JP7241034B2 - 人工肺の製造方法 - Google Patents
人工肺の製造方法 Download PDFInfo
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- JP7241034B2 JP7241034B2 JP2019564739A JP2019564739A JP7241034B2 JP 7241034 B2 JP7241034 B2 JP 7241034B2 JP 2019564739 A JP2019564739 A JP 2019564739A JP 2019564739 A JP2019564739 A JP 2019564739A JP 7241034 B2 JP7241034 B2 JP 7241034B2
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- Prior art keywords
- hollow fiber
- blood
- fiber membrane
- polymer compound
- oxygenator
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- USHAGKDGDHPEEY-UHFFFAOYSA-L potassium persulfate Chemical compound [K+].[K+].[O-]S(=O)(=O)OOS([O-])(=O)=O USHAGKDGDHPEEY-UHFFFAOYSA-L 0.000 description 1
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- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
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- CHQMHPLRPQMAMX-UHFFFAOYSA-L sodium persulfate Substances [Na+].[Na+].[O-]S(=O)(=O)OOS([O-])(=O)=O CHQMHPLRPQMAMX-UHFFFAOYSA-L 0.000 description 1
- 229940001482 sodium sulfite Drugs 0.000 description 1
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- 125000001424 substituent group Chemical group 0.000 description 1
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- OPQYOFWUFGEMRZ-UHFFFAOYSA-N tert-butyl 2,2-dimethylpropaneperoxoate Chemical compound CC(C)(C)OOC(=O)C(C)(C)C OPQYOFWUFGEMRZ-UHFFFAOYSA-N 0.000 description 1
- VNJISVYSDHJQFR-UHFFFAOYSA-N tert-butyl 4,4-dimethylpentaneperoxoate Chemical compound CC(C)(C)CCC(=O)OOC(C)(C)C VNJISVYSDHJQFR-UHFFFAOYSA-N 0.000 description 1
- NMOALOSNPWTWRH-UHFFFAOYSA-N tert-butyl 7,7-dimethyloctaneperoxoate Chemical compound CC(C)(C)CCCCCC(=O)OOC(C)(C)C NMOALOSNPWTWRH-UHFFFAOYSA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
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- 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
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- 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
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- 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
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Description
本発明に係る人工肺の詳細を、図面を参照しながら以下で説明する。
本発明に係る人工肺の製造方法は、外表面と、内腔を形成する内表面と、前記外表面と前記内表面とを連通する開口部と、を有する複数のガス交換用多孔質中空糸膜からなる中空糸膜束がハウジング内に収容され、前記ハウジング内における前記中空糸膜束の外側を血液流路として、当該血液流路の上流側および下流側にそれぞれ血液流入口および血液流出口を有する、人工肺の製造方法であって、前記血液流路に抗血栓性高分子化合物を含むコロイド溶液を充填し、前記血液流入口と前記血液流出口との間で前記コロイド溶液を運動させることを特徴とする。
本工程では、中空糸膜の外表面にコーティングするための、コロイド液を調製する。上述のように、本発明に係る方法において用いられるコロイド液は、抗血栓性高分子化合物を含む。
本発明において用いられる抗血栓性高分子化合物は、中空糸膜に塗布されることにより、人工肺に抗血栓性を付与する化合物である。また、「抗血栓性」とは、血液と接触する表面において血液の凝固を低減する性質をいう。
で示されるアルコキシアルキル(メタ)アクリレート由来の構成単位を有すると好ましい。上記の式(I)で示される構成単位を有する化合物は、抗血栓性生体適合性(血小板の粘着/付着の抑制・防止効果、および血小板の活性化の抑制・防止効果)、特に血小板の粘着/付着の抑制・防止効果に優れる。ゆえに、上記構成単位を有する化合物を用いることにより、抗血栓性生体適合性(血小板の粘着/付着の抑制・防止効果、および血小板の活性化の抑制・防止効果)、特に血小板の粘着/付着の抑制・防止効果に優れた人工肺を製造することが可能となる。
抗血栓性高分子化合物を含む溶液(コロイド液)の調製に使用される溶媒は、抗血栓性高分子化合物を適度に分散させてコロイド液を調製することができるものであれば特に制限されない。中空糸膜の細孔の外表面または内表面(酸素含有ガスが流れる側の表面)までのコロイド液の浸透をより有効に防止する観点から、溶媒が水を含むことが好ましい。ここで、水は、純水、イオン交換水または蒸留水であると好ましく、なかでも、逆浸透膜により精製した純水(RO水)であると好ましい。
次に、上記の通り調製したコロイド液を、中空糸膜の外表面にコーティングする。具体的には、人工肺(例えば、前述の図1または図3のような構造のもの)を組み立てた後、上記工程(1)において調製したコロイド液を血液流路に充填し、前記コロイド液を血液流入口と血液流出口との間で運動させることにより、中空糸膜の外表面を抗血栓性高分子化合物でコーティングする。
製造例1:重量平均分子量35万のPMEAの合成
2-メトキシエチルアクリレート(MEA)35g(0.27mol)をメタノール160gに溶解し、四ツ口フラスコに入れ、50℃でN2バブリングを1時間行い、モノマー溶液を調製した。別途、2,2’-アゾビス(4-メトキシ-2,4-ジメチルバレロニトリル)(V-70、和光純薬工業(株)製)0.035gをメタノール5gに溶解して、重合開始剤溶液を調製した。次に、この重合開始剤溶液をモノマー溶液に添加し、50℃で5時間重合反応を行った。所定時間重合後、重合溶液をエタノールに滴下し、析出した重合体(PMEA)を回収した。なお、回収した重合体の重量平均分子量を測定したところ、350,000であった。
実施例1-1:PMEA濃度0.04質量%のコロイド液
上記製造例1で合成したPMEA(重量平均分子量=35万)0.48gを、48gのメタノールに溶解した。別の容器にRO水1140gを添加し、上記PMEAのメタノール溶液を2400g/分の添加速度で添加した。その後、25℃で3分間撹拌し、白濁したコロイド液を得た。コロイド液は、PMEAのコロイドが分散されたコロイド液であった。
内径が195μm、外径が295μm、肉厚が50μm、空孔率が約35体積%、外表面の孔径(すなわち、開口部の平均直径)が80nmの多孔質ポリプロピレン製のガス交換用多孔質中空糸膜が巻きつけられた、膜面積(中空糸膜の外表面の面積)が0.5m2である血液外部灌流型中空糸膜人工肺を作製した。
上記人工肺の血液流入口、血液流出口にそれぞれチューブ(内径9.5mm×外径14.2mm)を接続し、血液流入口に接続したチューブをアルミニウム製の2枚板ではさんだ。人工肺、チューブに上記で調製したコロイド液96gを入れ、血液流入口に接続したチューブの端をクランプした。人工肺のガス流入口からガス流出口に炭酸ガスをガスポートから4L/分・m2の流量で流しながら、アルミニウム製の板の片方(長さ91mm)をモーターで1秒間に2往復で前後運動して、コロイド液を1分間往復させた。二つのアルミニウムの板が最も近くなった時の距離は4.5mmだった。この際、中空糸膜の膜面積(m2)に対して、運動させたコロイド液の量は3L/分・m2であった。人工肺からチューブを外して液を排出して回収した後、空気を80L/分で吹送し、さらに液を回収した。そのまま空気を流し続け乾燥した。
コロイド液および水は、同程度に炭酸ガスを溶解すると考えられるため、コロイド液中の炭酸ガス濃度を測定する代わりに、同じ条件下での水中の炭酸ガス濃度を測定した。
上記人工肺のハウジングを超音波カッターで切断、分解し、中空糸膜をカッターで切りだした。中空子糸膜全量をキャップ付きガラス瓶に入れ、アセトンを加え、超音波洗浄機で1時間抽出した。アセトン抽出液を別のキャップ付きガラス瓶に46g回収し、ヒートブロックでアセトンを蒸発させた後、蒸発乾固物にテトラヒドロフラン10mLを添加し溶解させた。振盪機で1時間振盪した後、超音波洗浄機で1時間溶解した。0.45μmフィルターでろ過した後、ゲル浸透クロマトグラフィー(GPC)で定量した。具体的には、1mg/mLのPMEAを含有するTHF溶液(標準液)についてGPCを用いて分析し、PMEAに相当するピークの面積を算出した。続いて蒸発乾固物THF溶解液(試験液)についてGPCを用いて分析し、同様にPMEAに相当するピークの面積を算出した。その後、下記の式(3)を用いて試験液中のPMEA量を、式(5)を用いて人工肺膜1m2(中空糸膜の外表面の面積1m2)あたりのPMEAコート量をそれぞれ算出した。
コーティング後にコロイド液の一部32mLを排出し、排出したコロイド液をヒートブロック、真空乾燥により乾燥した後、テトラヒドロフラン1.5mLに溶解した。振盪機で1時間振盪した後、超音波洗浄機で1時間溶解した。0.45μmフィルターでろ過した後、ゲル浸透クロマトグラフィー(GPC)で定量した。具体的には、上記式(3)と同じ方法で、排出したコロイド液中のPMEA量を算出した。その後、下記の式(6)を用いて、コーティング後の全コロイド液中のPMEA量を算出し、さらに、次式(7)によりコロイド利用効率を計算した。
上記人工肺の血液流入部、血液流出部にチューブ(内径9.5×外径14.2mm)を接続し、血液流入部に接続したチューブをアルミニウム製の2枚板ではさんだ。人工肺、チューブに上記コロイド液を入れ、血液流入部に接続したチューブの端をクランプした。二酸化炭素は使用せず、アルミニウム製の板の片方(長さ91mm)をモーターで1秒間に2往復で前後運動して、コーティング液を1分間往復させた。二つのアルミニウムの板が最も近くなった時の距離は4.5mmだった。人工肺からチューブを外して液を排出して回収した後、空気を80L/分で吹送し、さらに液を回収した。そのまま空気を流し続け乾燥した。
上記人工肺の血液流入部、血液流出部にチューブ(内径9.5×外径14.2mm)を接続し、人工肺、チューブに上記コロイド液を入れ、コーティング液を1分間保持した。人工肺からチューブを外して液を排出して回収した後、空気を80L/分で吹送し、さらに液を回収した。そのまま空気を流し続け乾燥した。
本出願は、2018年1月10日に出願された日本特許出願番号2018-001806号に基づいており、その開示内容は、参照され、全体として、組み入れられている。
2…ハウジング、
3…中空糸膜、
3a…外面層、
3a’…外表面、
3b…内部層、
3c…内面層、
3c’…内表面、
3d…通路、
3e…開口部、
4,5…隔壁、
6…血液流入口、
7…血液流出口、
8…ガス流入口、
9…ガス流出口、
10…ガス流入側ヘッダー、
11…ガス流出側ヘッダー、
12…血液室、
13…ガス流入室、
14…ガス流出室、
17…血液室、
17a…血液流入口、
17b…第1の血液室、
17c…第2の血液室、
18…抗血栓性高分子化合物、
20…中空糸膜外部血液灌流型人工肺、
22…筒状中空糸膜束、
23…ハウジング、
24…ガス流入口、
25,26…隔壁、
27…ガス流出口、
28…血液流入口、
29a,29b…血液流出口、
31…内側筒状部材、
32…血液流通用開口、
33…外側筒状部件、
35…内筒体、
41…ガス流入用部件、
42…ガス流出用部件。
Claims (6)
- 外表面と、内腔を形成する内表面と、前記外表面と前記内表面とを連通する開口部と、を有する複数のガス交換用多孔質中空糸膜からなる中空糸膜束がハウジング内に収容され、前記ハウジング内における前記中空糸膜束の外側を血液流路として、当該血液流路の上流側および下流側にそれぞれ血液流入口および血液流出口を有する、人工肺の製造方法であって、
前記血液流路に抗血栓性高分子化合物を含むコロイド溶液を充填し、前記血液流入口と前記血液流出口との間で前記コロイド溶液を運動させることを有し、
前記血液流入口と前記血液流出口との間で前記コロイド溶液を運動させながら、前記中空糸膜の内腔をガス流路として、当該ガス流路に炭酸ガスを流通させる、人工肺の製造方法。 - 前記血液流入口と前記血液流出口との間で前記コロイド溶液を往復運動させる、請求項1に記載の人工肺の製造方法。
- 前記炭酸ガスの流通速度は、中空糸膜の膜面積(m2)に対して、0.5L/分・m2以上20L/分・m2以下である、請求項1または2に記載の人工肺の製造方法。
- 前記コロイド溶液は、抗血栓性高分子化合物を0.01質量%以上含む、請求項1~3のいずれか1項に記載の人工肺の製造方法。
- 前記抗血栓性高分子化合物の重量平均分子量は、200,000を超えて800,000未満である、請求項1~5のいずれか1項に記載の人工肺の製造方法。
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