JPWO2013129384A1 - Adsorption column - Google Patents
Adsorption column Download PDFInfo
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- JPWO2013129384A1 JPWO2013129384A1 JP2013526244A JP2013526244A JPWO2013129384A1 JP WO2013129384 A1 JPWO2013129384 A1 JP WO2013129384A1 JP 2013526244 A JP2013526244 A JP 2013526244A JP 2013526244 A JP2013526244 A JP 2013526244A JP WO2013129384 A1 JPWO2013129384 A1 JP WO2013129384A1
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- hollow fiber
- fiber membrane
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- blood
- treatment liquid
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Classifications
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
- B01J20/28—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof characterised by their form or physical properties
- B01J20/28014—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof characterised by their form or physical properties characterised by their form
- B01J20/28033—Membrane, sheet, cloth, pad, lamellar or mat
- B01J20/28038—Membranes or mats made from fibers or filaments
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D63/00—Apparatus in general for separation processes using semi-permeable membranes
- B01D63/02—Hollow fibre modules
- B01D63/021—Manufacturing thereof
- B01D63/022—Encapsulating hollow fibres
- B01D63/0222—Encapsulating hollow fibres using centrifugal forces
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D63/00—Apparatus in general for separation processes using semi-permeable membranes
- B01D63/02—Hollow fibre modules
- B01D63/04—Hollow fibre modules comprising multiple hollow fibre assemblies
- B01D63/043—Hollow fibre modules comprising multiple hollow fibre assemblies with separate tube sheets
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D65/00—Accessories or auxiliary operations, in general, for separation processes or apparatus using semi-permeable membranes
- B01D65/02—Membrane cleaning or sterilisation ; Membrane regeneration
- B01D65/022—Membrane sterilisation
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
- B01J20/22—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof comprising organic material
- B01J20/26—Synthetic macromolecular compounds
- B01J20/261—Synthetic macromolecular compounds obtained by reactions only involving carbon to carbon unsaturated bonds
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
- B01J20/22—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof comprising organic material
- B01J20/26—Synthetic macromolecular compounds
- B01J20/262—Synthetic macromolecular compounds obtained otherwise than by reactions only involving carbon to carbon unsaturated bonds, e.g. obtained by polycondensation
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
- B01J20/28—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof characterised by their form or physical properties
- B01J20/28014—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof characterised by their form or physical properties characterised by their form
- B01J20/28016—Particle form
- B01J20/28021—Hollow particles, e.g. hollow spheres, microspheres or cenospheres
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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
- A61M1/14—Dialysis systems; Artificial kidneys; Blood oxygenators ; Reciprocating systems for treatment of body fluids, e.g. single needle systems for hemofiltration or pheresis
- A61M1/16—Dialysis systems; Artificial kidneys; Blood oxygenators ; Reciprocating systems for treatment of body fluids, e.g. single needle systems for hemofiltration or pheresis with membranes
-
- 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
- A61M1/36—Other treatment of blood in a by-pass of the natural circulatory system, e.g. temperature adaptation, irradiation ; Extra-corporeal blood circuits
- A61M1/3679—Other treatment of blood in a by-pass of the natural circulatory system, e.g. temperature adaptation, irradiation ; Extra-corporeal blood circuits by absorption
Landscapes
- Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Analytical Chemistry (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Manufacturing & Machinery (AREA)
- External Artificial Organs (AREA)
- Separation Using Semi-Permeable Membranes (AREA)
Abstract
本発明の課題は、中空糸膜を用いて、膜の内外の両方に処理液を流すことにより被吸着物質の吸着性能を向上させることの可能な吸着カラムを提供することにある。そして、解決手段は、中空糸膜束がケースに内蔵され、ケースの両端のそれぞれに処理液導入部と処理液導出部を備えた吸着カラムであって、前記処理液導入部から流入する処理液が前記中空糸膜の内表面及び外表面に直接接触する構造を有し、前記中空糸膜は多孔質構造を有しており、前記中空糸膜内径をRi、外径をRo、長さをL、前記中空糸膜本数をN、ケース内径をR、空糸膜とヘッダー部分を区画する隔壁の厚みをl、外部流通用孔の平均直径をRP、外部流通用孔の数をn、前記中空糸膜内部の圧力損失をα、前記中空糸膜外部の圧力損失をβとして、α=A?L/(N?Ri4)、β=A?{L?(R+N?Ro)2/(R2−N?Ro2)3+l/(n?RP4)}としたときに、0.15<β/α<2であることを特徴とする吸着カラム。The subject of this invention is providing the adsorption column which can improve the adsorption | suction performance of a to-be-adsorbed substance by flowing a process liquid into both inside and outside of a membrane using a hollow fiber membrane. The solving means is an adsorption column in which a hollow fiber membrane bundle is built in the case, and a treatment liquid introduction part and a treatment liquid lead-out part are provided at both ends of the case, respectively, and the treatment liquid flowing from the treatment liquid introduction part Has a structure in direct contact with the inner surface and the outer surface of the hollow fiber membrane, the hollow fiber membrane has a porous structure, the inner diameter of the hollow fiber membrane Ri, the outer diameter Ro, the length L, the number of hollow fiber membranes is N, the inner diameter of the case is R, the thickness of the partition wall partitioning the hollow fiber membrane and the header portion is l, the average diameter of external circulation holes is RP, the number of external circulation holes is n, Α = A? L / (N? Ri4), β = A? {L? (R + N? Ro) 2 / (R2) where α is the pressure loss inside the hollow fiber membrane and β is the pressure loss outside the hollow fiber membrane. -N? Ro2) 3 + 1 / (n? RP4)} where 0.15 <β / α <2 Mu.
Description
本発明は、血液や血液成分等の処理液から被吸着物質を吸着する用途に好適に用いられる吸着カラムに関する。この吸着カラムは特定の被吸着物質を除去しなければならない疾患、例えば、タンパク質であるβ2−ミクログロブリンや、サイトカイン、自己免疫抗体、脂質・タンパク質複合体である低密度リポタンパク質などを除去するための体外循環カラムに好適に用いられる。The present invention relates to an adsorption column suitably used for the purpose of adsorbing an adsorbed substance from a treatment liquid such as blood or blood components. This adsorption column removes diseases that require removal of specific adsorbed substances, such as β 2 -microglobulin, which is a protein, cytokines, autoimmune antibodies, and low-density lipoprotein, which is a lipid / protein complex. Therefore, it is suitably used for an extracorporeal circulation column.
血液等の処理液を体外に取り出し、処理液中の病因物質などを吸着カラムによって除去し、浄化してから戻す治療としては、人工透析以外に、アフェレシスと呼ばれる血液浄化療法が普及している。アフェレシス療法としては主に単純血漿交換療法、二重濾過血漿交換療法、血液から血漿を分離した後で血漿の有害物質を除去する血漿吸着療法、ならびに全血のまま有害物質を除去する血液吸着療法がある。 A blood purification therapy called apheresis is widespread in addition to artificial dialysis as a treatment that removes a treatment liquid such as blood from the body, removes pathogenic substances in the treatment liquid by an adsorption column, purifies them, and returns them. Apheresis mainly includes simple plasma exchange therapy, double filtration plasma exchange therapy, plasma adsorption therapy that removes plasma harmful substances after separating plasma from blood, and blood adsorption therapy that removes harmful substances from whole blood There is.
血漿吸着療法や血液吸着療法において、特定の物質を吸着除去するために、特定の物質と相互作用するリガンドを吸着担体に固定化する試みが行われてきた(特許文献1〜6)。 In plasma adsorption therapy and blood adsorption therapy, attempts have been made to immobilize a ligand that interacts with a specific substance on an adsorption carrier in order to adsorb and remove the specific substance (Patent Documents 1 to 6).
実際に、血漿吸着療法においては、自己抗体を吸着除去する「イムソーバ」(登録商標)(旭化成クラレメディカル株式会社)や、低密度リポ蛋白質を吸着除去する「リポソーバ」(登録商標)(株式会社カネカ)などの吸着カラムが実用化されている。血液吸着療法においては、エンドトキシンを吸着除去する「トレミキシン」(登録商標)(東レ株式会社)や、β2−ミクログロブリン(以下、β2−MG)を吸着除去する「リクセル」(登録商標)(株式会社カネカ)などの吸着カラムが実用化されている。これらの何れも除去対象物質と相互作用するリガンドが吸着担体に固定されたものである。Actually, in plasma adsorption therapy, "Imsorba" (registered trademark) (Asahi Kasei Kuraray Medical Co., Ltd.) that absorbs and removes autoantibodies, and "Liposorba" (registered trademark) (Kaneka Corporation) that adsorbs and removes low-density lipoproteins. ) And other adsorption columns have been put into practical use. In the blood apheresis, endotoxin adsorption removal "Toremikishin" (registered trademark) (Toray Industries, Inc.) and, beta 2 - microglobulin (hereinafter, beta 2 -MG) to adsorb and remove "Rikuseru" (registered trademark) ( Adsorption columns such as Kaneka Corporation) have been put into practical use. In any of these, a ligand that interacts with a substance to be removed is fixed to an adsorption carrier.
また、吸着担体の形態として「トレミキシン」が通常の糸を編み地として用いていることを除けば、上記すべての製品においてビーズが用いられている。ビーズが用いられる理由としては、ビーズ形状の吸着担体は、吸着カラム内に均一に充填できるため、血液流れの偏りが少なく、カラム設計をしやすい利点を有することが挙げられる。 Also, beads are used in all the above products except that “tremixin” uses ordinary yarn as a knitted fabric as an adsorbent carrier. The reason why the beads are used is that the bead-shaped adsorption carrier can be uniformly packed in the adsorption column, and thus has an advantage of less uneven blood flow and easy column design.
一方で、吸着カラムにおける被吸着物質の吸着性能を向上させようとすると、一般的には吸着カラムの容積を増やし、吸着担体量を増やすことが考えられる。しかし、体外循環処理される液量も増え、処理液が血液の場合は血圧低下や貧血などの副作用を惹起することになり、必ずしも好ましい解決手段ではない。吸着性能向上のための他の手段としては、吸着担体の体積あたりの表面積を増やすことが挙げられる。しかし、吸着担体がビーズ状である場合は、ビーズ径を小さくすると、各ビーズ間の隙間が狭くなり、流路抵抗が高くなって圧力損失の増加により、処理液を流すことが困難になる。 On the other hand, in order to improve the adsorption performance of the substance to be adsorbed in the adsorption column, it is generally considered that the volume of the adsorption column is increased and the amount of the adsorption carrier is increased. However, the amount of liquid to be subjected to extracorporeal circulation treatment increases, and when the treatment liquid is blood, it causes side effects such as blood pressure reduction and anemia, which is not necessarily a preferable solution. Another means for improving the adsorption performance is to increase the surface area per volume of the adsorption carrier. However, when the adsorption carrier is in the form of beads, if the bead diameter is reduced, the gap between the beads is narrowed, the flow resistance is increased, and the pressure loss increases, making it difficult to flow the treatment liquid.
また、ビーズ以外の吸着担体の形態として、編み地や中空糸膜などが挙げられる。編み地の場合は、流路抵抗を抑えた設計にすることはできるが、繊維に吸着孔を設けるための多孔質化が製造上容易でない。 In addition, examples of the form of the adsorption carrier other than the beads include a knitted fabric and a hollow fiber membrane. In the case of a knitted fabric, it is possible to make a design in which the flow resistance is suppressed, but it is not easy in manufacturing to make the fiber porous for providing adsorption holes.
中空糸膜の場合は、特許文献7に、血液透析膜の用途において、中空糸膜の細孔半径を制御することでβ2−MGの除去性能を向上させることが記載されている。しかしながら、血液透析治療においては中空糸内側から外側に向けて濾過をかけており、濾過と拡散を合わせた効果により血液から水を除去し、尿毒素物質の除去効率も高めていることから、細孔径は濾過をかけることを前提とした設計となる。しかしながら、血液透析器ではない吸着カラムでは濾過をかけることもないので、被吸着物質の中空糸膜表面から中空糸膜内部への移動は拡散のみに支配される。血液透析器においては、中空糸膜の外側を透析液が効率的に流れるように中空糸の配置やケース形状が設計される。一方、透析液を流すことのない吸着カラムの設計において、これらの設計思想で設計した場合では、β2−MGを含めたタンパク質等の被吸着物質を効率的に吸着することができない。In the case of a hollow fiber membrane, Patent Document 7 describes that in the use of a hemodialysis membrane, β 2 -MG removal performance is improved by controlling the pore radius of the hollow fiber membrane. However, in hemodialysis treatment, filtration is applied from the inside to the outside of the hollow fiber, and water is removed from the blood by the combined effect of filtration and diffusion, and the efficiency of removing uremic toxins is increased. The pore size is designed on the assumption that filtration is applied. However, since the adsorption column that is not a hemodialyzer does not perform filtration, the movement of the substance to be adsorbed from the surface of the hollow fiber membrane to the inside of the hollow fiber membrane is governed only by diffusion. In the hemodialyzer, the arrangement of the hollow fiber and the shape of the case are designed so that the dialysate efficiently flows outside the hollow fiber membrane. On the other hand, in the design of an adsorption column that does not flow dialysate, it is not possible to efficiently adsorb an adsorbed substance such as protein including β 2 -MG when designed with these design concepts.
また、特許文献8には、血球除去用吸着体に関し、中空糸についても記載され、ケーシングに装填した中空糸束の両端をメッシュで押さえてヘッダーを取り付け、血液が中空糸の内外両方に流れる構造としたものが記載されている。しかしながら、ここでは単に中空糸の表面に白血球および血小板を吸着させることを目的として表面の凹凸を制御することが記載されたのみである。当該文献の実施例では中空糸膜の製造段階においてあえて相分離が生じない工夫がされている。当該文献の発明では、本発明のように中空糸内部の相分離によって孔を形成をしたものの使用についての思想はない。さらに、被吸着物質を中空糸内部、外部の両方に効率的に吸着させるためには、本発明が開示するように中空糸膜の内側および外側に流れる血液流量の分配比についての設計が重要となるが、それらの思想は当該文献には記載されていない。 Patent Document 8 also relates to an adsorbent for removing blood cells, and also describes a hollow fiber, a structure in which a hollow fiber bundle loaded in a casing is pressed with a mesh to attach headers, and blood flows both inside and outside the hollow fiber. Is described. However, here, it is only described that the unevenness of the surface is controlled for the purpose of adsorbing leukocytes and platelets on the surface of the hollow fiber. In the examples of this document, a device is devised that does not cause phase separation in the manufacturing stage of the hollow fiber membrane. In the invention of this document, there is no idea about the use of a material in which holes are formed by phase separation inside the hollow fiber as in the present invention. Furthermore, in order to efficiently adsorb the substance to be adsorbed both inside and outside the hollow fiber, it is important to design the distribution ratio of the blood flow rate flowing inside and outside the hollow fiber membrane as disclosed in the present invention. However, those ideas are not described in the literature.
本発明の目的は、従来技術の欠点を改良し、被吸着物質の吸着性能を向上させ、かつ血液を被処理液とした場合、残血が少ない吸着カラムを提供することにある。 An object of the present invention is to provide an adsorption column that improves the disadvantages of the prior art, improves the adsorption performance of a substance to be adsorbed, and has little residual blood when blood is used as a liquid to be treated.
本発明者らは上記課題を達成するため鋭意検討を進めた結果、被吸着物質の吸着性能を向上させた吸着カラムは、下記の構成によって達成されることを見出した。
中空糸膜の束がケースに内蔵され、
ケースの一方の端に処理液導入部、他方の端に処理液導出部を備え、
ヘッダーの一方の端に処理液導入部、他方のヘッダーの端に処理液導出部を備え、
(1)前記処理液導入部から流入する処理液が前記中空糸膜の内表面及び外表面に直接接触しうる構造を有し、
(2)前記中空糸膜は多孔質構造を有しており、
(3)前記中空糸膜の内径をRi、外径をRo、長さをL、束を構成する中空糸膜の本数をN、ケース内径をR、隔壁の厚みをl、外部流通用孔の平均直径をRP、外部流通用孔の数をn、前記中空糸膜内部の圧力損失をα、前記中空糸膜外部の圧力損失をβとして、α=A×L/(N×Ri4)、β=A×{L×(R+N×Ro)2/(R2−N×Ro 2)3+l/(n×RP 4)}としたときに、0.15<β/α<2であることを特徴とする吸着カラム。As a result of intensive studies to achieve the above-mentioned problems, the present inventors have found that an adsorption column with improved adsorption performance of a substance to be adsorbed can be achieved by the following configuration.
A bundle of hollow fiber membranes is built into the case,
A treatment liquid introduction part at one end of the case, a treatment liquid lead-out part at the other end,
A treatment liquid introduction part is provided at one end of the header, and a treatment liquid lead-out part is provided at the end of the other header.
(1) The treatment liquid flowing from the treatment liquid introduction part has a structure that can directly contact the inner surface and the outer surface of the hollow fiber membrane,
(2) The hollow fiber membrane has a porous structure,
(3) The inner diameter of the hollow fiber membrane is R i , the outer diameter is R o , the length is L, the number of hollow fiber membranes constituting the bundle is N, the inner diameter of the case is R, the thickness of the partition is l, for external circulation The average diameter of the holes is R P , the number of external circulation holes is n, the pressure loss inside the hollow fiber membrane is α, the pressure loss outside the hollow fiber membrane is β, and α = A × L / (N × Ri 4 ), β = A × {L × (R + N × R o ) 2 / (R 2 −N × R o 2 ) 3 + l / (n × R P 4 )}, 0.15 <β / An adsorption column characterized by α <2.
本発明の吸着カラムは、処理液を体外に取り出し、効率的に病因タンパク質を吸着、除去し、処理液を浄化してから体内に戻すことができ、治療後の吸着カラムに残る血液も少なくすることができる。β2−MGを除去する吸着カラムであれば透析アミロイド治療に好適に用いることができる。また、抗体を吸着するカラムであれば、自己免疫疾患治療に好適に用いることができる。The adsorption column of the present invention takes the treatment liquid out of the body, efficiently adsorbs and removes pathogenic proteins, purifies the treatment liquid and returns it to the body, and reduces the blood remaining in the adsorption column after treatment be able to. Any adsorption column that removes β 2 -MG can be suitably used for dialysis amyloid treatment. In addition, any column that adsorbs antibodies can be suitably used for autoimmune disease treatment.
本発明は、上記、課題を解決するための手段の欄に記載したとおりの構成からなる。 The present invention is configured as described in the above section for solving the problems.
ここで、課題を解決するための手段の欄に記載した(1)の特徴は、カラムの入口から流入した血液や血液成分などの処理液が中空糸膜内部、外部の両方に流れ、導出部から出るという、本発明に係る吸着カラムの基本構成を評点している。 Here, the feature of (1) described in the section for solving the problem is that the treatment liquid such as blood and blood components flowing from the column inlet flows both inside and outside the hollow fiber membrane, The basic constitution of the adsorption column according to the present invention is evaluated.
また、課題を解決するための手段の欄に記載した(2)の特徴は、吸着カラムにおける吸着担体として、多孔質を有する中空糸膜が有用であることを見出したものである。処理液から中空糸膜に吸着される被吸着物質が拡散現象により中空糸膜に効率的に吸着されるためのカラムの構造上の条件であり、主に生物の体液、特に血液に含まれるタンパク質、中でもβ2−MGの効率的な除去が図られる。その他、サイトカイン、自己抗体なども効率的に除去できる。The feature (2) described in the section for solving the problem is that a hollow fiber membrane having a porous structure is useful as an adsorption carrier in the adsorption column. It is a structural condition of the column for the substance to be adsorbed from the treatment liquid to be adsorbed to the hollow fiber membrane by the diffusion phenomenon, and it is a structural condition of the column. In particular, β 2 -MG can be efficiently removed. In addition, cytokines, autoantibodies, etc. can be removed efficiently.
さらに、課題を解決するための手段の欄に示した(3)の特徴は、中空糸膜内外の両方に処理液を流す構造として、中空糸膜の内外の構造およびカラム内の処理液の流れに着目したものである。中空糸膜内部と外部のそれぞれの圧力損失の比は、中空糸膜内外における処理液の流量の分配比に影響を及ぼす。かかる中空糸膜内部の圧力損失は中空糸膜の内径、長さおよびケース内での中空糸膜の充填率などを調整することで制御できる。 Furthermore, the feature of (3) shown in the column of means for solving the problem is that the treatment liquid flows both inside and outside the hollow fiber membrane, and the structure inside and outside the hollow fiber membrane and the flow of the treatment liquid in the column Is focused on. The ratio of the pressure loss inside and outside the hollow fiber membrane affects the distribution ratio of the flow rate of the treatment liquid inside and outside the hollow fiber membrane. The pressure loss inside the hollow fiber membrane can be controlled by adjusting the inner diameter and length of the hollow fiber membrane, the filling rate of the hollow fiber membrane in the case, and the like.
本発明の吸着カラムは、中空糸の束がケースに内蔵されている。通常はケースの両端にヘッダーを有し、そしてヘッダーの一方の端に処理液導入部、他方のヘッダーの端に処理液導出部を備えている。以下、本発明では、血液などの体液を処理する場合には、前者を血液側入口(Bi)、後者を血液側出口(Bo)と言うことがある。そして、通常は、ひとつのヘッダーと中空糸膜の束との間、別のヘッダーと中空糸膜の束との間は、それぞれ隔壁によって区画されている。そして隔壁は処理液の一部を中空糸膜の内部に通じさせる複数の孔および処理液の残りを中空糸膜の外部に通じさせる複数の孔を有している。ひとつの孔に注目した場合、この孔が処理液を中空糸膜の内部および外部両方に通じさせる構造であってもいい。 In the adsorption column of the present invention, a bundle of hollow fibers is built in the case. Usually, the case has headers at both ends, and is provided with a processing liquid inlet at one end of the header and a processing liquid outlet at the end of the other header. Hereinafter, in the present invention, when processing a body fluid such as blood, the former may be referred to as a blood side inlet (Bi) and the latter as a blood side outlet (Bo). Usually, a partition is partitioned between one header and a bundle of hollow fiber membranes, and another header and a bundle of hollow fiber membranes. The partition wall has a plurality of holes for allowing a part of the treatment liquid to communicate with the inside of the hollow fiber membrane and a plurality of holes for allowing the remainder of the treatment liquid to communicate with the outside of the hollow fiber membrane. When attention is paid to one hole, the hole may have a structure that allows the treatment liquid to communicate both inside and outside the hollow fiber membrane.
中空糸膜の束はケースに直接または間接に固定されていることが好ましく、さらに前記隔壁を介してケースに間接に固定されていることが好ましい。 The bundle of hollow fiber membranes is preferably fixed directly or indirectly to the case, and more preferably indirectly fixed to the case via the partition wall.
次に、本発明の多孔質を有する中空糸膜について説明する。中空糸膜が多孔質となっていることは、被吸着物質の吸着に影響を及ぼす要素である。特に、平均細孔径が小さいと、被吸着物質が孔に入らないため、吸着効率が低下する傾向がある。一方で細孔径が大きすぎても、空隙部分に被吸着物質が吸着されないため、逆に吸着効率が低下する傾向がある。一般的には、中空糸膜の平均細孔径(半径)を7〜50nmとすれば低分子物質や、タンパク質、低密度リポ蛋白質などのタンパク質・脂質集合体等の物質の吸着が可能となり、好ましくは10nm以上がよく、一方で40nm以下が好ましい。特にβ2−MG等のタンパク質吸着のためには20nm以下が好ましい。なお、除去対象がβ2−MGよりも小さい分子の場合は、孔径はさらに小さいほうが好ましく、β2−MGよりも大きい分子の場合は、孔径は大きいほうが好ましい。中空糸膜の繊維方向と垂直の断面構造としては、吸着効率の観点から、均一な構造が好適である。β2−MGの吸着性能の測定方法については後述するが、血液流速が200mL/minのときの循環1時間後のクリアランスは50以上が好ましく、70以上がより好ましく、さらには90以上が好ましい。Next, the porous hollow fiber membrane of the present invention will be described. The hollow fiber membrane being porous is an element that affects the adsorption of the substance to be adsorbed. In particular, when the average pore diameter is small, the adsorbed substance does not enter the pores, so that the adsorption efficiency tends to decrease. On the other hand, even if the pore diameter is too large, the adsorbed substance is not adsorbed in the void portion, so that the adsorption efficiency tends to decrease. In general, if the average pore diameter (radius) of the hollow fiber membrane is 7 to 50 nm, it is possible to adsorb low-molecular substances and substances such as proteins and lipid aggregates such as proteins and low-density lipoproteins. Is preferably 10 nm or more, while 40 nm or less is preferred. In particular, 20 nm or less is preferable for protein adsorption such as β 2 -MG. When the removal target is a molecule smaller than β 2 -MG, the pore diameter is preferably smaller, and when the molecule is larger than β 2 -MG, the pore diameter is preferably larger. The cross-sectional structure perpendicular to the fiber direction of the hollow fiber membrane is preferably a uniform structure from the viewpoint of adsorption efficiency. The method for measuring the adsorption performance of β 2 -MG will be described later. The clearance after 1 hour of circulation when the blood flow rate is 200 mL / min is preferably 50 or more, more preferably 70 or more, and further preferably 90 or more.
中空糸膜の平均細孔径についての測定方法の詳細は後述するが、示差走査熱量(DSC)測定により、細孔内の水の毛管凝集による氷点降下度を測ることで細孔径(半径)を求めることができる。(参考文献1:Ishikiriyama, K.,Todoki M., Morimura, M., J. Colloid Interface Sci., 171, 92-102, 1995、 参考文献2:Ishikiriyama, K.,Todoki, M., J. Colloid Interface Sci., 171, 103-111,1995)。 Although details of the measurement method for the average pore diameter of the hollow fiber membrane will be described later, the pore diameter (radius) is obtained by measuring the freezing point depression due to capillary aggregation of water in the pores by differential scanning calorimetry (DSC) measurement. be able to. (Reference 1: Ishikiriyama, K., Todoki M., Morimura, M., J. Colloid Interface Sci., 171, 92-102, 1995, Reference 2: Ishikiriyama, K., Todoki, M., J. Colloid Interface Sci., 171, 103-111, 1995).
また、中空糸膜の膜厚が大きいと吸着容量が大きくなるが、被吸着物質の膜内での拡散抵抗も大きくなるために、十分に吸着性能が発揮できないことがある。一方で、膜厚が小さいと吸着容量が小さくなり、処理液を中空糸膜の内外両方から接触させる効果が小さくなる傾向にある。このため、中空糸の膜厚は25μm以上が好ましく、30μm以上がより好ましく、さらには35μm以上が好ましく、一方で100μm以下が好ましく、70μm以下がより好ましく、さらには60μm以下が好ましい。 In addition, when the film thickness of the hollow fiber membrane is large, the adsorption capacity increases. However, the diffusion resistance of the substance to be adsorbed in the membrane also increases, so that the adsorption performance may not be sufficiently exhibited. On the other hand, when the film thickness is small, the adsorption capacity is small, and the effect of bringing the treatment liquid into contact with both the inside and outside of the hollow fiber membrane tends to be small. For this reason, the film thickness of the hollow fiber is preferably 25 μm or more, more preferably 30 μm or more, further preferably 35 μm or more, on the other hand 100 μm or less, more preferably 70 μm or less, and further preferably 60 μm or less.
また、中空糸膜の表面構造は、膜内部への被吸着物質の拡散に影響を及ぼすため、重要な因子である。さらに、中空糸膜の内側と外側の両方に処理液が接触し、両側から被吸着物質が中空糸膜内部に拡散することになるので、血液透析膜のように、中空糸膜の内側の構造だけでなく、外側の表面の構造も意識すべきである。すなわち、膜表面の開孔率が小さいと、タンパク質は膜内部に拡散しにくい傾向にある。一方で開孔率が大きすぎると、中空糸膜強度が低下する傾向にある。したがって、膜内の表面および外の表面の開孔率(表面を観察したとき、孔が存在している面積の割合)は1%以上が好ましく、2%以上がより好ましく、さらには4%以上が好ましく、一方で40%以下が好ましく、30%以下がより好ましく、さらには20%以下が好ましい。 The surface structure of the hollow fiber membrane is an important factor because it affects the diffusion of the adsorbed substance into the membrane. Furthermore, since the treatment liquid comes into contact with both the inside and outside of the hollow fiber membrane, and the adsorbed substance diffuses into the hollow fiber membrane from both sides, the structure inside the hollow fiber membrane like a hemodialysis membrane. Not only should you be aware of the structure of the outer surface. That is, if the porosity of the membrane surface is small, proteins tend to hardly diffuse into the membrane. On the other hand, when the hole area ratio is too large, the hollow fiber membrane strength tends to decrease. Therefore, the porosity of the surface in the membrane and the outer surface (ratio of the area where pores are present when the surface is observed) is preferably 1% or more, more preferably 2% or more, and further 4% or more. On the other hand, it is preferably 40% or less, more preferably 30% or less, and further preferably 20% or less.
開孔率についての測定方法の詳細は後述するが、中空糸膜表面の電子顕微鏡像を撮影し、画像処理を行い、算出することができる。 Although details of the measurement method for the open area ratio will be described later, an electron microscope image of the surface of the hollow fiber membrane can be taken, subjected to image processing, and can be calculated.
また、中空糸膜は、構成成分として疎水性ポリマーを有していることが好ましい。疎水性相互作用によりタンパク質等の疎水性物質の吸着効果を期待できるためである。ただし疎水性が強すぎると、タンパク質が膜内部に拡散せずに、膜表面に吸着、堆積し、細孔を塞いでしまうことがある。したがって、ポリマーをフィルムに成形した際に、水の接触角が40°以上が好ましく、50°以上がより好ましく、さらには60°以上が好ましく、一方で120°以下が好ましく、また110°以下が好ましく、100°以下がより好ましく、さらには90°以下であることが好ましい。疎水性ポリマーとしては、ポリスルホン系ポリマー、ポリアリレート、ポリカーボネート、ポリメチルメタクリレートや酢酸セルロース系ポリマーなどのエステル基含有ポリマー、ポリスチレン、ポリプロピレン、ポリアクリロニトリルが挙げられる。ポリスルホン系ポリマーとしてはポリスルホン、ポリエーテルスルホン、ポリアリルエーテルがあり、エステル基含有ポリマーとしてはポリメチルメタクリレート、酢酸セルロース系ポリマーなどが挙げられ、酢酸セルロース系ポリマーとしてはセルロースの誘導体であるセルロースジアセテート、セルローストリアセテートがある。また、繰り返しモノマーあたり、10mol%以下、さらには5mol%以下ならば、他の共重合成分が混在している誘導体であっても構わない。特にイオン性基や親水性基は、中空糸膜に適度な親水性を付与し、膜表面への付着による細孔を塞ぐことを防ぐ効果がある。 The hollow fiber membrane preferably has a hydrophobic polymer as a constituent component. This is because the hydrophobic interaction can be expected to adsorb hydrophobic substances such as proteins. However, if the hydrophobicity is too strong, the protein may not be diffused inside the membrane, but may be adsorbed and deposited on the membrane surface to block the pores. Therefore, when the polymer is formed into a film, the contact angle of water is preferably 40 ° or more, more preferably 50 ° or more, further preferably 60 ° or more, while 120 ° or less is preferable, and 110 ° or less is preferable. The angle is preferably 100 ° or less, and more preferably 90 ° or less. Examples of the hydrophobic polymer include polysulfone-based polymers, polyarylate, polycarbonate, ester group-containing polymers such as polymethyl methacrylate and cellulose acetate-based polymers, polystyrene, polypropylene, and polyacrylonitrile. Examples of polysulfone polymers include polysulfone, polyethersulfone, and polyallyl ether. Examples of ester group-containing polymers include polymethyl methacrylate and cellulose acetate polymers. Cellulose acetate polymers include cellulose diacetate, which is a derivative of cellulose. There is cellulose triacetate. Moreover, as long as it is 10 mol% or less and further 5 mol% or less per repeating monomer, it may be a derivative in which other copolymerization components are mixed. In particular, the ionic group or the hydrophilic group has an effect of imparting appropriate hydrophilicity to the hollow fiber membrane and preventing the pores from being blocked by adhesion to the membrane surface.
中空糸膜の表面構造および細孔径を制御する方法としては、紡糸時の原料であるポリマー溶液からポリマーが相分離していく現象を利用する方法が用いられる。相分離を利用した手法としては大きく分類して、誘起相分離法と非溶媒誘起分離法に分けることができ、何れの方法が好適かは、ポリマーの種類や望ましい孔径の範囲によって変わる。 As a method for controlling the surface structure and pore diameter of the hollow fiber membrane, a method utilizing a phenomenon in which a polymer phase separates from a polymer solution which is a raw material at the time of spinning is used. Methods using phase separation can be broadly classified into induced phase separation methods and non-solvent induced separation methods, and which method is suitable depends on the type of polymer and the range of desired pore sizes.
中空糸膜の製造工程の概要としては、次の方法が例示される。まず、ポリマーを溶媒に溶かした紡糸用の原液を調整する。次いで、紡糸用の原液を二重管環状スリット型口金から吐出する。その際、中空糸膜の内側には注入液体もしくは気体を入れる。口金から吐出後、一定の雰囲気に制御された空中部分(乾式部)を通した後に凝固浴に導く。ここまでの工程で、中空糸膜の膜厚および内外表面の構造は、ほぼ決定される。その後、水洗工程を経てから、巻き取って糸束を得る。水の乾燥により膜性能が変化する場合は、グリセリンなどの保湿剤を付与する工程があっても良い。 The following method is illustrated as an outline of the manufacturing process of the hollow fiber membrane. First, a stock solution for spinning in which a polymer is dissolved in a solvent is prepared. Next, the stock solution for spinning is discharged from the double tube annular slit die. At that time, an injection liquid or gas is put inside the hollow fiber membrane. After discharging from the die, it is guided to a coagulation bath after passing through an aerial part (dry part) controlled to a constant atmosphere. Through the steps so far, the thickness of the hollow fiber membrane and the structure of the inner and outer surfaces are almost determined. Then, after passing through a water washing process, it winds up and obtains a yarn bundle. When the membrane performance changes due to water drying, there may be a step of applying a humectant such as glycerin.
本願発明の膜構造を達成するには、上記の疎水性ポリマーののうち、エステル結合を有するポリマーが好適に用いられ、中でもポリメチルメタクリレートが好適に用いられる。疎水性が強すぎると、タンパク質などの被吸着物質が膜内部に拡散する前に膜表面に吸着してファウリング層を形成し、膜内部を吸着のために有効に活用できないことがある。したがって、膜の素材としてはある程度の親水性も重要であり、かかる親水−疎水バランスを膜表面に付与するためには極性基としてのエステル結合が有効である。また、ポリメチルメタクリレートのように、繰り返し単位の分子量が110で、エステル基を1個有するポリマーは親水性と疎水性のバランスが良く好適である。なお、エステル基としてはポリマーの主鎖よりもポリマー側鎖にあることが好ましい。ポリメチルメタクリレートを膜素材として中空糸膜を製造する場合は、ポリマー濃度が15〜30重量%になるように、ジメチルスルホキシドなどの良溶媒に溶解する。この溶液を環状紡糸口金から吐出して、乾式部を通過させた後、凝固浴に導く。 In order to achieve the membrane structure of the present invention, among the above hydrophobic polymers, a polymer having an ester bond is preferably used, and among them, polymethyl methacrylate is preferably used. If the hydrophobicity is too strong, an adsorbed substance such as a protein may be adsorbed on the surface of the film before diffusing into the film to form a fouling layer, and the inside of the film may not be effectively used for adsorption. Accordingly, a certain degree of hydrophilicity is also important as a material for the membrane, and an ester bond as a polar group is effective for imparting such a hydrophilic-hydrophobic balance to the membrane surface. Further, a polymer having a repeating unit molecular weight of 110 and one ester group, such as polymethyl methacrylate, is preferable because it has a good balance between hydrophilicity and hydrophobicity. The ester group is preferably in the polymer side chain rather than the polymer main chain. When producing a hollow fiber membrane using polymethyl methacrylate as a membrane material, it is dissolved in a good solvent such as dimethyl sulfoxide so that the polymer concentration is 15 to 30% by weight. This solution is discharged from the annular spinneret, passed through the dry part, and then led to the coagulation bath.
この際、中空糸内側には、注入液体もしくは気体を入れることで、内表面構造を制御できる。注入液体としては、紡糸原液が溶解可能な溶媒、水やアルコールなどの凝固剤、これらの混合物、あるいはこれらに溶解可能な重合体やそれとの混合物の非溶媒であるような疎水性の液体、たとえば、n−オクタン、流動パラフィンなどの脂肪族炭化水素、ミリスチン酸イソプロピルの様な脂肪酸エステルなども使用できる。また、気体としては窒素ガスやアルゴンガスなどの不活性気体のほか、二酸化炭素や空気なども用いることができる。 At this time, the inner surface structure can be controlled by putting an injection liquid or gas inside the hollow fiber. The injection liquid includes a solvent in which the spinning dope is soluble, a coagulant such as water or alcohol, a mixture thereof, or a hydrophobic liquid that is a non-solvent of a polymer or mixture thereof soluble in these, for example, N-octane, aliphatic hydrocarbons such as liquid paraffin, and fatty acid esters such as isopropyl myristate can also be used. Further, as the gas, in addition to an inert gas such as nitrogen gas or argon gas, carbon dioxide or air can be used.
また、乾式部においては、中空糸外側に外側から冷却気体を吹き付ける。この際、冷却気体は乾球温度5〜20℃、さらには8〜17℃が好ましい。また、含有水分の尺度である露点は0〜20℃、さらには5〜15℃であることが好ましい。外側の雰囲気は外表面構造に大きく影響を及ぼす。冷風は糸条に対して垂直方向から当てることが好ましい。さらに冷風流速としては、3〜10m/秒、さらには6〜8m/秒が好ましい。 In the dry part, cooling gas is blown from the outside to the outside of the hollow fiber. At this time, the cooling gas preferably has a dry bulb temperature of 5 to 20 ° C, more preferably 8 to 17 ° C. Moreover, it is preferable that the dew point which is a scale of a moisture content is 0-20 degreeC, Furthermore, it is preferable that it is 5-15 degreeC. The outer atmosphere has a great influence on the outer surface structure. The cold air is preferably applied from the direction perpendicular to the yarn. Further, the cold air flow rate is preferably 3 to 10 m / second, more preferably 6 to 8 m / second.
吐出した糸が乾式部を通過する時間としては、0.01〜2秒、さらには0.1〜1秒が好ましい。 The time for the discharged yarn to pass through the dry part is preferably 0.01 to 2 seconds, more preferably 0.1 to 1 second.
吐出時のドラフト率について、製膜原液の紡糸口金から出る速度及び生成された中空糸膜の引き取り速度の比として定義されるパラメータであるが、このドラフト率が大きいと、膜の細孔が引き延ばされて楕円状となり、球状の細孔に比べて空間あたりの表面積が小さくなる。一方でドラフト率が小さいと紡糸安定性が悪くなる。以上のことから、ドラフト率は1.5〜30、さらには3〜20が好ましい。 The draft rate at the time of discharge is a parameter defined as the ratio of the speed of the film-forming stock solution exiting from the spinneret and the take-up speed of the produced hollow fiber membrane. When this draft rate is large, the pores of the membrane are pulled. It is elongated to be elliptical and has a smaller surface area per space than spherical pores. On the other hand, if the draft rate is small, the spinning stability is deteriorated. From the above, the draft rate is preferably 1.5 to 30, more preferably 3 to 20.
次いで、吐出した糸を、水を主成分とした液体が入った凝固浴に導いて、固化、脱溶媒する。凝固浴温度を高くすることにより、細孔径を大きくすることが出来る。この機序は正確には明らかではないが、原液からの脱溶媒と凝固収縮との競争反応で、高温浴では脱溶媒が速く、収縮する前に凝固固定されるからではないかと考えられる。しかしながら、凝固浴温度が高くなりすぎると、前述のように細孔径が大きくなりすぎることから、凝固浴温度は40℃以上が好ましく、さらには42℃以上が好ましく、一方で55℃以下が好ましく、さらには48℃以下が好ましい。また、水以外にジメチルスルホキシドなどの膜形成ポリマーにとっての良溶媒を少量添加することで、細孔径の大きさを均一に制御できる。ただし、多すぎると、紡糸安定性が悪くなるので、水以外の良溶媒の濃度としては、1〜40重量%が好ましく、さらには10〜30重量%が好ましい。糸が凝固浴に浸漬している時間が長いほうが、細孔の大きさを均一に制御できる。一方で、長すぎると紡糸安定性が悪い。以上のことから、糸が凝固浴に浸漬している時間は0.01〜2秒が好ましく、さらには0.1〜1秒が好ましい。 Next, the discharged yarn is guided to a coagulation bath containing a liquid mainly composed of water, and solidified and desolvated. By increasing the coagulation bath temperature, the pore diameter can be increased. Although this mechanism is not exactly clear, it is thought that the solvent reaction in the high temperature bath is fast and the solvent is solidified and fixed before shrinkage due to the competitive reaction between the solvent removal from the stock solution and the solidification shrinkage. However, if the coagulation bath temperature becomes too high, the pore diameter becomes too large as described above, so the coagulation bath temperature is preferably 40 ° C or higher, more preferably 42 ° C or higher, while 55 ° C or lower is preferable, Furthermore, 48 degrees C or less is preferable. Further, by adding a small amount of a good solvent for a film-forming polymer such as dimethyl sulfoxide in addition to water, the size of the pore diameter can be uniformly controlled. However, if the amount is too large, the spinning stability is deteriorated. Therefore, the concentration of a good solvent other than water is preferably 1 to 40% by weight, and more preferably 10 to 30% by weight. The longer the time that the yarn is immersed in the coagulation bath, the more uniform the size of the pores can be controlled. On the other hand, if it is too long, the spinning stability is poor. From the above, the time that the yarn is immersed in the coagulation bath is preferably 0.01 to 2 seconds, and more preferably 0.1 to 1 second.
なお、中空糸膜を紡糸後、弛まないように両端を固定化し、加温することで、膜の細孔を大きくする方法もある。 In addition, after spinning the hollow fiber membrane, there is also a method of enlarging the pores of the membrane by fixing both ends so as not to loosen and heating.
次いで、凝固した中空糸膜に付着している溶媒を洗浄する。中空糸膜を洗浄する手段は特に限定されないが、多段の水を張った浴(水洗浴)中に中空糸膜を通過させる方法が好んで用いられる。水洗浴中の水の温度は、洗浄効率の観点から、30〜50℃が好適である。 Next, the solvent adhering to the solidified hollow fiber membrane is washed. The means for washing the hollow fiber membrane is not particularly limited, but a method of allowing the hollow fiber membrane to pass through a multi-staged water bath (water washing bath) is preferably used. The temperature of the water in the washing bath is preferably 30 to 50 ° C. from the viewpoint of washing efficiency.
また、中空糸膜の孔径を保持するために、保湿成分を付与する工程があってもよく、好適には上記水洗工程の後に行われる。保湿成分の代表例としてはグリセリンやその水溶液などがある。 Moreover, in order to hold | maintain the hole diameter of a hollow fiber membrane, there may exist the process of providing a moisturizing component, and it is suitably performed after the said water washing process. Typical examples of moisturizing ingredients include glycerin and its aqueous solutions.
また、収縮性の高い中空糸膜の寸法安定性を高めるため、中空糸膜を保湿成分の水溶液が満たされている加熱された浴の中を通過させることも可能であり、好適には上記水洗工程、保湿工程の後に行われる。熱処理浴には加熱した保湿成分の水溶液が満たされており、中空糸膜がこの熱処理浴を通過することで、熱的な作用を受けて収縮する。そうすると以後の工程で収縮しにくくなり、膜の構造を安定させることが出来る。このときの熱処理温度は、75℃以上が好ましく、83℃以上がより好ましい一方、90℃以下が好ましく、86℃以下がより好ましい温度として設定される。そして得られた中空糸を巻き取る。 Further, in order to enhance the dimensional stability of the highly shrinkable hollow fiber membrane, the hollow fiber membrane can be passed through a heated bath filled with an aqueous solution of a moisturizing component. It is performed after the process and the moisturizing process. The heat treatment bath is filled with a heated aqueous solution of a moisturizing component, and when the hollow fiber membrane passes through the heat treatment bath, it contracts due to a thermal action. If it does so, it will become difficult to shrink | contract in a subsequent process and the structure of a film | membrane can be stabilized. The heat treatment temperature at this time is preferably 75 ° C. or higher, more preferably 83 ° C. or higher, while 90 ° C. or lower is preferable, and 86 ° C. or lower is set as a more preferable temperature. And the obtained hollow fiber is wound up.
次に、中空糸膜を有する吸着カラムの製造方法の例を示す。まず、中空糸膜を必要な長さに切断し、必要本数を束ねた後、吸着カラムの構成部分であり筒形状の中空糸膜ケースに挿入する。この中空糸膜ケースは好ましくは、プラスチック製、また透明であることが好ましい。 Next, an example of a method for producing an adsorption column having a hollow fiber membrane will be shown. First, the hollow fiber membrane is cut into a required length, bundled in a necessary number, and then inserted into a cylindrical hollow fiber membrane case which is a constituent part of the adsorption column. The hollow fiber membrane case is preferably made of plastic and transparent.
次に、前記処理液導入部から流入する処理液が前記中空糸膜の内表面及び外表面に直接接触しうる構造を作成する。通常は、中空糸膜ケースの両端にヘッダーをとりつけたものが、吸着カラムのケースとなる。そして、中空糸膜とヘッダー部分を区画する隔壁を設ける。その際、処理液導入部から流入する処理液を中空糸膜の内表面と外表面に直接しうる構造とするためには、以下の2つの方法が例示される。 Next, a structure is created in which the processing liquid flowing from the processing liquid introduction part can directly contact the inner surface and the outer surface of the hollow fiber membrane. Usually, the case of attaching the header to both ends of the hollow fiber membrane case is the case of the adsorption column. And the partition which divides a hollow fiber membrane and a header part is provided. At that time, the following two methods are exemplified in order to make the treatment liquid flowing from the treatment liquid introduction part directly into the inner surface and the outer surface of the hollow fiber membrane.
1つめは、図5に示すように、中空糸1の束の端面部にメッシュ21を配置し、メッシュを隔壁とする方法である。処理液は図5の矢印のように流れていく。メッシュの場合、メッシュの目開き部分の一部が外部流通用の孔に相当する。外部流通用孔の平均均直径RPは、目開き部分の相当直径(目開きの面積と同じ円の面積の直径)の平均値とする。また、RPの値は中空糸膜の外径よりも2倍以下、好ましくは1.2倍以下であれば、処理液を通液しているときに中空糸膜が目開き部分を通してカラム外に流れる懸念は少ない。The first is a method in which a mesh 21 is disposed on the end face of the bundle of hollow fibers 1 as shown in FIG. The treatment liquid flows as shown by the arrows in FIG. In the case of a mesh, part of the mesh opening corresponds to a hole for external circulation. Mean average diameter R P of the external circulation hole is the average value of the equivalent diameter (diameter of the area of the same circle as the area of the mesh) of sieve opening portion. The value of R P is less than twice the outer diameter of the hollow fiber membrane, preferably not more than 1.2 times, extra-column through a hollow fiber membrane mesh opening portion when it is passed through the processing solution There are few concerns about
2つめは、ポッティング材を用いて隔壁とする方法である。この場合、中空糸膜の外側にも処理液を流すために、ポッティング部にヘッダー内と中空糸外側と連通した孔を形成させる必要がある。連通した孔としては、複数個あるほうが好ましい。製造方法を図6を用いて説明する。図6−Aに示すように中空糸を集束する。そして図6−Bに示すように中空糸の束をポッティング材注入口24を有するケースに挿入する。そして図6−Cに示すように、中空糸の束の両端に連通孔形成用の柱状のピン26を複数差込み、中空糸膜ケースの両端にキャップ25を取り付ける。そしてそれを遠心装置にとりつけ、ポッティング材注入口からポッティング材を注入し、図6−Dに示すように遠心により両方のキャップ端部にポッティング材を集める。ポッティング材が硬化した後、図6−Eに示すようにキャップとピンとを取り外す。図6−Fに示すように、硬化したポッティング材の端部を中空糸と共に切り落とす。そして図6−Gに示すようにヘッダーを取り付ける。なおポッティング材注入口は封鎖してある。その結果、ヘッダー部と中空糸膜の内側との間、およびヘッダー部と中空糸膜の外側との間に処理液流路ができている。なお、ポット層の開口部について、ヘッダー側端面の穴と中空糸側の穴で、大きさが異なる場合、小さい方の穴についての直径を下記の数式2に採用する。 The second is a method of using a potting material as a partition wall. In this case, it is necessary to form a hole communicating with the inside of the header and the outside of the hollow fiber in the potting portion in order to flow the treatment liquid to the outside of the hollow fiber membrane. It is preferable that there are a plurality of communicating holes. A manufacturing method will be described with reference to FIG. The hollow fibers are bundled as shown in FIG. Then, as shown in FIG. 6-B, the bundle of hollow fibers is inserted into the case having the potting material inlet 24. 6C, a plurality of columnar pins 26 for forming communication holes are inserted into both ends of the bundle of hollow fibers, and caps 25 are attached to both ends of the hollow fiber membrane case. Then, it is attached to a centrifuge, and a potting material is injected from a potting material injection port, and the potting material is collected at both cap ends by centrifugation as shown in FIG. 6-D. After the potting material is cured, the cap and the pin are removed as shown in FIG. As shown to FIG. 6-F, the edge part of the hardened potting material is cut off with a hollow fiber. Then, a header is attached as shown in FIG. The potting material injection port is sealed. As a result, a treatment liquid channel is formed between the header portion and the inside of the hollow fiber membrane and between the header portion and the outside of the hollow fiber membrane. In addition, about the opening part of a pot layer, when a magnitude | size differs in the hole by the side of a header side, and the hole by the side of a hollow fiber, the diameter about a smaller hole is employ | adopted for following Numerical formula 2.
この後、処理液導入部を有するヘッダー、処理液導出部を有するヘッダーをケースの両端にを取り付けて吸着カラムを得ることができる。 Thereafter, an adsorption column can be obtained by attaching a header having a treatment liquid introduction part and a header having a treatment liquid lead-out part to both ends of the case.
本発明では、中空糸膜の内側もしくは外側のどちらかに処理液が優先的に流れると、被吸着物質の中空糸膜への吸着効率が低下することに着目している。中空糸膜の内側、外側への処理液の流れは、ケースに内蔵させる中空糸膜の内径、外径および本数と中空糸膜ケースの内径に依存する。円管の圧力損失はハーゲン・ポアズイユの式から算出することができる。ここで、中空糸膜の内径をRi(cm)、中空糸膜の外径をRo(cm)、中空糸膜の長さをL(cm)、中空糸膜本数をN、中空糸膜ケース内径をR(cm)、隔壁の厚みをl(cm)、外部流通用孔の平均直径をRP(cm)、外部流通用孔の数をnとすると、中空糸膜内側の圧力損失(単位Pa)は下記の数式1で与えられる。
α=A×L/(N×Ri4)・・・数式1
ここで、A(Pa・mL)は入口部の処理液の流速、処理液粘度に依存する係数である。また、中空糸膜外側の圧力損失(単位Pa)は、下記数式2で与えられる。
β=A×{L×(R+N×Ro)2/(R2−N×Ro 2)3+l/(n×RP 4)}・・・数式2
なお、メッシュが中空糸端部と接着していない場合は、中空糸束の端部とメッシュで隙間が生じるので、中空糸膜内側および外側の圧力損失には影響を及ぼさない。すなわち、数式2におけるl/(n×RP 4)項は無視できる。一方で、メッシュが中空糸端部と接着している場合で、RpがRiよりも小さい場合は、メッシュの目開きが中空糸内側、外側に、ほぼ均等に配置されることになり、数式2のl/(n×RP 4)項は無視できる。メッシュが中空糸端部と接着している場合で、RpがRiよりも大きい場合は、数式2のl/(n×RP 4)項を計算する。
αは中空糸膜内側の圧力損失に関するパラメータであり、βは中空糸膜外側の圧力損失に関するパラメータである。したがって、αがβよりも大きい場合は、中空糸膜の外側を処理液が流れやすい。逆にαがβよりも小さい場合は、中空糸膜の内側を処理液が流れやすい。この流量比が吸着には重要であることがわかった。すなわちβ/αは0.15より大きく、さらには0.2より大きいことが好ましく、一方でβ/αは2より小さく、好ましくは1.8より小さく、さらには1.5より小さいことが好ましい。処理液流れの観点からは理想的にはβ/αが1に近い方がよい。本発明では被吸着物質がβ2−MGの場合に0.2より大きく0.6より小さい範囲でも十分な吸着除去性を有することを見出している。In the present invention, attention is paid to the fact that the adsorption efficiency of the substance to be adsorbed to the hollow fiber membrane decreases when the treatment liquid flows preferentially either inside or outside the hollow fiber membrane. The flow of the processing liquid to the inside and outside of the hollow fiber membrane depends on the inner diameter, outer diameter and number of hollow fiber membranes incorporated in the case and the inner diameter of the hollow fiber membrane case. The pressure loss of the circular tube can be calculated from the Hagen-Poiseuille equation. Here, the inner diameter of the hollow fiber membrane is R i (cm), the outer diameter of the hollow fiber membrane is R o (cm), the length of the hollow fiber membrane is L (cm), the number of hollow fiber membranes is N, the hollow fiber membranes When the inner diameter of the case is R (cm), the partition wall thickness is 1 (cm), the average diameter of the external circulation holes is R P (cm), and the number of external circulation holes is n, the pressure loss (inside the hollow fiber membrane) The unit Pa) is given by Equation 1 below.
α = A × L / (N × Ri 4 ) Equation 1
Here, A (Pa · mL) is a coefficient depending on the flow rate of the processing liquid at the inlet and the viscosity of the processing liquid. Moreover, the pressure loss (unit Pa) outside the hollow fiber membrane is given by the following mathematical formula 2.
β = A × {L × (R + N × R o ) 2 / (R 2 −N × R o 2 ) 3 + l / (n × R P 4 )} Equation 2
When the mesh is not bonded to the end portion of the hollow fiber, a gap is generated between the end portion of the hollow fiber bundle and the mesh, so that the pressure loss inside and outside the hollow fiber membrane is not affected. That is, the 1 / (n × R P 4 ) term in Equation 2 can be ignored. On the other hand, when the mesh is bonded to the end portion of the hollow fiber and Rp is smaller than Ri, the mesh openings of the mesh are arranged almost uniformly on the inner side and the outer side of the hollow fiber. The 1 / (n × R P 4 ) term is negligible. When the mesh is bonded to the end of the hollow fiber and Rp is larger than Ri, the 1 / (n × R P 4 ) term of Equation 2 is calculated.
α is a parameter related to pressure loss inside the hollow fiber membrane, and β is a parameter related to pressure loss outside the hollow fiber membrane. Therefore, when α is larger than β, the treatment liquid tends to flow outside the hollow fiber membrane. Conversely, when α is smaller than β, the treatment liquid tends to flow inside the hollow fiber membrane. This flow ratio was found to be important for adsorption. That is, β / α is preferably greater than 0.15, and more preferably greater than 0.2, while β / α is less than 2, preferably less than 1.8, and more preferably less than 1.5. . Ideally, β / α should be close to 1 from the viewpoint of the flow of the processing liquid. In the present invention, when the substance to be adsorbed is β 2 -MG, it has been found that sufficient adsorption removal property is obtained even in a range larger than 0.2 and smaller than 0.6.
体外循環治療後に生理食塩液を用いて、カラムや回路内の血液を体内に戻す返血という操作を行った際、カラム内に血液が残る現象を残血と呼ぶ。残血の起きる原因としては、生理食塩液のカラム内の流れが悪いため血液が残る場合がある。また血液の凝固系が活性化し、血液粘度が上昇して血液が残る場合がある。本発明の吸着カラムは中空糸膜の外側の返血性についても考慮する必要がある。血液が中空糸膜の内側と外側のどちらかが流れすい場合には、タンパク質の吸着効率が低くなるだけでなく、残血も多くなる。このような観点からも、β/αは0.15以上、1.5以下が好ましい。また、中空糸膜の外側は、紡糸時や巻き取り時、糸束挿入時に傷がついてしまうことが多い。中空糸膜の外側に傷がついて、表面に凹凸がある場合には、血小板や白血球が刺激されることで、血液の凝固系が活性化され、血球成分がその部位に付着し、残血の原因となりうる。すなわち、糸を導くためのローラーやガイドなど、糸と接触する部位の粗度を小さくすることが好ましい。 A phenomenon in which blood remains in the column when the operation of returning the blood in the column or circuit back to the body using physiological saline after the extracorporeal circulation treatment is called residual blood. As a cause of residual blood, blood may remain due to poor flow of physiological saline in the column. In addition, the blood coagulation system is activated, blood viscosity increases, and blood may remain. In the adsorption column of the present invention, it is necessary to consider the blood returnability outside the hollow fiber membrane. When the blood flows either inside or outside the hollow fiber membrane, not only the protein adsorption efficiency is lowered, but also the residual blood is increased. Also from such a viewpoint, β / α is preferably 0.15 or more and 1.5 or less. Also, the outside of the hollow fiber membrane is often damaged when spinning, winding, or inserting a yarn bundle. When the outside of the hollow fiber membrane is scratched and the surface is uneven, the blood coagulation system is activated by stimulating platelets and leukocytes, and blood cell components adhere to the site, causing residual blood It can be a cause. That is, it is preferable to reduce the roughness of a portion that comes into contact with the yarn, such as a roller or a guide for guiding the yarn.
また、中空糸の束をケースに挿入する際に、外周部の糸が捻れることがあり、そのような場合は、中空糸膜内側は、あまり影響を受けないが、中空糸膜の束の外周部の返血性は悪くなる。以上のことから、カラム長手方向を0°とした場合、カラム長手方向に対して、中空糸膜の挿入角度が10°以上の糸が外周部の糸の本数の10%以下、さらには5%以下が好ましい。ここでいう、外周部の糸とは、カラムの側面から目視で存在を確認できる糸のことを指す。また、一方、余りに中空糸表面の平坦であれば、中空糸表面の素材と血球成分との接触面積が大きくなり、血小板や白血球の付着が多くなる。したがって、表面の凹凸として、表面の中心線平均粗さ(Ra)は0.1μm以上が好ましく、さらには0.2μm以上が好ましく、一方で5μm以下が好ましく、さらには2μm以下が好ましい。 In addition, when inserting a bundle of hollow fibers into the case, the threads on the outer periphery may be twisted. In such a case, the inner side of the hollow fiber membrane is not significantly affected, but the bundle of hollow fiber membranes is not affected. The blood returnability at the outer periphery is poor. From the above, when the column longitudinal direction is set to 0 °, the yarn whose hollow fiber membrane insertion angle is 10 ° or more with respect to the column longitudinal direction is 10% or less, more preferably 5% of the number of yarns on the outer peripheral portion. The following is preferred. As used herein, the outer peripheral yarn refers to a yarn whose presence can be confirmed visually from the side of the column. On the other hand, if the surface of the hollow fiber is too flat, the contact area between the material on the surface of the hollow fiber and the blood cell component increases, and adhesion of platelets and leukocytes increases. Therefore, the surface center line average roughness (Ra) is preferably 0.1 μm or more, more preferably 0.2 μm or more, and on the other hand, 5 μm or less, and more preferably 2 μm or less, as surface irregularities.
以下実施例と比較例を挙げて本発明を説明するが、本発明はこれらの例によって限定されるものではない。
1.吸着カラムの作製
重量平均分子量が51万のアイソタクチックポリメチルメタクリレート(iso−PMMA)3.5重量部と、重量平均分子量が89万のシンジオタクチックポリメチルメタクリレート(syn−PMMA)13.3重量部と、パラスチレンスルホン酸ソーダを1.5mol%含む重量平均分子量30万の共重合シンジオタクチックポリメチルメタクリレート(syn−PMMA)4.2重量部をジメチルスルホキシド79重量部と混合し、110℃で8時間撹拌し紡糸原液を調製した。EXAMPLES Hereinafter, although an Example and a comparative example are given and this invention is demonstrated, this invention is not limited by these examples.
1. Production of adsorption column 3.5 parts by weight of isotactic polymethyl methacrylate (iso-PMMA) having a weight average molecular weight of 510,000 and syndiotactic polymethyl methacrylate (syn-PMMA) 13.3 having a weight average molecular weight of 890,000. 110 parts by weight of dimethyl sulfoxide were mixed with 4.2 parts by weight of a copolymer syndiotactic polymethyl methacrylate (syn-PMMA) having a weight average molecular weight of 300,000 containing 1.5 mol% of parastyrene sulfonic acid soda. The mixture was stirred at 0 ° C. for 8 hours to prepare a spinning dope.
得られた紡糸原液を96℃に保温された環状スリット部分の外径/内径=2.1/1.95mmφの二重管中空糸膜用口金から、空気中に吐出した。中空糸内径、外径、凝固浴温度は表1に記載した各種条件で紡糸した。 The obtained spinning dope was discharged into air from a double tube hollow fiber membrane die having an outer diameter / inner diameter of 2.1 / 1.95 mmφ of an annular slit portion kept at 96 ° C. The hollow fiber inner diameter, outer diameter, and coagulation bath temperature were spun under various conditions described in Table 1.
ここで、同時に二重管の内管部分には窒素ガスを注入し、50cmに設定した乾式部を走行させた後、凝固浴に導いた。乾式部および凝固浴の通過時間はそれぞれ0.5秒、2秒とした。乾式部では、温度15℃、露点12℃の冷風を7m/秒の速度で中空糸の糸条に対して垂直に当てた。また、凝固浴には水85重量%、ジメチルスルホキシド15重量%の混合水溶液を入れ、浴温は後述の各実施例、比較例に示す通り40℃〜47℃の各種条件とした。 At the same time, nitrogen gas was injected into the inner tube portion of the double tube, and after running the dry section set to 50 cm, it was led to a coagulation bath. The passing times of the dry part and the coagulation bath were 0.5 seconds and 2 seconds, respectively. In the dry section, cold air having a temperature of 15 ° C. and a dew point of 12 ° C. was applied perpendicularly to the hollow fiber yarn at a speed of 7 m / sec. Further, a mixed aqueous solution of 85% by weight of water and 15% by weight of dimethyl sulfoxide was placed in the coagulation bath, and the bath temperature was set to various conditions of 40 ° C. to 47 ° C. as shown in Examples and Comparative Examples described later.
凝固浴を経た後、水洗浴に導き、保湿剤としてグリセリンを63重量%水溶液として付与し、83℃の熱処理工程を経た後、余分のグリセリンをスクレーパーで除去し、巻き取り、中空糸膜を得た。 After passing through the coagulation bath, it is led to a water washing bath, glycerin is added as a 63% by weight aqueous solution as a moisturizing agent, and after a heat treatment step of 83 ° C., excess glycerin is removed with a scraper and wound up to obtain a hollow fiber membrane It was.
得られた中空糸膜について、さらに孔径を大きくする場合には、両端を固定し、加熱する処理を行った。PMMA中空糸膜は熱により収縮するが、両端が固定されることで、張力がかかり、孔径が大きくなる。具体的には以下の方法である。中空糸膜の束をケースに組み込み、ポッティング材で両端を固定化する。中空糸膜の束を水で洗浄し、水に浸漬した状態で、40℃で2週間保管する。 In order to further increase the pore diameter of the obtained hollow fiber membrane, both ends were fixed and heated. The PMMA hollow fiber membrane shrinks due to heat, but by fixing both ends, tension is applied and the hole diameter increases. Specifically, the following method is used. A bundle of hollow fiber membranes is assembled in the case, and both ends are fixed with a potting material. The bundle of hollow fiber membranes is washed with water and stored in water at 40 ° C. for 2 weeks.
この後、中空糸膜を切り出し、束ねて、図1に示す中空糸ケース2に挿入し、目開き247μm、線径(厚み)71μmの格子状のメッシュ21、ヘッダー22を付け吸着カラムを作成した。なお、メッシュと中空糸膜とは接着させなかった。カラムの密閉を確実にするために、中空糸膜ケース2とヘッダー22との間にはOリング23を介在させている。中空糸の長さLは21cmとした。中空糸にグリセリンが残っている場合、グリセリンを水で洗浄した、そしてカラム内に処理液導入部から水を導入し、水を充填した後、25kGyのγ線で滅菌した。
2.測定方法
(1)表面の開孔率測定
中空糸膜の内表面に関しては、中空糸膜を片刃で半円筒状にそぎ切り、内表面を露出させ、外表面に関しては、そのままで、スパッタリングを行い、Pt−Pdの薄膜を中空糸膜表面に形成させて、試料とした。この中空糸膜の内・外表面をフィールドエミッション型走査型電子顕微鏡(日立社製S800)にて倍率1000倍で観察した。このとき、画像の明るさ、コントラストは装置の自動機能を用いた。次に、Microsoft(登録商標) Paint(Microsoft Ltd.)を用いて、孔の部分を黒く塗りつぶした。二値化した後、Matrox Inspector2.2(Matrox Electronic Systems Ltd.)を用いて、孔の部分を白く、それ以外の部分を黒く反転させる画像処理を行い、白い孔の個数及び白い孔の部分の総開孔面積を求め、開孔率を算出した。また、孔の全体が写っておらず、端が切れている場合でも、画像に写っている箇所については、算出対象とした。これらの測定作業を、中空糸3本につきそれぞれランダムに5箇所ずつ、計15枚の画像についての平均値を得た。
孔の形が円でない場合は、その孔の面積と同面積の円に相当する直径を算出して孔径とし、孔径が0.2μm未満のものはノイズとみなし、計数しなかった。
(2)平均細孔径の測定
中空糸膜の平均細孔径は示差走査熱量(DSC)測定によって求めた。ナノメートルサイズの細孔に閉じ込められた氷の融点は、通常のバルク氷(融点:0℃)に比べて低下する。この現象を利用して、DSC曲線の融点の分布からLaplaceの式とGibbs-Duhemの式を組み合わせることで、細孔径分布が算出され、平均細孔径を求めることができる。Thereafter, the hollow fiber membrane was cut out, bundled and inserted into the hollow fiber case 2 shown in FIG. 1, and an adsorption column was prepared by attaching a grid-like mesh 21 having an opening of 247 μm and a wire diameter (thickness) of 71 μm and a header 22. . The mesh and the hollow fiber membrane were not bonded. In order to ensure the sealing of the column, an O-ring 23 is interposed between the hollow fiber membrane case 2 and the header 22. The length L of the hollow fiber was 21 cm. When glycerin remained in the hollow fiber, the glycerin was washed with water, and water was introduced into the column from the treatment liquid introduction part, filled with water, and then sterilized with 25 kGy γ rays.
2. Measurement method (1) Measurement of surface area porosity For the inner surface of the hollow fiber membrane, the hollow fiber membrane is cut into a semi-cylindrical shape with a single blade, the inner surface is exposed, and the outer surface is sputtered as it is, A thin film of Pt—Pd was formed on the surface of the hollow fiber membrane to prepare a sample. The inner and outer surfaces of the hollow fiber membrane were observed with a field emission type scanning electron microscope (S800 manufactured by Hitachi, Ltd.) at a magnification of 1000 times. At this time, the brightness and contrast of the image used the automatic function of the apparatus. Next, the hole portion was painted black using Microsoft (registered trademark) Paint (Microsoft Ltd.). After binarization, Matrox Inspector 2.2 (Matrox Electronic Systems Ltd.) is used to perform image processing that inverts the holes in white and other areas in black. The total opening area was determined, and the opening ratio was calculated. In addition, even when the whole hole is not shown and the end is cut off, a portion that is shown in the image is a calculation target. For these measurement operations, average values were obtained for a total of 15 images, each of 5 hollow fibers randomly at 5 locations.
When the shape of the hole was not a circle, the diameter corresponding to the circle having the same area as the hole area was calculated as the hole diameter, and those having a hole diameter of less than 0.2 μm were regarded as noise and were not counted.
(2) Measurement of average pore diameter The average pore diameter of the hollow fiber membrane was determined by differential scanning calorimetry (DSC) measurement. The melting point of ice confined in nanometer-sized pores is lower than that of normal bulk ice (melting point: 0 ° C.). By utilizing this phenomenon and combining the Laplace equation and Gibbs-Duhem equation from the melting point distribution of the DSC curve, the pore size distribution is calculated, and the average pore size can be obtained.
測定方法としては、水中に浸漬してあった中空糸膜試料の内外表面の付着水を除いた後、約5mmの長さにしたもの約30本を密閉パンにつめて秤量し、DSCにかけた。試料は−55℃に冷却してから、0.3℃/minの昇温速度で加温して測定した。DSCの装置としてTA Instruments 社製 DSC Q100を用いた。
(3)β2−MG クリアランス(β2−MG CL)測定
吸着カラムの性能評価として、β2−MGのクリアランスを測定した。β2−MGは、長期透析合併症である透析アミロイドーシスの原因タンパク質であることが知られている。
エチレンジアミン四酢酸二ナトリウムを添加した牛血液について、ヘマトクリットが30±3%、総タンパク量が6.5±0.5g/dLとなるように牛血漿と生理食塩水を添加し、調製した。As a measuring method, after removing the adhering water on the inner and outer surfaces of the hollow fiber membrane sample that had been immersed in water, about 30 pieces having a length of about 5 mm were put in a closed pan, weighed, and subjected to DSC. . The sample was cooled to −55 ° C. and then heated at a rate of temperature increase of 0.3 ° C./min. A DSC Q100 manufactured by TA Instruments was used as the DSC apparatus.
(3) β 2 -MG Clearance (β 2 -MG CL) Measurement As a performance evaluation of the adsorption column, β 2 -MG clearance was measured. β 2 -MG is known to be a causative protein of dialysis amyloidosis, which is a long-term dialysis complication.
Bovine blood added with disodium ethylenediaminetetraacetate was prepared by adding bovine plasma and physiological saline so that the hematocrit was 30 ± 3% and the total protein amount was 6.5 ± 0.5 g / dL.
次に、該牛血液にβ2−MG濃度が1mg/lになるように加え、撹拌した。かかる牛血液について、その2Lを循環用に、1.5Lをクリアランス測定用として分けた。Next, the bovine blood was added with a β 2 -MG concentration of 1 mg / l and stirred. The cow blood was divided into 2 L for circulation and 1.5 L for clearance measurement.
回路を図2のように設定した。 The circuit was set up as in FIG.
調製した牛血液2L(37℃)の入ったビーカー内に入れ、循環用牛血液14とした。流速を200mL/minとしてBiポンプ11をスタートし、Bi回路16、そして中空糸膜モジュール10、そしてBo回路17を通じて出てくる液体を90秒間廃棄用容器13に廃棄した。ただちにBo回路17を通じて流れてくる液体を循環用ビーカー14に入れて、Bo回路17からBi回路16、そして中空糸膜モジュール10へ液体が通じる状態として、循環を行った。 It was put into a beaker containing 2 L of prepared bovine blood (37 ° C.) to obtain circulating bovine blood 14. The Bi pump 11 was started at a flow rate of 200 mL / min, and the liquid coming out through the Bi circuit 16, the hollow fiber membrane module 10, and the Bo circuit 17 was discarded in the disposal container 13 for 90 seconds. Immediately after that, the liquid flowing through the Bo circuit 17 was put into the circulation beaker 14, and the circulation was performed in such a state that the liquid was communicated from the Bo circuit 17 to the Bi circuit 16 and then to the hollow fiber membrane module 10.
循環を1時間行った後Biポンプ11を停止した。 After 1 hour of circulation, the Bi pump 11 was stopped.
次に、調整したクリアランス測定用牛血液15からBi回路16に通じるようにして、中空糸膜モジュール10、そしてBo回路17を通じて出てくる液体を廃棄用容器13に廃棄した。 Next, the liquid coming out through the hollow fiber membrane module 10 and the Bo circuit 17 was discarded to the disposal container 13 so as to communicate from the adjusted clearance measuring bovine blood 15 to the Bi circuit 16.
流速は200mL/minとして、Biポンプ11をスタートしてから2分経過後、37℃のクリアランス測定用牛血液15からサンプルを10ml採取し、Bi液とした。スタートから4分30秒経過後に、Bo回路17のから流れ出た液体を10ml採取し、Bo液とした。これらのサンプルは−20℃以下の冷凍庫で保存した。 The flow rate was 200 mL / min, and after 2 minutes from the start of the Bi pump 11, 10 ml of a sample was taken from the bovine blood 15 for clearance measurement at 37 ° C. and used as Bi solution. After 4 minutes and 30 seconds from the start, 10 ml of the liquid flowing out from the Bo circuit 17 was collected and used as Bo liquid. These samples were stored in a freezer at -20 ° C or lower.
各液のβ2−MGの濃度からクリアランスを下記数式3によって算出した。牛血液のロットによって測定値が異なる場合があるので、実施例、比較例には全て同一ロットの牛血液を使用した。The clearance was calculated from the β 2 -MG concentration of each solution according to the following Equation 3. Since measured values may differ depending on the lot of bovine blood, bovine blood of the same lot was used in all of the examples and comparative examples.
Co(ml/min)=(CBi−CBo)×QB/CBi 数式3
数式3において、COはβ2−MGクリアランス(ml/min)、CBiはBiに入る牛血液のβ2−MG濃度(mg/mL)、CBoはBoから出る牛血液のβ2−MG濃度(mg/mL)、QBはBiポンプ流量(ml/min)である。Co (ml / min) = (CBi−CBo) × Q B / CBi Formula 3
In Equation 3, C O is beta 2 -MG Clearance (ml / min), CBi is beta 2 -MG concentration (mg / mL) of bovine blood entering the Bi, CB o the beta 2 -MG bovine blood exiting Bo concentration (mg / mL), Q B is Bi pump flow rate (ml / min).
なお、人工腎臓モジュールにおけるβ2−MGクリアランスの測定方法は以下のとおりである。In addition, the measuring method of (beta) 2- MG clearance in an artificial kidney module is as follows.
上記吸着カラムの性能評価時と同様の牛血液を調製した。図3のように回路を組立て、モジュールをセットした。評価装置としては、東レメディカル株式会社製 TR2000Sを用いた。TR2000Sは、図3のうち、Biポンプ11、Fポンプ12、および透析装置9を有する装置である。 The same bovine blood as that used in the performance evaluation of the adsorption column was prepared. As shown in FIG. 3, the circuit was assembled and the module was set. As an evaluation apparatus, TR2000S manufactured by Toray Medical Co., Ltd. was used. TR2000S is an apparatus having the Bi pump 11, the F pump 12, and the dialysis apparatus 9 in FIG.
透析装置9に、透析液(キンダリー液AF2号 扶桑薬品工業株式会社製)A液およびB液をセットした。透析液側から血液側に向けて逆浸透膜を通した水(RO水)を流した。透析液濃度13〜15mS/cm、温度37℃、透析液側流量(QD)を500mL/minに設定した。Dialysate 9 (Kindary fluid AF2 Fuso Yakuhin Kogyo Co., Ltd.) A solution and B solution were set in the dialyzer 9. Water (RO water) that passed through the reverse osmosis membrane was allowed to flow from the dialysate side toward the blood side. The dialysate concentration was 13 to 15 mS / cm, the temperature was 37 ° C., and the dialysate side flow rate (Q D ) was set to 500 mL / min.
透水装置の除水速度(QF)を10mL/(min・m2)に設定した。37℃の牛血液2Lを入ったビーカーに入れ、循環用牛血液14とした。Biポンプ11をスタートし、Bo回路16を通じて出てくる液体90秒間分を廃棄用容器に蓄積し、それを廃棄した。
ただちにBo17回路を通じる液体を循環用ビーカー14に入れて、Bo回路17からBi回路16、Biポンプ11そして中空糸膜モジュール10へ液体が通じる状態として、循環を行った。The water removal rate (Q F ) of the water permeable device was set to 10 mL / (min · m 2 ). It was put into a beaker containing 2 L of 37 ° C. bovine blood to obtain circulating bovine blood 14. The Bi pump 11 was started, 90 seconds of liquid coming out through the Bo circuit 16 was accumulated in the waste container, and was discarded.
Immediately after that, the liquid passing through the Bo17 circuit was put in the circulation beaker 14, and the circulation was performed in such a state that the liquid could be communicated from the Bo circuit 17 to the Bi circuit 16, the Bi pump 11, and the hollow fiber membrane module 10.
血液側流量(QB)は200mL/minとした。The blood flow rate (Q B ) was 200 mL / min.
続いて透析装置のFポンプ12を動かし、循環を1時間行った(QB200mL/min、QD0mL/min、QF10mL/(min・m2))。その後、Biポンプ11およびFポンプ12を停止した。Subsequently, the F pump 12 of the dialysis machine was moved and circulated for 1 hour (Q B 200 mL / min, Q D 0 mL / min, Q F 10 mL / (min · m 2 )). Thereafter, the Bi pump 11 and the F pump 12 were stopped.
調整したクリアランス測定用牛血液15からBi回路16、Biポンプ11そして中空糸膜モジュール10、Bo回路17を通じるようにして、Biポンプ11を起動し、Bo回路17から出てくる液体を廃棄用容器13に入れ、液体を廃棄した。 The Bi pump 11 is started by passing the adjusted clearance measuring bovine blood 15 through the Bi circuit 16, the Bi pump 11, the hollow fiber membrane module 10, and the Bo circuit 17, and the liquid discharged from the Bo circuit 17 is discarded. Placed in container 13 and discarded the liquid.
透析液流量QDを制御するDiポンプ(透析装置9に内蔵されており、図示していない。)をスタートした(QB200mL/min、QD500mL/min、QF10mL/(min・m2))。Dialysate flow Q D (which is incorporated in the dialyzer 9, not shown.) Di pump controls were started (Q B 200mL / min, Q D 500mL / min, Q F 10mL / (min · m 2 )).
Bi液、Boのサンプリング、これらのサンプルの保存も上記吸着カラムの性能評価時と同様とした。クリアランスも同様に数式3によって算出した。
(4)残血性試験
吸着カラムを、生理食塩水を、吸着カラムの下にある血液側出口から上に流速200mL/minで700mL流して洗浄した。このとき、吸着カラムに振動を与えるなどの泡抜き操作は実施しなかった。Sampling of Bi liquid and Bo and storage of these samples were the same as in the performance evaluation of the adsorption column. Similarly, the clearance was also calculated by Equation 3.
(4) Residual blood test The adsorption column was washed by flowing 700 mL of physiological saline from the blood side outlet under the adsorption column at a flow rate of 200 mL / min. At this time, a bubble removal operation such as applying vibration to the adsorption column was not performed.
その後、牛血液を流速200mL/minで、吸着カラムの下にある血液側出口から導入した。牛血液にはヘパリンを添加し、ヘマトクリットが30%、総タンパク量が6.5g/dLとなるように調整したものを用いた。牛血液が中空糸膜を通って上側のヘッダー内に流出たことを確認してから牛血液の供給を停止した。吸着カラムを上下反転させ、血液が上から下に流れるようにした。この状態で1時間循環させた。 Then, bovine blood was introduced at a flow rate of 200 mL / min from the blood side outlet under the adsorption column. Heparin was added to the bovine blood, and the hematocrit adjusted to 30% and the total protein amount to 6.5 g / dL was used. After confirming that bovine blood flowed into the upper header through the hollow fiber membrane, the supply of bovine blood was stopped. The adsorption column was turned upside down to allow blood to flow from top to bottom. It was circulated for 1 hour in this state.
返血は生理食塩水を用いて上から下に流速100mL/minで500mL流して洗浄した。その後、吸着カラムに残っている残血糸の本数を側面の外観から計数した。50本以上の残血糸がある場合に残血性が不良であると判断した。 Returning blood was washed by flowing 500 mL from top to bottom at a flow rate of 100 mL / min using physiological saline. Thereafter, the number of residual blood threads remaining in the adsorption column was counted from the appearance of the side surface. When there were 50 or more residual blood yarns, it was judged that the residual blood properties were poor.
人工腎臓モジュールについては、透析液側のノズルに栓をして、上記吸着カラムの場合と同様に残血性試験を行った。
(実施例1)
上述の「1.吸着カラムの作製」にしたがって吸着カラムを作成した。中空糸膜の製造における凝固浴温度は45℃とした。中空糸膜両端を固定しての加熱処理は行わなかった。中空糸膜の表面の開孔率、平均細孔径を測定した。表1に示す条件で吸着カラムを組み立て、β2−MGクリアランス、残血性について試験を行った。結果は表1に示したとおり、高いβ2−MGクリアランスと良好な残血特性が得られた。
(実施例2)
上述の「1.吸着カラムの作製」にしたがって吸着カラムを作成した。中空糸膜の製造における凝固浴温度は47℃とした。中空糸膜両端を固定して40℃で2週間加熱処理を行った。
中空糸膜の表面の開孔率、平均細孔径を測定した。表1に示す条件で吸着カラムを組み立て、β2−MGクリアランス、残血性について試験を行った。結果は表1に示したとおり、高いβ2−MGクリアランスと良好な残血特性が得られた。
(実施例3)
上述の「1.吸着カラムの作製」にしたがって吸着カラムを作成した。中空糸膜の製造における凝固浴温度は47℃とした。中空糸膜両端を固定して40℃で2週間加熱処理を行った。For the artificial kidney module, the nozzle on the dialysate side was capped and a residual blood test was performed in the same manner as in the case of the adsorption column.
Example 1
An adsorption column was prepared according to “1. Preparation of adsorption column” described above. The coagulation bath temperature in the production of the hollow fiber membrane was 45 ° C. Heat treatment with both ends of the hollow fiber membrane fixed was not performed. The surface area of the hollow fiber membrane and the average pore diameter were measured. An adsorption column was assembled under the conditions shown in Table 1 and tested for β 2 -MG clearance and residual blood. As a result, as shown in Table 1, high β 2 -MG clearance and good residual blood characteristics were obtained.
(Example 2)
An adsorption column was prepared according to “1. Preparation of adsorption column” described above. The coagulation bath temperature in the production of the hollow fiber membrane was 47 ° C. Both ends of the hollow fiber membrane were fixed and heat treatment was performed at 40 ° C. for 2 weeks.
The surface area of the hollow fiber membrane and the average pore diameter were measured. An adsorption column was assembled under the conditions shown in Table 1 and tested for β 2 -MG clearance and residual blood. As a result, as shown in Table 1, high β 2 -MG clearance and good residual blood characteristics were obtained.
(Example 3)
An adsorption column was prepared according to “1. Preparation of adsorption column” described above. The coagulation bath temperature in the production of the hollow fiber membrane was 47 ° C. Both ends of the hollow fiber membrane were fixed and heat treatment was performed at 40 ° C. for 2 weeks.
中空糸膜の表面の開孔率、平均細孔径を測定した。表1に示す条件で吸着カラムを組み立て、β2−MGクリアランス、残血性について試験を行った。結果は表1に示したとおり、高いβ2−MGクリアランスと良好な残血特性が得られた。
(実施例4)
上述の「1.吸着カラムの作製」にしたがって吸着カラムを作成した。中空糸膜の製造における凝固浴温度は35℃とした。中空糸膜両端を固定しての加熱処理は行わなかった。中空糸膜の表面の開孔率、平均細孔径を測定した。表1に示す条件で吸着カラムを組み立て、β2−MGクリアランス、残血性について試験を行った。結果は表1に示したとおりであり、平均細孔径が小さいためにβ2−MGクリアランスは実施例1よりも低かった。しかし、同じ中空糸膜を用いて人工腎臓モジュールとした比較例4に比べると高い値を示した。なお、このような孔径は、β2−MGよりも小さい蛋白質の除去に適していることがわかる。残血特性は良好であった。
(実施例5)
上述の「1.吸着カラムの作製」にしたがって吸着カラムを作成した。中空糸膜は実施例1のものを使用した。中空糸膜を用いて、表1に示す条件で吸着カラムを組み立て、β2−MGクリアランス、残血性について試験を行った。結果は表1に示したとおり、高いβ2−MGクリアランスと良好な残血特性が得られた。
(実施例6)
上述の「1.吸着カラムの作製」にしたがって吸着カラムを作成した。中空糸膜は実施例1のものを使用した。中空糸膜を用いて、表1に示す条件で吸着カラムを組み立て、β2−MGクリアランス、残血性について試験を行った。結果は表1に示したとおり、高いβ2−MGクリアランスと良好な残血特性が得られた。
(実施例7)
上述の「1.吸着カラムの作製」にしたがって吸着カラムを作成した。中空糸膜は実施例1のものを使用した。中空糸膜を用いて、表1に示す条件で吸着カラムを組み立て、β2−MGクリアランス、残血性について試験を行った。結果は表1に示したとおり、高いβ2−MGクリアランスと良好な残血特性が得られた。
(比較例1)
上述の「1.吸着カラムの作製」にしたがって吸着カラムを作成した。中空糸膜の製造における凝固浴温度は45℃とした。中空糸膜両端を固定して40℃で2週間加熱処理を行った。中空糸膜の表面の開孔率、平均細孔径を測定した。表1に示す条件で吸着カラムを組み立て、β2−MGクリアランス、残血性について試験を行った。結果は表1に示したとおり、β/αが0.15よりも小さく、β2−MGクリアランスは良好であったが、残血特性は悪かった。
(比較例2)
上述の「1.吸着カラムの作製」にしたがって吸着カラムを作成した。中空糸膜の製造における凝固浴温度は45℃とした。中空糸膜両端を固定しての加熱処理は行わなかった。中空糸膜の表面の開孔率、平均細孔径を測定した。表1に示す条件で吸着カラムを組み立て、β2−MGクリアランス、残血性について試験を行った。結果は表1に示したとおり、β/αが2よりも大きく、β2−MGクリアランスは良好であったが、残血特性は不良であった。
(比較例3)
上述の「1.吸着カラムの作製」にしたがって吸着カラムを作成した。中空糸膜の製造における凝固浴温度は45℃とした。中空糸膜両端を固定しての加熱処理は行わなかった。この中空糸膜を用いて人工腎臓モジュールを作製した。すなわち、当該中空糸膜15200本を内径4cm、長さ22cmの透析液ノズルを2カ所有する円筒ケースに挿入した。その後両端に仮のキャップをし、遠心機でモジュールを回転させながら透析液ノズルを通じてポッティング剤を入れた。ポッティング剤が固化した後、中空糸膜の両端が開口するように両端部を切断した。ポッティング端面にヘッダーを取り付け、図4に示す人工腎臓モジュールを得た。中空糸膜の両側を十分に水洗し、グリセリンを除去した。その後、モジュールに水を充填した状態で、25kGyのγ線で滅菌した。The surface area of the hollow fiber membrane and the average pore diameter were measured. An adsorption column was assembled under the conditions shown in Table 1 and tested for β 2 -MG clearance and residual blood. As a result, as shown in Table 1, high β 2 -MG clearance and good residual blood characteristics were obtained.
Example 4
An adsorption column was prepared according to “1. Preparation of adsorption column” described above. The coagulation bath temperature in the production of the hollow fiber membrane was 35 ° C. Heat treatment with both ends of the hollow fiber membrane fixed was not performed. The surface area of the hollow fiber membrane and the average pore diameter were measured. An adsorption column was assembled under the conditions shown in Table 1 and tested for β 2 -MG clearance and residual blood. The results are as shown in Table 1, and the β 2 -MG clearance was lower than that of Example 1 due to the small average pore diameter. However, the value was higher than that of Comparative Example 4 in which the same hollow fiber membrane was used as an artificial kidney module. In addition, it turns out that such a hole diameter is suitable for the removal of the protein smaller than (beta) 2- MG. Residual blood characteristics were good.
(Example 5)
An adsorption column was prepared according to “1. Preparation of adsorption column” described above. The hollow fiber membrane used in Example 1 was used. Using a hollow fiber membrane, an adsorption column was assembled under the conditions shown in Table 1, and tested for β 2 -MG clearance and residual blood. As a result, as shown in Table 1, high β 2 -MG clearance and good residual blood characteristics were obtained.
(Example 6)
An adsorption column was prepared according to “1. Preparation of adsorption column” described above. The hollow fiber membrane used in Example 1 was used. Using a hollow fiber membrane, an adsorption column was assembled under the conditions shown in Table 1, and tested for β 2 -MG clearance and residual blood. As a result, as shown in Table 1, high β 2 -MG clearance and good residual blood characteristics were obtained.
(Example 7)
An adsorption column was prepared according to “1. Preparation of adsorption column” described above. The hollow fiber membrane used in Example 1 was used. Using a hollow fiber membrane, an adsorption column was assembled under the conditions shown in Table 1, and tested for β 2 -MG clearance and residual blood. As a result, as shown in Table 1, high β 2 -MG clearance and good residual blood characteristics were obtained.
(Comparative Example 1)
An adsorption column was prepared according to “1. Preparation of adsorption column” described above. The coagulation bath temperature in the production of the hollow fiber membrane was 45 ° C. Both ends of the hollow fiber membrane were fixed and heat treatment was performed at 40 ° C. for 2 weeks. The surface area of the hollow fiber membrane and the average pore diameter were measured. An adsorption column was assembled under the conditions shown in Table 1 and tested for β 2 -MG clearance and residual blood. As shown in Table 1, β / α was smaller than 0.15 and β 2 -MG clearance was good, but residual blood characteristics were poor.
(Comparative Example 2)
An adsorption column was prepared according to “1. Preparation of adsorption column” described above. The coagulation bath temperature in the production of the hollow fiber membrane was 45 ° C. Heat treatment with both ends of the hollow fiber membrane fixed was not performed. The surface area of the hollow fiber membrane and the average pore diameter were measured. An adsorption column was assembled under the conditions shown in Table 1 and tested for β 2 -MG clearance and residual blood. As shown in Table 1, β / α was larger than 2 and β 2 -MG clearance was good, but residual blood characteristics were poor.
(Comparative Example 3)
An adsorption column was prepared according to “1. Preparation of adsorption column” described above. The coagulation bath temperature in the production of the hollow fiber membrane was 45 ° C. Heat treatment with both ends of the hollow fiber membrane fixed was not performed. An artificial kidney module was produced using this hollow fiber membrane. That is, 15200 hollow fiber membranes were inserted into a cylindrical case having two dialysate nozzles having an inner diameter of 4 cm and a length of 22 cm. Then, a temporary cap was put on both ends, and the potting agent was put through the dialysate nozzle while rotating the module with a centrifuge. After the potting agent was solidified, both ends were cut so that both ends of the hollow fiber membrane were open. A header was attached to the end surface of the potting to obtain an artificial kidney module shown in FIG. Both sides of the hollow fiber membrane were sufficiently washed with water to remove glycerin. Thereafter, the module was filled with water and sterilized with 25 kGy of γ rays.
人工腎臓モジュールから中空糸膜を切り出し、中空糸膜の表面の開孔率、平均細孔径を測定した。人工腎臓モジュールとしてβ2−MGクリアランス、残血性について試験を行った。結果は表1に示したとおり、β/αが2よりも大きいが、人工腎臓モジュールでは、中空糸膜内側にしか血液が流れないため、残血特性に問題はなかった。一方で、透析液を流し、濾過をかけているにも関わらず、中空糸膜の内側しか血液が流れていないため、β2−MGクリアランスは、低い値となった。
(比較例4)
実施例4の中空糸膜12800本を用いて比較例3と同様に人工腎臓モジュールを作製し、水洗後、25kGyのγ線で滅菌した。人工腎臓モジュールでは、血液が中空糸膜内側のみに流れるため、中空糸膜外側における残血特性の問題はなかった。しかし一方で、透析液を流して濾過をかけているにも関わらず、中空糸膜の外側を血液が流れていないため、β2−MGクリアランスは、実施例4と比べて低い値となった。
(比較例5)
1の吸着カラムの作製において、実施例1と同様の中空糸膜を用いて、表1に示す条件で吸着カラムを組み立て、β2−MGクリアランス、残血性について試験を行った。結果は表1に示す条件で吸着カラムを組み立て、β2−MGクリアランス、残血性について試験を行った。結果は表1に示したとおり、β/αが0.15よりも小さく、β2−MGクリアランスは良好であったが、残血特性は不良であった。
実施例1,5および6、比較例1,2および5の結果を表2にまとめた。実施例1,5,6および比較例2,5は同一の中空糸膜を用いているが、β/αが0.15より小さい場合の比較例5およびβ/αが2より大きい場合の比較例2では、残血糸が多く、β2−MGクリアランスも低かった。また、比較例1は比較例2に比べて、細孔径および中空糸膜外表面開孔率が高い糸を用いているため、β2−MGクリアランスは高い値を示した。しかしながら、比較例1のβ/αは比較例2と同じ値であり、残血糸は同程度に多かった。A hollow fiber membrane was cut out from the artificial kidney module, and the open area ratio and average pore diameter of the surface of the hollow fiber membrane were measured. As an artificial kidney module, β 2 -MG clearance and residual blood were tested. As shown in Table 1, β / α is larger than 2, but the artificial kidney module has no problem in residual blood characteristics because blood flows only inside the hollow fiber membrane. On the other hand, since the blood was flowing only inside the hollow fiber membrane in spite of the dialysate flowing and filtering, the β 2 -MG clearance was low.
(Comparative Example 4)
An artificial kidney module was prepared using 12800 hollow fiber membranes of Example 4 in the same manner as in Comparative Example 3, washed with water, and sterilized with 25 kGy γ rays. In the artificial kidney module, since blood flows only inside the hollow fiber membrane, there was no problem of residual blood characteristics outside the hollow fiber membrane. However, on the other hand, despite the fact that the dialysate was flowed and filtered, blood did not flow outside the hollow fiber membrane, so the β 2 -MG clearance was lower than that in Example 4. .
(Comparative Example 5)
In the production of No. 1 adsorption column, the same hollow fiber membrane as in Example 1 was used to assemble the adsorption column under the conditions shown in Table 1 and tested for β 2 -MG clearance and residual blood. As a result, an adsorption column was assembled under the conditions shown in Table 1 and tested for β 2 -MG clearance and residual blood. As shown in Table 1, β / α was smaller than 0.15 and β 2 -MG clearance was good, but residual blood characteristics were poor.
The results of Examples 1, 5, and 6 and Comparative Examples 1, 2, and 5 are summarized in Table 2. Examples 1, 5, 6 and Comparative Examples 2 and 5 use the same hollow fiber membrane, but Comparative Example 5 when β / α is smaller than 0.15 and Comparison when β / α is larger than 2 In Example 2, there were many residual blood threads and β 2 -MG clearance was also low. Moreover, since the comparative example 1 uses the thread | yarn with a high pore diameter and a hollow fiber membrane outer surface open area ratio compared with the comparative example 2, (beta) 2- MG clearance showed the high value. However, β / α in Comparative Example 1 was the same value as in Comparative Example 2, and the residual blood thread was as high as the same.
実施例2,3および7の結果を表3にまとめた。中空糸内径、膜厚、中空糸本数、内・外表面開孔率、細孔径などが異なっているが、いずれもβ/αが0.15以上、2以下であり、高いβ2−MGクリアランス、少ない残血糸という特性を有していた。The results of Examples 2, 3 and 7 are summarized in Table 3. Hollow fiber inner diameter, film thickness, number of hollow fibers, inner / outer surface open area ratio, pore diameter, etc. are all different, but all have β / α of 0.15 or more and 2 or less, and high β 2 -MG clearance It had the characteristic of few residual blood threads.
実施例4,5および比較例2,3,4の結果について表4にまとめた。実施例5と比較例2,3は同一の中空糸膜を用いている。比較例3は血液透析器として使用しており、血液は中空糸膜内側しか流れない。一方で、比較例2は吸着カラムとして使用しており、血液は中空糸膜の内側と外側の両方に流れる。このため、比較例2のほうが、β2−MGクリアランスは高かった。しかしながら、比較例2は、β/αが0.15より小さいため、残血糸が多かった。なお、比較例3では血液は中空糸膜内側しか流れていないため、残血糸が少ないと考えられる。実施例5では、β/αを1.75にしたことで、比較例2、3よりも高いβ2−MGクリアランスを達成し、残血糸本数を低減することができたと考えられる。また、実施例4と比較例4について、同一の中空糸膜で、中空糸膜ケース内に同一の中空糸膜本数である。この場合も少ない残血糸で血液透析器よりも高いβ2−MGクリアランスを達成した。The results of Examples 4 and 5 and Comparative Examples 2, 3, and 4 are summarized in Table 4. Example 5 and Comparative Examples 2 and 3 use the same hollow fiber membrane. Comparative Example 3 is used as a hemodialyzer, and blood flows only inside the hollow fiber membrane. On the other hand, Comparative Example 2 is used as an adsorption column, and blood flows both inside and outside the hollow fiber membrane. For this reason, the β 2 -MG clearance was higher in Comparative Example 2. However, in Comparative Example 2, since β / α was smaller than 0.15, there were many residual blood threads. In Comparative Example 3, since blood flows only inside the hollow fiber membrane, it is considered that there are few residual blood threads. In Example 5, when β / α was set to 1.75, it is considered that β 2 -MG clearance higher than Comparative Examples 2 and 3 was achieved, and the number of residual blood threads could be reduced. Moreover, about Example 4 and the comparative example 4, it is the same hollow fiber membrane, and is the same number of hollow fiber membranes in a hollow fiber membrane case. Again, a higher β 2 -MG clearance was achieved than with hemodialyzers with less residual blood thread.
本発明に係る吸着カラムは、処理液として血液を用いてβ2−MG等のタンパク質を吸着除去する用途に好適に用いることができ、血液に限らず、生体の体液、排液に含まれるタンパク質の吸着除去用途に用いることも可能である。また、中空糸膜の平均細孔径を適宜設計することで、タンパク質の吸着除去に限らず、広く被吸着物質の吸着除去に用いることが可能である。The adsorption column according to the present invention can be suitably used for the purpose of adsorbing and removing proteins such as β 2 -MG using blood as a treatment liquid, and is not limited to blood, but is also included in body fluids and drainage of living organisms. It is also possible to use it for adsorption removal. Further, by appropriately designing the average pore diameter of the hollow fiber membrane, it can be widely used not only for adsorption removal of proteins but also for adsorption removal of substances to be adsorbed.
1:中空糸膜
2:中空糸膜ケース
3:ポッティング剤
4:血液側入口(Bi)
5:血液側出口(Do)
6:透析液側入口(Di)
7:透析液側出口(Do)
8:基準線
9:透析装置
10:中空糸膜モジュール
11:Biポンプ
12:Fポンプ
13:廃棄用容器
14:循環用牛血液
15:クリアランス測定用牛血液
16:Bi回路
17:Bo回路
18:Di回路
19:Do回路
20:温水槽
21:メッシュ
22:ヘッダー
23:Oリング
24:ポッティング材注入口
25:キャップ
26:ピン
27:ポッティング材1: Hollow fiber membrane 2: Hollow fiber membrane case 3: Potting agent 4: Blood side inlet (Bi)
5: Blood side outlet (Do)
6: Dialysate side inlet (Di)
7: Dialysate side outlet (Do)
8: Reference line 9: Dialyzer 10: Hollow fiber membrane module 11: Bi pump 12: F pump 13: Disposal container 14: Circulating bovine blood 15: Clearance measuring bovine blood 16: Bi circuit 17: Bo circuit 18: Di circuit 19: Do circuit 20: Hot water tank 21: Mesh 22: Header 23: O-ring 24: Potting material inlet 25: Cap 26: Pin 27: Potting material
Claims (10)
ケースの一方の端に処理液導入部、他方の端に処理液導出部を備え、
前記処理液導入部から流入する処理液が前記中空糸膜の内表面及び外表面に直接接触しうる構造を有し、
前記中空糸膜は多孔質構造を有しており、
前記中空糸膜の内径をRi、外径をRo、長さをL、束を構成する中空糸膜の本数をN、ケース内径をR、隔壁の厚みをl、外部流通用孔の平均直径をRP、外部流通用孔の数をn、前記中空糸膜内部の圧力損失をα、前記中空糸膜外部の圧力損失をβとして、α=A×L/(N×Ri4)、β=A×{L×(R+N×Ro)2/(R2−N×Ro 2)3+l/(n×RP 4)}としたときに、0.15<β/α<2であることを特徴とする吸着カラム。A bundle of hollow fiber membranes is built into the case,
A treatment liquid introduction part at one end of the case, a treatment liquid lead-out part at the other end,
The treatment liquid flowing from the treatment liquid introduction part has a structure that can directly contact the inner surface and the outer surface of the hollow fiber membrane,
The hollow fiber membrane has a porous structure,
The inner diameter of the hollow fiber membrane is R i , the outer diameter is R o , the length is L, the number of hollow fiber membranes constituting the bundle is N, the inner diameter of the case is R, the thickness of the partition is l, the average of the holes for external circulation Α = A × L / (N × Ri 4 ), where R P is the diameter, n is the number of external circulation holes, α is the pressure loss inside the hollow fiber membrane, and β is the pressure loss outside the hollow fiber membrane. When β = A × {L × (R + N × R o ) 2 / (R 2 −N × R o 2 ) 3 + l / (n × R P 4 )}, 0.15 <β / α <2 An adsorption column characterized by
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