JPH0211263B2 - - Google Patents
Info
- Publication number
- JPH0211263B2 JPH0211263B2 JP58116174A JP11617483A JPH0211263B2 JP H0211263 B2 JPH0211263 B2 JP H0211263B2 JP 58116174 A JP58116174 A JP 58116174A JP 11617483 A JP11617483 A JP 11617483A JP H0211263 B2 JPH0211263 B2 JP H0211263B2
- Authority
- JP
- Japan
- Prior art keywords
- hollow fiber
- plasma
- fiber membrane
- average pore
- pore diameter
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
- 239000012510 hollow fiber Substances 0.000 claims description 87
- 239000012528 membrane Substances 0.000 claims description 79
- 239000011148 porous material Substances 0.000 claims description 43
- 102000009027 Albumins Human genes 0.000 claims description 23
- 108010088751 Albumins Proteins 0.000 claims description 23
- 238000000034 method Methods 0.000 claims description 23
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 21
- 230000035699 permeability Effects 0.000 claims description 16
- 239000012466 permeate Substances 0.000 claims description 14
- 108060003951 Immunoglobulin Proteins 0.000 claims description 10
- 102000018358 immunoglobulin Human genes 0.000 claims description 10
- 238000010438 heat treatment Methods 0.000 claims description 8
- 238000000108 ultra-filtration Methods 0.000 claims description 4
- 238000005371 permeation separation Methods 0.000 claims 1
- 238000000926 separation method Methods 0.000 description 28
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 21
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 14
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 14
- 210000004369 blood Anatomy 0.000 description 13
- 239000008280 blood Substances 0.000 description 13
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
- 238000001914 filtration Methods 0.000 description 12
- 238000009987 spinning Methods 0.000 description 12
- 230000000052 comparative effect Effects 0.000 description 10
- 239000007864 aqueous solution Substances 0.000 description 9
- 239000000126 substance Substances 0.000 description 9
- 239000000203 mixture Substances 0.000 description 8
- 239000011550 stock solution Substances 0.000 description 8
- 238000005345 coagulation Methods 0.000 description 7
- 230000015271 coagulation Effects 0.000 description 7
- 235000011187 glycerol Nutrition 0.000 description 7
- 241000283690 Bos taurus Species 0.000 description 6
- 210000000601 blood cell Anatomy 0.000 description 6
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 5
- 229920002678 cellulose Polymers 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 229940027941 immunoglobulin g Drugs 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 230000036760 body temperature Effects 0.000 description 4
- 229920002301 cellulose acetate Polymers 0.000 description 4
- -1 nitrogen-containing compound Chemical class 0.000 description 4
- 229920000642 polymer Polymers 0.000 description 4
- 238000012545 processing Methods 0.000 description 4
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 3
- 239000001110 calcium chloride Substances 0.000 description 3
- 229910001628 calcium chloride Inorganic materials 0.000 description 3
- 235000011148 calcium chloride Nutrition 0.000 description 3
- 239000004202 carbamide Substances 0.000 description 3
- 239000000470 constituent Substances 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 108010074605 gamma-Globulins Proteins 0.000 description 3
- NIQQIJXGUZVEBB-UHFFFAOYSA-N methanol;propan-2-one Chemical compound OC.CC(C)=O NIQQIJXGUZVEBB-UHFFFAOYSA-N 0.000 description 3
- 239000011259 mixed solution Substances 0.000 description 3
- 229920002492 poly(sulfone) Polymers 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 229920002803 thermoplastic polyurethane Polymers 0.000 description 3
- JOYRKODLDBILNP-UHFFFAOYSA-N Ethyl urethane Chemical compound CCOC(N)=O JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 description 2
- 239000002033 PVDF binder Substances 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 238000001493 electron microscopy Methods 0.000 description 2
- RHFLVCTUYKRSDV-UHFFFAOYSA-N formamide;methanol Chemical group OC.NC=O RHFLVCTUYKRSDV-UHFFFAOYSA-N 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 238000000691 measurement method Methods 0.000 description 2
- 239000012452 mother liquor Substances 0.000 description 2
- 238000002616 plasmapheresis Methods 0.000 description 2
- 230000010287 polarization Effects 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 229920002981 polyvinylidene fluoride Polymers 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 238000007711 solidification Methods 0.000 description 2
- 230000008023 solidification Effects 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- BQCIDUSAKPWEOX-UHFFFAOYSA-N 1,1-Difluoroethene Chemical compound FC(F)=C BQCIDUSAKPWEOX-UHFFFAOYSA-N 0.000 description 1
- 208000023275 Autoimmune disease Diseases 0.000 description 1
- FRPHFZCDPYBUAU-UHFFFAOYSA-N Bromocresolgreen Chemical compound CC1=C(Br)C(O)=C(Br)C=C1C1(C=2C(=C(Br)C(O)=C(Br)C=2)C)C2=CC=CC=C2S(=O)(=O)O1 FRPHFZCDPYBUAU-UHFFFAOYSA-N 0.000 description 1
- 229920001747 Cellulose diacetate Polymers 0.000 description 1
- 229920002284 Cellulose triacetate Polymers 0.000 description 1
- 229920006370 Kynar Polymers 0.000 description 1
- 208000024556 Mendelian disease Diseases 0.000 description 1
- 239000000020 Nitrocellulose Substances 0.000 description 1
- 239000004952 Polyamide Substances 0.000 description 1
- 239000004372 Polyvinyl alcohol Substances 0.000 description 1
- NNLVGZFZQQXQNW-ADJNRHBOSA-N [(2r,3r,4s,5r,6s)-4,5-diacetyloxy-3-[(2s,3r,4s,5r,6r)-3,4,5-triacetyloxy-6-(acetyloxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6s)-4,5,6-triacetyloxy-2-(acetyloxymethyl)oxan-3-yl]oxyoxan-2-yl]methyl acetate Chemical compound O([C@@H]1O[C@@H]([C@H]([C@H](OC(C)=O)[C@H]1OC(C)=O)O[C@H]1[C@@H]([C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](COC(C)=O)O1)OC(C)=O)COC(=O)C)[C@@H]1[C@@H](COC(C)=O)O[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O NNLVGZFZQQXQNW-ADJNRHBOSA-N 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 230000021736 acetylation Effects 0.000 description 1
- 238000006640 acetylation reaction Methods 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000000427 antigen Substances 0.000 description 1
- 102000036639 antigens Human genes 0.000 description 1
- 108091007433 antigens Proteins 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 230000005465 channeling Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 230000001112 coagulating effect Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000003370 dye binding method Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 125000002573 ethenylidene group Chemical group [*]=C=C([H])[H] 0.000 description 1
- 239000000835 fiber Substances 0.000 description 1
- 208000006454 hepatitis Diseases 0.000 description 1
- 231100000283 hepatitis Toxicity 0.000 description 1
- 230000001900 immune effect Effects 0.000 description 1
- 230000000951 immunodiffusion Effects 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 150000002605 large molecules Chemical class 0.000 description 1
- 229920002521 macromolecule Polymers 0.000 description 1
- 238000005374 membrane filtration Methods 0.000 description 1
- JNFLYZVFQQWLHM-UHFFFAOYSA-N methanol;oxepan-2-one Chemical compound OC.O=C1CCCCCO1 JNFLYZVFQQWLHM-UHFFFAOYSA-N 0.000 description 1
- STZCRXQWRGQSJD-GEEYTBSJSA-M methyl orange Chemical compound [Na+].C1=CC(N(C)C)=CC=C1\N=N\C1=CC=C(S([O-])(=O)=O)C=C1 STZCRXQWRGQSJD-GEEYTBSJSA-M 0.000 description 1
- 229940012189 methyl orange Drugs 0.000 description 1
- 206010028417 myasthenia gravis Diseases 0.000 description 1
- 201000008383 nephritis Diseases 0.000 description 1
- 229920001220 nitrocellulos Polymers 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 238000005192 partition Methods 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- 238000005191 phase separation Methods 0.000 description 1
- 229920002239 polyacrylonitrile Polymers 0.000 description 1
- 229920002647 polyamide Polymers 0.000 description 1
- 229920000515 polycarbonate Polymers 0.000 description 1
- 239000004417 polycarbonate Substances 0.000 description 1
- 238000006116 polymerization reaction Methods 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 238000004445 quantitative analysis Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- PAPBSGBWRJIAAV-UHFFFAOYSA-N ε-Caprolactone Chemical compound O=C1CCCCCO1 PAPBSGBWRJIAAV-UHFFFAOYSA-N 0.000 description 1
Landscapes
- Investigating Or Analysing Biological Materials (AREA)
- External Artificial Organs (AREA)
- Separation Using Semi-Permeable Membranes (AREA)
- Artificial Filaments (AREA)
- Spinning Methods And Devices For Manufacturing Artificial Fibers (AREA)
Description
＜技術分野＞
本発明は中空糸膜による血漿成分分離に関する
ものである。さらに詳しくは本発明は、血漿の濾
過処理における血漿中の有用成分と不要成分の分
離能を向上させ、かつ、有用成分を多量に回収す
る方法及びその装置等に関するものである。
＜従来技術＞
近年、腎炎，血小枝減少症，重症筋無力症，慢
性リウマチなどの自己免疫疾患に血漿交換法が用
いられている。これらの疾患における血液中の病
因物質または障害物質は、分子量約66000（分子サ
イズ38×150Å）のアルブミンよりもかなり分子
量の大きい、免疫複合体、抗原などで分子量約百
万以上であるといわれ、好ましくは分子量約16万
のγ―グロブリンの除去が望ましい。
血漿交換療法では患者から取り出された血液を
遠心分離器または膜による血漿分離器を用いて血
球成分と血漿に分離し、健康人の血漿をほぼ等量
交換し、患者に血球成分と共に返すものである。
この場合、血漿交換する量は１回３―５であり
アルブミンを主体とする大量の新鮮血漿が必要で
あるが新鮮血漿は極めて高価で、かつ供給量の制
約および肝炎感染などの危険を伴うなどの問題が
残されている。
従つて、これらの問題を解決するために患者血
漿中の不要成分のみを分離除去し、アルブミンな
どの有用成分を捨てることなく回収し、体内に返
還する方法が考えられている。すなわち、血漿を
冷却して高分子の病因蛋白質をゲル化させてから
比較的細孔径の大きい膜で濾別するクライオフイ
ルトレーシヨン法が研究されている。また、室温
で血漿を比較的小さい細孔径の膜で濾別する二重
濾過法が研究されている。しかし、何れも分離効
率が低く、濾過期間中に膜の目ずまりにより圧力
が異常に上昇し、膜の取替え又は洗滌を要するな
どの重大な問題点が多く残されている。
一般に、アルブミンと不要物質の膜による濾過
分離は極めて難かしく、アルブミンの透過率を上
げると不要物質の分離阻止率が低下し、また不要
物質の分離阻止率を上げるとアルブミンの透過率
が低下すると言う現象が認められている。それ故
簡単な操作法で、これらの二つの物質の分離能を
向上させ、かつアルブミンの回収率を向上させる
方法は、これまでに見い出されていない。
＜発明の目的＞
本発明の目的は、以上の如き欠点をなくし、効
率よくアルブミン等の有用血漿成分を回収するた
めの選択透過性中空糸膜を得ることにある。本発
明のもう１つの目的は、有用血漿成分の透過性が
高く、且つγ―グロブリン，免疫複合体等の不要
成分の透過性が低い選択透過性中空糸膜を得るこ
とにある。本発明のさらに他の目的はかかる選択
透過性中空糸膜を用いて有用血漿成分を効率よく
且つ長時間にわたつて安定に分離し得る血漿成分
分離器及びかかる血漿成分分離器を用いた効率よ
く安定に運転可能な血漿成分分離装置を得ること
にある。
＜発明の構成＞
本発明者らは、かかる目的を達成すべく鋭意研
究し、中空糸膜の微細構造によつて血漿成分の分
離特性が大きく変化することを見い出した。さら
には血漿を用いて濾過条件と中空糸膜のポアーサ
イズとの関係を詳細に研究した結果、濾過温度が
例えば室温以下の低温よりも体温である37℃近く
の温度における方がパアーサイズの小さい中空糸
膜によつても良好な濾過特性が得られ目詰りも少
ないことを見い出した。
本発明者らは、これらの知見に基づき分離操作
時の目詰り機構及び濃度分極等をも考慮して、さ
らに研究を進めた結果、驚くべきことには中空糸
膜のポアーサイズ及びその異方性を制御すること
によつて血漿中のアルブミン等の有効成分と免疫
複合体等の不要成分を非常に効率よく分離しうる
ことを見い出し本発明に到達した。
即ち本発明は、微多孔性中空糸膜であつて、そ
の外側表面の平均細孔径D1が内側表面の平均細
孔径D2よりも小さい異方性を有し、且つ該膜の
水透過法による平均細孔径Ｄが200〜700Åである
ことを特徴とする選択透過性中空糸膜；該選択透
過性中空糸膜を構成部材とし、該中空糸膜の外観
を血漿流通部，該中空糸膜の内側を透過液流通部
としたことを特徴とする血漿成分分離器；さらに
は(a)該血漿成分分離器と(b)その分離する血漿を加
温する手段とを有したことを特徴とする血漿成分
分離装置に関するものである。
以下本発明について詳細に説明する。
本発明における選択透過性中空糸膜の素材とし
ては、繊維形成性を有する高分子化合物であれば
よく、好ましいものとしては例えばセルロースエ
ステル，ポリビニルアルコール，ポリメチルメタ
リレート，ポリアクリロニトリル，ポリスルホ
ン，ポリツ化ビニリデン，ポリアミド，及びエス
テル等が挙げられ、中でも特に好ましいものはセ
ルロースエステル，ポリスルホン，ポリフツ化ビ
ニリデン等である。ここで言うセルロースエステ
ルとしてはセルロースジアセテート，セルロース
トリアセテート及びこれらの部分ケン化された物
等のセルロースアセテート類，ニトロセルロース
等が挙げられる。尚、本発明における中空糸膜
は、これらの高分子化合物の１種を用いたもので
あつてもよく、または２種以上を用いたものでも
よい。
本発明の選択透過性中空糸膜は、微多孔性中空
糸膜であつて、その外側表面の平均細孔径D1が
内側表面の平均細孔径D2よりも小さい所謂異方
性膜であることを特徴としている。該中空糸膜の
外側及び内側の平均細孔径の比D2／D1が1.2以上
であるものが好ましく、特に好ましくはD2／D1
が２以上である。また該比D2／D1の上限として
は、中空糸膜の強度等の特性が保たれる範囲内で
あれば大きい程好ましい。尚かかる外側表面及び
内側表面における平均細孔径は、電子顕微鏡観察
により評価されるものである。
また本発明の中空糸膜は、前記異方性に加えて
水透過法によつて得られる平均細孔径Ｄが200〜
700Åであることを特徴としている。ここで言う
水透過法による平均細孔径Ｄは、該中空糸膜の細
孔に一定量の水を透過せしめた時のその流速と圧
力損失を測定し、その結果から次式を用いて算出
されるものである。
Ｄ＝（32η・ｔ・Ｊ／Pr・△Ｐ）１／２
（但し式中、Ｄは該平均細孔径，ｔは膜厚，Ｊは
水の透過速度，ηは水の粘度，Prは膜の空孔率，
△Ｐは圧力損失を表わす。）
かかる平均細孔径Ｄは、300〜600Åの範囲にあ
ることがより望ましい。
さらに本発明の中空糸膜は、優れた選択透過特
性を有し、特に血漿成分中のアルブミン等の有効
成分を透過するがγ―グロブリン，免疫複合体等
の不要成分の透過を阻止する特異的な選択透過性
を有する。即ち該中空糸膜は、その外側から内側
の方向に血漿成分を透過せしめた際のアルブミン
透過率QAが70％以上であり、且つ該QAとイムノ
グロブリンＭの透過率QMの比QA／QMが３以上で
ある優れた特性を有する。該透過特性としては
QAが75％以上，さらには80％以上が好ましく、
またQA／QMが４以上，さらには4.5以上が好まし
い。
尚、かかる血漿成分の透過率QA，QMは以下の
測定法によつて得られる値を意味する。即ち、中
空糸膜の外側面積で約１m2を有する中空糸型分離
器に成型したものを用いて、30〜40℃のほぼ一定
温度において、該中空糸膜の外側から内側の方向
に血漿成分を10〜30ml・m2・minの範囲のほぼ一
定の透過速度で透過せしめた時の中空糸外側血漿
中の成分濃度及び中空糸内側血漿即ち透過液中の
成分濃度を測定し次式により算出される。
QA＝（透過液中のアルブミン濃度）／
（中空糸外側血漿中のアルブミン濃度）×100
QM＝（透過液中のイムノグロブリンＭ
濃度）／（中空糸外側血漿中のイムノグロブリンＭ濃度
）×100
但し、この測定法において、使用する血漿には
１当り5000単位のヘバリンを添加すること、及
び該中空糸膜に血漿成分を透過せしめる際の差圧
（即ち中空糸外側の圧力−中空糸内側の圧力）を
約100mmHg以下とすることを採用するのが望まし
い。またアルブミン，イムノグロブリンＭの濃度
分析は、精度が満足されればいかなる方法でもよ
いが、具体的にはアルブミンについては色素結合
法（例えばブロムクレゾールグリーン法，メチル
オレンジ法），イムノグロブリンＭについては抗
イムノグロブリンＭ抗体を用いた免疫学的定量法
（例えば―元平板免疫拡散法，免疫比濁法）が挙
げられる。
さらに本発明の中空糸膜は、優れた透過性を有
するものであり、その望ましいものとしては限外
濾過係数が100〜2000ml／m2・mmHg・hrの範囲に
あるものである。
また本発明の中空糸膜は、内径が100〜500μの
範囲，好ましくは200〜400μの範囲にあり、膜厚
が30〜200μの範囲，好ましくは50〜100μの範囲
にある。
本発明の選択透過性中空糸膜の製造法として
は、前記の如き異方性及び細孔径を有する中空糸
膜が得られる方法であれば、いかなる方法であつ
てもよい。
例えばセルロースエステルの該中空糸膜の製造
法としては、以下の方法が有利である。即ちホル
ムアミド，尿素，ジメチルホルムアミド，Ｎ―メ
チルピロリドン，ε―カプロラタム等の含窒素化
合物の少なくとも１種，セルロースエステル，ア
セトン，メタノール及び塩化カルシウムから実質
的になる紡糸原液を環状紡糸孔より吐出すると共
に、環状紡糸孔の中央より例えば水，メタノー
ル，ホルムアミド等の混合溶液を定量的に流出さ
せ、水，メタノール等を含有する凝固浴に導き、
更に水洗して巻取り、グリセリンを付着して乾燥
する。ポアーサイズはホルムアミド，尿素等の含
窒素化合物，塩化カルシウム等を増減することに
より調節可能である。凝固浴には水―メタノール
等を含有する混合液を用いるが溶媒であるアセト
ンを添加することにより凝固速度を調節可能であ
り、例えばアセトン添加量を少なくすれば外側の
ポアーサイズは小さくなる。即ち、外側の凝固速
度を内側より大きくすることで本発明の異方性を
もたせることが可能であり、各々の凝固速度の制
御は凝固液組成を変更することで行ない得る。他
の高分子化合物を用いた中空糸膜においても同様
にして異方性及び細孔径を制御することは可能で
ある。尚、一般的に言うと、溶剤と膨潤剤に高分
子を溶解し相分離が起りにくい場合には、少量の
塩類を添加した紡糸原液を紡糸し、非溶剤中で凝
固するが、膨潤剤の添加量によつても中空糸膜の
細孔径が制御出来る。
本発明における血漿成分分離器は、前記した如
き選択透過性中空糸膜を用い、該中空糸膜の外側
から内側の方向に血漿成分を透過せしめることを
特徴とする。
該血漿成分分離器を使用する場合、その中空糸
膜の強度，分離等の特性が失なわれない範囲内で
あれば、その分離条件はいかなるものでもよく特
に限定されるものではない。その分離温度として
は例えば50℃以下であつて、中でも人の体温に近
い30〜45℃の範囲が好ましく、特に32〜42℃が好
ましい。また中空糸膜の外側と内側の差圧として
は、約500mmHg以下、好ましくは約300mmHg以下
の範囲が望ましい。
尚その場合において用いられる血漿としては、
特に限定されるものではなく、例えば血液から血
球を除いた通常の血漿，それを部分的に濃縮され
た血漿あるいは他のもので希釈された血漿等のい
かなるものであつてもよい。
この様に本発明の血漿成分分離器は、前記した
選択透過性中空糸膜を構成部材として用い該中空
糸膜の外側を血漿原液部，中空糸膜内側を透過液
部としたことを特徴としている。
即ち該血漿成分分離器は中空糸膜，分離用容
器，中空糸膜支持隔壁，原液用導管及び透過液用
導管等を構成部材とする中空糸型分離器におい
て、その中空糸膜として前記の選択透過性中空糸
膜を用い、その中空糸外側を血漿原液部，内側を
透過液部としたものであり該中空糸膜の外側から
内側の方向に血漿成分を透過せしめることにより
血漿成分の選択的分離を行なうものである。
該分離器において、中空糸膜以外の構成部材の
材料及び構造は、中空糸型分離器として使用され
るいかなものであつてもよく、特に限定されるも
のではない。また該中空糸膜の配列、本数等につ
いても特に限定されるものではないが、分離する
血漿の濃度分極やチヤンネリングの起こりにくい
中空糸膜の配列及び分離器の構造とすることが望
ましい。
また本発明の血漿成分分離装置は、前記した如
き血漿成分分離器と分離する血漿を加温する手段
とを有することを特徴としたものである。即ち本
発明の血漿成分分離は、前記の如く50℃以下で行
なうことが望ましく、さらには人体の体温である
約37℃に近い30〜45℃の範囲の温度，特に32〜42
℃の範囲の温度であれば、血漿成分の選択透過性
が高く長時間にわたつて安定に分離を行なうこと
ができる。かかる温度が高く例えば50℃を超えた
場合には、血漿中の例えば蛋白質が変質する可能
性が生じ、特にその温度での長時間の加熱によつ
てその可能性が高くなるので好ましくない。
本発明の血漿成分分離装置は、かかる分離特性
を有効に生かすべく分離する血漿を加温する手段
を有する。加温手段としては、前記した温度に血
漿を加温することができるものであればいかなる
ものであつてもよく、例えば恒温槽，熱交換器等
が挙げられる。
かかる本発明の血漿成分分離装置を、第１図〜
第３図に例示するが、本発明の該分離装置はこれ
らの例示に何ら限定されるものではない。第１図
は加温手段３を血漿成分分離器４の前に位置させ
た場合であり、第２図は加温手段８の中に血漿成
分分離器４を組み込んだ場合である。また第１図
及び第２図は、ポンプ例えばローラーポンプによ
り中空糸膜を透過しなかつた血漿を部分循環する
場合を示し、第３はその部分循環のない場合を示
す。尚これらの図において、血漿の希釈装置，圧
力測定器，流量測定器，流量制御装置，温度測定
及び制御装置等は省略されているが、必要に応じ
て用いることができる。
尚本発明の血漿成分分離装置は、血球含有物と
血漿とに分離する血液分離装置と組み合わせて血
液処理装置として用いることができる。該血液分
離装置としては、血液を血球含有物とに分離でき
るものであれば、いかなるものでもよく、例えば
中空糸状，平板状あるいはコイル状の選択透過性
濾過膜を用いた装置等が挙げられる。
かかる血液処理装置を第４図に例示するが、該
処理装置は第４図により何ら限定されるものでは
ない。即ち該処理装置において、第２図及び第３
図に例示される本発明の血漿成分分離装置を用い
ることも可能であり、さらには血液の希釈装置，
加温装置等をも必要に応じて使用することもでき
る。
以下実施例をあげてさらに詳細に説明するが本
発明はこれらの実施例によつて何ら限定されるも
のではない。
実施例１，比較例１
酢化度53％，重合度180のセルロースアセテー
ト18.5重量％，ホルムアミド30重量％，CaCl2・
2H2O1.5重量％，アセトン37.5重量％，メタノー
ル12.5重量％の組成の紡糸原液を作成し、環状紡
糸孔より吐出させ、その中央部の内部凝固液はメ
タノールホルムアミド（５：１）混合液の50重量
％水溶液を流出させ、メタノール―アセトン
（５：１）混合液の50％水溶液の凝固溶中に導き、
凝固した中空糸を水中で洗滌しグリセリンを付着
して乾燥した。得られた中空糸は内径250μ，膜
厚50μで、外表面積が１m2になる様に両端をウレ
タン樹脂で固定し、中空糸型分離器を作成した。
水透過法による平均細孔径は300Åであり、電子
顕微鏡観察により外表面と内表面の各々の平均細
孔径の比は１：８であつた。またその限外濾過係
数は330ml／m2・mmHg・hrであつた。
次に、あらかじめ準備しておいた牛血漿にベバ
リンを１当り5000単位加え、この血漿を20ml／
minで外側から内側へ濾過実験を３時間実施し
た。尚その際に100ml／minの部分循環法を適用
した。温度は牛血漿及び分離器共に体温の37℃に
夫々保つた。また４ml／minの割合で血漿母液を
引き抜いた。血漿母液及び透過液中のアルブミ
ン，イムノグロブリンＭ（分子量約900000），イム
ノグロブリンＧ（分子量約160000）を夫々定量し
て濾過効率をしらべた。また、濾過時の差圧も併
せ測定した。さらに比較例１として同じ中空糸型
分離器を用いて、従来法と同様に中空糸の内側か
ら外側の方向への濾過実験を行なつた。
これらの結果を合わせて第１表に示す。
<Technical Field> The present invention relates to plasma component separation using hollow fiber membranes. More specifically, the present invention relates to a method and an apparatus for improving the ability to separate useful components from unnecessary components in plasma during plasma filtration treatment, and recovering a large amount of useful components. <Prior Art> In recent years, plasmapheresis has been used for autoimmune diseases such as nephritis, hemopenia, myasthenia gravis, and chronic rheumatism. The pathogenic or harmful substances in the blood in these diseases are said to be immune complexes and antigens, which have a molecular weight of approximately 66,000 (molecular size: 38 x 150 Å), which is considerably larger than albumin, and have a molecular weight of approximately 1 million or more. Preferably, γ-globulin having a molecular weight of about 160,000 is removed. In plasmapheresis therapy, blood is removed from the patient and separated into blood cell components and plasma using a centrifuge or membrane plasma separator. Approximately equal amounts of a healthy person's plasma are exchanged and the blood cells are returned to the patient along with the blood cell components. be.
In this case, the amount of plasma exchange is 3 to 5 times a time, and a large amount of fresh plasma containing mainly albumin is required, but fresh plasma is extremely expensive, has limited supply, and is associated with risks such as hepatitis infection. The problem remains. Therefore, in order to solve these problems, methods have been considered in which only unnecessary components in patient plasma are separated and removed, and useful components such as albumin are recovered without being discarded and returned to the body. Specifically, a cryofiltration method is being researched in which plasma is cooled to gel the high-molecular disease-causing proteins and then filtered through a membrane with relatively large pores. Further, a double filtration method in which plasma is filtered through a membrane with a relatively small pore size at room temperature is being studied. However, many serious problems remain, such as low separation efficiency and abnormal pressure rise due to membrane clogging during filtration, requiring replacement or cleaning of the membrane. In general, it is extremely difficult to separate albumin and unnecessary substances by membrane filtration; increasing the permeability of albumin lowers the separation rejection rate of unnecessary substances, and increasing the separation rejection rate of unnecessary substances lowers the permeability of albumin. This phenomenon has been recognized. Therefore, no method has been found to date to improve the separation ability of these two substances and to improve the recovery rate of albumin using a simple operation method. <Object of the Invention> An object of the present invention is to eliminate the above-mentioned drawbacks and to obtain a permselective hollow fiber membrane for efficiently recovering useful plasma components such as albumin. Another object of the present invention is to obtain a permselective hollow fiber membrane that has high permeability to useful plasma components and low permeability to unnecessary components such as γ-globulin and immune complexes. Still other objects of the present invention are a plasma component separator capable of efficiently and stably separating useful plasma components over a long period of time using such a permselective hollow fiber membrane; The object of the present invention is to obtain a plasma component separation device that can operate stably. <Structure of the Invention> The present inventors have conducted intensive research to achieve the above object, and have discovered that the separation characteristics of plasma components vary greatly depending on the fine structure of the hollow fiber membrane. Furthermore, as a result of detailed research on the relationship between filtration conditions and hollow fiber membrane pore size using plasma, it was found that hollow fibers with smaller pore size when the filtration temperature is close to body temperature, 37℃, than at low temperatures below room temperature. It has been found that the membrane also provides good filtration characteristics and is less likely to become clogged. Based on these findings, the present inventors conducted further research, taking into consideration the clogging mechanism during separation operation, concentration polarization, etc. As a result, surprisingly, the pore size of the hollow fiber membrane and its anisotropy were determined. The present inventors have discovered that active components such as albumin and unnecessary components such as immune complexes in plasma can be separated very efficiently by controlling this, and have thus arrived at the present invention. That is, the present invention provides a microporous hollow fiber membrane having anisotropy in which the average pore diameter D 1 of the outer surface is smaller than the average pore diameter D 2 of the inner surface, and the water permeation method of the membrane is A permselective hollow fiber membrane characterized by an average pore diameter D of 200 to 700 Å; the permselective hollow fiber membrane is used as a constituent member, and the appearance of the hollow fiber membrane is A plasma component separator characterized in that the inside of the plasma component separator is used as a permeate flow part; further characterized in that it has (a) the plasma component separator and (b) means for heating the plasma to be separated. The present invention relates to a plasma component separation device. The present invention will be explained in detail below. The material for the permselective hollow fiber membrane in the present invention may be any polymeric compound that has fiber-forming properties, and preferred examples include cellulose ester, polyvinyl alcohol, polymethyl metharylate, polyacrylonitrile, polysulfone, and polycarbonate. Examples include vinylidene, polyamide, and ester, and particularly preferred among them are cellulose ester, polysulfone, polyvinylidene fluoride, and the like. The cellulose ester mentioned here includes cellulose acetates such as cellulose diacetate, cellulose triacetate, and partially saponified products thereof, nitrocellulose, and the like. Note that the hollow fiber membrane in the present invention may be one using one type of these polymer compounds, or may be one using two or more types. The permselective hollow fiber membrane of the present invention is a microporous hollow fiber membrane, and is a so-called anisotropic membrane in which the average pore diameter D 1 of the outer surface is smaller than the average pore diameter D 2 of the inner surface. It is characterized by The hollow fiber membrane preferably has a ratio of outer and inner average pore diameters D 2 /D 1 of 1.2 or more, particularly preferably D 2 /D 1
is 2 or more. Further, the upper limit of the ratio D 2 /D 1 is preferably as large as possible within a range in which properties such as strength of the hollow fiber membrane are maintained. Note that the average pore diameters on the outer surface and the inner surface are evaluated by electron microscopic observation. In addition to the above-mentioned anisotropy, the hollow fiber membrane of the present invention has an average pore diameter D of 200 to 200, which is obtained by a water permeation method.
It is characterized by a thickness of 700 Å. The average pore diameter D determined by the water permeation method here is calculated by measuring the flow rate and pressure loss when a certain amount of water permeates through the pores of the hollow fiber membrane, and using the following formula from the results. It is something that D=(32η・t・J/Pr・△P)1/2 (where, D is the average pore diameter, t is the membrane thickness, J is the water permeation rate, η is the viscosity of water, and Pr is the membrane porosity of,
ΔP represents pressure loss. ) The average pore diameter D is more preferably in the range of 300 to 600 Å. Furthermore, the hollow fiber membrane of the present invention has excellent selective permeation properties, and has a specific property that allows effective components such as albumin in plasma components to pass through, but blocks unnecessary components such as γ-globulin and immune complexes. It has selective permeability. That is, the hollow fiber membrane has an albumin permeability Q A of 70% or more when plasma components are permeated from the outside to the inside, and the ratio Q of the Q A and the permeability Q M of immunoglobulin M is 70% or more. It has excellent properties with A /Q M of 3 or more. The transmission characteristics are
Q A of 75% or more, preferably 80% or more,
Further, Q A /Q M is preferably 4 or more, more preferably 4.5 or more. Incidentally, the permeability Q A and Q M of the plasma components mean values obtained by the following measurement method. That is, using a hollow fiber separator formed into a hollow fiber separator having an outer area of about 1 m 2 , plasma components are separated from the outside of the hollow fiber membrane toward the inside at a nearly constant temperature of 30 to 40°C. The component concentration in the plasma outside the hollow fiber and the plasma inside the hollow fiber, i.e. , the permeate, are measured and calculated using the following formula: be done. Q A = (albumin concentration in permeate) /
(Albumin concentration in plasma outside the hollow fiber) × 100 Q M = (Immunoglobulin M in the permeate
Concentration)/(Immunoglobulin M concentration in plasma outside the hollow fiber) x 100 However, in this measurement method, 5000 units of hebarin should be added to the plasma used, and the plasma components should be permeated through the hollow fiber membrane. It is desirable to adopt a pressure difference (i.e., pressure on the outside of the hollow fibers - pressure on the inside of the hollow fibers) when tightening the fibers to about 100 mmHg or less. Concentration analysis of albumin and immunoglobulin M may be performed using any method as long as the accuracy is satisfied; specifically, dye-binding methods (e.g., bromcresol green method, methyl orange method) are used for albumin; Immunological quantitative methods using anti-immunoglobulin M antibodies (eg, original plate immunodiffusion method, immunoturbidimetry) can be mentioned. Furthermore, the hollow fiber membrane of the present invention has excellent permeability, and desirably has an ultrafiltration coefficient in the range of 100 to 2000 ml/m 2 ·mmHg ·hr. Further, the hollow fiber membrane of the present invention has an inner diameter in the range of 100 to 500μ, preferably in the range of 200 to 400μ, and a membrane thickness in the range of 30 to 200μ, preferably in the range of 50 to 100μ. The permselective hollow fiber membrane of the present invention may be produced by any method as long as a hollow fiber membrane having the above-described anisotropy and pore size can be obtained. For example, the following method is advantageous for producing the hollow fiber membrane of cellulose ester. That is, a spinning stock solution consisting essentially of at least one nitrogen-containing compound such as formamide, urea, dimethylformamide, N-methylpyrrolidone, and ε-caprolatam, cellulose ester, acetone, methanol, and calcium chloride is discharged from an annular spinning hole. For example, a mixed solution of water, methanol, formamide, etc. is quantitatively flowed out from the center of the annular spinning hole and introduced into a coagulation bath containing water, methanol, etc.
Further, it is washed with water, rolled up, coated with glycerin, and dried. The pore size can be adjusted by increasing or decreasing the amount of formamide, nitrogen-containing compounds such as urea, calcium chloride, etc. A mixed solution containing water, methanol, etc. is used in the coagulation bath, and the coagulation rate can be adjusted by adding acetone as a solvent. For example, by reducing the amount of acetone added, the outer pore size becomes smaller. That is, it is possible to provide the anisotropy of the present invention by making the solidification rate on the outside larger than that on the inside, and each solidification rate can be controlled by changing the composition of the coagulation liquid. It is possible to control the anisotropy and pore diameter in the same manner in hollow fiber membranes using other polymer compounds. Generally speaking, when a polymer is dissolved in a solvent and a swelling agent and phase separation is difficult to occur, a spinning dope with a small amount of salt added is spun and coagulated in a non-solvent. The pore diameter of the hollow fiber membrane can also be controlled by the amount added. The plasma component separator according to the present invention is characterized in that it uses a permselective hollow fiber membrane as described above, and allows plasma components to permeate from the outside to the inside of the hollow fiber membrane. When using the plasma component separator, the separation conditions may be any and are not particularly limited as long as the strength, separation properties, etc. of the hollow fiber membrane are not lost. The separation temperature is, for example, 50°C or lower, preferably in the range of 30 to 45°C, which is close to human body temperature, and particularly preferably 32 to 42°C. The differential pressure between the outside and inside of the hollow fiber membrane is desirably within a range of about 500 mmHg or less, preferably about 300 mmHg or less. In addition, the plasma used in that case is:
The plasma is not particularly limited, and may be any plasma, such as normal plasma obtained by removing blood cells from blood, partially concentrated plasma, or plasma diluted with other substances. As described above, the plasma component separator of the present invention is characterized in that the above-described permselective hollow fiber membrane is used as a component, and the outside of the hollow fiber membrane is used as a plasma stock solution part, and the inside of the hollow fiber membrane is used as a permeate part. There is. That is, the plasma component separator is a hollow fiber separator whose constituent members include a hollow fiber membrane, a separation container, a hollow fiber membrane supporting partition, a conduit for stock solution, a conduit for permeate, etc. A permeable hollow fiber membrane is used, with the outside of the hollow fiber serving as a plasma stock solution section and the inside serving as a permeate section.By allowing plasma components to permeate from the outside to the inside of the hollow fiber membrane, plasma components can be selectively collected. It performs separation. In the separator, the materials and structures of the constituent members other than the hollow fiber membranes may be of any type used as a hollow fiber separator, and are not particularly limited. Further, the arrangement, number, etc. of the hollow fiber membranes are not particularly limited, but it is desirable that the arrangement of the hollow fiber membranes and the structure of the separator are such that concentration polarization and channeling of the plasma to be separated are unlikely to occur. Further, the plasma component separation apparatus of the present invention is characterized by having the above-described plasma component separator and means for warming the plasma to be separated. That is, the plasma component separation of the present invention is desirably carried out at a temperature of 50°C or lower as described above, and more preferably at a temperature in the range of 30 to 45°C, which is close to the human body temperature of about 37°C, especially at a temperature of 32 to 42°C.
If the temperature is in the range of .degree. C., the permselectivity of plasma components is high and stable separation can be carried out over a long period of time. If the temperature is high, for example exceeding 50°C, there is a possibility that proteins in the plasma will be denatured, and this possibility becomes particularly high with prolonged heating at that temperature, which is not preferable. The plasma component separation device of the present invention has means for heating the plasma to be separated in order to effectively utilize such separation characteristics. The heating means may be any means as long as it can warm the plasma to the above-mentioned temperature, such as a constant temperature bath, a heat exchanger, and the like. The plasma component separation device of the present invention is shown in FIGS.
Although illustrated in FIG. 3, the separation apparatus of the present invention is not limited to these examples in any way. FIG. 1 shows the case where the heating means 3 is located in front of the plasma component separator 4, and FIG. 2 shows the case where the plasma component separator 4 is incorporated into the heating means 8. Further, FIGS. 1 and 2 show a case in which plasma that has not passed through the hollow fiber membrane is partially circulated by a pump such as a roller pump, and FIG. 3 shows a case in which such partial circulation is not performed. In these figures, a plasma diluter, a pressure measuring device, a flow measuring device, a flow rate controlling device, a temperature measuring and controlling device, etc. are omitted, but they can be used if necessary. The plasma component separation device of the present invention can be used as a blood processing device in combination with a blood separation device that separates blood cell-containing substances and plasma. The blood separation device may be any device as long as it can separate blood into blood cell-containing substances, such as a device using a permselective filtration membrane in the form of a hollow fiber, a flat plate, or a coil. Although such a blood processing device is illustrated in FIG. 4, the processing device is not limited to FIG. 4 in any way. In other words, in the processing apparatus, FIGS. 2 and 3
It is also possible to use the plasma component separation device of the present invention illustrated in the figure, and furthermore, it is possible to use a blood dilution device,
A heating device or the like may also be used if necessary. The present invention will be described in more detail below with reference to Examples, but the present invention is not limited to these Examples in any way. Example 1, Comparative Example 1 Cellulose acetate with acetylation degree of 53%, polymerization degree of 180 18.5% by weight, formamide 30% by weight, CaCl2 .
A spinning stock solution with a composition of 1.5% by weight of 2H 2 O, 37.5% by weight of acetone, and 12.5% by weight of methanol is prepared and discharged from an annular spinning hole, and the internal coagulation liquid in the center is a methanol-formamide (5:1) mixed solution. A 50% by weight aqueous solution of is discharged and introduced into a coagulating solution of a 50% aqueous solution of methanol-acetone (5:1) mixture,
The coagulated hollow fibers were washed in water, coated with glycerin, and dried. The obtained hollow fiber had an inner diameter of 250 μm and a membrane thickness of 50 μm, and both ends were fixed with urethane resin so that the outer surface area was 1 m 2 to prepare a hollow fiber separator.
The average pore diameter determined by the water permeation method was 300 Å, and the ratio of the average pore diameters of the outer surface and the inner surface was 1:8 by observation with an electron microscope. Moreover, its ultrafiltration coefficient was 330 ml/m 2 ·mmHg ·hr. Next, add 5000 units of Bevalin to the bovine plasma prepared in advance, and add 20 ml of this plasma to the bovine plasma.
The filtration experiment was carried out from the outside to the inside for 3 hours at min. At that time, a partial circulation method of 100 ml/min was applied. The temperature of both the bovine plasma and the separator was maintained at 37°C, which is the same as body temperature. In addition, plasma mother liquor was withdrawn at a rate of 4 ml/min. Albumin, immunoglobulin M (molecular weight: approximately 900,000), and immunoglobulin G (molecular weight: approximately 160,000) in the plasma mother liquor and permeate were determined to examine the filtration efficiency. In addition, the differential pressure during filtration was also measured. Further, as Comparative Example 1, using the same hollow fiber separator, a filtration experiment was conducted from the inside to the outside of the hollow fiber in the same manner as in the conventional method. These results are shown in Table 1.
【表】
実施例２，比較例２
実施例１と同じセルロースアセテート18重量
％，ホルムアミド25％，尿素５％，CaCl2・
2H2O ２％，アセトン37.5％，メタノール12.5％
の組成の紡糸原液を作成し、環状紡糸孔より吐出
させ、その中央部の内液凝固液は、メタノールホ
ルムアミド（５：１）の50％混合水溶液を流出さ
せ、メタノールアセトン（５：１）の50％混水溶
液中に導き、凝固した中空糸を水中で洗滌し、グ
リセリンを付着した乾燥した。得られた中空糸は
内径250μ膜厚45μであつた。外表面積で１m2にな
る様に両端をウレタン樹脂で固定して分離器を作
成した。水透過法による平均ポアーサイズは450
Åであり電子顕微鏡観察により、外表面と内表面
のポアーの大きさの比は１：５であつた。またそ
の限外濾過係数は830ml／m2・mmHg・hrであつ
た。実施例１及び比較例１と同様にして濾過実験
を行なつた。各々の結果を第２表に合わせて示
す。[Table] Example 2, Comparative Example 2 Same as Example 1: 18% by weight of cellulose acetate, 25% formamide, 5% urea, CaCl 2 .
2H 2 O 2%, acetone 37.5%, methanol 12.5%
A spinning stock solution with the composition is prepared and discharged from an annular spinning hole, and the inner liquid coagulation liquid in the center is a 50% mixed aqueous solution of methanol formamide (5:1), and a mixture of methanol acetone (5:1). The hollow fibers were introduced into a 50% aqueous solution, and the coagulated hollow fibers were washed in water and dried with glycerin attached. The obtained hollow fiber had an inner diameter of 250μ and a membrane thickness of 45μ. A separator was created by fixing both ends with urethane resin so that the outer surface area was 1 m 2 . Average pore size by water permeation method is 450
According to electron microscopy, the size ratio of the pores on the outer surface and the inner surface was 1:5. Moreover, its ultrafiltration coefficient was 830 ml/m 2 ·mmHg·hr. A filtration experiment was conducted in the same manner as in Example 1 and Comparative Example 1. The respective results are shown in Table 2.
【表】
実施例３，比較例３
セルロースアセテート19重量％，ホルムアミド
25％，グリセリン２％，CaCl2・2H2O 2.0％，ア
セトン38％，メタノール14％の組成の紡糸原液を
作成し、環状紡糸孔より吐出させ、その中央部の
内液凝固液は、メタノールホルムアミド（6.5：
１）の50％混合水溶液を流出させ、メタノールア
セトン（５：１）の50％混水溶液中に導き、さら
に実施例１と同様の後処理を行つた。得られた中
空糸は内径230μ，膜厚30μであつた。外表面積で
１m2になる様に両端をウレタン樹脂で固定して分
離器を作成した。水透過法による平均ポアーサイ
ズは500Åであり電子顕微鏡観察により外表面と
内表面のポアーの大きさの比は（１：２）であつ
た。実施例１及び比較例１と同様に牛血漿を用い
て運転時間３時間におけるアルブミン，イムノグ
ロブリンＧ，イムノグロブリンＭの透過率を測定
した。それらの結果を第３表に示す。[Table] Example 3, Comparative Example 3 Cellulose acetate 19% by weight, formamide
A spinning stock solution with a composition of 25% glycerin, 2% glycerin, 2.0% CaCl 2 2H 2 O, 38% acetone, and 14% methanol was prepared and discharged from an annular spinning hole. Formamide (6.5:
The 50% mixed aqueous solution of 1) was discharged and introduced into a 50% mixed aqueous solution of methanol acetone (5:1), and the same post-treatment as in Example 1 was performed. The obtained hollow fiber had an inner diameter of 230μ and a membrane thickness of 30μ. A separator was created by fixing both ends with urethane resin so that the outer surface area was 1 m 2 . The average pore size determined by the water permeation method was 500 Å, and the ratio of the pore sizes on the outer surface and the inner surface was (1:2) by electron microscopy observation. In the same manner as in Example 1 and Comparative Example 1, the permeability of albumin, immunoglobulin G, and immunoglobulin M was measured using bovine plasma over a 3-hour driving time. The results are shown in Table 3.
【表】
実施例４，比較例４
ポリスルホン（米国ユニオンカーバイト社製ユ
ーデルUDEL）20重量％，ポリエチレングリコー
ル（分子量2000）30％，Ｎ―メチルピロリドン50
％の組成の紡糸原液を作成し、環状紡糸孔より吐
出させ、その中央部の内部凝固液はメタノール―
ポリエチレングリコール（１：１）の50％混合水
溶液を流出させ、Ｎ―メチルピロリドン10％水溶
液中に導き水洗後グリセリンを付着し乾燥した。
得られた中空糸は内径230μ，膜厚50μであつた。
外表面積で１m2になる様に両端をウレタンで固定
して分離器を作成した。
水透過法による平均ポアサイズは400Åであり、
電子顕微鏡観察により外表面と内表面のポアーの
大きさの比は１：５であつた。実施例１及び比較
例１と同様に牛血漿を用いて運転時間２時間にお
けるアルブミン，イムノグロブリンＧ，イムノグ
ロブリンＭの透過率を測定した。それらの結果を
第４表に示す。[Table] Example 4, Comparative Example 4 Polysulfone (Udel UDEL manufactured by Union Carbide, USA) 20% by weight, polyethylene glycol (molecular weight 2000) 30%, N-methylpyrrolidone 50%
A spinning stock solution with a composition of
A 50% mixed aqueous solution of polyethylene glycol (1:1) was poured out, introduced into a 10% aqueous N-methylpyrrolidone solution, washed with water, coated with glycerin, and dried.
The obtained hollow fiber had an inner diameter of 230μ and a membrane thickness of 50μ.
A separator was created by fixing both ends with urethane so that the outer surface area was 1 m 2 . The average pore size by water permeation method is 400Å,
Observation with an electron microscope revealed that the pore size ratio between the outer surface and the inner surface was 1:5. In the same manner as in Example 1 and Comparative Example 1, the permeability of albumin, immunoglobulin G, and immunoglobulin M was measured using bovine plasma over a 2-hour operating time. The results are shown in Table 4.
【表】
実施例５，比較例５
ポリフツ化ビニリデン（米国ペンオール社製カ
イナーKynar）25重量％，ε―カプロラクトン30
％，Ｎ―メチルピロリドン45％の組成の紡糸原液
を作成し、環状紡糸孔より吐出させ、その中央部
の内部凝固液はメタノール―ε―カプロラクトン
（１：１）の50％混合水溶液を流出させ、Ｎ―メ
チルピロリドン20％水溶液中に導き、水洗後グリ
セリンを付着し乾燥した。得られた中空糸は内径
230μ，膜厚45μであつた。外表面積で１m2になる
様にウレタンで両端を固定して分離器を作成し
た。
水透過法による平均ポアサイズは370Åであり、
電子顕微鏡観察により外表面と内表面のポアーの
大きさの比は１：３であつた。実施例１及び比較
例１と同様に牛血漿を用いて運転時間１時間目に
おいてアルブミン，イムノグロブリンＧ，イムノ
グロブリンＭの透過率を測定した。その結果を第
５表に示す。[Table] Example 5, Comparative Example 5 Polyvinylidene fluoride (Kynar manufactured by Penall, USA) 25% by weight, ε-caprolactone 30
%, N-Methylpyrrolidone 45% composition was prepared and discharged from an annular spinning hole, and the internal coagulation liquid in the center was a 50% mixed aqueous solution of methanol-ε-caprolactone (1:1). , introduced into a 20% aqueous solution of N-methylpyrrolidone, washed with water, coated with glycerin, and dried. The obtained hollow fiber has an inner diameter
The film thickness was 230μ and the film thickness was 45μ. A separator was created by fixing both ends with urethane so that the outer surface area was 1 m 2 . The average pore size by water permeation method is 370Å,
Observation with an electron microscope revealed that the ratio of the pore sizes on the outer surface and the inner surface was 1:3. As in Example 1 and Comparative Example 1, the permeability of albumin, immunoglobulin G, and immunoglobulin M was measured using bovine plasma during the first hour of operation. The results are shown in Table 5.
【表】
＜発明の効果＞
以上説明した様に、本発明によつて非常に効率
よく血漿中のアルブミン等の有用成分を選択的に
回収することの出来る選択透過性中空糸膜を得る
ことができる。
本発明の血漿成分分離器によれば、透過液とし
て得られるアルブミンの回収率が高いこと加え
て、血漿中の不要な大分子の代表物質なるイムノ
グロブリンＭをアルブミン等の有用成分から非常
に効率よく除去できるという効果が得られる。
さらに血漿中の不要成分で除去が困難とされる
イムノグロブリンＧの分離除去効率も相対的によ
くなるという驚くべき効果も得られる。
また本発明の血漿成分分離器の効果としては、
血漿成分透過時の目詰りが非常に少なく長時間安
定した選択透過性が維持されることも挙げられ
る。
さらに本発明の血漿成分分離装置によれば、上
記の効果を実用的により安定に発現させることが
できる。[Table] <Effects of the Invention> As explained above, the present invention makes it possible to obtain a permselective hollow fiber membrane that can selectively recover useful components such as albumin in plasma with high efficiency. can. According to the plasma component separator of the present invention, in addition to a high recovery rate of albumin obtained as a permeate, immunoglobulin M, which is a representative substance of unnecessary large molecules in plasma, is very efficiently separated from useful components such as albumin. The effect is that it can be removed well. Furthermore, the surprising effect of relatively improving the efficiency of separating and removing immunoglobulin G, which is an unnecessary component in plasma and is difficult to remove, can also be obtained. Furthermore, the effects of the plasma component separator of the present invention include:
Another advantage is that there is very little clogging during permeation of plasma components, and stable selective permselectivity is maintained for a long period of time. Furthermore, according to the plasma component separation device of the present invention, the above-mentioned effects can be achieved more stably in practical terms.
第１図〜第３図は、本発明の血漿成分分離装置
を例示したものである。又第４図は本発明の血漿
成分分離器を用いた血液分離装置を例示したもの
である。
これらの図において１は血漿導入部、２，５，
１１及び２１はポンプ、３及び８は加温器、４は
血漿成分分離器、６は排出部、７は透過血漿導出
部、１０は補充液、１２は血漿導出部、２０は血
液導入部、２２は血液分離器、２３は血液導出部
である。
1 to 3 illustrate the plasma component separation device of the present invention. Moreover, FIG. 4 illustrates a blood separation apparatus using the plasma component separator of the present invention. In these figures, 1 is the plasma introduction part, 2, 5,
11 and 21 are pumps, 3 and 8 are warmers, 4 is a plasma component separator, 6 is a discharge section, 7 is a permeated plasma discharge section, 10 is a replenisher, 12 is a plasma discharge section, 20 is a blood introduction section, 22 is a blood separator, and 23 is a blood outlet.
Claims (1)
平均細孔径D1が内側表面の平均細孔径D2よりも
小さい異方性を有し、且つ該膜の水透過法による
平均細孔径Ｄが200〜700Åであることを特徴とる
選択透過性中空糸膜。 ２ 該異方性が、その外側表面における平均細孔
径D1と内側表面における平均細孔径D2の比D2／
D1が1.2以上で表わされる特許請求の範囲第１項
記載の選択透過性中空糸膜。 ３ 該選択透過性が、該中空糸膜の外側から内側
方向に血漿成分を透過せしめた際のアルブミン透
過率QAが70％以上で、且つ該QAとイムノグロブ
リンＭの透過率QMの比QA／QMが３以上で表わさ
れる特許請求の範囲第１項記載の選択透過性中空
糸膜。 ４ 該透過性が、限外濾過係数100〜2000ml／
m2・mmHg・hrで示される特許請求の範囲第１項
記載の選択透過性中空糸膜。 ５ 該中空糸膜の内径が100〜500μであり、膜厚
が30〜200μである特許請求の範囲第１項に記載
の選択透過性中空糸膜。 ６ 中空糸型分離器において、微多孔性中空糸膜
であつて、その外側表面の平均細孔径D1が内側
表面の平均細孔径D2よりも小さい異方性を有し、
且つ該膜の水透過法による平均細孔径Ｄが200〜
700Åである選択透過性中空糸膜を構成部材とし、
該中空糸膜の外側を血漿流通部，該中空糸膜の内
側を透過液流通部としたことを特徴とする血漿成
分分離器。 ７ 血漿成分の選択的透過分離を行なう装置にお
いて、(a)微多孔性中空糸膜であつて、その外側表
面の平均細孔径D1が内側表面の平均細孔径D2よ
り小さい異方性を有し、且つ該膜の水透過法によ
る平均細孔径Ｄが200〜700Åである選択透過性中
空糸膜を構成部材とし、該中空糸膜の外側を血漿
流通部，該中空糸膜の内側を透過液流通部とした
血漿成分分離器と、(b)その分離する血漿を加温す
る手段とを有したことを特徴とする血漿成分分離
装置。[Scope of Claims] 1. A microporous hollow fiber membrane having anisotropy in which the average pore diameter D 1 of the outer surface is smaller than the average pore diameter D 2 of the inner surface, and A permselective hollow fiber membrane characterized by an average pore diameter D of 200 to 700 Å measured by a permeation method. 2 The anisotropy is determined by the ratio D 2 / of the average pore diameter D 1 on the outer surface to the average pore diameter D 2 on the inner surface.
The permselective hollow fiber membrane according to claim 1, wherein D 1 is 1.2 or more. 3. The permselectivity is such that the albumin permeability Q A when plasma components are permeated from the outside to the inside of the hollow fiber membrane is 70% or more, and the permeability Q A and the permeability Q M of immunoglobulin M are The permselective hollow fiber membrane according to claim 1, wherein the ratio Q A /Q M is 3 or more. 4 The permeability is an ultrafiltration coefficient of 100 to 2000ml/
The permselective hollow fiber membrane according to claim 1, which is represented by m 2 · mmHg · hr. 5. The permselective hollow fiber membrane according to claim 1, wherein the hollow fiber membrane has an inner diameter of 100 to 500μ and a membrane thickness of 30 to 200μ. 6. In a hollow fiber separator, a microporous hollow fiber membrane has anisotropy in which the average pore diameter D 1 of the outer surface is smaller than the average pore diameter D 2 of the inner surface,
And the average pore diameter D of the membrane measured by water permeation method is 200~
A permselective hollow fiber membrane of 700 Å is used as a component,
A plasma component separator characterized in that the outside of the hollow fiber membrane is a plasma flow section, and the inside of the hollow fiber membrane is a permeate flow section. 7 In an apparatus for selective permeation separation of plasma components, (a) a microporous hollow fiber membrane having anisotropy in which the average pore diameter D 1 of the outer surface is smaller than the average pore diameter D 2 of the inner surface; The component is a selectively permeable hollow fiber membrane having an average pore diameter D of 200 to 700 Å measured by a water permeation method, the outside of the hollow fiber membrane being a plasma distribution part, and the inside of the hollow fiber membrane being a plasma distribution part. 1. A plasma component separator comprising: a plasma component separator serving as a permeate flow section; and (b) means for heating the plasma to be separated.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP58116174A JPS607853A (en) | 1983-06-29 | 1983-06-29 | Permselective hollow yarn membrane, serum component separation method using same, serum separator, serum component separating apparatus and blood treating apparatus |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP58116174A JPS607853A (en) | 1983-06-29 | 1983-06-29 | Permselective hollow yarn membrane, serum component separation method using same, serum separator, serum component separating apparatus and blood treating apparatus |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS607853A JPS607853A (en) | 1985-01-16 |
| JPH0211263B2 true JPH0211263B2 (en) | 1990-03-13 |
Family
ID=14680624
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP58116174A Granted JPS607853A (en) | 1983-06-29 | 1983-06-29 | Permselective hollow yarn membrane, serum component separation method using same, serum separator, serum component separating apparatus and blood treating apparatus |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS607853A (en) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0227832B1 (en) * | 1985-06-27 | 1990-09-19 | Mitsubishi Rayon Co., Ltd. | Composite hollow yarn and a process for producing the same |
| JPS6260562A (en) * | 1985-09-10 | 1987-03-17 | 株式会社 ニツシヨ− | Method for detecting breakage of hollow yarn separator for plasma sampler |
| JP2612851B2 (en) * | 1986-08-21 | 1997-05-21 | 東洋紡績株式会社 | Sampler |
| JP2813452B2 (en) * | 1990-10-29 | 1998-10-22 | 株式会社クラレ | Method for producing hydrophilic membrane |
| US6802820B1 (en) * | 2000-04-13 | 2004-10-12 | Transvivo, Inc. | Specialized hollow fiber membranes for in-vivo plasmapheresis and ultrafiltration |
| JP5397722B2 (en) * | 2007-04-14 | 2014-01-22 | 真鍋 征一 | A method for removing and concentrating a membrane separator of fine particles having a size of 15 nm or less. |
-
1983
- 1983-06-29 JP JP58116174A patent/JPS607853A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| JPS607853A (en) | 1985-01-16 |
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