JPH0470047B2 - - Google Patents
Info
- Publication number
- JPH0470047B2 JPH0470047B2 JP63136653A JP13665388A JPH0470047B2 JP H0470047 B2 JPH0470047 B2 JP H0470047B2 JP 63136653 A JP63136653 A JP 63136653A JP 13665388 A JP13665388 A JP 13665388A JP H0470047 B2 JPH0470047 B2 JP H0470047B2
- Authority
- JP
- Japan
- Prior art keywords
- membrane
- dialyzer
- regenerated cellulose
- cellulose membrane
- acid
- 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
- 239000012528 membrane Substances 0.000 claims description 133
- 239000004627 regenerated cellulose Substances 0.000 claims description 69
- 210000004369 blood Anatomy 0.000 claims description 46
- 239000008280 blood Substances 0.000 claims description 46
- 238000005886 esterification reaction Methods 0.000 claims description 46
- 230000001954 sterilising effect Effects 0.000 claims description 36
- 230000032050 esterification Effects 0.000 claims description 32
- 238000011049 filling Methods 0.000 claims description 26
- 239000007788 liquid Substances 0.000 claims description 25
- 239000003054 catalyst Substances 0.000 claims description 16
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 15
- 150000001735 carboxylic acids Chemical class 0.000 claims description 12
- 239000012429 reaction media Substances 0.000 claims description 11
- 125000002252 acyl group Chemical group 0.000 claims description 8
- 238000004519 manufacturing process Methods 0.000 claims description 8
- 125000004432 carbon atom Chemical group C* 0.000 claims description 6
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 3
- 239000002202 Polyethylene glycol Substances 0.000 claims description 3
- 150000007933 aliphatic carboxylic acids Chemical class 0.000 claims description 3
- 229920001223 polyethylene glycol Polymers 0.000 claims description 3
- 229920006395 saturated elastomer Polymers 0.000 claims description 3
- 229930195734 saturated hydrocarbon Natural products 0.000 claims description 3
- 229930195735 unsaturated hydrocarbon Natural products 0.000 claims description 3
- 238000004659 sterilization and disinfection Methods 0.000 description 34
- 239000012510 hollow fiber Substances 0.000 description 33
- 238000000502 dialysis Methods 0.000 description 29
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 24
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 18
- -1 erucic acid Chemical compound 0.000 description 17
- 230000000295 complement effect Effects 0.000 description 16
- 238000000034 method Methods 0.000 description 16
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 14
- 238000006243 chemical reaction Methods 0.000 description 14
- 239000000243 solution Substances 0.000 description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 14
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 230000008859 change Effects 0.000 description 12
- 102000009027 Albumins Human genes 0.000 description 11
- 108010088751 Albumins Proteins 0.000 description 11
- 230000000694 effects Effects 0.000 description 9
- 238000001179 sorption measurement Methods 0.000 description 9
- 229940022682 acetone Drugs 0.000 description 8
- 210000000265 leukocyte Anatomy 0.000 description 7
- 102000004169 proteins and genes Human genes 0.000 description 7
- 108090000623 proteins and genes Proteins 0.000 description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 6
- 230000004913 activation Effects 0.000 description 6
- 238000004140 cleaning Methods 0.000 description 6
- 239000012046 mixed solvent Substances 0.000 description 6
- 229920005597 polymer membrane Polymers 0.000 description 6
- 239000004698 Polyethylene Substances 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 5
- 230000007423 decrease Effects 0.000 description 5
- 230000003292 diminished effect Effects 0.000 description 5
- 230000005251 gamma ray Effects 0.000 description 5
- 229920000573 polyethylene Polymers 0.000 description 5
- 238000005406 washing Methods 0.000 description 5
- RGUKYNXWOWSRET-UHFFFAOYSA-N 4-pyrrolidin-1-ylpyridine Chemical compound C1CCCN1C1=CC=NC=C1 RGUKYNXWOWSRET-UHFFFAOYSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 4
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 150000008065 acid anhydrides Chemical class 0.000 description 4
- 230000023555 blood coagulation Effects 0.000 description 4
- 150000001244 carboxylic acid anhydrides Chemical class 0.000 description 4
- POULHZVOKOAJMA-UHFFFAOYSA-N dodecanoic acid Chemical compound CCCCCCCCCCCC(O)=O POULHZVOKOAJMA-UHFFFAOYSA-N 0.000 description 4
- 238000004388 gamma ray sterilization Methods 0.000 description 4
- 230000002209 hydrophobic effect Effects 0.000 description 4
- 229940027941 immunoglobulin g Drugs 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- 102000004506 Blood Proteins Human genes 0.000 description 3
- 108010017384 Blood Proteins Proteins 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000003963 antioxidant agent Substances 0.000 description 3
- 235000006708 antioxidants Nutrition 0.000 description 3
- 150000001718 carbodiimides Chemical class 0.000 description 3
- 229920002678 cellulose Polymers 0.000 description 3
- 230000004087 circulation Effects 0.000 description 3
- ZURAKLKIKYCUJU-UHFFFAOYSA-N copper;azane Chemical compound N.[Cu+2] ZURAKLKIKYCUJU-UHFFFAOYSA-N 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N ethylene glycol Natural products OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- 229940012952 fibrinogen Drugs 0.000 description 3
- 239000012530 fluid Substances 0.000 description 3
- 229930195733 hydrocarbon Natural products 0.000 description 3
- 150000002430 hydrocarbons Chemical class 0.000 description 3
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 3
- WQEPLUUGTLDZJY-UHFFFAOYSA-N pentadecanoic acid Chemical compound CCCCCCCCCCCCCCC(O)=O WQEPLUUGTLDZJY-UHFFFAOYSA-N 0.000 description 3
- 230000035699 permeability Effects 0.000 description 3
- 239000002504 physiological saline solution Substances 0.000 description 3
- ZTGSNOLGYUVZDM-UHFFFAOYSA-N propan-2-one;1,1,2-trichloro-1,2,2-trifluoroethane Chemical compound CC(C)=O.FC(F)(Cl)C(F)(Cl)Cl ZTGSNOLGYUVZDM-UHFFFAOYSA-N 0.000 description 3
- 239000000376 reactant Substances 0.000 description 3
- 230000009257 reactivity Effects 0.000 description 3
- 230000001052 transient effect Effects 0.000 description 3
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 3
- 238000009736 wetting Methods 0.000 description 3
- AJDIZQLSFPQPEY-UHFFFAOYSA-N 1,1,2-Trichlorotrifluoroethane Chemical compound FC(F)(Cl)C(F)(Cl)Cl AJDIZQLSFPQPEY-UHFFFAOYSA-N 0.000 description 2
- KZEVSDGEBAJOTK-UHFFFAOYSA-N 1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)-2-[5-[2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidin-5-yl]-1,3,4-oxadiazol-2-yl]ethanone Chemical compound N1N=NC=2CN(CCC=21)C(CC=1OC(=NN=1)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)=O KZEVSDGEBAJOTK-UHFFFAOYSA-N 0.000 description 2
- HMUNWXXNJPVALC-UHFFFAOYSA-N 1-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperazin-1-yl]-2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)N1CCN(CC1)C(CN1CC2=C(CC1)NN=N2)=O HMUNWXXNJPVALC-UHFFFAOYSA-N 0.000 description 2
- LDXJRKWFNNFDSA-UHFFFAOYSA-N 2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)-1-[4-[2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidin-5-yl]piperazin-1-yl]ethanone Chemical compound C1CN(CC2=NNN=C21)CC(=O)N3CCN(CC3)C4=CN=C(N=C4)NCC5=CC(=CC=C5)OC(F)(F)F LDXJRKWFNNFDSA-UHFFFAOYSA-N 0.000 description 2
- WZFUQSJFWNHZHM-UHFFFAOYSA-N 2-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperazin-1-yl]-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)N1CCN(CC1)CC(=O)N1CC2=C(CC1)NN=N2 WZFUQSJFWNHZHM-UHFFFAOYSA-N 0.000 description 2
- YJLUBHOZZTYQIP-UHFFFAOYSA-N 2-[5-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]-1,3,4-oxadiazol-2-yl]-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C1=NN=C(O1)CC(=O)N1CC2=C(CC1)NN=N2 YJLUBHOZZTYQIP-UHFFFAOYSA-N 0.000 description 2
- CONKBQPVFMXDOV-QHCPKHFHSA-N 6-[(5S)-5-[[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperazin-1-yl]methyl]-2-oxo-1,3-oxazolidin-3-yl]-3H-1,3-benzoxazol-2-one Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)N1CCN(CC1)C[C@H]1CN(C(O1)=O)C1=CC2=C(NC(O2)=O)C=C1 CONKBQPVFMXDOV-QHCPKHFHSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 description 2
- 102000008946 Fibrinogen Human genes 0.000 description 2
- 108010049003 Fibrinogen Proteins 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- 239000005639 Lauric acid Substances 0.000 description 2
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 2
- 241000283973 Oryctolagus cuniculus Species 0.000 description 2
- 208000007536 Thrombosis Diseases 0.000 description 2
- WNLRTRBMVRJNCN-UHFFFAOYSA-N adipic acid Chemical compound OC(=O)CCCCC(O)=O WNLRTRBMVRJNCN-UHFFFAOYSA-N 0.000 description 2
- YZXBAPSDXZZRGB-DOFZRALJSA-N arachidonic acid Chemical compound CCCCC\C=C/C\C=C/C\C=C/C\C=C/CCCC(O)=O YZXBAPSDXZZRGB-DOFZRALJSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 230000017531 blood circulation Effects 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 239000004202 carbamide Substances 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 239000011248 coating agent Substances 0.000 description 2
- 238000000576 coating method Methods 0.000 description 2
- GHVNFZFCNZKVNT-UHFFFAOYSA-N decanoic acid Chemical compound CCCCCCCCCC(O)=O GHVNFZFCNZKVNT-UHFFFAOYSA-N 0.000 description 2
- UKMSUNONTOPOIO-UHFFFAOYSA-N docosanoic acid Chemical compound CCCCCCCCCCCCCCCCCCCCCC(O)=O UKMSUNONTOPOIO-UHFFFAOYSA-N 0.000 description 2
- ZQPPMHVWECSIRJ-MDZDMXLPSA-N elaidic acid Chemical compound CCCCCCCC\C=C\CCCCCCCC(O)=O ZQPPMHVWECSIRJ-MDZDMXLPSA-N 0.000 description 2
- 235000019441 ethanol Nutrition 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- KEMQGTRYUADPNZ-UHFFFAOYSA-N heptadecanoic acid Chemical compound CCCCCCCCCCCCCCCCC(O)=O KEMQGTRYUADPNZ-UHFFFAOYSA-N 0.000 description 2
- MNWFXJYAOYHMED-UHFFFAOYSA-N heptanoic acid Chemical compound CCCCCCC(O)=O MNWFXJYAOYHMED-UHFFFAOYSA-N 0.000 description 2
- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 2
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 2
- VKOBVWXKNCXXDE-UHFFFAOYSA-N icosanoic acid Chemical compound CCCCCCCCCCCCCCCCCCCC(O)=O VKOBVWXKNCXXDE-UHFFFAOYSA-N 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- KQNPFQTWMSNSAP-UHFFFAOYSA-N isobutyric acid Chemical compound CC(C)C(O)=O KQNPFQTWMSNSAP-UHFFFAOYSA-N 0.000 description 2
- 239000012948 isocyanate Substances 0.000 description 2
- 150000002513 isocyanates Chemical class 0.000 description 2
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- ISYWECDDZWTKFF-UHFFFAOYSA-N nonadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCCC(O)=O ISYWECDDZWTKFF-UHFFFAOYSA-N 0.000 description 2
- BDJRBEYXGGNYIS-UHFFFAOYSA-N nonanedioic acid Chemical compound OC(=O)CCCCCCCC(O)=O BDJRBEYXGGNYIS-UHFFFAOYSA-N 0.000 description 2
- FBUKVWPVBMHYJY-UHFFFAOYSA-N nonanoic acid Chemical compound CCCCCCCCC(O)=O FBUKVWPVBMHYJY-UHFFFAOYSA-N 0.000 description 2
- WWZKQHOCKIZLMA-UHFFFAOYSA-N octanoic acid Chemical compound CCCCCCCC(O)=O WWZKQHOCKIZLMA-UHFFFAOYSA-N 0.000 description 2
- 102000013415 peroxidase activity proteins Human genes 0.000 description 2
- 108040007629 peroxidase activity proteins Proteins 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- NMHMNPHRMNGLLB-UHFFFAOYSA-N phloretic acid Chemical compound OC(=O)CCC1=CC=C(O)C=C1 NMHMNPHRMNGLLB-UHFFFAOYSA-N 0.000 description 2
- 230000000704 physical effect Effects 0.000 description 2
- WLJVNTCWHIRURA-UHFFFAOYSA-N pimelic acid Chemical compound OC(=O)CCCCCC(O)=O WLJVNTCWHIRURA-UHFFFAOYSA-N 0.000 description 2
- 229920000642 polymer Polymers 0.000 description 2
- 229920005749 polyurethane resin Polymers 0.000 description 2
- 238000004382 potting Methods 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 230000005855 radiation Effects 0.000 description 2
- CXMXRPHRNRROMY-UHFFFAOYSA-N sebacic acid Chemical compound OC(=O)CCCCCCCCC(O)=O CXMXRPHRNRROMY-UHFFFAOYSA-N 0.000 description 2
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 2
- 235000010262 sodium metabisulphite Nutrition 0.000 description 2
- TYFQFVWCELRYAO-UHFFFAOYSA-N suberic acid Chemical compound OC(=O)CCCCCCC(O)=O TYFQFVWCELRYAO-UHFFFAOYSA-N 0.000 description 2
- 230000001629 suppression Effects 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- SZHOJFHSIKHZHA-UHFFFAOYSA-N tridecanoic acid Chemical compound CCCCCCCCCCCCC(O)=O SZHOJFHSIKHZHA-UHFFFAOYSA-N 0.000 description 2
- ZDPHROOEEOARMN-UHFFFAOYSA-N undecanoic acid Chemical compound CCCCCCCCCCC(O)=O ZDPHROOEEOARMN-UHFFFAOYSA-N 0.000 description 2
- 238000001291 vacuum drying Methods 0.000 description 2
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 2
- OYHQOLUKZRVURQ-NTGFUMLPSA-N (9Z,12Z)-9,10,12,13-tetratritiooctadeca-9,12-dienoic acid Chemical compound C(CCCCCCC\C(=C(/C\C(=C(/CCCCC)\[3H])\[3H])\[3H])\[3H])(=O)O OYHQOLUKZRVURQ-NTGFUMLPSA-N 0.000 description 1
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 1
- AVQQQNCBBIEMEU-UHFFFAOYSA-N 1,1,3,3-tetramethylurea Chemical compound CN(C)C(=O)N(C)C AVQQQNCBBIEMEU-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- OHVLMTFVQDZYHP-UHFFFAOYSA-N 1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)-2-[4-[2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidin-5-yl]piperazin-1-yl]ethanone Chemical compound N1N=NC=2CN(CCC=21)C(CN1CCN(CC1)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)=O OHVLMTFVQDZYHP-UHFFFAOYSA-N 0.000 description 1
- RTBFRGCFXZNCOE-UHFFFAOYSA-N 1-methylsulfonylpiperidin-4-one Chemical compound CS(=O)(=O)N1CCC(=O)CC1 RTBFRGCFXZNCOE-UHFFFAOYSA-N 0.000 description 1
- XYHKNCXZYYTLRG-UHFFFAOYSA-N 1h-imidazole-2-carbaldehyde Chemical compound O=CC1=NC=CN1 XYHKNCXZYYTLRG-UHFFFAOYSA-N 0.000 description 1
- JVIPLYCGEZUBIO-UHFFFAOYSA-N 2-(4-fluorophenyl)-1,3-dioxoisoindole-5-carboxylic acid Chemical compound O=C1C2=CC(C(=O)O)=CC=C2C(=O)N1C1=CC=C(F)C=C1 JVIPLYCGEZUBIO-UHFFFAOYSA-N 0.000 description 1
- JQMFQLVAJGZSQS-UHFFFAOYSA-N 2-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperazin-1-yl]-N-(2-oxo-3H-1,3-benzoxazol-6-yl)acetamide Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)N1CCN(CC1)CC(=O)NC1=CC2=C(NC(O2)=O)C=C1 JQMFQLVAJGZSQS-UHFFFAOYSA-N 0.000 description 1
- AZYTZQYCOBXDGY-UHFFFAOYSA-N 2-pyrrolidin-1-ylpyridine Chemical compound C1CCCN1C1=CC=CC=N1 AZYTZQYCOBXDGY-UHFFFAOYSA-N 0.000 description 1
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 1
- GWYFCOCPABKNJV-UHFFFAOYSA-M 3-Methylbutanoic acid Natural products CC(C)CC([O-])=O GWYFCOCPABKNJV-UHFFFAOYSA-M 0.000 description 1
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 1
- 235000021357 Behenic acid Nutrition 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- 102000015081 Blood Coagulation Factors Human genes 0.000 description 1
- 108010039209 Blood Coagulation Factors Proteins 0.000 description 1
- DPUOLQHDNGRHBS-UHFFFAOYSA-N Brassidinsaeure Natural products CCCCCCCCC=CCCCCCCCCCCCC(O)=O DPUOLQHDNGRHBS-UHFFFAOYSA-N 0.000 description 1
- 239000005632 Capric acid (CAS 334-48-5) Substances 0.000 description 1
- 239000005635 Caprylic acid (CAS 124-07-2) Substances 0.000 description 1
- 241000700199 Cavia porcellus Species 0.000 description 1
- 102000000989 Complement System Proteins Human genes 0.000 description 1
- 108010069112 Complement System Proteins Proteins 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- 229920001425 Diethylaminoethyl cellulose Polymers 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- URXZXNYJPAJJOQ-UHFFFAOYSA-N Erucic acid Natural products CCCCCCC=CCCCCCCCCCCCC(O)=O URXZXNYJPAJJOQ-UHFFFAOYSA-N 0.000 description 1
- 206010018910 Haemolysis Diseases 0.000 description 1
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- 108060003951 Immunoglobulin Proteins 0.000 description 1
- 239000002211 L-ascorbic acid Substances 0.000 description 1
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- 235000021353 Lignoceric acid Nutrition 0.000 description 1
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- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 description 1
- 239000005642 Oleic acid Substances 0.000 description 1
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- 238000000944 Soxhlet extraction Methods 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 1
- 229940045942 acetone sodium bisulfite Drugs 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000001361 adipic acid Substances 0.000 description 1
- 235000011037 adipic acid Nutrition 0.000 description 1
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- 125000000217 alkyl group Chemical group 0.000 description 1
- DTOSIQBPPRVQHS-PDBXOOCHSA-N alpha-linolenic acid Chemical compound CC\C=C/C\C=C/C\C=C/CCCCCCCC(O)=O DTOSIQBPPRVQHS-PDBXOOCHSA-N 0.000 description 1
- 235000020661 alpha-linolenic acid Nutrition 0.000 description 1
- JFCQEDHGNNZCLN-UHFFFAOYSA-N anhydrous glutaric acid Natural products OC(=O)CCCC(O)=O JFCQEDHGNNZCLN-UHFFFAOYSA-N 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 229940127219 anticoagulant drug Drugs 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 235000021342 arachidonic acid Nutrition 0.000 description 1
- 229940114079 arachidonic acid Drugs 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 229940116226 behenic acid Drugs 0.000 description 1
- GWYFCOCPABKNJV-UHFFFAOYSA-N beta-methyl-butyric acid Natural products CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 210000000601 blood cell Anatomy 0.000 description 1
- 239000003114 blood coagulation factor Substances 0.000 description 1
- 238000004820 blood count Methods 0.000 description 1
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- KJDZDTDNIULJBE-QXMHVHEDSA-N cetoleic acid Chemical compound CCCCCCCCCC\C=C/CCCCCCCCCC(O)=O KJDZDTDNIULJBE-QXMHVHEDSA-N 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- FDJOLVPMNUYSCM-WZHZPDAFSA-L cobalt(3+);[(2r,3s,4r,5s)-5-(5,6-dimethylbenzimidazol-1-yl)-4-hydroxy-2-(hydroxymethyl)oxolan-3-yl] [(2r)-1-[3-[(1r,2r,3r,4z,7s,9z,12s,13s,14z,17s,18s,19r)-2,13,18-tris(2-amino-2-oxoethyl)-7,12,17-tris(3-amino-3-oxopropyl)-3,5,8,8,13,15,18,19-octamethyl-2 Chemical compound [Co+3].N#[C-].N([C@@H]([C@]1(C)[N-]\C([C@H]([C@@]1(CC(N)=O)C)CCC(N)=O)=C(\C)/C1=N/C([C@H]([C@@]1(CC(N)=O)C)CCC(N)=O)=C\C1=N\C([C@H](C1(C)C)CCC(N)=O)=C/1C)[C@@H]2CC(N)=O)=C\1[C@]2(C)CCC(=O)NC[C@@H](C)OP([O-])(=O)O[C@H]1[C@@H](O)[C@@H](N2C3=CC(C)=C(C)C=C3N=C2)O[C@@H]1CO FDJOLVPMNUYSCM-WZHZPDAFSA-L 0.000 description 1
- 230000024203 complement activation Effects 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000006866 deterioration Effects 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 238000007598 dipping method Methods 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- DPUOLQHDNGRHBS-KTKRTIGZSA-N erucic acid Chemical compound CCCCCCCC\C=C/CCCCCCCCCCCC(O)=O DPUOLQHDNGRHBS-KTKRTIGZSA-N 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 1
- FARYTWBWLZAXNK-WAYWQWQTSA-N ethyl (z)-3-(methylamino)but-2-enoate Chemical compound CCOC(=O)\C=C(\C)NC FARYTWBWLZAXNK-WAYWQWQTSA-N 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 235000019197 fats Nutrition 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 238000001506 fluorescence spectroscopy Methods 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- 238000001631 haemodialysis Methods 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 230000000322 hemodialysis Effects 0.000 description 1
- 230000008588 hemolysis Effects 0.000 description 1
- 229960002897 heparin Drugs 0.000 description 1
- 229920000669 heparin Polymers 0.000 description 1
- PKHMTIRCAFTBDS-UHFFFAOYSA-N hexanoyl hexanoate Chemical compound CCCCCC(=O)OC(=O)CCCCC PKHMTIRCAFTBDS-UHFFFAOYSA-N 0.000 description 1
- 238000007654 immersion Methods 0.000 description 1
- 238000003018 immunoassay Methods 0.000 description 1
- 102000018358 immunoglobulin Human genes 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
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- 150000002576 ketones Chemical class 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
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- 229960004488 linolenic acid Drugs 0.000 description 1
- KQQKGWQCNNTQJW-UHFFFAOYSA-N linolenic acid Natural products CC=CCCC=CCC=CCCCCCCCC(O)=O KQQKGWQCNNTQJW-UHFFFAOYSA-N 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
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Description
〔産業上の利用分野〕
本発明は、改良された再生セルロース膜系透析
器に関する。さらに詳しくは、血液に対する適合
性が改良されたウエツト型再生セルロース膜系透
析器およびその製造法に関する。
〔従来の技術〕
近年、人工腎臓、人工肺、血漿分離装置等の膜
を用いた人工臓器が、長歩の発展を遂げてきてい
る。周知のように、特に人工透析療法に於いて、
再生セルロース膜、とりわけ銅アンモニウム法再
生セルロース膜を使用した透析器は、広く用いら
れ、透析装置や透析技術の進歩とともに、腎不全
患者の延命、社会復帰に大きな役割を果たしてい
る。これは、再生セルロース膜を使用した透析器
が、優れた透析性能や機械的強度を有するととも
に、長年の実績に裏付けられた高い安全性を有し
ているからに他ならない。
しかしながら、透析療法の進歩にもかかわら
ず、透析に伴う種々の問題がまだ未解決で残され
ている。例えば、抗凝固剤が長期間大量投与さ
れ、そのために生じると考えられる種々の副作用
の問題、また、再生セルロース膜やその他一部の
膜を使用した透析器で血液透析を行つた場合の一
過性の白血球減少や補体成分の活性化の問題等が
指摘されている。後者の現象については、臨床症
状との関連、或いは臨床的意義は明らかではない
が、再生セルロース膜透析器において、他の優れ
た性能を損なわず、これらの現象を軽減すること
が望まれている。
また、透析器には、組み込まれた透析膜が乾燥
した状態で滅菌したドライ型透析器と、充填液で
透析膜を湿潤した状態で滅菌したウエツト型透析
器があるが、使用前の洗浄操作の容易性から後者
の透析器が望まれている。
かかる要望に対して、血液親和性を改良した再
生セルロース膜系透析器が種々提案されている。
例えば、各種ポリマーやビタミンを表面にコーテ
イングした再生セルロース膜系透析器が提案され
ているが、湿潤状態での滅菌では被膜の安定性の
問題点が指摘される。また、特開昭61−8105には
イソシアネートプレポリマーを反応させた再生セ
ルロース膜系透析器が、特開昭60−118203にはブ
リツジ剤を介してポリマー酸を化学的に結合させ
た再生セルロース膜系透析器がそれぞれ提案され
ている。これらの透析器は湿潤状態での滅菌でも
改質された性能は保持されると思われるが、透析
膜製造の際の反応物質安定性及び反応工程の複雑
さなどの問題がある。さらに、特開昭61−113459
にはジエチルアミノエチルセルロース等の改変セ
ルロースを用いて製膜した再生セルロース膜系透
析器が提案されている。この透析器は湿潤状態で
の滅菌でも改質された性能は保持されるが、血液
凝固を軽減する面での改良は十分とは言えない。
〔発明が解決しようとする問題点〕
上記のように、再生セルロース膜系ウエツト型
透析器の血液に対する適合性を向上させる試みに
は、一長一短がある。そこで、本発明の目的は、
再生セルロース膜の優れた透析性能を損なうこと
なく、血液に対する適合性が改良されている、湿
潤状態で滅菌された再生セルロース膜系透析器を
提供することにある。
〔問題点を解決するための手段及び作用〕
再生セルロース膜を用いた場合生じる補体成分
の活性化や白血球の一過性減少には、膜表面の水
酸基が関与していると考えられている。一方、こ
の膜表面の水酸基は種々の官能基と反応し分子鎖
を結合することができる。結合した分子鎖は、膜
上の水酸基をマスキングし、補体蛋白や血球と水
酸基の直接の接触を妨げる。これにより、補体成
分の活性化を抑制できるたけでなく、膜表面の物
理化学的性質に影響を与え、他の血液親和性をも
改善できる。分子鎖の構造及び官能基には多くの
組合せが可能であるが、生体安全性、生体親和
性、経済性、化学反応性などに加えて、湿潤した
状態での滅菌の際改良された血液に対する適合性
が保持されることを考慮し、種々研究を重ねた結
果、本発明の完成に到つた。
すなわち、本発明によれば、再生セルロース膜
系透析器において、少なくとも血液側の膜表面の
水酸基に下記
(イ) 一般式が、
HO2CCH2−（OCH2CH2）o−OCH2CO2H
（上式中、ｎは１〜150の整数を表わす）で示
されるポリエチレングライコールジカルボン
酸、
(ロ) 一般式が、
HO2CCH2−（OCH2CH2）o−OR
（上式中、ｎは１〜150の整数を表わし、Ｒは
炭素数１〜20個の飽和または不飽和炭化水素を
表わす）示されるポリエチレングライコールモ
ノカルボン酸、ならびに、
(ハ) 炭素数５個以上の脂肪族カルボン酸、
からなる群より選ばれる有機カルボン酸のいずれ
か少なくとも１種のアシル残基がエステル結合に
よりグラフトされている再生セルロース膜が組み
込まれ、かつ充填液で該再生セルロース膜が湿潤
された状態で滅菌されていることを特徴とする再
生セルロース膜系透析器、が提供される。
本発明によれば、さらに、有機カルボン酸また
はその官能性誘導体及びエステル化触媒を反応媒
体に溶解または分散させた溶液で再生セルロース
膜を処理し、膜表面の水酸基とエステル化反応を
行なわしめ、続いて後処理した該膜を透析器に組
み込んだ後、充填液で該膜を湿潤させ滅菌するこ
とを特徴とする再生セルロース膜系透析器の製造
法が提供される。
本発明によれば、さらに、有機カルボン酸また
はその官能性誘導体及びエステル化触媒を反応媒
体に溶解または分散させた溶液を、再生セルロー
ス膜を組み込んだ透析器の少なくとも血液側に循
環または充填放置し、膜表面の水酸基とエステル
化反応を行なわしめ、続いて後処理した後、充填
液で該膜を湿潤させ滅菌することを特徴とする再
生セルロース膜系透析器の製造法が提供される。
本発明で使用する「再生セルロース膜」とは、
天然セルロースを一旦化学的に或いは物理的に変
化させた後再生した膜であつて、例えば、銅アン
モニウム法再生セルロース膜、ビスコースレーヨ
ン膜、セルロースエステルを鹸化した膜が含まれ
るが、透析性能及び長年の実績により裏付けられ
た高い安全性等が銅アンモニウム法再生セルロー
ス膜が好んで用いられる。
再生セルロース膜の形状は、平膜または中空糸
膜等何れの形状に成型されたものも用いることが
できるが、中空糸膜が好ましい。例えば、特公昭
50−40168及び特開昭59−204912に開示されてい
るような、膜厚が数μｍ〜60μｍであり、外径が
10μｍ〜数百μｍの真円形の横断面を有する中空
糸膜等が用いられる。
本発明では、透析器に組み込まれる再生セルロ
ース膜は、その表面の改質によつて血液に対する
適合性の改良が行なわれるが、充填液が湿潤され
た状態での滅菌によつて改質された表面の性質が
変化することなく改良された血液に対する適合性
が保持されることが要求される。例えば、表面を
コーテイングすることにより血液に対する適合性
を改良した再生セルロース膜系透析器では湿潤状
態での滅菌の際、コーテイング化合物のコンフオ
メーシヨン変化が生じ、改良された血液に対する
適合性が失われることがある。また、表面の水酸
基の反応性を利用して分子鎖を結合させることに
よつて再生セルロース膜の表面改質を行なつて
も、湿潤状態での滅菌の際、その結合が開裂した
り、結合した分子鎖のコンフオメーシヨン変化が
生じ、血液に対する適合性が失われる恐れがあ
る。これらのことを考慮し、本発明では、少なく
とも血液側の膜表面に有機カルボン酸のアシル残
基がエステル結合によりグラフトされている再生
セルロース膜が採用される。このような膜の表面
改質は、再生セルロース膜表面の水酸基と有機カ
ルボン酸またはその酸無水物や酸ハロゲン化物等
の官能性誘導体をエステル化反応させ、有機カル
ボン酸のアシル残基がグラフトさせることにより
行なわれる。有機カルボン酸として、下記(イ)〜(ハ)
からなる群より選ばれるものが使用できる。
(イ) 一般式が、
HO2CCH2−（OCH2CH2）o−OCH2CO2H
（上式中、ｎは１〜150の整数を表わす）で示
されるポリエチレングライコールジカルボン
酸、
(ロ) 一般式が、
HO2CCH2−（OCH2CH2）o−OR
（上式中、ｎは１〜150の整数を表わし、Ｒは
炭素数１〜20個の飽和または不飽和炭化水素を
表わす）示されるポリエチレングライコールモ
ノカルボン酸、ならびに、
(ハ) 炭素数５個以上の脂肪族カルボン酸。
なお、上記脂肪族カルボン酸の具体的な化合物
としては、例えば、吉草酸、カプロン酸、エナン
ト酸、カプリル酸、ペラルゴン酸、カプリン酸、
ウンデシル酸、ラウリル酸、トリデシル酸、ミリ
スチン酸、ペンタデシル酸、パルミチン酸、ヘプ
タデシル酸、ステアリン酸、ノナデカン酸、アラ
キン酸、ベヘン酸、リグノセリン酸等の飽和脂肪
酸、オレイン酸、エライジン酸、セトレイン酸、
エルカ酸、ブラシジン酸、ソルビン酸、リノール
酸、リノレン酸、アラキドン酸等の不飽和脂肪
酸、及びグルタル酸、アジピン酸、ピメリン酸、
スベリン酸、アゼライン酸、セバシン酸等の脂肪
族ジカルボン酸等が挙げられる。
再生セルロース膜表面の水酸基とのエステル化
反応は、上記有機カルボン酸そのものを用いても
可能だが、有機カルボン酸ハロゲン化物、有機カ
ルボン酸無水物等の官能性誘導体を用いても可能
である。有機カルボン酸ハロゲン化物としては、
取り扱い性及び残留時の安全性の面から有機カル
ボン酸クロライドが好ましい。また有機カルボン
酸無水物としては、上記有機カルボン酸を２分子
もしくはそれ以上を脱水縮合させた単独の酸無水
物、または上記有機カルボン酸とその他の有機カ
ルボン酸との混成酸無水物を用いることができ
る。後者の場合、目的とする有機カルボン酸を優
先的にエステル結合させるために、その他の有機
カルボン酸として、立体障害の大きい有機カルボ
ン酸、例えばイソ酪酸、イソ吉草酸を用いた混成
酸無水物や、炭酸水素アルキル（HOCO2R；Ｒ
＝アルキル基）を用いた混成酸無水物が好まし
い。
これらの有機カルボン酸または官能性誘導体
は、0.5〜50ｍmol／Ｌの濃度で用いられ、エス
テル化の反応性、膜への付着残留、経済性の点か
ら１〜10ｍmol／Ｌの濃度で好んで使用される。
再生セルロース膜表面の水酸基とのエステル化
反応には、公知の低分子のアルコールと低分子の
カルボン酸またはその官能性誘導体との反応が適
応できる。処理条件として、再生セルロース膜の
物性に影響を与えないように、処理温度を低く抑
え、処理時間をできるだけ短くすることが好まし
い。これらの事項は経済性の面からも有利であ
る。
また、エステル化触媒を使用してエステル化を
促進することが好ましい。反応を促進させるエス
テル化触媒として、有機カルボン酸の場合、硫
酸、塩酸などの鉱酸、芳香族スルホン酸などの有
機酸、三フツ化ホウ素エーテラートなどのルイス
酸、ジシクロヘキシルカルボジイミドなどのカル
ボジイミド誘導体、及びカルボジイミド誘導体と
４−ジメチルアミノピリジン及び／または４−ピ
ロリジノピリジンとの混合触媒等が、有機カルボ
ン酸ハロゲン化物の場合、副生するハロゲン化物
を除去するため、ピリジン、ジメチルアニリン、
トリエチルアミン、テトラメチル尿素、或いは金
属マグネシウム等、及びこれらの除去剤と４−ジ
メチルアミノピリジン及び／または４−ピロリジ
ノピリジンとの混合触媒等が、有機カルボン酸無
水物の場合、硫酸、ｐ−トルエンスルホン酸、塩
化亜鉛、硫酸ナトリウム、ピリジン、４−ジメチ
ルアミノピリジン、４−ピロリジノピリジン等が
知られている。
本発明では、これらの触媒を単独または適宜組
合せて用いることができるが、反応を円滑に進め
る点や反応後の除去の点から、反応媒体に可溶の
ものをできるだけ少量使用することが好ましい。
このような観点から、カルボン酸をジシクロヘキ
シルカルボジイミドなどのカルボジイミド誘導体
と４−ジメチルアミノピリジン及び／または４−
ピロリジノピリジンとの混合触媒でエステル化反
応をさせる方法、及び有機カルボン酸無水物を４
−ジメチルアミノピリジン及び／または４−ピロ
リジノピリジンでエステル化反応をさせる方法が
好んで用いられる。
反応媒体としては、有機カルボン酸またはその
官能性誘導体と反応しないこと、エステル化触媒
を失活させないこと、再生セルロース膜からなる
高分子膜に大きな形態変化を生じせしめないこと
が必要である。従つて、反応媒体として、上記の
要件を満たし、有機カルボン酸またはその官能性
誘導体及びエステル化触媒を分散または溶解させ
る溶剤で、全て用いられる。反応の均一性、円滑
性及び反応後の除去を考慮すると有機カルボン酸
またはその官能性誘導体及びエステル化触媒を溶
解させる溶剤が好ましい。このような反応媒体と
して、例えば、ｎ−ヘキサン、ｎ−ヘプタン、シ
クロヘキサン、石油エーテル、石油ベンゼン、ベ
ンゼン、トルエン等の炭化水素等、アセトン、メ
チルエチルケトン等のケトン類、酢酸メチル、酢
酸エチル、酢酸プロピル等のエステル類、エチル
エーテル、イソプロピルエーテル、ジオキサン等
のエーテル類、１，１，２−トリクロロ−１，
２，２−トリフルオロエタン、トリクロロフルオ
ロメタン、１，１，２，２−テトラクロロ−１，
２−ジフルオロエタン等の塩化弗化炭化水素等が
挙げられる。これらの反応媒体は、単独または混
合して使用できる。生体への安全性や反応後の除
去の観点から、塩化弗化炭化水素、特に１，１，
２−トリクロロ−１，２，２−トリフルオロエタ
ンを含む反応媒体が好ましく、１，１，２−トリ
クロロ−１，２，２−トリフルオロエタンとアセ
トンの混合溶媒が好んで用いられる。
エステル化反応処理は、透析器に再生セルロー
ス膜を組み込む前に行なう方法と組み込だ後に行
なう方法とがある。即ち、前者の方法では、有機
カルボン酸またはその官能性誘導体及びエステル
化触媒を反応媒体に分散または溶解させた処理液
に、再生セルロース膜を投入し撹拌する、また
は、処理液を充填した浸漬槽内に高分子膜を浸漬
させる、または、高分子膜を充填した処理槽に処
理液を循環することによりエステル化反応処理が
行なわれる。改質された再生セルロース膜は公知
の方法によつて透析器に組み込まれる。すなわ
ち、中空糸の場合、透析器ハウジングに挿入され
た中空糸束の両末端をポリウレタン樹脂でポツテ
イングすることにより組み立てられる。また、後
者の方法では、再生セルロース膜が組み込まれた
透析器の少なくとも血液を流通させる側に、処理
液を循環させるまたは充填して放置させることに
よりエステル化反応処理が行なわれる。
上記いずれの方法でも、エステル化反応終了
後、後処理操作が行なわれる。すなわち、過剰の
処理液が除去され、反応試薬、エステル化触媒ま
たは副反応生成物等が膜に残留しない場合には省
略されるが、通常これらを除去するため洗浄が行
われる。この洗浄操作には、反応に使用した溶
媒、またはメチルアルコール、エチルアルコール
など再生セルロース膜に大きな形態変化を起こさ
せない溶媒を用い、浸漬抽出、またはソツクスレ
ー抽出が行われる。最後に、減圧乾燥、送風乾燥
等により残留溶媒の除去が行われる。
このようにして得られる透析器は、充填液によ
り改質された再生セルロース膜を湿潤させた後、
滅菌される。充填液としては、水、生理食塩水、
グリセリン水溶液、及びこれらに抗酸化剤を添加
した水溶液が用いられる。特に、抗酸化剤の添加
は、滅菌により再生セルロース膜の酸化劣化等が
生じる場合には好んで用いられる。すなわち、ピ
ロ亜硫酸ナトリウム、アセトンソジウムバイサル
フアイト、ソジウムホルムアルデヒドスルホキシ
レート、ソジウムハイドロサルフアイト、Ｌ−ア
スコルビン酸等の抗酸化剤等が添加された充填液
が使用される。充填液による改質された再生セル
ロース膜の湿潤は、再生セルロース膜重量に対し
て水が200％以上含有されておれば十分であり、
大抵、透析器に充填液を封入することにより行な
われる。
改質された再生セルロース膜が充填液が湿潤さ
れた透析器は、滅菌操作にかけられる。滅菌法と
して加熱法、照射法、薬液法等の公知の方法が使
用でき、高圧蒸気滅菌、放射線（ガンマー線）滅
菌が好んで用いられる。
上記のようにして得られる本発明の透析器は、
実施例に示されるように用いる再生セルロース膜
の優れた透析性能が損なわれることなく、補体成
分の活性化作用が制御され、白血球一過性減少が
軽微になる。このような効果は、本発明に於いて
エステル化反応が再生セルロース膜表面でのみ起
こり、膜内部の化学的及び物理的構造が維持され
ているためと考えられる。また、表面にエステル
化される量が、表面の物理化学的及び生物化学的
性質を改良するに十分な量であるが、水や物質の
透過に悪影響を与えない程度の極微量であるため
と考えられる。
また、滅菌前後で透析性能の変化がなく、補体
成分の活性化作用の抑制においても変化がない。
このことは、上述のように再生セルロース膜表面
にのみ有機カルボン酸のアシル残基が極微量グラ
フトしているにもかかわらず、湿潤状態での滅菌
に対してエステル結合が安定であり、開裂するこ
ともなく、このアシル残基が膜表面の水酸基を有
効に遮蔽しているためと考えられる。
このため本発明では、上述のようにエステル結
合される有機カルボン酸またはその官能性誘導体
を低濃度で使用することができる。このことは、
これまで予想だにできなかつたことである。即
ち、イソシアナートを反応させているEP−
155534に開示されている実施例では、反応物質の
濃度が１〜15容量％とかなりの高濃度であるが、
本発明では、僅か数百ppmの低濃度でも十分に効
果を発揮している。低濃度の場合、コスト面で有
利になるとともに、膜への反応物質の付着残留も
少なく、反応後の膜の洗浄操作も容易であり、使
用時の安全性の面でも有利であると言える。
膜表面の物理化学的及び生物化学的性質の改良
の効果は、他の血液親和性にも指摘できる。即
ち、有機カルボン酸のアシル残基が親水性の場合
には、血漿タンパク質の吸着が抑制されている。
この現象の一つの理論的根拠は、ワイ・イカダ
（Y.Ikada））：アドバンス・イン・ポリマー・サ
イエンス（Advance in Polymer Sciencs）、第
57巻、1984年、第103頁以下に与えられているが、
簡単に要約すると、親水性グラフト鎖が植え付け
られた血液接触表面では、多量の水を含んだその
グラフト鎖が材料の実質表面へのタンパク質吸着
や血小板等の細胞の付着を防止するという考えで
ある。このため、血液凝固の原因になる血小板の
血液接触表面への粘着や活性化が起こり難く、ま
た凝固因子の接触相活性化が生じ難い。即ち、こ
のような蛋白質吸着が抑制されている血液接触表
面では血栓の生成が抑制されると考えられてい
る。
一方、グラフトされる有機カルボン酸のアシル
残基が疎水性の場合には、血漿タンパクのうちア
ルブミンが選択的に吸着される。アルブミンは、
血液中で脂肪酸のキヤリアーとして働き、分子軸
中心の疎水性のポケツトを有しているといわれて
いる。このポケツに、疎水性のグラフト鎖が、結
合するため選択的な吸着が起こると考えられる。
このようにアルブミンが選択吸着する血液接触表
面では、血液凝固が起こり難いと考えられてい
る。その理論的根拠として、フイブリノーゲンや
免疫グロブリンのような糖鎖を有する蛋白質は、
この糖鎖を介して血小板と結合するが、アルブミ
ンは、このような糖鎖を持たず、血小板との特異
的な結合を起こさないため、血液中からアルブミ
ンを優先的に吸着する血液接触表面では血液凝固
が起こり難いと考えられている。
上記のような蛋白質の吸着抑制及びアルブミン
の選択吸着には、グラフト鎖が二箇所以上で高分
子膜表面に結合し、鎖の運動が抑制された状態よ
りも、一端が結合し他の末端が自由に運動できる
ほうが好ましい。これは自由なグラフト鎖のほう
が、高分子膜の実質表面を遮蔽し、蛋白質の吸着
を抑制するためであり、親水性グラフト鎖の場
合、水分の含有が増大する効果が加わる。
〔実施例〕
次に、実施例により本発明の内容をさらに詳細
に述べる。
なお以下の実施例中に記載されている測定項目
は、各々次の方法で測定したものである。
(1) 透水量
透析器の血液側および透析液側を1500ｍＬ水
で洗浄後、血液側の一方のノズルを閉じて、も
う一方のノズルから400mmHgの圧力をかけなが
ら水を入れ、単位時間当たりの透水量を測定す
る。透析器の膜面積は、中空糸膜の内径、有効
長及び充填本数から算出される。
(2) クリアランス
(1)と同様に透析器を洗浄した後、透析液側に
水を500ｍＬ／分の流量が流通させながら、血
液側に1000ppm尿素水溶液、または10ppmビタ
ミンＢ−12（VB12）水溶液を流通させる。血液
側入口及び出口でサンプリングし、尿素または
VB12の濃度の吸光度から求めて、次式よりク
リアランスを計算する。
クリアランス＝（１分間当たりの血液側液量）×（血液
側入口の濃度）−（血液側出口の濃度）／（血液側入口
の濃度）
(3) 補体消費率
(1)と同様に透析器を洗浄した後、洗浄水を乾
燥空気で排出し、透析器ハウジングを解体して
再生セルロース膜を取り出す。次いで、真空乾
燥により乾燥した再生セルロース膜を取得す
る。この膜を２mm長に細断し、ポリエチレン管
に入れ、これにGVバツフアーで４倍に稀釈し
たモルモツト補体200μを加え、37℃で１時
間インキユベートする。上清液中の補体価をマ
イヤー変法（エム・エム・マイヤー（M.M.
Mayer）：イムノケミストリー
（immunochemisuy）第２版、第133頁、シ
ー・シー・トーマス（C.C.Thomas）出版者、
1961年、参照）によつて求める。即ち補体の50
％溶血価（CH50値）を求め、コントロールに
対する補体消費率（％CH50）を算出する。
実施例 １
ラウリン酸0.51ｇ、４−ジメチルアミノピリジ
ン0.02ｇ、ジシクロヘキシルカルボジイミド0.26
ｇ及び１，１，２−トリクロロ−１，２，２−ト
リフルオロエタン−アセトン混合溶媒（アセトン
12.5wt％）700mlを加え、処理液に調合した。こ
の処理液に再生セルロース中空糸膜（内径200μ
ｍ、膜厚13μｍ、長さ30cm）の束（本数約7000
本）を、時々上下しながら30分間垂直に浸漬し
た。処理後の再生セルロース中空糸膜束をメチル
アルコール中に一昼夜浸漬した後、室温で減圧乾
燥することによつてエステル化された中空糸膜束
を得た。
この中空糸膜束を透析器ハウジングに挿入し、
両末端をポリウレタン樹脂でポツテイングするこ
とにより透析器を組み立てた。次いで、透析器の
血液側と透析液側を各々1500ｍＬの注射用蒸留水
で洗浄充填した。この中空糸膜を湿潤させた透析
器をポリエチレン製の袋に封入した状態で、121
℃、１Kg／cm2の条件下、高圧蒸気滅菌を施し、滅
菌された透析器を取得した。
この滅菌された透析器、上記と同様にエステル
化された中空糸膜束を組み込んだ滅菌前の透析
器、及び未処理の再生セルロース中空糸膜束の組
み込み上記と同様に高圧蒸気滅菌した透析器につ
いて、透析器の透析性能及び補体消費率の測定を
実施した。結果を第１表に示す。エステル化処理
により血液に対する適合性は改善され、滅菌操作
により減ずることはない。また、透析性能はエス
テル化処理および滅菌操作により変動しない。
[Industrial Field of Application] The present invention relates to an improved regenerated cellulose membrane dialyzer. More specifically, the present invention relates to a wet type regenerated cellulose membrane dialyzer with improved compatibility with blood and a method for manufacturing the same. [Prior Art] In recent years, artificial organs using membranes, such as artificial kidneys, artificial lungs, and plasma separation devices, have made great progress. As is well known, especially in artificial dialysis therapy,
Dialyzers using regenerated cellulose membranes, especially copper ammonium regenerated cellulose membranes, are widely used, and along with advances in dialysis equipment and dialysis technology, they play a major role in prolonging the lives of renal failure patients and reintegrating them into society. This is because dialyzers using regenerated cellulose membranes have excellent dialysis performance and mechanical strength, as well as high safety backed by many years of experience. However, despite advances in dialysis therapy, various problems associated with dialysis still remain unsolved. For example, there are problems with the various side effects that may occur when large doses of anticoagulants are administered over a long period of time, and transient effects when performing hemodialysis with a dialyzer that uses regenerated cellulose membranes or some other membranes. Problems such as decreased white blood cells and activation of complement components have been pointed out. Regarding the latter phenomenon, the relationship with clinical symptoms or clinical significance is not clear, but it is desired to reduce these phenomena in regenerated cellulose membrane dialyzers without compromising other excellent performance. . In addition, there are two types of dialyzers: dry type dialyzers, which are sterilized with the built-in dialysis membrane dry, and wet type dialyzers, which are sterilized with the dialysis membrane moistened with filling fluid. The latter type of dialyzer is desired because of its ease of use. In response to such demands, various regenerated cellulose membrane dialyzers with improved blood affinity have been proposed.
For example, a regenerated cellulose membrane dialyzer whose surface is coated with various polymers and vitamins has been proposed, but problems with the stability of the coating have been pointed out when sterilized in a wet state. In addition, JP-A-61-8105 describes a regenerated cellulose membrane dialyzer made by reacting an isocyanate prepolymer, and JP-A-60-118203 describes a regenerated cellulose membrane with a polymeric acid chemically bonded to it through a bridging agent. Each type of dialyzer has been proposed. Although these dialyzers appear to retain their improved performance even when sterilized in a wet state, there are problems such as reactant stability and complexity of the reaction process during dialysis membrane manufacturing. Furthermore, JP-A-61-113459
A regenerated cellulose membrane dialyzer made of modified cellulose such as diethylaminoethylcellulose has been proposed. Although this dialyzer retains its improved performance even when sterilized in a wet state, the improvement in reducing blood coagulation is not sufficient. [Problems to be Solved by the Invention] As described above, attempts to improve the compatibility of regenerated cellulose membrane-based wet dialyzers with blood have advantages and disadvantages. Therefore, the purpose of the present invention is to
To provide a regenerated cellulose membrane dialyzer that is sterilized in a wet state and has improved compatibility with blood without impairing the excellent dialysis performance of the regenerated cellulose membrane. [Means and effects for solving the problem] Hydroxyl groups on the membrane surface are thought to be involved in the activation of complement components and the temporary decrease in white blood cells that occur when a regenerated cellulose membrane is used. . On the other hand, the hydroxyl groups on the surface of this membrane can react with various functional groups to bond molecular chains. The bound molecular chains mask the hydroxyl groups on the membrane, preventing direct contact between the hydroxyl groups and complement proteins and blood cells. This not only suppresses the activation of complement components, but also affects the physicochemical properties of the membrane surface and improves other blood affinities. Many combinations of molecular chain structures and functional groups are possible, but in addition to biosafety, biocompatibility, economic efficiency, and chemical reactivity, improvements in blood resistance during wet sterilization are important. As a result of various studies in consideration of maintaining compatibility, the present invention has been completed. That is, according to the present invention, in a regenerated cellulose membrane dialyzer, at least the hydroxyl group on the membrane surface on the blood side has the following general formula (a): HO 2 CCH 2 −(OCH 2 CH 2 ) o −OCH 2 CO 2 Polyethylene glycol dicarboxylic acid represented by H (in the above formula, n represents an integer from 1 to 150), (b) whose general formula is HO 2 CCH 2 −(OCH 2 CH 2 ) o −OR (in the above formula , n represents an integer of 1 to 150, R represents a saturated or unsaturated hydrocarbon having 1 to 20 carbon atoms), and (c) a fat having 5 or more carbon atoms. A regenerated cellulose membrane in which at least one acyl residue of an organic carboxylic acid selected from the group consisting of carboxylic acids is grafted with an ester bond is incorporated, and the regenerated cellulose membrane is wetted with a filling liquid. A regenerated cellulose membrane dialyzer is provided which is characterized in that it is sterilized. According to the present invention, the regenerated cellulose membrane is further treated with a solution in which an organic carboxylic acid or a functional derivative thereof and an esterification catalyst are dissolved or dispersed in a reaction medium to perform an esterification reaction with hydroxyl groups on the membrane surface, A method for producing a regenerated cellulose membrane dialyzer is provided, which comprises subsequently incorporating the post-treated membrane into a dialyzer, and then moistening and sterilizing the membrane with a filling liquid. According to the present invention, a solution in which an organic carboxylic acid or a functional derivative thereof and an esterification catalyst are dissolved or dispersed in a reaction medium is further circulated or filled at least on the blood side of a dialyzer incorporating a regenerated cellulose membrane. Provided is a method for producing a regenerated cellulose membrane dialyzer, which comprises carrying out an esterification reaction with hydroxyl groups on the surface of the membrane, followed by post-treatment, and then wetting the membrane with a filling liquid to sterilize it. The “regenerated cellulose membrane” used in the present invention is
Membranes that are regenerated after chemically or physically changing natural cellulose include, for example, copper ammonium regenerated cellulose membranes, viscose rayon membranes, and membranes made by saponifying cellulose ester, but they have improved dialysis performance and The copper ammonium method regenerated cellulose membrane is preferably used because of its high safety, which has been proven through many years of experience. The regenerated cellulose membrane may be formed into any shape such as a flat membrane or a hollow fiber membrane, but a hollow fiber membrane is preferable. For example, Tokko Akira
50-40168 and JP-A-59-204912, the film thickness is from several μm to 60 μm and the outer diameter is
A hollow fiber membrane or the like having a perfectly circular cross section of 10 μm to several hundred μm is used. In the present invention, the regenerated cellulose membrane incorporated in the dialyzer is improved in compatibility with blood by modifying its surface, but the regenerated cellulose membrane is modified by sterilization while the filling liquid is wet. It is required that improved blood compatibility be maintained without changes in surface properties. For example, in a regenerated cellulose membrane dialyzer whose surface is coated to improve its compatibility with blood, during sterilization in a wet state, the coating compound undergoes a conformational change and the improved compatibility with blood is lost. Sometimes. Furthermore, even if the surface of a regenerated cellulose membrane is modified by bonding molecular chains using the reactivity of the hydroxyl groups on the surface, the bonds may cleave or bond during sterilization in a wet state. Conformation changes in the molecular chains may occur, resulting in loss of compatibility with blood. Taking these into consideration, the present invention employs a regenerated cellulose membrane in which acyl residues of organic carboxylic acids are grafted onto at least the blood side membrane surface through ester bonds. Surface modification of such membranes involves an esterification reaction between hydroxyl groups on the surface of the regenerated cellulose membrane and organic carboxylic acids or functional derivatives such as their acid anhydrides and acid halides, resulting in grafting of the acyl residues of the organic carboxylic acids. This is done by As organic carboxylic acids, the following (a) to (c)
Those selected from the group consisting of can be used. (a) Polyethylene glycol dicarboxylic acid whose general formula is HO 2 CCH 2 −(OCH 2 CH 2 ) o −OCH 2 CO 2 H (in the above formula, n represents an integer from 1 to 150), ( b) The general formula is HO 2 CCH 2 −(OCH 2 CH 2 ) o −OR (In the above formula, n represents an integer from 1 to 150, and R is a saturated or unsaturated hydrocarbon having 1 to 20 carbon atoms. and (c) an aliphatic carboxylic acid having 5 or more carbon atoms. Specific examples of the aliphatic carboxylic acids include valeric acid, caproic acid, enanthic acid, caprylic acid, pelargonic acid, capric acid,
Saturated fatty acids such as undecylic acid, lauric acid, tridecylic acid, myristic acid, pentadecylic acid, palmitic acid, heptadecylic acid, stearic acid, nonadecanoic acid, arachidic acid, behenic acid, lignoceric acid, oleic acid, elaidic acid, cetoleic acid,
Unsaturated fatty acids such as erucic acid, brassic acid, sorbic acid, linoleic acid, linolenic acid, arachidonic acid, and glutaric acid, adipic acid, pimelic acid,
Examples include aliphatic dicarboxylic acids such as suberic acid, azelaic acid, and sebacic acid. The esterification reaction with the hydroxyl groups on the surface of the regenerated cellulose membrane can be carried out by using the organic carboxylic acid itself, but it is also possible by using functional derivatives such as organic carboxylic acid halides and organic carboxylic acid anhydrides. As organic carboxylic acid halides,
Organic carboxylic acid chlorides are preferred from the viewpoint of ease of handling and safety when remaining. Further, as the organic carboxylic acid anhydride, a single acid anhydride obtained by dehydrating and condensing two or more molecules of the above organic carboxylic acid, or a mixed acid anhydride of the above organic carboxylic acid and another organic carboxylic acid may be used. I can do it. In the latter case, in order to preferentially form an ester bond with the target organic carboxylic acid, a mixed acid anhydride or a sterically hindered organic carboxylic acid such as isobutyric acid or isovaleric acid is used as the other organic carboxylic acid. , alkyl hydrogen carbonate (HOCO 2 R; R
=alkyl group) is preferred. These organic carboxylic acids or functional derivatives are used at a concentration of 0.5 to 50 mmol/L, and are preferably used at a concentration of 1 to 10 mmol/L from the viewpoint of esterification reactivity, residual adhesion to the membrane, and economic efficiency. be done. For the esterification reaction with the hydroxyl groups on the surface of the regenerated cellulose membrane, a known reaction between a low-molecular alcohol and a low-molecular carboxylic acid or a functional derivative thereof can be applied. As for the treatment conditions, it is preferable to keep the treatment temperature low and the treatment time as short as possible so as not to affect the physical properties of the regenerated cellulose membrane. These matters are also advantageous from an economic point of view. It is also preferred to use an esterification catalyst to promote esterification. As an esterification catalyst for accelerating the reaction, in the case of organic carboxylic acids, mineral acids such as sulfuric acid and hydrochloric acid, organic acids such as aromatic sulfonic acids, Lewis acids such as boron trifluoride etherate, carbodiimide derivatives such as dicyclohexylcarbodiimide, and When a mixed catalyst of a carbodiimide derivative and 4-dimethylaminopyridine and/or 4-pyrrolidinopyridine is an organic carboxylic acid halide, pyridine, dimethylaniline,
When triethylamine, tetramethylurea, metallic magnesium, etc. and a mixed catalyst of these removers and 4-dimethylaminopyridine and/or 4-pyrrolidinopyridine are organic carboxylic acid anhydrides, sulfuric acid, p-toluene, etc. Sulfonic acid, zinc chloride, sodium sulfate, pyridine, 4-dimethylaminopyridine, 4-pyrrolidinopyridine and the like are known. In the present invention, these catalysts can be used alone or in appropriate combinations, but from the viewpoint of smooth reaction and removal after the reaction, it is preferable to use as little as possible of catalysts that are soluble in the reaction medium.
From this point of view, carboxylic acids are combined with carbodiimide derivatives such as dicyclohexylcarbodiimide and 4-dimethylaminopyridine and/or 4-
A method of carrying out an esterification reaction with a mixed catalyst with pyrrolidinopyridine, and an organic carboxylic acid anhydride
A method of carrying out an esterification reaction with -dimethylaminopyridine and/or 4-pyrrolidinopyridine is preferably used. The reaction medium must not react with organic carboxylic acids or functional derivatives thereof, do not deactivate the esterification catalyst, and do not cause large changes in the morphology of the polymer membrane made of regenerated cellulose membrane. Therefore, as reaction medium all solvents which meet the above requirements and which disperse or dissolve the organic carboxylic acid or its functional derivative and the esterification catalyst are used. In consideration of uniformity and smoothness of the reaction and removal after the reaction, a solvent that can dissolve the organic carboxylic acid or its functional derivative and the esterification catalyst is preferred. Such reaction media include, for example, hydrocarbons such as n-hexane, n-heptane, cyclohexane, petroleum ether, petroleum benzene, benzene, toluene, etc., ketones such as acetone, methyl ethyl ketone, methyl acetate, ethyl acetate, propyl acetate, etc. esters such as ethyl ether, isopropyl ether, dioxane, 1,1,2-trichloro-1,
2,2-trifluoroethane, trichlorofluoromethane, 1,1,2,2-tetrachloro-1,
Examples include chlorofluorinated hydrocarbons such as 2-difluoroethane. These reaction media can be used alone or in mixtures. From the viewpoint of biological safety and post-reaction removal, chlorinated fluorinated hydrocarbons, especially 1, 1,
A reaction medium containing 2-trichloro-1,2,2-trifluoroethane is preferred, and a mixed solvent of 1,1,2-trichloro-1,2,2-trifluoroethane and acetone is preferably used. The esterification reaction treatment can be carried out either before or after incorporating the regenerated cellulose membrane into the dialyzer. That is, in the former method, a regenerated cellulose membrane is added to and stirred in a treatment solution in which an organic carboxylic acid or its functional derivative and an esterification catalyst are dispersed or dissolved in a reaction medium, or a dipping tank filled with the treatment solution is used. The esterification reaction treatment is carried out by immersing the polymer membrane in the polymer membrane or by circulating the treatment liquid in a treatment tank filled with the polymer membrane. The modified regenerated cellulose membrane is incorporated into a dialyzer by known methods. That is, in the case of hollow fibers, it is assembled by potting both ends of the hollow fiber bundle inserted into the dialyzer housing with polyurethane resin. In the latter method, the esterification reaction treatment is carried out by circulating or filling a treatment liquid into at least the side through which blood flows of a dialyzer incorporating a regenerated cellulose membrane and allowing it to stand. In any of the above methods, a post-treatment operation is performed after the esterification reaction is completed. That is, cleaning is usually performed to remove excess treatment liquid and is omitted if the reaction reagent, esterification catalyst, side reaction product, etc. do not remain in the membrane. In this washing operation, immersion extraction or Soxhlet extraction is performed using the solvent used in the reaction or a solvent such as methyl alcohol or ethyl alcohol that does not cause a large change in the form of the regenerated cellulose membrane. Finally, residual solvent is removed by vacuum drying, blow drying, or the like. After wetting the modified regenerated cellulose membrane with the filling liquid, the dialyzer obtained in this way is
Sterilized. Filling liquids include water, physiological saline,
Glycerin aqueous solutions and aqueous solutions containing antioxidants are used. In particular, the addition of an antioxidant is preferably used when sterilization causes oxidative deterioration of the regenerated cellulose membrane. That is, a filling liquid to which antioxidants such as sodium pyrosulfite, acetone sodium bisulfite, sodium formaldehyde sulfoxylate, sodium hydrosulfite, and L-ascorbic acid are added is used. Wetting of the modified regenerated cellulose membrane with the filling liquid is sufficient if the water content is 200% or more based on the weight of the regenerated cellulose membrane.
This is usually done by filling the dialyzer with a filler fluid. The dialyzer, in which the modified regenerated cellulose membrane is wetted with the filling liquid, is subjected to a sterilization operation. Known methods such as heating, irradiation, and chemical methods can be used as sterilization methods, and high-pressure steam sterilization and radiation (gamma ray) sterilization are preferably used. The dialyzer of the present invention obtained as described above is
As shown in the examples, the activation effect of complement components is controlled without impairing the excellent dialysis performance of the regenerated cellulose membrane used, and the transient decrease in leukocytes is made slight. This effect is thought to be due to the fact that in the present invention, the esterification reaction occurs only on the surface of the regenerated cellulose membrane, and the chemical and physical structure inside the membrane is maintained. In addition, the amount of esterification on the surface is sufficient to improve the physicochemical and biochemical properties of the surface, but is so small that it does not adversely affect the permeation of water or substances. Conceivable. Further, there is no change in dialysis performance before and after sterilization, and there is no change in suppression of activation of complement components.
This means that even though a very small amount of acyl residue of an organic carboxylic acid is grafted only on the surface of the regenerated cellulose membrane as mentioned above, the ester bond is stable against sterilization in a wet state and cannot be cleaved. This is probably because this acyl residue effectively blocks the hydroxyl groups on the membrane surface. Therefore, in the present invention, the ester-bonded organic carboxylic acid or its functional derivative can be used at a low concentration as described above. This means that
This is something that could never have been predicted. That is, EP− in which isocyanate is reacted
In the example disclosed in No. 155534, the concentration of the reactant is quite high, 1 to 15% by volume.
The present invention is sufficiently effective even at a low concentration of only several hundred ppm. When the concentration is low, it is advantageous in terms of cost, there is little residual reactant attached to the membrane, cleaning of the membrane after reaction is easy, and it can be said that it is advantageous in terms of safety during use. The effects of improving the physicochemical and biochemical properties of the membrane surface can also be noted on other blood affinities. That is, when the acyl residue of the organic carboxylic acid is hydrophilic, adsorption of plasma proteins is suppressed.
One rationale for this phenomenon is Y. Ikada: Advance in Polymer Sciences, Vol.
Volume 57, 1984, pages 103 et seq.
Briefly summarized, the idea is that on blood-contact surfaces implanted with hydrophilic graft chains, the graft chains, which contain a large amount of water, prevent protein adsorption and the adhesion of cells such as platelets to the material's parenchymal surface. . Therefore, adhesion and activation of platelets to the blood contact surface, which causes blood coagulation, is less likely to occur, and contact phase activation of coagulation factors is less likely to occur. That is, it is thought that the formation of blood clots is suppressed on blood contact surfaces where such protein adsorption is suppressed. On the other hand, when the acyl residue of the organic carboxylic acid to be grafted is hydrophobic, albumin among plasma proteins is selectively adsorbed. Albumin is
It acts as a carrier for fatty acids in the blood and is said to have a hydrophobic pocket at the center of its molecular axis. It is thought that selective adsorption occurs because hydrophobic graft chains bind to this pocket.
It is thought that blood coagulation is unlikely to occur on blood contact surfaces where albumin is selectively adsorbed. The rationale is that proteins with sugar chains, such as fibrinogen and immunoglobulin,
Albumin binds to platelets via these sugar chains, but albumin does not have such sugar chains and does not bind specifically to platelets, so albumin does not bind to platelets through blood contact surfaces that preferentially adsorb albumin from blood. It is thought that blood clotting is less likely to occur. For the above-mentioned suppression of protein adsorption and selective adsorption of albumin, the graft chain is bound to the polymer membrane surface at two or more places, and the movement of the chain is suppressed. It is better to be able to exercise freely. This is because free graft chains shield the substantial surface of the polymer membrane and suppress protein adsorption, and in the case of hydrophilic graft chains, the effect of increasing water content is added. [Example] Next, the content of the present invention will be described in more detail with reference to Examples. Note that the measurement items described in the following examples were measured by the following methods. (1) Water permeation rate After washing the blood side and dialysate side of the dialyzer with 1500 mL of water, close one nozzle on the blood side, and add water from the other nozzle while applying a pressure of 400 mmHg. Measure water permeability. The membrane area of the dialyzer is calculated from the inner diameter, effective length, and number of hollow fiber membranes filled. (2) Clearance After cleaning the dialyzer in the same manner as in (1), while flowing water at a flow rate of 500 mL/min to the dialysate side, add 1000 ppm urea aqueous solution or 10 ppm vitamin B-12 (VB 12 ) to the blood side. Flow the aqueous solution. Sample at the blood side inlet and outlet, urea or
Obtain it from the absorbance of the concentration of VB 12 and calculate the clearance using the following formula. Clearance = (Blood side fluid volume per minute) x (Blood side inlet concentration) - (Blood side outlet concentration) / (Blood side inlet concentration) (3) Complement consumption rate Same as (1), dialysis After washing the vessel, the wash water is evacuated with dry air, and the dialyzer housing is disassembled to remove the regenerated cellulose membrane. Next, a dried regenerated cellulose membrane is obtained by vacuum drying. This membrane is cut into pieces of 2 mm length, placed in a polyethylene tube, 200 µ of guinea pig complement diluted 4 times with GV buffer is added thereto, and the mixture is incubated at 37°C for 1 hour. The complement value in the supernatant was calculated using the modified Mayer method (MM
Mayer: Immunochemistry, 2nd edition, page 133, CCThomas Publisher,
(1961, Reference). i.e. 50 of complement
Determine the % hemolysis value (CH50 value) and calculate the complement consumption rate (% CH50) relative to the control. Example 1 Lauric acid 0.51g, 4-dimethylaminopyridine 0.02g, dicyclohexylcarbodiimide 0.26
g and 1,1,2-trichloro-1,2,2-trifluoroethane-acetone mixed solvent (acetone
12.5wt%) was added to the treatment solution. This treatment solution was added to a regenerated cellulose hollow fiber membrane (inner diameter 200μ).
bundle (approx. 7000 pieces) (film thickness 13μm, length 30cm)
(book) was soaked vertically for 30 minutes, occasionally raising and lowering it. The treated regenerated cellulose hollow fiber membrane bundle was immersed in methyl alcohol for a day and night, and then dried under reduced pressure at room temperature to obtain an esterified hollow fiber membrane bundle. Insert this hollow fiber membrane bundle into the dialyzer housing,
The dialyzer was assembled by potting both ends with polyurethane resin. Next, the blood side and dialysate side of the dialyzer were each washed and filled with 1500 mL of distilled water for injection. With the dialysis machine moistened with this hollow fiber membrane sealed in a polyethylene bag,
A sterilized dialyzer was obtained by high-pressure steam sterilization at a temperature of 1 Kg/cm 2 . This sterilized dialyzer, an unsterilized dialyzer incorporating an esterified hollow fiber membrane bundle as above, and a dialyzer incorporating an untreated regenerated cellulose hollow fiber membrane bundle and autoclaving as above. The dialysis performance and complement consumption rate of the dialyzer were measured. The results are shown in Table 1. Blood compatibility is improved by the esterification process and is not diminished by sterilization. Furthermore, dialysis performance does not change due to esterification treatment and sterilization operations.
【表】
実施例 ２
実施例１と同様にしてエステル化を行ない、次
いで、組み立てた透析器の血液側及び透析液側を
各々1500ｍＬの0.01ｇ／dLピロ亜硫酸ナトリウム
水溶液で洗浄充填した。この中空糸膜を湿潤させ
た透析器をポリエチレン製の袋に封入し、さらに
段ボールケースに入れて包装した。この状態でカ
ンマー線2.5メガラドを照射して滅菌処理を施し、
滅菌された透析器を取得した。
この滅菌された透析器、上記と同様にエステル
化された中空糸膜束を組み込んだ滅菌前の透析
器、及び未処理の再生セルロース中空糸膜束を組
み込み上記と同様にガンマー線滅菌した透析器に
ついて、透析器の透析性能及び補体消費率の測定
を実施した。結果を第２表に示す。エステル化処
理により血液に対する適合性は改善され、滅菌操
作により減することはない。また、透析性能はエ
ステル化処理および滅菌操作により変動しない。[Table] Example 2 Esterification was carried out in the same manner as in Example 1, and then the blood side and dialysate side of the assembled dialyzer were each washed and filled with 1500 mL of 0.01 g/dL sodium pyrosulfite aqueous solution. The dialyzer with the hollow fiber membrane moistened was sealed in a polyethylene bag, and then packaged in a cardboard case. In this state, sterilization was performed by irradiating with 2.5 megarads of commer radiation.
A sterile dialyzer was obtained. This sterilized dialyzer, an unsterilized dialyzer incorporating an esterified hollow fiber membrane bundle in the same manner as above, and a dialyzer incorporating an untreated regenerated cellulose hollow fiber membrane bundle and gamma ray sterilization in the same manner as above. The dialysis performance and complement consumption rate of the dialyzer were measured. The results are shown in Table 2. Blood compatibility is improved by esterification and is not reduced by sterilization. Furthermore, dialysis performance does not change due to esterification treatment and sterilization operations.
【表】【table】
【表】
実施例 ３
処理液として、無水カプロン酸0.44ｇ、ジメチ
ルアミノピリジン0.02ｇ及び１，１，２−トリク
ロロ−１，２，２−トリフルオロエタン−アセト
ン混合溶媒（アセトン12.5wt％）700mlを加え調
合した液を用いた以外実施例１と同様にエステル
化処理、透析器の組み立て、充填液の洗浄充填及
び高圧蒸気滅菌を施し、滅菌された透析器（実施
例３−１）を取得した。
また、上記と同様にエステル化処理した中空糸
膜束を使用して、実施例２と同様に透析器に組み
立て、充填液の洗浄充填及びガンマー線滅菌を施
し、滅菌された透析器（実施例３−２）を取得し
た。
実施例３−１、実施例３−２及び上記と同様に
エステル化された中空糸膜束を組み込だ滅菌前の
透析器について、透析器の透析性能及び補体消費
率の測定を実施した。結果を第３表に示す。エス
テル化処理により血液に対する適合性は改善さ
れ、滅菌操作により減ずることはない。また、透
析性能はエステル化処理および滅菌操作により変
動しない。[Table] Example 3 As a treatment liquid, 0.44 g of caproic anhydride, 0.02 g of dimethylaminopyridine, and 700 ml of 1,1,2-trichloro-1,2,2-trifluoroethane-acetone mixed solvent (acetone 12.5 wt%) A sterilized dialyzer (Example 3-1) was obtained by carrying out the esterification treatment, assembling the dialyzer, cleaning and filling the filling liquid, and high-pressure steam sterilization in the same manner as in Example 1 except that a solution prepared by adding did. In addition, using the hollow fiber membrane bundle esterified in the same manner as above, it was assembled into a dialyzer in the same manner as in Example 2, and the filling solution was washed and filled and gamma ray sterilized, and the sterilized dialyzer (Example 3-2) was obtained. The dialysis performance and complement consumption rate of the dialyzers were measured for the dialyzers incorporating esterified hollow fiber membrane bundles in the same manner as Example 3-1, Example 3-2, and the above before sterilization. . The results are shown in Table 3. Blood compatibility is improved by esterification and is not diminished by sterilization. Furthermore, dialysis performance does not change due to esterification treatment and sterilization operations.
【表】
実施例 ４
処理液として、アルコキシポリエチレングライ
コールモノカルボン酸
C13H27−（OCH2CH2）7−OCH2CO2H0.64ｇ、
４−ジメチルアミノピリジン0.02ｇ、ジシクロヘ
キシルカルボジイミド0.26ｇ及び１，１，２−ト
リクロロ−１，２−２，−トリフルオロエタン−
アセトン−混合溶媒（アセトン12.5wt％）700ml
を加え調合した液を用いた以外実施例１と同様に
エステル化処理、透析器の組み立、充填液の洗浄
充填及び高圧蒸気滅菌を施し、滅菌された透析器
（実施例４−１）を取得した。
また、上記と同様にエステル化処理した中空糸
膜束を使用して、実施例２と同様に透析器の組み
立て、充填液の洗浄充填及びガンマー線滅菌を施
し、滅菌された透析器（実施例４−２）を取得し
た。
実施例４−１、実施例４−２及び上記と同様に
エステル化された中空糸膜束を組み込だ滅菌前の
透析器について、透析器の透析性能及び補体消費
率の測定を実施した。結果を第４表に示す。エス
テル化処理により血液に対する適合性は改善さ
れ、滅菌操作により減するごとはない。また、透
析性能はエステル化処理および滅菌操作により変
動しない。[Table] Example 4 As a treatment liquid, alkoxypolyethylene glycol monocarboxylic acid C 13 H 27 −(OCH 2 CH 2 ) 7 −OCH 2 CO 2 H0.64 g,
0.02 g of 4-dimethylaminopyridine, 0.26 g of dicyclohexylcarbodiimide and 1,1,2-trichloro-1,2-2,-trifluoroethane-
Acetone-mixed solvent (acetone 12.5wt%) 700ml
A sterilized dialyzer (Example 4-1) was obtained by carrying out the esterification treatment, assembling the dialyzer, cleaning and filling the filling liquid, and high-pressure steam sterilization in the same manner as in Example 1, except that a solution prepared by adding . did. In addition, using the hollow fiber membrane bundle that had been esterified in the same manner as above, a dialyzer was assembled, the filling solution was cleaned and filled, and gamma ray sterilization was performed in the same manner as in Example 2. 4-2) was obtained. The dialysis performance and complement consumption rate of the dialyzers were measured for the dialyzers incorporating esterified hollow fiber membrane bundles in the same manner as Example 4-1, Example 4-2, and the above before sterilization. . The results are shown in Table 4. Blood compatibility is improved by esterification and is not diminished by sterilization. Furthermore, dialysis performance does not change due to esterification treatment and sterilization operations.
【表】
実施例 ５
処理液として、メトキシポリエチレングライコ
ールモノカルボン酸
CH3−（OCH2CH2）7−OCH2CO2H0.64ｇ、４
−ジメチルアミノピリジン0.02ｇ、ジシクロヘキ
シルカルボジイミド0.26ｇ及び１，１，２−トリ
クロロ−１，２，２−トリフルオロエタン−アセ
トン混合溶媒（アセトン12.5wt％）700mlを加え
調合した液を用いた以外実施例１と同様にエステ
ル化処理、透析器の組み立て、充填液の洗浄充填
及び高圧蒸気滅菌を施し、滅菌された透析器（実
施例５−１）を取得した。
また、上記と同様にエステル化処理した中空糸
膜束を使用して、実施例２と同様に透析器の組み
立て、充填液の洗浄充填及びガンマー線滅菌を施
し、滅菌された透析器（実施例５−２）を取得し
た。
実施例５−１、実施例５−２及び上記と同様に
エステル化された中空糸膜束を組み込だ滅菌前の
透析器について、透析器の透析性能及び補体消費
率の測定を実施した。結果を第５表に示す。エス
テル化処理により血液に対する適合性は改善さ
れ、滅菌操作により減ずることはない。また、透
析性能はエステル化処理および滅菌操作により変
動しない。[Table] Example 5 As a treatment liquid, methoxypolyethylene glycol monocarboxylic acid CH 3 −(OCH 2 CH 2 ) 7 −OCH 2 CO 2 H0.64 g, 4
-Executed except using a solution prepared by adding 0.02 g of dimethylaminopyridine, 0.26 g of dicyclohexylcarbodiimide, and 700 ml of a mixed solvent of 1,1,2-trichloro-1,2,2-trifluoroethane-acetone (acetone 12.5 wt%). In the same manner as in Example 1, esterification treatment, assembly of the dialyzer, cleaning and filling of the filling liquid, and high-pressure steam sterilization were performed to obtain a sterilized dialyzer (Example 5-1). In addition, using the hollow fiber membrane bundle that had been esterified in the same manner as above, a dialyzer was assembled, the filling solution was cleaned and filled, and gamma ray sterilization was performed in the same manner as in Example 2. 5-2) was obtained. The dialysis performance and complement consumption rate of the dialyzers were measured for the dialyzers incorporating esterified hollow fiber membrane bundles in the same manner as Example 5-1, Example 5-2, and the above before sterilization. . The results are shown in Table 5. Blood compatibility is improved by esterification and is not diminished by sterilization. Furthermore, dialysis performance does not change due to esterification treatment and sterilization operations.
【表】
実施例 ６
アルコキシポリエチレングライコールモノカル
ボン酸
C13H27−（OCH2CH2）7−OCH2CO2H0.32ｇ、
４−ジメチルアミノピリジン0.01ｇ、ジシクロヘ
キシルカルボジイミド0.13ｇ及び１，１，２−ト
リクロロ−１，２−２，−トリフルオロエタン−
アセトン混合溶媒（アセトン12.5wt％）350mlを
加え、処理液を調合した。この処理液を再生セル
ロース中空糸膜が組み込まれた透析器の血液側及
び透析液側に流量150ｍＬ／分で室温、60分循環
させエステル化処理を施した。過剰な処理液を排
出させた後、メタノールで20分循環洗浄し、メタ
ノールを排出した。次いで真空乾燥し、中空糸膜
がエステル化処理された透析器を取得した。
この透析器に対して実施例１と同様に、充填液
の洗浄充填及び高圧蒸気滅菌を施し、滅菌された
透析器（実施例６−１）を取得した。
また、上記と同様にエステル化処理された透析
器に対して実施例２と同様に、充填液の洗浄充
填、及びガンマー線滅菌を施し、滅菌された透析
器（実施例６−２）を取得した。
実施例６−１、実施例６−２及び上記と同様に
エステル化された滅菌前の透析器について、透析
器の透析性能及び補体消費率の測定を実施した。
結果を第６表に示す。エステル化処理により血液
に対する適合性は改善され、滅菌操作により減ず
ることはない。また、透析性能はエステル化処理
および滅菌操作により変動しない。[Table] Example 6 Alkoxypolyethylene glycol monocarboxylic acid C 13 H 27 −(OCH 2 CH 2 ) 7 −OCH 2 CO 2 H0.32g,
0.01 g of 4-dimethylaminopyridine, 0.13 g of dicyclohexylcarbodiimide and 1,1,2-trichloro-1,2-2,-trifluoroethane-
A treatment solution was prepared by adding 350 ml of acetone mixed solvent (acetone 12.5 wt%). This treated solution was circulated at room temperature for 60 minutes at a flow rate of 150 mL/min through the blood side and dialysate side of a dialyzer equipped with a regenerated cellulose hollow fiber membrane to carry out an esterification treatment. After draining the excess treatment liquid, the sample was washed with methanol for 20 minutes in circulation, and the methanol was discharged. The membrane was then vacuum dried to obtain a dialyzer whose hollow fiber membranes were esterified. This dialyzer was washed and filled with filling liquid and autoclaved in high pressure steam in the same manner as in Example 1 to obtain a sterilized dialyzer (Example 6-1). In addition, the dialyzer that had been esterified in the same manner as above was washed and filled with filling liquid and subjected to gamma ray sterilization in the same manner as in Example 2 to obtain a sterilized dialyzer (Example 6-2). did. The dialysis performance and complement consumption rate of the dialyzers were measured for Example 6-1, Example 6-2, and dialyzers before sterilization that had been esterified in the same manner as above.
The results are shown in Table 6. Blood compatibility is improved by esterification and is not diminished by sterilization. Furthermore, dialysis performance does not change due to esterification treatment and sterilization operations.
【表】
実施例 ７
実施例１、２、３−１、４−１、５−２、６−
１の透析器及び未処理の再生セルロース中空糸膜
が組み込まれた透析器（高圧蒸気滅菌及びガンマ
ー線滅菌）に対して、それぞれ犬による体外循環
を行つた。犬は体重約10Kgのピーグル犬を用い、
頚部に造設したシヤントから100ml／minの血流
をとつて透析器血液側に流した。なお、体外循環
に先だつて、生理食塩水で透析器内を洗浄した
後、ヘパリン6000U／Ｌ含有の生理食塩水で透析
器及び血液回路内を充填し、その後血液を流し
た。透析器入口部で血液を採取し白血球数を測定
した。透析直前の白血球数を100とした時、透析
後15分及び30分の値を第７表に示す。本発明の透
析器ではいずれも白血球の低下が改善されてい
る。[Table] Example 7 Examples 1, 2, 3-1, 4-1, 5-2, 6-
Extracorporeal circulation was performed by a dog on the dialyzer No. 1 and the dialyzer (autoclaved and gamma ray sterilized) incorporating an untreated regenerated cellulose hollow fiber membrane. The dog used was a peagle dog weighing approximately 10 kg.
A blood flow of 100 ml/min was taken from a shunt placed in the neck and directed to the blood side of the dialyzer. Note that, prior to extracorporeal circulation, the inside of the dialyzer was washed with physiological saline, and then the inside of the dialyzer and blood circuit were filled with physiological saline containing 6000 U/L of heparin, and then blood was allowed to flow. Blood was collected at the inlet of the dialyzer and the number of white blood cells was measured. Table 7 shows the values 15 minutes and 30 minutes after dialysis, assuming that the white blood cell count immediately before dialysis is 100. In all dialyzers of the present invention, the decrease in white blood cells is improved.
【表】
実施例 ８
実施例１、２、３−１、３−２の透析器及び未
処理の再生セルロース中空糸膜が組み込まれた透
析器（高圧蒸気滅菌及びガンマー線滅菌）を使用
して、血漿蛋白質の選択吸着をEIA（酵素免疫測
定）法で測定した。すなわち、透析器の血液側お
よび透析液側を水1500ｍＬで洗浄し、洗浄液を排
出後、透析器ハウジングを解体して中空糸膜を取
り出した。この中空糸膜内にウサギ血漿を充填
し、37℃で１時間インキユベートする。その後ウ
サギ血漿を押し出し、リン酸バツフアーで数回洗
浄する。この中空糸膜内表面に血漿を吸着させた
サンプル内にそれぞれアルブミン、イムノグロブ
リン・ジー（IgG）、フイブリノーゲンに対する
ペルオキシダーゼ標識抗体（カペル社製）を充填
し、吸着している蛋白質と抗原抗体反応させる。
PBSバツフアーで充分洗浄した後、中空糸膜を
２mm長に細断し、ポリエチレン管に入れる。この
ポリエチレン管にペルオキシダーゼの基質である
３−（ｐ−ヒドロキシフエニル）プロピオン酸及
び過酸化水素を加え、酸素反応を１時間行わしめ
て、生成する酸化物を蛍光分光で測定する。
得られた結果を第８表に示す。すなわち、抗ア
ルブミン抗体、抗イムノグロブリン・ジー抗体、
または抗フイブリノーゲン抗体を用いて測定され
る蛍光強度をそれぞれIa、Ii、Ifとした時、Ia／
Ii及びIa／Ifの値を求め、滅菌法が同じである未
処理透析器（高圧蒸気滅菌またはガンマー線滅
菌）からの中空糸膜での値で除して、（Alb／
IgG）及び（Alb／Fib）とした。このようにして
得られた値は、1.00より大きく、これら改良され
た透析器の中空糸巻では、未処理の中空糸膜より
もアルブミンを選択吸着してると言える。[Table] Example 8 Using the dialyzers of Examples 1, 2, 3-1, and 3-2 and the dialyzer incorporating an untreated regenerated cellulose hollow fiber membrane (autoclaved and gamma ray sterilized) , selective adsorption of plasma proteins was measured by EIA (enzyme immunoassay) method. That is, the blood side and dialysate side of the dialyzer were washed with 1500 mL of water, and after draining the washing liquid, the dialyzer housing was disassembled and the hollow fiber membrane was taken out. This hollow fiber membrane is filled with rabbit plasma and incubated at 37°C for 1 hour. The rabbit plasma is then extruded and washed several times with phosphate buffer. Peroxidase-labeled antibodies (manufactured by Capel) for albumin, immunoglobulin G (IgG), and fibrinogen are filled into the sample with plasma adsorbed on the inner surface of the hollow fiber membrane, and antigen-antibody reactions are caused with the adsorbed proteins. .
After thoroughly washing with PBS buffer, the hollow fiber membrane is cut into pieces of 2 mm length and placed in a polyethylene tube. 3-(p-hydroxyphenyl)propionic acid, which is a substrate for peroxidase, and hydrogen peroxide are added to this polyethylene tube, an oxygen reaction is allowed to proceed for 1 hour, and the produced oxide is measured by fluorescence spectroscopy. The results obtained are shown in Table 8. That is, anti-albumin antibodies, anti-immunoglobulin G antibodies,
Or, when the fluorescence intensity measured using anti-fibrinogen antibody is Ia, Ii, If, respectively, Ia/
Determine the values of Ii and Ia/If, divide by the value for the hollow fiber membrane from an untreated dialyzer using the same sterilization method (autoclaved or gamma ray sterilized), and calculate (Alb/If).
IgG) and (Alb/Fib). The value thus obtained is greater than 1.00, and it can be said that the hollow fiber membranes of these improved dialyzers selectively adsorb albumin more than the untreated hollow fiber membranes.
本発明は次のような顕著な効果を奏する。
イ 第１表〜第６表に示されるように、滅菌操作
に関係なく補体の活性化が抑制され、従つて、
第７表に示されるように、本発明の透析器では
白血球一過性減少が大幅に軽減される。
ロ また、第１表〜第６表に示されるように、膜
の透水性能や透過性能は、エステル化処理や滅
菌操作によつて殆ど変動しない。
ハ 第８表、第９表に示されるように、表面の生
物学的性質に効果があり、親水性の有機カルボ
ン酸アシル残基が結合した場合、蛋白質の吸着
量が減少し、疎水性の有機カルボン酸アシル残
基が結合した場合、アルブミンの選択吸着清が
増大し、何れも血栓生成を抑制し、膜の血液親
和性を向上させる。
ニ 製造に要する反応温度が低く、また反応時間
も短いので、この点からも再生セルロース膜の
物性が変化することがない。
ホ 製造が容易であり、用いた試薬等を除去する
ことも容易であるので、本発明により経済的で
安全性の高い透析器が得られる。
The present invention has the following remarkable effects. B. As shown in Tables 1 to 6, complement activation is suppressed regardless of the sterilization procedure, and therefore,
As shown in Table 7, the dialyzer of the present invention significantly reduces the transient decrease in white blood cells. Furthermore, as shown in Tables 1 to 6, the water permeability and permeability of the membrane hardly change due to esterification treatment or sterilization operation. C. As shown in Tables 8 and 9, it has an effect on the biological properties of the surface, and when hydrophilic organic carboxylic acid acyl residues are bonded, the amount of protein adsorbed decreases and hydrophobic When organic carboxylic acid acyl residues are bound, the selective adsorption of albumin increases, both of which suppress thrombus formation and improve the blood affinity of the membrane. D. Since the reaction temperature and reaction time required for production are low, the physical properties of the regenerated cellulose membrane do not change from this point of view as well. (e) The present invention provides an economical and highly safe dialyzer because it is easy to manufacture and the reagents used are easy to remove.
Claims (1)
とも血液側の膜表面の水酸基に下記(イ)〜(ハ)からな
る群より選ばれる有機カルボン酸のいずれか少な
くとも１種のアシル残基がエステル結合によりグ
ラフトされてい再生セルロース膜が組み込まれ、
かつ充填液で該再生セルロース膜が湿潤された状
態で滅菌されていることを特徴とする再生セルロ
ース膜系透析器。 (イ) 一般式が、 HO2CCH2−（OCH2CH2）o−OCH2CO2H （上式中、ｎは１〜150の整数を表わす） で示されるポリエチレングライコールジカルボ
ン酸、 (ロ) 一般式が、 HO2CCH2−（OCH2CH2）o−OR （上式中、ｎは１〜150の整数を表わし、Ｒは
炭素数１〜20個の飽和または不飽和炭化水素を
表わす） で示されるポリエチレングライコールモノカル
ボン酸、ならびに、 (ハ) 炭素数５個以上の脂肪族カルボン酸。 ２ 有機カルボン酸またはその官能性誘導体及び
エステル化触媒を反応媒体に溶解または分散させ
た溶液で再生セルロース膜を処理し、膜表面の水
酸基とエステル化反応を行なわしめ、続いて後処
理した該膜を透析器に組み込んだ後、充填液で該
膜を湿潤させ滅菌することを特徴とする再生セル
ロース膜系透析器の製造法。 ３ 有機カルボン酸またはその官能性誘導体及び
エステル化触媒を反応媒体に溶解または分散させ
た溶液を、再生セルロース膜を組み込だ透析器の
少なくとも血液側に循環または充填放置し、膜表
面の水酸基とエステル化反応を行なわしめ、続い
て後処理した後、充填液で該膜を湿潤させ滅菌す
ることを特徴とする再生セルロース膜系透析器の
製造法。[Scope of Claims] 1. In a regenerated cellulose membrane dialyzer, at least one acyl residue of an organic carboxylic acid selected from the group consisting of (a) to (c) below is attached to a hydroxyl group on the membrane surface on the blood side. A regenerated cellulose membrane is incorporated into which the groups are grafted by ester bonds,
A regenerated cellulose membrane dialyzer, characterized in that the regenerated cellulose membrane is sterilized in a wet state with a filling liquid. (a) Polyethylene glycol dicarboxylic acid whose general formula is HO 2 CCH 2 −(OCH 2 CH 2 ) o −OCH 2 CO 2 H (in the above formula, n represents an integer from 1 to 150), ( b) The general formula is HO 2 CCH 2 −(OCH 2 CH 2 ) o −OR (In the above formula, n represents an integer from 1 to 150, and R is a saturated or unsaturated hydrocarbon having 1 to 20 carbon atoms. and (iii) an aliphatic carboxylic acid having 5 or more carbon atoms. 2. A regenerated cellulose membrane is treated with a solution in which an organic carboxylic acid or its functional derivative and an esterification catalyst are dissolved or dispersed in a reaction medium to perform an esterification reaction with hydroxyl groups on the membrane surface, and the membrane is subsequently post-treated. 1. A method for producing a regenerated cellulose membrane dialyzer, which comprises incorporating the membrane into the dialyzer, and then moistening and sterilizing the membrane with a filling liquid. 3. A solution in which an organic carboxylic acid or its functional derivative and an esterification catalyst are dissolved or dispersed in a reaction medium is circulated or filled into at least the blood side of a dialyzer incorporating a regenerated cellulose membrane, and the hydroxyl groups on the membrane surface are 1. A method for producing a regenerated cellulose membrane dialyzer, which comprises carrying out an esterification reaction, followed by post-treatment, and then moistening the membrane with a filling liquid to sterilize it.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP63136653A JPH01307406A (en) | 1988-06-04 | 1988-06-04 | Dialyzer provided with improved regenerated cellulose membrane and production thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP63136653A JPH01307406A (en) | 1988-06-04 | 1988-06-04 | Dialyzer provided with improved regenerated cellulose membrane and production thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH01307406A JPH01307406A (en) | 1989-12-12 |
| JPH0470047B2 true JPH0470047B2 (en) | 1992-11-09 |
Family
ID=15180361
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP63136653A Granted JPH01307406A (en) | 1988-06-04 | 1988-06-04 | Dialyzer provided with improved regenerated cellulose membrane and production thereof |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH01307406A (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9139661B2 (en) * | 2012-06-25 | 2015-09-22 | Yagna Limited | Methods for biocompatible derivitization of cellulosic surfaces |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS6099260A (en) * | 1983-11-02 | 1985-06-03 | 東洋紡績株式会社 | Autoclave pasturization of cellulose ester hollow fiber typeseparation membrane |
-
1988
- 1988-06-04 JP JP63136653A patent/JPH01307406A/en active Granted
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS6099260A (en) * | 1983-11-02 | 1985-06-03 | 東洋紡績株式会社 | Autoclave pasturization of cellulose ester hollow fiber typeseparation membrane |
Also Published As
| Publication number | Publication date |
|---|---|
| JPH01307406A (en) | 1989-12-12 |
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