JPH0459008B2 - - Google Patents
Info
- Publication number
- JPH0459008B2 JPH0459008B2 JP63277415A JP27741588A JPH0459008B2 JP H0459008 B2 JPH0459008 B2 JP H0459008B2 JP 63277415 A JP63277415 A JP 63277415A JP 27741588 A JP27741588 A JP 27741588A JP H0459008 B2 JPH0459008 B2 JP H0459008B2
- Authority
- JP
- Japan
- Prior art keywords
- membrane
- regenerated cellulose
- acid
- polyethylene glycol
- monocarboxylic 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 64
- 239000004627 regenerated cellulose Substances 0.000 claims description 42
- 239000002202 Polyethylene glycol Substances 0.000 claims description 23
- 229920001223 polyethylene glycol Polymers 0.000 claims description 23
- 150000002762 monocarboxylic acid derivatives Chemical class 0.000 claims description 21
- 239000002253 acid Substances 0.000 claims description 16
- 238000005886 esterification reaction Methods 0.000 claims description 15
- 239000003054 catalyst Substances 0.000 claims description 14
- 239000012429 reaction media Substances 0.000 claims description 11
- 230000032050 esterification Effects 0.000 claims description 10
- 229920005597 polymer membrane Polymers 0.000 claims description 10
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 8
- 238000004519 manufacturing process Methods 0.000 claims description 7
- 150000002148 esters Chemical group 0.000 claims description 4
- 125000004432 carbon atom Chemical group C* 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 2
- 230000003993 interaction Effects 0.000 claims 1
- 229920006254 polymer film Polymers 0.000 claims 1
- 238000000034 method Methods 0.000 description 19
- 239000012510 hollow fiber Substances 0.000 description 17
- 238000000502 dialysis Methods 0.000 description 15
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 12
- 238000006243 chemical reaction Methods 0.000 description 12
- 230000000295 complement effect Effects 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 10
- 210000004369 blood Anatomy 0.000 description 10
- 239000008280 blood Substances 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- -1 monocarboxylic acid halide Chemical class 0.000 description 7
- 230000001954 sterilising effect Effects 0.000 description 7
- 238000004659 sterilization and disinfection Methods 0.000 description 7
- 210000000265 leukocyte Anatomy 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- RGUKYNXWOWSRET-UHFFFAOYSA-N 4-pyrrolidin-1-ylpyridine Chemical compound C1CCCN1C1=CC=NC=C1 RGUKYNXWOWSRET-UHFFFAOYSA-N 0.000 description 5
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical class C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 5
- 150000008065 acid anhydrides Chemical class 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-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
- 229920002678 cellulose Polymers 0.000 description 4
- 239000001913 cellulose Substances 0.000 description 4
- 239000012046 mixed solvent Substances 0.000 description 4
- 239000000376 reactant Substances 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 230000001052 transient effect Effects 0.000 description 4
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- 241000282472 Canis lupus familiaris Species 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
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 230000004913 activation Effects 0.000 description 3
- 150000001718 carbodiimides Chemical class 0.000 description 3
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N ethylene glycol Natural products OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 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
- 239000007788 liquid Substances 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
- 239000000126 substance Substances 0.000 description 3
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 230000017531 blood circulation Effects 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 239000004202 carbamide Substances 0.000 description 2
- 150000001735 carboxylic acids Chemical class 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 230000004087 circulation Effects 0.000 description 2
- 238000004140 cleaning Methods 0.000 description 2
- ZURAKLKIKYCUJU-UHFFFAOYSA-N copper;azane Chemical compound N.[Cu+2] ZURAKLKIKYCUJU-UHFFFAOYSA-N 0.000 description 2
- 235000019441 ethanol Nutrition 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- 238000004388 gamma ray sterilization Methods 0.000 description 2
- 150000004820 halides Chemical class 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
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 210000000056 organ Anatomy 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- 230000000704 physical effect Effects 0.000 description 2
- 229920000642 polymer Polymers 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 2
- UJPMYEOUBPIPHQ-UHFFFAOYSA-N 1,1,1-trifluoroethane Chemical compound CC(F)(F)F UJPMYEOUBPIPHQ-UHFFFAOYSA-N 0.000 description 1
- UGCSPKPEHQEOSR-UHFFFAOYSA-N 1,1,2,2-tetrachloro-1,2-difluoroethane Chemical compound FC(Cl)(Cl)C(F)(Cl)Cl UGCSPKPEHQEOSR-UHFFFAOYSA-N 0.000 description 1
- AJDIZQLSFPQPEY-UHFFFAOYSA-N 1,1,2-Trichlorotrifluoroethane Chemical compound FC(F)(Cl)C(F)(Cl)Cl AJDIZQLSFPQPEY-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
- 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
- GWYFCOCPABKNJV-UHFFFAOYSA-M 3-Methylbutanoic acid Natural products CC(C)CC([O-])=O GWYFCOCPABKNJV-UHFFFAOYSA-M 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
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 1
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 1
- 239000002841 Lewis acid Substances 0.000 description 1
- 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
- 239000004698 Polyethylene Substances 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 208000001647 Renal Insufficiency Diseases 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 238000000944 Soxhlet extraction Methods 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
- 239000000853 adhesive Substances 0.000 description 1
- 230000001070 adhesive effect Effects 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 230000002785 anti-thrombosis Effects 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 229940127219 anticoagulant drug 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
- 210000000601 blood cell Anatomy 0.000 description 1
- 230000023555 blood coagulation Effects 0.000 description 1
- 238000004820 blood count Methods 0.000 description 1
- 238000000861 blow drying Methods 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 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
- 150000002170 ethers Chemical class 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000000835 fiber Substances 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 238000001631 haemodialysis Methods 0.000 description 1
- 230000000322 hemodialysis Effects 0.000 description 1
- 230000002949 hemolytic effect Effects 0.000 description 1
- 229960002897 heparin Drugs 0.000 description 1
- 229920000669 heparin Polymers 0.000 description 1
- 238000007654 immersion Methods 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 201000006370 kidney failure Diseases 0.000 description 1
- 150000007517 lewis acids Chemical class 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000011707 mineral Chemical class 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 150000002763 monocarboxylic acids Chemical class 0.000 description 1
- YKYONYBAUNKHLG-UHFFFAOYSA-N n-Propyl acetate Natural products CCCOC(C)=O YKYONYBAUNKHLG-UHFFFAOYSA-N 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 229940090181 propyl acetate Drugs 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 239000013557 residual solvent Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 238000012414 sterilization procedure Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 229920001059 synthetic polymer Polymers 0.000 description 1
- CYRMSUTZVYGINF-UHFFFAOYSA-N trichlorofluoromethane Chemical compound FC(Cl)(Cl)Cl CYRMSUTZVYGINF-UHFFFAOYSA-N 0.000 description 1
- 229940029284 trichlorofluoromethane Drugs 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 239000011592 zinc chloride Substances 0.000 description 1
- 235000005074 zinc chloride Nutrition 0.000 description 1
Description
【発明の詳細な説明】
〔産業上の利用分野〕
本発明は、人工臓器等に用いられる改良された
再生セルロース膜及びその製造法に関する。更に
詳しくは、血液に対する適合性が改良された再生
セルロース膜及びその製造法に関する。DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] The present invention relates to an improved regenerated cellulose membrane used for artificial organs, etc., and a method for producing the same. More specifically, the present invention relates to a regenerated cellulose membrane with improved blood compatibility and a method for producing the same.
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
生セルロース膜は広く用いられ、透析装置や透析
技術の進歩と共に、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、長年の実績に裏付られた高い安全性を
有しているからに他ならない。
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,
Regenerated cellulose membranes, especially copper ammonium regenerated cellulose membranes, are widely used and, along with advances in dialysis equipment and dialysis technology, play a major role in prolonging the lives of renal failure patients and reintegrating them into society. This is because the regenerated cellulose membrane has excellent dialysis performance and mechanical strength, as well as high safety backed by many years of experience.
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
床適意義は明らかではないが、再生セルロース膜
の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。 However, despite advances in dialysis therapy, various problems associated with dialysis still remain unsolved. For example, anticoagulants are administered in large doses over a long period of time,
Problems with various side effects that are thought to occur as a result of this, as well as problems with transient white blood cell reduction and activation of complement components when performing hemodialysis using regenerated cellulose membranes and some other membranes, have been pointed out. ing. Regarding the latter phenomenon, although the relationship with clinical symptoms or the clinical relevance thereof is not clear, it is desired to alleviate these phenomena without impairing the other excellent performance of the regenerated cellulose membrane.
かかる問題や現象に対して、合成高分子からな
る膜が、比較的軽微な面があると提案されている
が、これらの膜では機械的強度が弱くピンホール
が発生し易いこと、耐熱性が十分でないため滅菌
法が限定されること、及び性能のバランス、即ち
透水量と物質透過量のバランスが悪くその使用方
法が特定されるといつた欠点がある。 Films made of synthetic polymers have been proposed to be relatively minor in dealing with such problems and phenomena, but these films have weak mechanical strength, are prone to pinholes, and have poor heat resistance. There are disadvantages such as the sterilization method is limited because it is not sufficient, and the method of use is difficult to specify due to the poor balance of performance, ie, the balance between water permeation amount and material permeation amount.
一方、再生セルロース膜の血液親和性を改良す
る方法が種々提案されている。例えば、膜表面を
ヘパリン化することにより抗血栓性を付与する方
法が特開昭51−194で提案されているが、充分な
効果が得られず、またコストも割高になるため実
用化されていない。また、各種ポリマーやビタミ
ンを再生セルロース膜の表面にコーテイングする
方法も提案されているが、被膜の安定性や滅菌の
方法が限定されるなどの問題点がある。また、特
開昭61−8105には再生セルロース膜にイソシアネ
ートプレポリマーを反応させる方法が、特開昭60
−118203にはブリツジ剤を介してポリマー酸を化
学的に結合させる方法がそれぞれ提案されている
が、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
を用いて製膜した透析膜が提案されているが、血
液凝固を軽減する面での改良は十分とは言えな
い。 On the other hand, various methods have been proposed for improving the blood affinity of regenerated cellulose membranes. For example, a method of imparting antithrombotic properties by heparinizing the membrane surface was proposed in 1977, but it has not been put to practical use because it is not sufficiently effective and is expensive. do not have. In addition, methods have been proposed in which the surface of regenerated cellulose membranes is coated with various polymers and vitamins, but these methods have problems such as the stability of the coating and limited sterilization methods. In addition, JP-A-61-8105 describes a method of reacting isocyanate prepolymer with a regenerated cellulose membrane.
-118203 proposes a method of chemically bonding polymer acids via a bridging agent, but there are problems such as stability of reactants and complexity of the reaction process. Further, Japanese Patent Application Laid-Open No. 113459/1983 proposes a dialysis membrane made of modified cellulose such as diethylaminoethyl cellulose, but the improvement in reducing blood coagulation is not sufficient.
上記のように、再生セルロース膜の血液親和性
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、再生セルロースからなる高
分子膜の優れた透析性能を損なうことなく、血液
親和性を向上させた、改良された再生セルロース
膜及びその製造法を提供することにある。
As mentioned above, attempts to improve the blood affinity of regenerated cellulose membranes have advantages and disadvantages. SUMMARY OF THE INVENTION Therefore, an object of the present invention is to provide an improved regenerated cellulose membrane that has improved blood affinity without impairing the excellent dialysis performance of a polymer membrane made of regenerated cellulose, and a method for producing the same.
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だけでなく、膜表面の物
理科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、化学反応性などを考慮し、種々研究
を重ねた結果、本発明の完成に到つた。
Hydroxyl groups on the membrane surface are thought to be involved in the activation of complement components and the transient 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 physical and scientific properties of the membrane surface and improves other blood affinities. Although many combinations of molecular chain structures and functional groups are possible, we have completed the present invention after conducting various studies in consideration of biosafety, biocompatibility, economic efficiency, chemical reactivity, etc. Ivy.
すなわち、本発明によれば、再生セルロース膜
の少なくとも血液と接触する膜面にポリエチレン
グライコールモノカルボン酸またはその酸の官能
性誘導体をエステル結合させたことを特徴とする
改良された再生セルロース膜が提供される。 That is, according to the present invention, there is provided an improved regenerated cellulose membrane characterized in that polyethylene glycol monocarboxylic acid or a functional derivative of the acid is ester bonded to at least the surface of the regenerated cellulose membrane that comes into contact with blood. provided.
本発明によれば、さらにポリエチレングライコ
ールモノカルボン酸またはその酸の官能性誘導体
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することに
より、ポリエチレングライコールモノカルボン酸
またはその酸の官能性誘導体と膜表面の水酸基と
のエステル化反応を行うことを特徴とする改良さ
れた再生セルロース膜の製造法が提供される。 According to the invention, polyethylene glycol monocarboxylic acid is further produced by treating the regenerated cellulose membrane with a solution of polyethylene glycol monocarboxylic acid or a functional derivative of the acid and an esterification catalyst dissolved or dispersed in the reaction medium. There is also provided an improved method for producing a regenerated cellulose membrane, characterized by carrying out an esterification reaction between a functional derivative of the acid or a hydroxyl group on the surface of the membrane.
本発明で使用する「再生セルロース」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
させた後再生したものであつて、例えば、銅アン
モニウム法再生セルロース、ビスコースレーヨ
ン、セルロースエステルを鹸化したものが含まれ
るが、透析性能及び長年の実績により裏付けられ
た高い安全性等から銅アンモニウム法再生セルロ
ースが好んで用いられる。 The "regenerated cellulose" used in the present invention is natural cellulose that has been chemically or physically changed and then regenerated. However, copper ammonium regenerated cellulose is preferably used due to its dialysis performance and high safety backed by many years of experience.
再生セルロースの形状は、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。 The regenerated cellulose 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,
-40168 and JP-A No. 59-204912, the film thickness is 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.
本発明で用いられるポリエチレングライコール
モノカルボン酸は、一般式が、
HO2CCH2−（OCH2CH2）o−OR
（ｎ＝１〜150；
Ｒ＝炭素数が３〜20の飽和または不飽和炭
化水素）
で示される。従つて、本発明では、エステル結合
したポリエチレングライコールモノカルボン酸残
基が分子鎖に相当する。 The polyethylene glycol monocarboxylic acid used in the present invention has a general formula of HO2CCH2- ( OCH2CH2 ) o -OR (n=1 to 150; R=saturated or unsaturated with 3 to 20 carbon atoms ) . saturated hydrocarbon). Therefore, in the present invention, the ester-bonded polyethylene glycol monocarboxylic acid residue corresponds to the molecular chain.
本発明では、上記ポリエチレングライコールモ
ノカルボン酸のハロゲン化物、酸無水物等の官能
性誘導体も使用できる。ポリエチレングライコー
ルモノ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ポリエチレング
ライコールモノカルボン酸クロライドが好まし
い。また、ポリエチレングライコールモノカルボ
ン酸無水物としては、上記ポリエチレングライコ
ールモノカルボン酸を２分子脱水縮合させた単独
の酸無水物、または上記ポリエチレングライコー
ルモノカルボン酸とその他の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
的とするポリエチレングライコールモノカルボン
酸を優先的にエステル結合させるために、その他
のカルボン酸として、立体障害の大きいカルボン
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。 In the present invention, functional derivatives of the polyethylene glycol monocarboxylic acid such as halides and acid anhydrides can also be used. As the polyethylene glycol monocarboxylic acid halide, polyethylene glycol monocarboxylic acid chloride is preferred from the viewpoint of ease of handling and safety when remaining. In addition, as the polyethylene glycol monocarboxylic acid anhydride, a single acid anhydride obtained by dehydrating and condensing two molecules of the above-mentioned polyethylene glycol monocarboxylic acid, or a mixed acid of the above-mentioned polyethylene glycol monocarboxylic acid and other carboxylic acids. Anhydrous can be used. In the latter case, in order to preferentially ester bond the target polyethylene glycol monocarboxylic acid, a mixed acid anhydride using a highly sterically hindered carboxylic acid, such as isobutyric acid or isovaleric acid, is used as the other carboxylic acid. or alkyl hydrogen carbonate (HOCO 2 R; R=
A mixed acid anhydride using an alkyl group) is preferred.
これらのポリエチレングライコールモノカルボ
ン酸またはその官能性誘導体は、0.5〜50mmol／
Ｌの低濃度で用いられ、膜への付着残留や経済性
の点から１〜10mmol／Ｌの濃度で有利に使用さ
れる。 These polyethylene glycol monocarboxylic acids or their functional derivatives can be used in amounts of 0.5 to 50 mmol/
It is used at a low concentration of L, and is advantageously used at a concentration of 1 to 10 mmol/L from the viewpoint of residual adhesion to the membrane and economic efficiency.
再生セルロース膜の表面へのエステル結合は、
膜表面に存在する水酸基とのエステル化反応によ
つて行われ、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酸の官能性誘導体との反
応が適用できる。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。すなわち、５℃以上かつ120℃または
用いる反応媒体の沸点のいずれか低い方の温度以
下で、１分〜24時間の処理時間の条件が用いら
れ、好ましくは15℃以上かつ90℃または用いる反
応媒体の沸点のいずれか低い方の温度以下の処理
温度、３〜180分の処理時間が用いられる。これ
らの条件は経済性の面からも有利である。 The ester bond to the surface of the regenerated cellulose membrane is
This is carried out by an esterification reaction with the hydroxyl groups present on the membrane surface, and a known reaction between a low-molecular alcohol and a low-molecular carboxylic acid or a functional derivative of that acid 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. That is, a treatment time of 1 minute to 24 hours is used at a temperature of 5°C or higher and 120°C or the boiling point of the reaction medium used, whichever is lower, preferably 15°C or higher and 90°C or the boiling point of the reaction medium used. A treatment temperature of 3 to 180 minutes is used. These conditions are also advantageous from an economic point of view.
反応を促進させるために、エステル化触媒を使
用することが好ましい。エステル化触媒として、
カルボン酸の場合、硫酸、塩酸などの鉱酸、芳香
酸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
触媒等が用いられ、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用
いられ、また、酸無水物の場合、硫酸、ｐ−トル
エンスルホン酸、塩化亜鉛、酢酸ナトリウム、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用いられる。 Preferably, an esterification catalyst is used to accelerate the reaction. As an esterification catalyst,
In the case of carboxylic acids, mineral acids such as sulfuric acid and hydrochloric acid, organic acids such as aromatic acid sulfonic acids, Lewis acids such as boron trifluoride etherate, carbodiimide derivatives such as dicyclohexylcarbodiimide, and carbodiimide derivatives and 4-dimethylaminopyridine and/or Alternatively, a mixed catalyst with 4-pyrrolidinopyridine is used, and in the case of acid halides, pyridine, dimethylaniline, triethylamine, tetramethylurea, or metallic magnesium, etc., and these A mixed catalyst of a removing agent and 4-dimethylaminopyridine and/or 4-pyrrolidinopyridine is used, and in the case of acid anhydrides, sulfuric acid, p-toluenesulfonic acid, zinc chloride, sodium acetate, pyridine, -dimethylaminopyridine, 4-pyrrolidinopyridine, etc. are used.
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、ポリエチレングライコール
モノ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、
及びポリエチレングライコールモノカルボン酸無
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。 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, a method of esterifying polyethylene glycol monocarboxylic acid with a mixed catalyst of a carbodiimide derivative such as dicyclohexylcarbodiimide and 4-dimethylaminopyridine and/or 4-pyrrolidinopyridine,
A method of esterifying polyethylene glycol monocarboxylic acid anhydride with 4-dimethylaminopyridine and/or 4-pyrrolidinopyridine is preferably used.
反応媒体としては、ポリエチレングライコール
モノカルボン酸またはその酸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おおき
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、上記の用件を満たし、
ポリエチレングライコールモノカルボン酸または
その酸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は、全て用いられる。反応
の均一性、円滑性及び反応後の除去から、ポリエ
チレングライコールモノカルボン酸またはその酸
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、石油ベンジン、ベンゼン、
トルエン等の炭化水素類、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，トテ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。 The reaction medium should not react with polyethylene glycol monocarboxylic acid or functional derivatives of that acid, should not deactivate the esterification catalyst, and should not cause major changes in the morphology of the polymer membrane made of regenerated cellulose membrane. is necessary.
Therefore, as a reaction medium, it satisfies the above requirements,
Any solvent that will disperse or dissolve the polyethylene glycol monocarboxylic acid or functional derivative of that acid and the esterification catalyst may be used. A solvent that dissolves polyethylene glycol monocarboxylic acid or a functional derivative of the acid and the esterification catalyst is preferred from the viewpoint of reaction uniformity, smoothness, and post-reaction removal. Such reaction media include, for example, n-hexane, n-heptane, cyclohexane, petroleum ether, petroleum benzine, benzene,
Hydrocarbons such as toluene, ketones such as acetone and methyl ethyl ketone, esters such as methyl acetate, ethyl acetate, and propyl acetate, ethers such as ethyl ether, isopropyl ether, and dioxane, 1,1,2-trichloro-1, 2,2-
Examples include chlorofluorinated hydrocarbons such as trifluoroethane, trichlorofluoromethane, and 1,1,2,2-tetrachloro-1,2-difluoroethane. These reaction media can be used alone or in mixtures. From the viewpoint of safety for living organisms and removal after the reaction, a reaction medium containing chlorofluorinated hydrocarbons, especially 1,1,2-trichloro-1,2,2-trifluoroethane, is preferred; A mixed solvent of -trichloro-1,2,2, totefluoroethane and acetone is preferably used.
再生セルロース膜を処理する方法としては種々
の方法がある。即ち、ポリエチレングライコール
モノカルボン酸または酸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方
法、処理液を充填した浸漬槽内に高分子膜を浸漬
させる方法、高分子膜を充填した処理槽に処理液
を循環する方法が採用できる。さらに、再生セル
ロースからなる高分子膜を透析器等に組み立てた
後、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方法も当然
採用できる。 There are various methods for treating regenerated cellulose membranes. That is, a method in which a regenerated cellulose membrane is added to a treatment solution in which polyethylene glycol monocarboxylic acid or a functional derivative of an acid and an esterification catalyst are dispersed or dissolved in a reaction medium and stirred; A method in which the polymer membrane is immersed, and a method in which the treatment liquid is circulated through a treatment tank filled with the polymer membrane can be adopted. Furthermore, after assembling a polymer membrane made of regenerated cellulose into a dialyzer or the like, it is naturally possible to adopt a method in which a treatment liquid is circulated or filled at least on the side through which blood flows and left to stand.
エステル化反応終了後、再生セルロース膜は処
理液と分離させ、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。 After the esterification reaction is completed, the regenerated cellulose membrane is separated from the processing solution, and is omitted if no reaction reagents, esterification catalysts, or side reaction products remain on the membrane, but washing is usually performed to remove these. be exposed. This washing operation includes the solvent used in the reaction,
Alternatively, immersion extraction or Soxhlet extraction is performed using 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.
このようにして膜表面の水酸基がエステル化さ
れた再生セルロースからなる高分子膜では、実施
例に示されるように用いる高分子膜の優れた透析
性能が損なわれることなく、補体成分の活性化作
用が抑制され、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
応が高分子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。 In this way, the polymer membrane made of regenerated cellulose in which the hydroxyl groups on the membrane surface have been esterified can activate complement components without impairing the excellent dialysis performance of the polymer membrane used, as shown in the examples. The effect is suppressed, and the transient decrease in white blood cells becomes 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 polymer 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.
このため、本発明では、上述のようにエステル
結合されるポリエチレングライコールモノカルボ
ン酸またはその酸の官能性誘導体は、低濃度で使
用されているにもかかわらず、再生セルロースを
十分に改良する。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で開示されている
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。 Therefore, in the present invention, polyethylene glycol monocarboxylic acid or a functional derivative of that acid which is ester-linked as described above sufficiently improves the regenerated cellulose even though it is used in a low concentration. This is something that could not have been predicted until now. That is, in the example disclosed in EP-155534 in which isocyanate is reacted, the concentration of the reactant is quite high, 1 to 15% by volume, but in the present invention, the concentration of the reactant is only a few hundred.
It is fully effective even at low concentrations of 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.
治療に使用する前に滅菌操作が必要であるが、
本発明の再生セルロース膜は、各種の滅菌法を利
用することができる。即ち、組み込んだ透析器
を、そのまま乾燥状態で滅菌する。エチレンオキ
サイドガス滅菌、高圧蒸気滅菌、及びガンマー線
滅菌等が利用でき、または組み込んだ透析器に水
または生理食塩水などを充填した後滅菌する、高
圧蒸気滅菌、またはガンマー線滅菌などが利用で
きる。このような滅菌操作によつて、改良された
血液親和性が変化することはない。 Sterilization is required before use for treatment, but
The regenerated cellulose membrane of the present invention can be sterilized using various sterilization methods. That is, the assembled dialyzer is sterilized in a dry state. Ethylene oxide gas sterilization, high-pressure steam sterilization, gamma ray sterilization, etc. can be used, or high-pressure steam sterilization, gamma ray sterilization, etc., in which a built-in dialyzer is filled with water or physiological saline and then sterilized, can be used. Such sterilization procedures do not alter the improved hemocompatibility.
次に、実施例により本発明の内容をさらに詳細
に述べる。
Next, the content of the present invention will be described in more detail with reference to Examples.
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。 Note that the measurement items described in the following examples were measured by the following methods.
(1) 透水量
100本の中空繊維の束の両端を接着剤で固定し
たモジユールを作り、中空部に水を満たした後、
片端を閉じ、開口部より200mmHg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。中空繊維の膜面積は、内径及びモジユール
の有効長を測って計算により求める。(1) Water permeability After making a module by fixing both ends of a bundle of 100 hollow fibers with adhesive and filling the hollow part with water,
Close one end, pour water through the opening while applying a pressure of 200 mmHg, and measure the amount of water permeation per unit time. The membrane area of the hollow fiber is calculated by measuring the inner diameter and the effective length of the module.
(2) クリアランス
(1)と同様のモジユールを作り、水の代わりに
1000ppmの尿素水溶液、または100ppmのビタミ
ンＢ−12（VB12）水溶液を用いて、(1)と同様の方
法で透析液中の濃度を、吸光度から求めて、次式
よりクリアランスを計算する。(2) Clearance Make a module similar to (1) and use water instead of water.
Using a 1000 ppm urea aqueous solution or a 100 ppm vitamin B-12 (VB 12 ) aqueous solution, the concentration in the dialysate is determined from the absorbance in the same manner as in (1), and the clearance is calculated from the following formula.
クリアランス＝（透析液中の濃度）×
（１分間当たりの透析液量）／（透析前の濃度）
(3) 補体消費率
試料が中空繊維の場合は、２mm長に細断し、ま
たフイルムの場合は2.5×2.5mm2の細片とし、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（コーデイス・ラボ）
200plを加え、37℃で１時間撹拌しながらインキ
ユベートした。補体価はマイヤー変法（エム・エ
ム・マイヤー（M.M.Mayer）：イムノケミスト
リー（Immunochemisrtry）第２版、第133頁、
シー・シー・トーマス（C.C.Thomas）出版者、
1961年、参照）によつて求めた。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）を算出した。 Clearance = (concentration in dialysate) ×
(Volume of dialysate per minute) / (Concentration before dialysis) (3) Complement consumption rate If the sample is a hollow fiber, cut it into 2 mm long pieces, or if it is a film, cut it into 2.5 x 2.5 mm 2 pieces. Guinea pig complement (Cordis Labs) was placed into pieces, placed in a polyethylene tube, and diluted 4 times with GV buffer.
200 pl was added and incubated at 37°C for 1 hour with stirring. Complement values are determined by Mayer's modified method (MMMayer: Immunochemistry, 2nd edition, p. 133,
CCThomas Publisher,
(1961, Reference). i.e. 50% of complement
The hemolytic value (CH50 value) was determined, and the complement consumption rate (% CH50) relative to the control was calculated.
実施例 １
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％）250mlに、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−（OCH2
CH2）7−OCH2CO2Ｈ）0.25g、４−ジメチルアミ
ノピリジン0.01g、及びジシクロヘキシルカルボ
ジイミド0.09gを加え、処理液を調合した。この
処理液に再生セルロース中空糸膜（内径200μm、
膜厚13μm、長さ約20cm）を約600本を垂直に２時
間時々上下に動かしながら浸漬した。処理した中
空糸膜をメタノール中に一昼夜浸漬した後室温で
減圧乾燥し、エステル化された再生セルロース中
空糸膜を得た。補体消費率を測定すると、11％で
あつた。Example 1 1,1,2-trichloro-1,2,2-trifluoroethane-acetone mixed solvent (acetone
12.5wt%) to 250ml of alkoxypolyethylene glycol monocarboxylic acid ( C13H27- ( OCH2
A treatment liquid was prepared by adding 0.25 g of CH 2 ) 7 -OCH 2 CO 2 H), 0.01 g of 4-dimethylaminopyridine, and 0.09 g of dicyclohexylcarbodiimide. This treatment solution was added to a regenerated cellulose hollow fiber membrane (inner diameter 200μm,
Approximately 600 fibers (film thickness: 13 μm, length: approximately 20 cm) were immersed vertically for 2 hours while occasionally moving up and down. The treated hollow fiber membrane was immersed in methanol overnight and then dried under reduced pressure at room temperature to obtain an esterified regenerated cellulose hollow fiber membrane. The complement consumption rate was determined to be 11%.
実施例 ２
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％）250ml、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−OCH2CO2Ｈ）0.25g、及びジシクロヘキシル
カルボジイミド0.09gを使用した以外実施例１と
同様にして、エステル化された中空糸膜を得た。
補体消費率を測定すると、13％であつた。Example 2 1,1,2-trichloro-1,2,2-trifluoroethane-acetone mixed solvent (acetone
12.5wt % ) 250ml, alkoxypolyethylene glycol monocarboxylic acid ( C13H27- ( OCH2CH2 )
An esterified hollow fiber membrane was obtained in the same manner as in Example 1 except that 0.25 g of 7 -OCH 2 CO 2 H) and 0.09 g of dicyclohexylcarbodiimide were used.
The complement consumption rate was determined to be 13%.
実施例 ３
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−OCH2CO2Ｈ）
0.64g、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％）700
mlを加え、処理液を調合した。この処理液に再生
セルロース中空糸膜（内径200μm、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。Example 3 Alkoxypolyethylene glycol monocarboxylic acid ( C13H27- ( OCH2CH2 ) 7 - OCH2CO2H )
0.64g, 4-dimethylaminopyridine 0.02g, dicyclohexylcarbodiimide 0.26g and 1,1,
2-Trichloro-1,2,2-trifluoroethane-acetone mixed solvent (acetone 12.5wt%) 700
ml was added to prepare a treatment solution. This treatment solution was coated with a regenerated cellulose hollow fiber membrane (inner diameter 200 μm, membrane thickness 13 μm,
A bundle (approximately 7,000 pieces) (length 30 cm) was soaked vertically for 30 minutes, with occasional up and down movements. 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.
この中空糸膜の透析性能を測定すると、透水量
4.5ml／mmHg／hr、尿素クリアランス168ml／
minVB12クリアランス47ml／minであり、補体消
費率は13％であつた。 When measuring the dialysis performance of this hollow fiber membrane, the water permeation rate was
4.5ml/mmHg/hr, urea clearance 168ml/
The minVB 12 clearance was 47 ml/min, and the complement consumption rate was 13%.
実施例 ４
実施例３のエステル化再生セルロース中空糸膜
及び未処理の再生セルロース中空糸膜を透析器に
組込み、それぞれ犬による体外循環を行つた。犬
は体重約10Kgのビーグル犬を用い、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、対外循環に先だつて、
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１表に示した。Example 4 The esterified regenerated cellulose hollow fiber membrane of Example 3 and the untreated regenerated cellulose hollow fiber membrane were incorporated into a dialyzer, and extracorporeal circulation was performed using a dog. The dog used was a beagle dog weighing approximately 10 kg, and blood flow at a rate of 100 ml/min was taken from a shunt created in the neck and sent to the blood side of the dialyzer. Furthermore, prior to external circulation,
After cleaning the inside of the dialyzer with physiological saline, add heparin
The dialyzer and blood circuit were filled with physiological saline containing 6000 U/L, 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 1 shows the values 15 minutes and 30 minutes after dialysis, assuming that the white blood cell count immediately before dialysis was 100.
第１表 中空糸膜 15分値 30分値 実施例３ 76 83 未処理 13 45 〔発明の効果〕 本発明は次のような顕著な効果を奏する。 Table 1 Hollow fiber membrane 15 minute value 30 minute value Example 3 76 83 Untreated 13 45 [Effects of the Invention] The present invention has the following remarkable effects.
イ 実施例１〜３に示されるように、補体の活性
化が抑制され、実施例４に示されるように、白
血球一過性減少が大幅に軽減される。B. As shown in Examples 1 to 3, complement activation is suppressed, and as shown in Example 4, transient decrease in white blood cells is significantly reduced.
ロ 実施例３に示されるように、膜の透水性能や
透過性能は未処理のセルロース膜と殆ど変化が
ない。(b) As shown in Example 3, the water permeability and permeability of the membrane are almost unchanged from those of an untreated cellulose membrane.
ハ 製造に要する反応温度が低く、また反応時間
も短いので、この点からもセルロース系高分子
膜の物性が変化することがない。C. Since the reaction temperature required for production is low and the reaction time is short, the physical properties of the cellulose polymer membrane do not change from this point of view as well.
ニ 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
安全性の高い透析膜が得られる。D. The present invention provides an economical and highly safe dialysis membrane because it is easy to manufacture and the reagents used are easy to remove.
Claims (1)
化水素 で示されるポリエチレングライコールモノカルボ
ン酸またはその酸の官能性誘導体をエステル結合
させたことを特徴とする改良された再生セルロー
ス膜。 ２ 式 HO2CCH2−（OCH2CH2）o−OR ｎ＝１〜150 Ｒ＝炭素数が３〜20の飽和または不飽和炭
化水素 で示されるポリエチレングライコールモノカルボ
ン酸またはその酸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解させた溶液で再
生セルロースからなる高分子膜を処理することに
より、ポリエチレングライコールモノカルボン酸
またはその酸の官能性誘導体と膜表面の水酸基と
のエステル化反応を行うことを特徴とする改良さ
れた再生セルロース膜の製造法。[Claims] 1. A polymer film made of regenerated cellulose containing the formula HO 2 CCH 2 −(OCH 2 CH 2 ) o −OR n=1 to 150 R=saturated or unsaturated hydrocarbon having 3 to 20 carbon atoms An improved regenerated cellulose membrane characterized in that polyethylene glycol monocarboxylic acid represented by the formula or a functional derivative of the acid is ester bonded. 2 Formula HO 2 CCH 2 −(OCH 2 CH 2 ) o −OR n=1 to 150 R=Polyethylene glycol monocarboxylic acid represented by a saturated or unsaturated hydrocarbon having 3 to 20 carbon atoms or the functionality of the acid By treating a polymer membrane made of regenerated cellulose with a solution in which a functional derivative and an esterification catalyst are dissolved or decomposed in a reaction medium, the interaction between polyethylene glycol monocarboxylic acid or a functional derivative of the acid and the hydroxyl groups on the membrane surface is achieved. An improved method for producing a regenerated cellulose membrane, characterized by carrying out an esterification reaction.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP87116444A EP0266795B2 (en) | 1986-11-07 | 1987-11-06 | Improved regenerated cellulose membrane and process for preparation thereof |
| EP87116444.8 | 1987-11-06 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH022848A JPH022848A (en) | 1990-01-08 |
| JPH0459008B2 true JPH0459008B2 (en) | 1992-09-21 |
Family
ID=8197429
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP27741588A Granted JPH022848A (en) | 1987-11-06 | 1988-11-04 | Improved regenerated cellulose membrane and its production |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH022848A (en) |
Families Citing this family (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SE514347C2 (en) * | 1998-08-06 | 2001-02-12 | Akzo Nobel Nv | Non-ionic cellulose ether and its use as a thickener in paint compositions |
| DE102010056578A1 (en) * | 2010-12-30 | 2012-07-05 | Clariant International Ltd. | Hydroxyl groups and ester-bearing polymers and processes for their preparation |
| EP3668940A1 (en) | 2017-08-15 | 2020-06-24 | Saudi Arabian Oil Company | Thermally stable surfactants for oil based drilling fluids |
| US10745606B2 (en) | 2017-08-15 | 2020-08-18 | Saudi Arabian Oil Company | Oil-based drilling fluid compositions which include layered double hydroxides as rheology modifiers |
| US10647903B2 (en) | 2017-08-15 | 2020-05-12 | Saudi Arabian Oil Company | Oil-based drilling fluid compositions which include layered double hydroxides as rheology modifiers and amino amides as emulsifiers |
| US10676658B2 (en) | 2017-08-15 | 2020-06-09 | Saudi Arabian Oil Company | Oil-based drilling fluids for high pressure and high temperature drilling operations |
| US10640696B2 (en) | 2017-08-15 | 2020-05-05 | Saudi Arabian Oil Company | Oil-based drilling fluids for high pressure and high temperature drilling operations |
| EP3668938A1 (en) * | 2017-08-15 | 2020-06-24 | Saudi Arabian Oil Company | Thermally stable surfactants for oil based drilling fluids |
| US10876039B2 (en) * | 2017-08-15 | 2020-12-29 | Saudi Arabian Oil Company | Thermally stable surfactants for oil based drilling fluids |
| US10988659B2 (en) | 2017-08-15 | 2021-04-27 | Saudi Arabian Oil Company | Layered double hydroxides for oil-based drilling fluids |
| US10793762B2 (en) | 2017-08-15 | 2020-10-06 | Saudi Arabian Oil Company | Layered double hydroxides for oil-based drilling fluids |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS63238869A (en) * | 1986-11-07 | 1988-10-04 | 筏 義人 | Blood compatible cellulosic dialytic membrane and its production |
-
1988
- 1988-11-04 JP JP27741588A patent/JPH022848A/en active Granted
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS63238869A (en) * | 1986-11-07 | 1988-10-04 | 筏 義人 | Blood compatible cellulosic dialytic membrane and its production |
Also Published As
| Publication number | Publication date |
|---|---|
| JPH022848A (en) | 1990-01-08 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US4999110A (en) | Regenerated cellulose membrane and processes for preparation thereof | |
| US4329383A (en) | Non-thrombogenic material comprising substrate which has been reacted with heparin | |
| KR100525604B1 (en) | Application of sulfone, ketone and ester containing polyalkyl ether units to medical materials | |
| US5496637A (en) | High efficiency removal of low density lipoprotein-cholesterol from whole blood | |
| US4008047A (en) | Blood compatible polymers for blood oxygenation devices | |
| US4800016A (en) | Extracorporeal blood de-heparinization system | |
| JPH0459008B2 (en) | ||
| US4415490A (en) | Non-thrombogenic material | |
| US4210529A (en) | Blood compatible polymers and applications thereof | |
| CN106943898A (en) | A kind of surface can be sustained the preparation method of anti-freezing polysulfones hemodialysis membrane | |
| JPH0323865A (en) | Medical material preparation thereof and medical appliance using the same material | |
| US4882106A (en) | Methods of manufacturing nucleophilic material modified for improved biocompatibility | |
| CN101966350A (en) | Anticoagulant treatment method for medical macromolecular material | |
| KR970007243B1 (en) | Water-soluble cellulose derivatives and biocompatible material | |
| JPS62172961A (en) | Blood contacting medical article and anti-thrombotic formation thereof | |
| JP3404514B2 (en) | Antithrombotic regenerated cellulose-based membrane | |
| JPS63238869A (en) | Blood compatible cellulosic dialytic membrane and its production | |
| JPH0529491B2 (en) | ||
| JPH0470047B2 (en) | ||
| JPH0556175B2 (en) | ||
| US5073265A (en) | Methods of manufacturing nucleophilic material modified for improved biocompatibility | |
| JPH0536065B2 (en) | ||
| JPH08299433A (en) | Method for preparing blood processing device and the blood processing device | |
| JPH0199609A (en) | Reformed regenerated cellulose membrane and production thereof | |
| Kim et al. | Protamine immobilization and heparin adsorption on the protamine‐bound cellulose fiber membrane |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| S533 | Written request for registration of change of name |
Free format text: JAPANESE INTERMEDIATE CODE: R313533 |
|
| R350 | Written notification of registration of transfer |
Free format text: JAPANESE INTERMEDIATE CODE: R350 |
|
| LAPS | Cancellation because of no payment of annual fees |