 4 and the filtrate of the protein solution that has flowed out to the inside of the hollow fiber membrane 4 flows out from the filtrate outlet (fluid inlet in the above embodiment).

以下の実施例により、本発明を更に詳細に説明するが、本発明はこれらによって限定されるものではない。   The following examples further illustrate the present invention in detail but are not to be construed to limit the scope thereof.

［疑似腹水の作製方法］
生体不要成分を含むタンパク質溶液として、ウシの血液を用いた血球成分を含む疑似腹水を作製した。まず、抗凝固剤としてヘパリンナトリウム注（１万単位／牛血液１Ｌ）を添加した牛血液を遠心分離し、血漿層、赤血球層およびバフィーコート層の各溶液を得て、これらを別々に回収した。次に血漿と生理食塩液を混和してタンパク質濃度を調製した希釈血漿を作製した。またそのアルブミン濃度も測定した。そして、希釈血漿にバフィーコート層を添加して白血球数を調製し、不足した赤血球として赤血球層の溶液を添加し、疑似腹水を作製した。[Production method of simulated ascites]
A pseudo ascites containing a blood cell component using bovine blood was prepared as a protein solution containing an unnecessary biological component. First, bovine blood to which heparin sodium injection (10,000 units / 1 L of bovine blood) was added as an anticoagulant was centrifuged to obtain plasma layer, red blood cell layer and buffy coat layer solutions, which were collected separately. . Next, plasma and physiological saline were mixed to prepare diluted plasma in which the protein concentration was adjusted. The albumin concentration was also measured. Then, the buffy coat layer was added to the diluted plasma to adjust the white blood cell count, and the red blood cell layer solution was added as the deficient red blood cells to prepare pseudo ascites.

タンパク質濃度は、ビューレット法により測定した。自動分析装置（東京貿易メディカルシステム（株）社製、Ｂｉｏｌｉｓ２４ｉ）、測定用試薬としてイアトロＴＰII（（株）ＬＳＩメディエンス社製）を用いた。   The protein concentration was measured by the burette method. An automatic analyzer (manufactured by Tokyo Trading Medical System Co., Ltd., Biolis 24i) and Iatro TPII (manufactured by LSI Medience Co., Ltd.) were used as measurement reagents.

アルブミン濃度は、ＢＣＧ法により測定した。自動分析装置（東京貿易メディカルシステム（株）社製、Ｂｉｏｌｉｓ２４ｉ）、測定用試薬としてイアトロファインＡＬＢII（（株）ＬＳＩメディエンス社製）を用いた。   The albumin concentration was measured by the BCG method. An automatic analyzer (manufactured by Tokyo Trading Medical System Co., Ltd., Biolis 24i) and Iatrofine ALBII (manufactured by LSI Medience Co., Ltd.) were used as measurement reagents.

赤血球数および白血球数は、ミクロセルカウンター（シスメックス（株）社製、ＸＴ−１８００ｉ）を用いて測定した。   The number of red blood cells and white blood cells were measured using a microcell counter (manufactured by Sysmex Corporation, XT-1800i).

（実施例１）
組成、タンパク質濃度４．１５ｇ／ｄＬ、アルブミン濃度２．１７ｇ／ｄＬ、白血球数１，０１０個／μＬ、赤血球数１９０，０００個／μＬの疑似腹水を作製した。Example 1
A pseudo ascites having a composition, a protein concentration of 4.15 g / dL, an albumin concentration of 2.17 g / dL, a white blood cell count of 1,010 / μL, and a red blood cell count of 190,000 / μL was prepared.

図２に示す装置を使用し、中空糸膜型体液濾過装置内を生理食塩液でプライミングした後、疑似腹水を濾過した。濾過は、回収容器入口の位置を中空糸膜型濾過器の中心位置と合わせ、ローラーポンプと中空糸膜型濾過器との間に圧力計を接続し、中空糸膜型濾過器の入口側圧力が４０ｋＰａに達するまで（濾過の開始から中空糸膜型濾過器の入口側圧力が４０ｋＰａに達するまでの時間を濾過時間とした。）流速５０ｍＬ／ｍｉｎで行った。その後一旦ポンプを停止し、中空糸膜型濾過器の入口側回路を鉗子でクランプし、ポンプ位置を中空糸膜型濾過器と回収容器との間に付け替え、中空糸膜型濾過器の濾液出口回路上にあるエアーベントフィルターのクランプを開け、中空糸膜外側空間にあるタンパク質溶液も回収した。使用した中空糸膜型濾過器の中空糸膜、下蓋を表１に示す。上蓋は下蓋と同一のものを使用した。なお、中空糸膜は、ポリエチレン製の中空糸膜に親水化剤としてエチレン・ビニルアルコール共重合体をコーティングしたものを用い、内径は２９１μｍ、膜厚は４５μｍ、平均孔径は０．２μｍ以下、透水量は１．０Ｌ／ｈｒ・ｍ２・ｍｍＨｇ、長さＬは２４４ｍｍであった。Using the apparatus shown in FIG. 2, the inside of the hollow fiber membrane type body fluid filtration device was primed with physiological saline, and then the pseudo ascites was filtered. For filtration, align the position of the collection container inlet with the center position of the hollow fiber membrane filter, connect a pressure gauge between the roller pump and the hollow fiber membrane filter, and set the pressure on the inlet side of the hollow fiber membrane filter. Was performed at a flow rate of 50 mL / min until the pressure reached 40 kPa (the time from the start of filtration until the pressure on the inlet side of the hollow fiber membrane filter reached 40 kPa was defined as the filtration time). Then stop the pump once, clamp the inlet side circuit of the hollow fiber membrane filter with forceps, change the pump position between the hollow fiber membrane filter and the collection container, and the filtrate outlet of the hollow fiber membrane filter The clamp of the air vent filter on the circuit was opened, and the protein solution in the outer space of the hollow fiber membrane was also collected. Table 1 shows the hollow fiber membrane and the lower lid of the hollow fiber membrane filter used. The upper lid was the same as the lower lid. The hollow fiber membrane used was a polyethylene hollow fiber membrane coated with an ethylene / vinyl alcohol copolymer as a hydrophilizing agent. The inner diameter was 291 μm, the film thickness was 45 μm, the average pore diameter was 0.2 μm or less, and the water permeability The amount was 1.0 L / hr · m 2 · mmHg, and the length L was 244 mm.

中空糸膜型濾過器の入口側圧力が４０ｋＰａに達するまでの時間と濾過液量、および回収したアルブミン溶液のアルブミン量を測定した。測定結果を表１に併せて示す。回収したアルブミン量は、回収したアルブミン溶液の液量にアルブミン濃度を乗じて求めた。   The time until the pressure on the inlet side of the hollow fiber membrane filter reached 40 kPa, the amount of filtrate, and the amount of albumin in the recovered albumin solution were measured. The measurement results are also shown in Table 1. The recovered albumin amount was determined by multiplying the recovered albumin solution volume by the albumin concentration.

（実施例２）
中空糸膜型濾過器に表１の実施例２欄に示すものを使用し、濾過流速を８０ｍＬ／ｍｉｎへ変更した以外実施例１と同様にして疑似腹水を濾過した。結果を表１に併せて示す。(Example 2)
The pseudo ascites was filtered in the same manner as in Example 1 except that the hollow fiber membrane type filter shown in Example 2 column of Table 1 was used and the filtration flow rate was changed to 80 mL / min. The results are also shown in Table 1.

（実施例３）
疑似腹水の組成を、タンパク質濃度２．９５ｇ／ｄＬ、アルブミン濃度１．５４ｇ／ｄＬ、白血球数５００個／μＬ、赤血球数１００，０００個／μＬへ変更した以外実施例１と同様にして疑似腹水を濾過した。結果を表１に併せて示す。(Example 3)
Simulated ascites in the same manner as in Example 1 except that the composition of the simulated ascites was changed to a protein concentration of 2.95 g / dL, an albumin concentration of 1.54 g / dL, a white blood cell count of 500 cells / μL, and a red blood cell count of 100,000 cells / μL. Was filtered. The results are also shown in Table 1.

（比較例１）
中空糸膜型濾過器の入口を下側に反転して配置した以外実施例１と同様にして疑似腹水を濾過した。なお、中空糸膜型濾過器の入口を下側に反転して配置する本比較例では、下蓋が上側に配置されていることになる（他の比較例においても同様。）。結果を表１に併せて示す。(Comparative Example 1)
Simulated ascites was filtered in the same manner as in Example 1 except that the inlet of the hollow fiber membrane filter was inverted and arranged downward. In this comparative example in which the inlet of the hollow fiber membrane type filter is inverted downward, the lower lid is disposed on the upper side (the same applies to other comparative examples). The results are also shown in Table 1.

（比較例２）
以下の操作以外比較例１と同様にして疑似腹水を濾過した。結果を表１に併せて示す。疑似腹水量を３，０００ｍＬ原液容器に入れ濾過を開始し、中空糸膜型濾過器の入口側圧力が４０ｋＰａに達するまで流速５０ｍＬ／ｍｉｎで濾過した。次にフラッシングを行った後、更に同じ濾過流速で濾過を継続し、疑似腹水が中空糸膜型濾過器の入口に達するまで濾過した。濾液は全て回収容器に回収した。最終圧力は４０ｋＰａであった。フラッシングは、ポンプを一旦停止し、濾液出口側回路を鉗子で閉鎖し、中空糸膜型濾過器の上側に配置された下蓋の通液口に回路を取り付け、ポンプを再開して中空糸膜内の溶液１３０ｍＬを排出する方法で行った。フラッシングの操作時間として４分を要した。(Comparative Example 2)
The pseudo ascites was filtered in the same manner as in Comparative Example 1 except for the following operations. The results are also shown in Table 1. The simulated ascites amount was placed in a 3,000 mL stock solution container, and filtration was started. Filtration was performed at a flow rate of 50 mL / min until the pressure on the inlet side of the hollow fiber membrane filter reached 40 kPa. Next, after flushing, filtration was continued at the same filtration flow rate, and filtration was performed until the simulated ascites reached the inlet of the hollow fiber membrane filter. All the filtrate was collected in a collection container. The final pressure was 40 kPa. For flushing, the pump is temporarily stopped, the filtrate outlet side circuit is closed with forceps, the circuit is attached to the liquid passage opening of the lower lid arranged on the upper side of the hollow fiber membrane filter, the pump is restarted and the hollow fiber membrane is restarted. This was performed by discharging 130 mL of the solution. Flushing operation time was 4 minutes.

（比較例３）
中空糸膜型濾過器の入口を下側に反転して配置した以外実施例２と同様にして疑似腹水を濾過した。結果を表１に併せて示す。(Comparative Example 3)
The pseudo ascites was filtered in the same manner as in Example 2 except that the inlet of the hollow fiber membrane filter was inverted and arranged downward. The results are also shown in Table 1.

（比較例４）
中空糸膜型濾過器の入口を下側に反転して配置した以外実施例３と同様にして疑似腹水を濾過した。結果を表１に併せて示す。(Comparative Example 4)
Simulated ascites was filtered in the same manner as in Example 3 except that the inlet of the hollow fiber membrane filter was inverted and arranged downward. The results are also shown in Table 1.

実施例１と比較例１、実施例２と比較例３、実施例３と比較例４の結果から、中空糸膜型濾過器の入口を上側になるように縦に配置し、疑似腹水を下方向へ濾過する方が、入口を下側に配置し疑似腹水を上方向に濾過するよりも圧上昇までの時間が延長し、結果得られたアルブミン量は多くなることが分かった。また比較例２の結果から、入口を下側に配置し疑似腹水を上方向に濾過する方法において操作が煩雑なフラッシングを行った場合、合計濾過時間は伸びるものの回収できるアルブミン量は減少することが分かった。   From the results of Example 1 and Comparative Example 1, Example 2 and Comparative Example 3, Example 3 and Comparative Example 4, the inlet of the hollow fiber membrane type filter was placed vertically so that the pseudo ascites was lowered. It was found that the time to increase the pressure was increased by filtering in the direction, and the amount of albumin obtained was increased as compared with the case where the inlet was placed on the lower side and the simulated ascites was filtered upward. Moreover, from the result of Comparative Example 2, when the flushing operation is complicated in the method in which the inlet is disposed on the lower side and the pseudo ascites is filtered upward, the amount of albumin that can be recovered may be reduced although the total filtration time is increased. I understood.

Figure 0006469123
Figure 0006469123

（実施例４〜７）
中空糸膜型濾過器の下蓋に表２の各実施例欄に記載の貯留部材を接続した以外実施例１と同様にして疑似腹水を濾過した。貯留部材として使用したチューブＡは内径３．４ｍｍのポリ塩化ビニル製チューブであり、チューブの一端にルアーコネクタを接着し、そのルアーコネクタを介して下蓋の通液口に接続した。また、プライミング時はチューブＡを介してプライミングを行い、濾過前にクランプで所定長さ部分を閉じて濾過した。結果を表２に併せて示す。(Examples 4 to 7)
The pseudo ascites was filtered in the same manner as in Example 1 except that the storage member described in each column of Table 2 was connected to the lower lid of the hollow fiber membrane filter. The tube A used as the storage member was a polyvinyl chloride tube having an inner diameter of 3.4 mm. A luer connector was bonded to one end of the tube, and the luer connector was connected to the liquid passing port of the lower lid through the luer connector. At the time of priming, priming was performed through the tube A, and a predetermined length portion was closed with a clamp before filtration before filtration. The results are also shown in Table 2.

（実施例８、１４）
中空糸膜型濾過器の下蓋に表２の各実施例欄に記載の貯留部材を接続した以外実施例１と同様にして疑似腹水を濾過した。貯留部材として使用した容器Ｃおよび容器Ｅはルアーコネクタを接着したポリ塩化ビニル製の軟質性バッグを用い、容器Ｃ容量は５０ｍＬ、容器Ｅ容量は１００ｍＬであり、プライミング後、バッグ内のエアを抜いた状態でルアーコネクタを下蓋の通気口に接続した。接続後容器内にプライミング液を満たした後に濾過を開始した。結果を表２に併せて示す。(Examples 8 and 14)
The pseudo ascites was filtered in the same manner as in Example 1 except that the storage member described in each column of Table 2 was connected to the lower lid of the hollow fiber membrane filter. Container C and container E used as storage members use a flexible bag made of polyvinyl chloride to which a luer connector is bonded, the capacity of container C is 50 mL, the capacity of container E is 100 mL, and after priming, the air in the bag is removed. In this state, the luer connector was connected to the vent of the lower lid. After the connection, filtration was started after filling the container with the priming solution. The results are also shown in Table 2.

（実施例９、１５）
中空糸膜型濾過器の下蓋に表２の各実施例欄に記載の貯留部材を接続した以外実施例１と同様にして疑似腹水を濾過した。貯留部材として使用したチューブＢは両端にルアーコネクタを接着した内径３．４ｍｍ、長さ１０ｃｍのポリ塩化ビニル製チューブであり、貯留部材として使用した容器Ｃおよび容器Ｅは実施例８および１４と同じものを用いた。プライミングは、中空糸膜型濾過器の下蓋にチューブＢを接続し、更にその他端に別途用意したプライミング用チューブを接続して行った。プライミング後、チューブＢを鉗子で閉じ、プライミングチューブを外し、容器Ｃまたは容器Ｅをバッグ内のエアを抜いた状態でチューブＢに接続し、鉗子を外した。鉗子を外した後容器Ｃまたは容器Ｅ内にプライミング液を満たした後濾過を開始した。結果を表２に併せて示す。(Examples 9 and 15)
The pseudo ascites was filtered in the same manner as in Example 1 except that the storage member described in each column of Table 2 was connected to the lower lid of the hollow fiber membrane filter. Tube B used as a storage member is a tube made of polyvinyl chloride having an inner diameter of 3.4 mm and a length of 10 cm with a luer connector bonded to both ends. Containers C and E used as storage members are the same as in Examples 8 and 14. A thing was used. The priming was performed by connecting the tube B to the lower lid of the hollow fiber membrane filter and connecting a separately prepared priming tube to the other end. After priming, the tube B was closed with forceps, the priming tube was removed, the container C or the container E was connected to the tube B with the air in the bag being evacuated, and the forceps were removed. After removing the forceps, the container C or E was filled with the priming solution, and then filtration was started. The results are also shown in Table 2.

（実施例１０〜１３、１６、１７）
中空糸膜型濾過器の下蓋に表２の各実施例欄に記載の貯留部材を接続し、チューブＢの鉗子を外すタイミングを濾過前の代わりに、濾過開始後、入口圧が一定値になった時点に変更する以外、実施例９と同様にして疑似腹水を濾過した。鉗子を外す時点まで容器内はエアおよびプライミング液は入っていない状態であった。貯留部材としてチューブＢおよび容器Ｃ、ＤもしくはＥを用い、容器Ｄは容器Ｃの形状を縦長に変えたものを用いた。また鉗子を外すタイミングである入口圧は表２（「貯留部材」の「形態」欄）に記載の圧力とした。結果を表２に併せて示す。(Examples 10-13, 16, 17)
The storage member described in each Example column of Table 2 is connected to the lower lid of the hollow fiber membrane filter, and the timing at which the forceps of the tube B are removed is set to a constant value after the start of filtration instead of before the filtration. The pseudo ascites was filtered in the same manner as in Example 9 except that the time was changed. Until the forceps were removed, air and priming liquid were not contained in the container. The tube B and the containers C, D, or E were used as the storage member, and the container D was obtained by changing the shape of the container C into a vertically long shape. In addition, the inlet pressure, which is the timing for removing the forceps, was set to the pressure described in Table 2 ("Form" column of "Storage member"). The results are also shown in Table 2.

（比較例５）
中空糸膜型濾過器の入口を下側に反転して配置した以外実施例６と同様にして疑似腹水を濾過した。結果を表２に併せて示す。(Comparative Example 5)
Simulated ascites was filtered in the same manner as in Example 6 except that the inlet of the hollow fiber membrane filter was inverted and arranged downward. The results are also shown in Table 2.

実施例１、４〜１７および比較例１、５の結果から、中空糸膜型濾過器の入口を上側になるように縦に配置し、疑似腹水を下方向へ濾過する方法において、中空糸膜濾過器の下端に貯留部材を接続すると、圧上昇までの時間が延長し、結果得られるアルブミン量が増加することが分かった。また実施例１０〜１３、１６、１７の結果から、中空糸膜型濾過器の入口圧が一定以上に上昇した後に貯留部材のチューブ上の鉗子を開けて容量を増すと、さらに濾過時間の延長効果が増した。更に、貯留部材のチューブ上の鉗子を開けた瞬間、ローラーポンプにより送られてくる疑似腹水の流速よりも貯留部材内へ流入する流速の方が速く、中空糸膜外側のタンパク質溶液が一時的に逆流を起こし、一部の濾過済みタンパク質溶液が中空糸膜内へ移動していることを目視で確認した。   From the results of Examples 1, 4 to 17 and Comparative Examples 1 and 5, in the method of vertically arranging the inlet of the hollow fiber membrane filter so as to be on the upper side and filtering the pseudo ascites downward, the hollow fiber membrane It was found that when the storage member was connected to the lower end of the filter, the time until the pressure was increased, and the resulting albumin amount increased. In addition, from the results of Examples 10 to 13, 16, and 17, when the inlet pressure of the hollow fiber membrane filter is increased above a certain level and the capacity is increased by opening the forceps on the tube of the storage member, the filtration time is further extended. Increased effectiveness. Further, at the moment when the forceps on the tube of the storage member are opened, the flow rate flowing into the storage member is faster than the flow rate of the pseudo ascites sent by the roller pump, and the protein solution outside the hollow fiber membrane is temporarily A reverse flow was caused, and it was visually confirmed that a part of the filtered protein solution had moved into the hollow fiber membrane.

Figure 0006469123
Figure 0006469123

（実施例１８〜２３）
中空糸膜型濾過器の下蓋に表３の実施例各欄に示すものを使用した以外実施例１と同様にして疑似腹水を濾過した。上蓋は実施例１の上蓋と同一のものを使用した。結果を表３に併せて示す。(Examples 18 to 23)
The pseudo ascites was filtered in the same manner as in Example 1 except that the lower lid of the hollow fiber membrane type filter used the one shown in each column of Example in Table 3. The upper lid was the same as the upper lid of Example 1. The results are also shown in Table 3.

（実施例２４）
中空糸膜型濾過器の下蓋を表３の実施例２４欄に示すものを使用した以外実施例１２と同様にして疑似腹水を濾過した。上蓋は実施例１の上蓋と同一のものを使用した。結果を表３に併せて記す。(Example 24)
Simulated ascites was filtered in the same manner as in Example 12 except that the lower lid of the hollow fiber membrane filter was used as shown in Example 24 column of Table 3. The upper lid was the same as the upper lid of Example 1. The results are also shown in Table 3.

（比較例６）
中空糸膜型濾過器の入口を下側に反転して配置した以外実施例２０と同様にして疑似腹水を濾過した。上蓋は実施例１の上蓋と同一のものを使用した。結果を表３に併せて記す。(Comparative Example 6)
Simulated ascites was filtered in the same manner as in Example 20 except that the inlet of the hollow fiber membrane filter was inverted and arranged downward. The upper lid was the same as the upper lid of Example 1. The results are also shown in Table 3.

実施例１、１８〜２３および比較例１、６の結果から、中空糸膜型濾過器の入口を上側になるように縦に配置し、疑似腹水を下方向へ濾過する方法において、中空糸膜濾過器の中空糸膜内容積または中空糸膜本数に対する下蓋の空間容量Ａの比が上がり、また下蓋の高さＥが大きくなると、圧上昇までの時間が延長し、結果得られるアルブミン量が増加することが分かった。また、実施例２４の結果から、更に貯留部材を組み合わせることにより、より効果が上がった。   From the results of Examples 1 and 18 to 23 and Comparative Examples 1 and 6, in the method of vertically arranging the inlet of the hollow fiber membrane filter so that the inlet of the hollow fiber membrane filter is on the upper side and filtering the pseudo ascites downward, the hollow fiber membrane When the ratio of the space capacity A of the lower lid to the hollow fiber membrane inner volume or the number of hollow fiber membranes of the filter is increased and the height E of the lower lid is increased, the time until the pressure is increased and the resulting albumin amount Was found to increase. Further, from the results of Example 24, the effect was further improved by further combining the storage members.

Figure 0006469123
Figure 0006469123

１ 中空糸膜型濾過器
４ 中空糸膜
９ 濾液出口
１１ 入口
２０ 中空糸膜型体液濾過装置DESCRIPTION OF SYMBOLS 1 Hollow fiber membrane type filter 4 Hollow fiber membrane 9 Filtrate outlet 11 Inlet 20 Hollow fiber membrane type body fluid filtration apparatus

Claims (16)

腹水および／又は胸水を濾過するための入口と濾液出口を有する中空糸膜型濾過器を含む中空糸膜型体液濾過装置であって、前記中空糸膜型濾過器は入口が上側になるように縦に配置され、前記入口から流入した生体不要成分を含むタンパク質溶液が中空糸膜内を下方向に通液し、中空糸膜外に流出した前記タンパク質溶液の濾液が濾液出口から流出するように構成され、
前記中空糸膜型濾過器における、中空糸膜型濾過器内に配置された中空糸膜の下端側接着材面と下蓋とが形成する空間容量が、中空糸膜内容積の０．０５倍以上、２．６０倍以下である、中空糸膜型体液濾過装置。 A hollow fiber membrane body fluid filtration device including a hollow fiber membrane filter having an inlet for filtering ascites and / or pleural effusion and a filtrate outlet, the hollow fiber membrane filter having an inlet on an upper side A protein solution containing a biologically unnecessary component that flows vertically from the inlet passes through the hollow fiber membrane downward, and the filtrate of the protein solution that flows out of the hollow fiber membrane flows out from the filtrate outlet. Configured,
In the hollow fiber membrane type filter, the space capacity formed by the lower end side adhesive material surface and the lower lid of the hollow fiber membrane arranged in the hollow fiber membrane type filter is 0.05 times the hollow fiber membrane internal volume. The hollow fiber membrane type body fluid filtration device, which is 2.60 times or less. 前記中空糸膜内を通過した溶液を貯留する貯留部を有する、請求項１に記載の中空糸膜型体液濾過装置。   The hollow fiber membrane-type body fluid filtration device according to claim 1, further comprising a reservoir that stores the solution that has passed through the hollow fiber membrane. 前記貯留部は、前記中空糸膜型濾過器の下端に接続された貯留部材を有する、請求項２に記載の中空糸膜型体液濾過装置。   The said storage part is a hollow fiber membrane type body fluid filtration apparatus of Claim 2 which has a storage member connected to the lower end of the said hollow fiber membrane type filter. 前記貯留部材がチューブおよび／または容器を含む、請求項３に記載の中空糸膜型体液濾過装置。   The hollow fiber membrane-type body fluid filtration device according to claim 3, wherein the storage member includes a tube and / or a container. 前記貯留部材が容器及び前記容器と前記中空糸膜型濾過器の下端とを接続するチューブを含み、前記チューブが開閉手段により開閉することのできる、請求項３に記載の中空糸膜型体液濾過装置。   The hollow fiber membrane type body fluid filtration according to claim 3, wherein the storage member includes a container and a tube connecting the container and a lower end of the hollow fiber membrane filter, and the tube can be opened and closed by an opening / closing means. apparatus. 前記貯留部の容量が５ｍＬ以上である、請求項２〜５のいずれか１項に記載の中空糸膜型体液濾過装置。   The hollow fiber membrane-type body fluid filtration device according to any one of claims 2 to 5, wherein a capacity of the reservoir is 5 mL or more. 前記中空糸膜型濾過器における、中空糸膜の下端側接着材面から下蓋の内面までの高さが２．０ｍｍ以上である、請求項１〜６のいずれか１項に記載の中空糸膜型体液濾過装置。   The hollow fiber according to any one of claims 1 to 6, wherein in the hollow fiber membrane type filter, a height from a lower end side adhesive surface of the hollow fiber membrane to an inner surface of the lower lid is 2.0 mm or more. Membrane type body fluid filtration device. 前記中空糸膜型濾過器における、中空糸膜型濾過器内に配置された中空糸膜の下端側接着材面と下蓋とが形成する空間容量を中空糸膜本数で割った値が、０．８８×１０-3ｍＬ／本以上である、請求項１〜７のいずれか１項に記載の中空糸膜型体液濾過装置。 In the hollow fiber membrane filter, the value obtained by dividing the space capacity formed by the lower end side adhesive material surface and the lower lid of the hollow fiber membrane disposed in the hollow fiber membrane filter by the number of hollow fiber membranes is 0. The hollow fiber membrane-type body fluid filtration device according to any one of claims 1 to 7, wherein the hollow fiber membrane-type body fluid filtration device is at least 88 × 10 -3 mL / tube. 前記入口が生体不要成分を含むタンパク質溶液を貯留する原液容器または患者に接続可能である、請求項１〜８のいずれか１項に記載の中空糸膜型体液濾過装置。   The hollow fiber membrane-type body fluid filtration device according to any one of claims 1 to 8, wherein the inlet is connectable to a stock solution container or a patient for storing a protein solution containing an unnecessary biological component. 前記濾液出口が生体不要成分を除去したタンパク質溶液を濃縮する濃縮器または回収容器に接続されている、請求項１〜９のいずれか１項に記載の中空糸膜型体液濾過装置。   The hollow fiber membrane-type body fluid filtration device according to any one of claims 1 to 9, wherein the filtrate outlet is connected to a concentrator or a collection container that concentrates a protein solution from which biological unnecessary components have been removed. 前記原液容器または患者と、前記中空糸膜型濾過器との間に流量の制御手段を備える、請求項９に記載の中空糸膜型体液濾過装置。   The hollow fiber membrane type body fluid filtration device according to claim 9, comprising a flow rate control means between the stock solution container or patient and the hollow fiber membrane type filter. 請求項１〜１１のいずれか１項に記載の中空糸膜型体液濾過装置を用いて、生体不要成分を含むタンパク質溶液から生体不要成分を除去する濾過方法を実現する際に、前記中空糸膜型濾過器の入口側に陽圧をかけて前記タンパク質溶液を入口から通液させるポンプが作動する、中空糸膜型体液濾過装置の作動方法。 When the hollow fiber membrane type body fluid filtration device according to any one of claims 1 to 11 is used to realize a filtration method for removing biological unnecessary components from a protein solution containing biological unnecessary components, the hollow fiber membrane is used. A method for operating a hollow-fiber membrane-type body fluid filtration device, wherein a pump that applies a positive pressure to the inlet side of the mold filter and passes the protein solution from the inlet is operated . 前記中空糸膜型濾過器の下端に接続された貯留部材の入口側にある開閉手段が、濾過の開始時に閉塞し、濾過中に開放するように作動する、請求項１２に記載の中空糸膜型体液濾過装置の作動方法。 The hollow fiber membrane according to claim 12, wherein the opening / closing means on the inlet side of the storage member connected to the lower end of the hollow fiber membrane type filter operates to close at the start of filtration and to open during filtration. Method of operating the mold body fluid filtration device. 前記開閉手段が、前記中空糸膜型濾過器の入口側の圧力及び／又は前記中空糸膜型濾過器の入口側の圧力から濾液出口側の圧力を減算した圧力に応じて、開放するように作動する、請求項１３に記載の中空糸膜型体液濾過装置の作動方法。 The switching means, in response to the pressure obtained by subtracting the pressure of the hollow fiber membrane type filter of inlet pressure and / or the filtrate outlet side from the pressure on the inlet side of the hollow fiber membrane type filter of, so as to open operating method for operating a hollow fiber membrane type body fluid filtration device of claim 13. 腹水および／又は胸水を濾過するための中空糸膜型濾過器を入口が上側になるように縦に配置し、原液容器から送られ、前記入口から流入した生体不要成分を含むタンパク質溶液を中空糸膜内を下方向に通液し、中空糸膜外に流出した前記タンパク質溶液の濾液を濾液出口から流出させ、
前記中空糸膜型濾過器における中空糸膜型濾過器内に配置された中空糸膜の下端側接着材面と下蓋とが形成する空間容量が中空糸膜内容積の０．０５倍以上、２．６０倍以下である、濾過方法。 A hollow fiber membrane type filter for filtering ascites and / or pleural effusion is arranged vertically so that the inlet is on the upper side, and a protein solution containing an unnecessary biological component fed from the stock solution container and flowing from the inlet is hollow fiber Through the membrane downward, let the filtrate of the protein solution that flowed out of the hollow fiber membrane flow out from the filtrate outlet,
The space capacity formed by the lower end side adhesive surface and the lower lid of the hollow fiber membrane disposed in the hollow fiber membrane filter in the hollow fiber membrane filter is 0.05 times or more the hollow fiber membrane internal volume, 2. The filtration method which is 60 times or less. 前記中空糸膜型濾過器を上下逆さまにして、前記生体不要成分を含むタンパク質溶液を下から上に向けて通液し、その後、前記中空糸膜型濾過器の上下を元に戻して、生体不要成分を含むタンパク質溶液を上から下に向けて通液する、請求項１５に記載の濾過方法。   The hollow fiber membrane filter is turned upside down, and the protein solution containing the biological unnecessary components is passed from the bottom to the top. The filtration method according to claim 15, wherein a protein solution containing unnecessary components is passed from top to bottom.
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