JPS6361024B2 - - Google Patents
Info
- Publication number
- JPS6361024B2 JPS6361024B2 JP57048830A JP4883082A JPS6361024B2 JP S6361024 B2 JPS6361024 B2 JP S6361024B2 JP 57048830 A JP57048830 A JP 57048830A JP 4883082 A JP4883082 A JP 4883082A JP S6361024 B2 JPS6361024 B2 JP S6361024B2
- Authority
- JP
- Japan
- Prior art keywords
- carrier
- gel
- adsorbent
- carboxylic acid
- vinyl ester
- 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
Links
- 210000001124 body fluid Anatomy 0.000 claims description 32
- 239000010839 body fluid Substances 0.000 claims description 32
- 239000003463 adsorbent Substances 0.000 claims description 29
- 239000000178 monomer Substances 0.000 claims description 23
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 19
- 229920001567 vinyl ester resin Polymers 0.000 claims description 19
- 238000000746 purification Methods 0.000 claims description 16
- 238000006116 polymerization reaction Methods 0.000 claims description 12
- 238000004132 cross linking Methods 0.000 claims description 11
- JYEUMXHLPRZUAT-UHFFFAOYSA-N 1,2,3-triazine Chemical group C1=CN=NN=C1 JYEUMXHLPRZUAT-UHFFFAOYSA-N 0.000 claims description 4
- 238000000354 decomposition reaction Methods 0.000 claims 1
- 230000036571 hydration Effects 0.000 claims 1
- 238000006703 hydration reaction Methods 0.000 claims 1
- 239000000499 gel Substances 0.000 description 45
- 239000000126 substance Substances 0.000 description 27
- 238000000034 method Methods 0.000 description 23
- 239000011148 porous material Substances 0.000 description 19
- 238000001179 sorption measurement Methods 0.000 description 18
- 210000004369 blood Anatomy 0.000 description 14
- 239000008280 blood Substances 0.000 description 14
- 239000003446 ligand Substances 0.000 description 14
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 13
- 102000004169 proteins and genes Human genes 0.000 description 13
- 108090000623 proteins and genes Proteins 0.000 description 13
- 239000000969 carrier Substances 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 230000007423 decrease Effects 0.000 description 9
- 229920000642 polymer Polymers 0.000 description 9
- 230000001954 sterilising effect Effects 0.000 description 8
- 238000004659 sterilization and disinfection Methods 0.000 description 8
- 102000009027 Albumins Human genes 0.000 description 7
- 108010088751 Albumins Proteins 0.000 description 7
- 230000004913 activation Effects 0.000 description 7
- 238000006243 chemical reaction Methods 0.000 description 7
- 230000000295 complement effect Effects 0.000 description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 210000000601 blood cell Anatomy 0.000 description 6
- 230000015271 coagulation Effects 0.000 description 6
- 238000005345 coagulation Methods 0.000 description 6
- 229920001577 copolymer Polymers 0.000 description 6
- 238000004108 freeze drying Methods 0.000 description 6
- -1 micropore structure Substances 0.000 description 6
- 238000001035 drying Methods 0.000 description 5
- 239000003960 organic solvent Substances 0.000 description 5
- 239000002245 particle Substances 0.000 description 5
- 238000007127 saponification reaction Methods 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- OZAIFHULBGXAKX-UHFFFAOYSA-N 2-(2-cyanopropan-2-yldiazenyl)-2-methylpropanenitrile Chemical compound N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- BRLQWZUYTZBJKN-UHFFFAOYSA-N Epichlorohydrin Chemical compound ClCC1CO1 BRLQWZUYTZBJKN-UHFFFAOYSA-N 0.000 description 4
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 4
- 238000001042 affinity chromatography Methods 0.000 description 4
- 230000004154 complement system Effects 0.000 description 4
- 230000006378 damage Effects 0.000 description 4
- 230000003993 interaction Effects 0.000 description 4
- 230000000704 physical effect Effects 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 238000010557 suspension polymerization reaction Methods 0.000 description 4
- 229920001059 synthetic polymer Polymers 0.000 description 4
- KOMNUTZXSVSERR-UHFFFAOYSA-N 1,3,5-tris(prop-2-enyl)-1,3,5-triazinane-2,4,6-trione Chemical compound C=CCN1C(=O)N(CC=C)C(=O)N(CC=C)C1=O KOMNUTZXSVSERR-UHFFFAOYSA-N 0.000 description 3
- 229920000936 Agarose Polymers 0.000 description 3
- 102000004506 Blood Proteins Human genes 0.000 description 3
- 108010017384 Blood Proteins Proteins 0.000 description 3
- 229920002307 Dextran Polymers 0.000 description 3
- IMROMDMJAWUWLK-UHFFFAOYSA-N Ethenol Chemical group OC=C IMROMDMJAWUWLK-UHFFFAOYSA-N 0.000 description 3
- 108060003951 Immunoglobulin Proteins 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 206010028980 Neoplasm Diseases 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- XTXRWKRVRITETP-UHFFFAOYSA-N Vinyl acetate Chemical compound CC(=O)OC=C XTXRWKRVRITETP-UHFFFAOYSA-N 0.000 description 3
- 210000001772 blood platelet Anatomy 0.000 description 3
- 201000011510 cancer Diseases 0.000 description 3
- MTHSVFCYNBDYFN-UHFFFAOYSA-N diethylene glycol Chemical compound OCCOCCO MTHSVFCYNBDYFN-UHFFFAOYSA-N 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 125000003700 epoxy group Chemical group 0.000 description 3
- 239000007789 gas Substances 0.000 description 3
- 208000006454 hepatitis Diseases 0.000 description 3
- 231100000283 hepatitis Toxicity 0.000 description 3
- 230000003100 immobilizing effect Effects 0.000 description 3
- 102000018358 immunoglobulin Human genes 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 230000003211 malignant effect Effects 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- 239000002609 medium Substances 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 206010039073 rheumatoid arthritis Diseases 0.000 description 3
- 235000011121 sodium hydroxide Nutrition 0.000 description 3
- 201000000596 systemic lupus erythematosus Diseases 0.000 description 3
- 238000005809 transesterification reaction Methods 0.000 description 3
- BBMCTIGTTCKYKF-UHFFFAOYSA-N 1-heptanol Chemical compound CCCCCCCO BBMCTIGTTCKYKF-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 208000023275 Autoimmune disease Diseases 0.000 description 2
- BPYKTIZUTYGOLE-IFADSCNNSA-N Bilirubin Chemical compound N1C(=O)C(C)=C(C=C)\C1=C\C1=C(C)C(CCC(O)=O)=C(CC2=C(C(C)=C(\C=C/3C(=C(C=C)C(=O)N\3)C)N2)CCC(O)=O)N1 BPYKTIZUTYGOLE-IFADSCNNSA-N 0.000 description 2
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 239000004372 Polyvinyl alcohol Substances 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 229920002684 Sepharose Polymers 0.000 description 2
- 208000007536 Thrombosis Diseases 0.000 description 2
- ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Chemical compound O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- RJURFGZVJUQBHK-UHFFFAOYSA-N actinomycin D Natural products CC1OC(=O)C(C(C)C)N(C)C(=O)CN(C)C(=O)C2CCCN2C(=O)C(C(C)C)NC(=O)C1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=CC=C3C(=O)NC4C(=O)NC(C(N5CCCC5C(=O)N(C)CC(=O)N(C)C(C(C)C)C(=O)OC4C)=O)C(C)C)=C3N=C21 RJURFGZVJUQBHK-UHFFFAOYSA-N 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 239000000427 antigen Substances 0.000 description 2
- 102000036639 antigens Human genes 0.000 description 2
- 108091007433 antigens Proteins 0.000 description 2
- 239000012736 aqueous medium Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 239000003431 cross linking reagent Substances 0.000 description 2
- OPTASPLRGRRNAP-UHFFFAOYSA-N cytosine Chemical compound NC=1C=CNC(=O)N=1 OPTASPLRGRRNAP-UHFFFAOYSA-N 0.000 description 2
- 229910001873 dinitrogen Inorganic materials 0.000 description 2
- FJKIXWOMBXYWOQ-UHFFFAOYSA-N ethenoxyethane Chemical compound CCOC=C FJKIXWOMBXYWOQ-UHFFFAOYSA-N 0.000 description 2
- 230000007717 exclusion Effects 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 230000002349 favourable effect Effects 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- UYTPUPDQBNUYGX-UHFFFAOYSA-N guanine Chemical compound O=C1NC(N)=NC2=C1N=CN2 UYTPUPDQBNUYGX-UHFFFAOYSA-N 0.000 description 2
- 229960002897 heparin Drugs 0.000 description 2
- 229920000669 heparin Polymers 0.000 description 2
- AOGQPLXWSUTHQB-UHFFFAOYSA-N hexyl acetate Chemical compound CCCCCCOC(C)=O AOGQPLXWSUTHQB-UHFFFAOYSA-N 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 210000004379 membrane Anatomy 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- 206010028417 myasthenia gravis Diseases 0.000 description 2
- 229920005615 natural polymer Polymers 0.000 description 2
- 201000008383 nephritis Diseases 0.000 description 2
- 108020004707 nucleic acids Proteins 0.000 description 2
- 150000007523 nucleic acids Chemical class 0.000 description 2
- 102000039446 nucleic acids Human genes 0.000 description 2
- 210000000056 organ Anatomy 0.000 description 2
- 238000012856 packing Methods 0.000 description 2
- 229920002689 polyvinyl acetate Polymers 0.000 description 2
- 239000011118 polyvinyl acetate Substances 0.000 description 2
- 229920002451 polyvinyl alcohol Polymers 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 230000000717 retained effect Effects 0.000 description 2
- 208000011580 syndromic disease Diseases 0.000 description 2
- RWQNBRDOKXIBIV-UHFFFAOYSA-N thymine Chemical compound CC1=CNC(=O)NC1=O RWQNBRDOKXIBIV-UHFFFAOYSA-N 0.000 description 2
- OOSZCNKVJAVHJI-UHFFFAOYSA-N 1-[(4-fluorophenyl)methyl]piperazine Chemical compound C1=CC(F)=CC=C1CN1CCNCC1 OOSZCNKVJAVHJI-UHFFFAOYSA-N 0.000 description 1
- DURPTKYDGMDSBL-UHFFFAOYSA-N 1-butoxybutane Chemical compound CCCCOCCCC DURPTKYDGMDSBL-UHFFFAOYSA-N 0.000 description 1
- HPILSDOMLLYBQF-UHFFFAOYSA-N 2-[1-(oxiran-2-ylmethoxy)butoxymethyl]oxirane Chemical compound C1OC1COC(CCC)OCC1CO1 HPILSDOMLLYBQF-UHFFFAOYSA-N 0.000 description 1
- LSTRKXWIZZZYAS-UHFFFAOYSA-N 2-bromoacetyl bromide Chemical compound BrCC(Br)=O LSTRKXWIZZZYAS-UHFFFAOYSA-N 0.000 description 1
- 229930024421 Adenine Natural products 0.000 description 1
- GFFGJBXGBJISGV-UHFFFAOYSA-N Adenine Chemical compound NC1=NC=NC2=C1N=CN2 GFFGJBXGBJISGV-UHFFFAOYSA-N 0.000 description 1
- 238000004438 BET method Methods 0.000 description 1
- 239000004342 Benzoyl peroxide Substances 0.000 description 1
- OMPJBNCRMGITSC-UHFFFAOYSA-N Benzoylperoxide Chemical compound C=1C=CC=CC=1C(=O)OOC(=O)C1=CC=CC=C1 OMPJBNCRMGITSC-UHFFFAOYSA-N 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- FRPHFZCDPYBUAU-UHFFFAOYSA-N Bromocresolgreen Chemical compound CC1=C(Br)C(O)=C(Br)C=C1C1(C=2C(=C(Br)C(O)=C(Br)C=2)C)C2=CC=CC=C2S(=O)(=O)O1 FRPHFZCDPYBUAU-UHFFFAOYSA-N 0.000 description 1
- 208000014181 Bronchial disease Diseases 0.000 description 1
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Natural products CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 1
- 108010009685 Cholinergic Receptors Proteins 0.000 description 1
- 208000027932 Collagen disease Diseases 0.000 description 1
- 108010062580 Concanavalin A Proteins 0.000 description 1
- 208000014311 Cushing syndrome Diseases 0.000 description 1
- 108010092160 Dactinomycin Proteins 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 102000006395 Globulins Human genes 0.000 description 1
- 108010044091 Globulins Proteins 0.000 description 1
- 206010018364 Glomerulonephritis Diseases 0.000 description 1
- 206010018910 Haemolysis Diseases 0.000 description 1
- 208000001204 Hashimoto Disease Diseases 0.000 description 1
- 208000030836 Hashimoto thyroiditis Diseases 0.000 description 1
- 241000700721 Hepatitis B virus Species 0.000 description 1
- 241000709721 Hepatovirus A Species 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 208000031226 Hyperlipidaemia Diseases 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 206010021245 Idiopathic thrombocytopenic purpura Diseases 0.000 description 1
- 108010093096 Immobilized Enzymes Proteins 0.000 description 1
- 102000018071 Immunoglobulin Fc Fragments Human genes 0.000 description 1
- 108010091135 Immunoglobulin Fc Fragments Proteins 0.000 description 1
- 108090001090 Lectins Proteins 0.000 description 1
- 102000004856 Lectins Human genes 0.000 description 1
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 1
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 102000007327 Protamines Human genes 0.000 description 1
- 108010007568 Protamines Proteins 0.000 description 1
- 201000004681 Psoriasis Diseases 0.000 description 1
- 208000031981 Thrombocytopenic Idiopathic Purpura Diseases 0.000 description 1
- 102000009843 Thyroglobulin Human genes 0.000 description 1
- 108010034949 Thyroglobulin Proteins 0.000 description 1
- 208000002474 Tinea Diseases 0.000 description 1
- 241000893966 Trichophyton verrucosum Species 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- 102000034337 acetylcholine receptors Human genes 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- RJURFGZVJUQBHK-IIXSONLDSA-N actinomycin D Chemical compound C[C@H]1OC(=O)[C@H](C(C)C)N(C)C(=O)CN(C)C(=O)[C@@H]2CCCN2C(=O)[C@@H](C(C)C)NC(=O)[C@H]1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=CC=C3C(=O)N[C@@H]4C(=O)N[C@@H](C(N5CCC[C@H]5C(=O)N(C)CC(=O)N(C)[C@@H](C(C)C)C(=O)O[C@@H]4C)=O)C(C)C)=C3N=C21 RJURFGZVJUQBHK-IIXSONLDSA-N 0.000 description 1
- 238000007259 addition reaction Methods 0.000 description 1
- 229960000643 adenine Drugs 0.000 description 1
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 230000007815 allergy Effects 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 230000000781 anti-lymphocytic effect Effects 0.000 description 1
- 230000003356 anti-rheumatic effect Effects 0.000 description 1
- 230000001715 anti-suppressor Effects 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 201000003710 autoimmune thrombocytopenic purpura Diseases 0.000 description 1
- 150000007514 bases Chemical class 0.000 description 1
- 235000019400 benzoyl peroxide Nutrition 0.000 description 1
- 230000005587 bubbling Effects 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000003508 chemical denaturation Methods 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 239000005515 coenzyme Substances 0.000 description 1
- 239000012050 conventional carrier Substances 0.000 description 1
- 238000007334 copolymerization reaction Methods 0.000 description 1
- 229940104302 cytosine Drugs 0.000 description 1
- 229960000640 dactinomycin Drugs 0.000 description 1
- 239000007857 degradation product Substances 0.000 description 1
- 238000004925 denaturation Methods 0.000 description 1
- 230000036425 denaturation Effects 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 238000009792 diffusion process Methods 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- DGLRDKLJZLEJCY-UHFFFAOYSA-L disodium hydrogenphosphate dodecahydrate Chemical compound O.O.O.O.O.O.O.O.O.O.O.O.[Na+].[Na+].OP([O-])([O-])=O DGLRDKLJZLEJCY-UHFFFAOYSA-L 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000007720 emulsion polymerization reaction Methods 0.000 description 1
- 150000002118 epoxides Chemical class 0.000 description 1
- 210000003743 erythrocyte Anatomy 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- UIWXSTHGICQLQT-UHFFFAOYSA-N ethenyl propanoate Chemical compound CCC(=O)OC=C UIWXSTHGICQLQT-UHFFFAOYSA-N 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 1
- DNJIEGIFACGWOD-UHFFFAOYSA-N ethyl mercaptane Natural products CCS DNJIEGIFACGWOD-UHFFFAOYSA-N 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 239000003527 fibrinolytic agent Substances 0.000 description 1
- 230000003480 fibrinolytic effect Effects 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 238000010528 free radical solution polymerization reaction Methods 0.000 description 1
- 239000007863 gel particle Substances 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 210000000585 glomerular basement membrane Anatomy 0.000 description 1
- JMANVNJQNLATNU-UHFFFAOYSA-N glycolonitrile Natural products N#CC#N JMANVNJQNLATNU-UHFFFAOYSA-N 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 229960000789 guanidine hydrochloride Drugs 0.000 description 1
- PJJJBBJSCAKJQF-UHFFFAOYSA-N guanidinium chloride Chemical compound [Cl-].NC(N)=[NH2+] PJJJBBJSCAKJQF-UHFFFAOYSA-N 0.000 description 1
- 230000035876 healing Effects 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 230000008588 hemolysis Effects 0.000 description 1
- 239000012510 hollow fiber Substances 0.000 description 1
- 229920001519 homopolymer Polymers 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000012051 hydrophobic carrier Substances 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 208000026278 immune system disease Diseases 0.000 description 1
- 208000030603 inherited susceptibility to asthma Diseases 0.000 description 1
- 239000003999 initiator Substances 0.000 description 1
- 208000017169 kidney disease Diseases 0.000 description 1
- 239000002523 lectin Substances 0.000 description 1
- 210000000265 leukocyte Anatomy 0.000 description 1
- 201000002364 leukopenia Diseases 0.000 description 1
- 231100001022 leukopenia Toxicity 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 208000019423 liver disease Diseases 0.000 description 1
- 210000004698 lymphocyte Anatomy 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 230000003228 microsomal effect Effects 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000002715 modification method Methods 0.000 description 1
- 230000002232 neuromuscular Effects 0.000 description 1
- 230000000269 nucleophilic effect Effects 0.000 description 1
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 description 1
- 238000011017 operating method Methods 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 230000000379 polymerizing effect Effects 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 201000009395 primary hyperaldosteronism Diseases 0.000 description 1
- 229940048914 protamine Drugs 0.000 description 1
- 230000017854 proteolysis Effects 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 239000007870 radical polymerization initiator Substances 0.000 description 1
- 230000001172 regenerating effect Effects 0.000 description 1
- 230000008929 regeneration Effects 0.000 description 1
- 238000011069 regeneration method Methods 0.000 description 1
- 206010048628 rheumatoid vasculitis Diseases 0.000 description 1
- 208000017520 skin disease Diseases 0.000 description 1
- 229940074545 sodium dihydrogen phosphate dihydrate Drugs 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 125000006850 spacer group Chemical group 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 238000010558 suspension polymerization method Methods 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 239000013076 target substance Substances 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
- 206010043554 thrombocytopenia Diseases 0.000 description 1
- 229940113082 thymine Drugs 0.000 description 1
- 229960002175 thyroglobulin Drugs 0.000 description 1
- 210000001685 thyroid gland Anatomy 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- 150000003918 triazines Chemical class 0.000 description 1
- 238000002604 ultrasonography Methods 0.000 description 1
- 229940035893 uracil Drugs 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
- DGVVWUTYPXICAM-UHFFFAOYSA-N β‐Mercaptoethanol Chemical compound OCCS DGVVWUTYPXICAM-UHFFFAOYSA-N 0.000 description 1
Description
本発明は、体液浄化用吸着材に用いられる担体
に関する。さらに詳しくは、体液中に発現する生
体にとつて有害な物質を特異的に除去する吸着材
に使用される担体に関する。
周知の如く、体液中に発現する自己抗体、免疫
複合体、蛋白質の分解物、ビリルビン、ある種の
中分子量物質等の悪性物質は、癌、免疫増殖性症
候群、慢性関節リウマチ、全身性エリテマトーデ
ス等の自己免疫疾患、アレルギー、臓器移殖時の
拒絶反応等の生体免疫機能に関係した疾患、ある
いは肝炎、腎炎等の疾患および現象の原因あるい
は進行と密接な関係をもつていると考えられてい
る。
そこで、血液、血漿等の体液成分から、上記の
ような悪性物質を特異的に吸着除去することによ
つて、上記の如き疾患の進行を防止し、症状を軽
減せしめ、さらには治癒を早めることが期待され
ていた。
本発明者らは、自己抗体、免疫複合体等の悪性
物質を高い効率で特異的に吸着し、非特異的な吸
着が少なく、安全性があり、滅菌操作も簡単に行
なうことができ、体液浄化あるいは再生用に適し
た吸着材を提供することを目的に鋭意研究した結
果、担体に被吸着物質と化学的な選択的相互作用
をなす特別な化学構造を有する物質を保持させて
なる種々の吸着材を見出し、先に特許出願した
（特願昭56−7152、特願昭56−18923、特願昭56−
76776、特願昭56−159444）。
また、担体についても種々検討し、担体として
比表面積が少なくとも５m2／ｇである硬質ゲルが
好ましく、また、ビニルアルコール単位を主構
成々分とする架橋合成高分子が優れた性能を持つ
ことを見出し、これについても先に特許出願した
（特願昭56−110817、特願昭56−112919）。
本発明は、先の発明に関して、ビニルアルコー
ル単位を主構成々分とする架橋合成高分子担体に
ついて、より詳細に検討した結果なされたもので
あり、上記担体の改良に関する。
従来、本目的を対象として特別に設計された担
体は知られていない。したがつて、通常アフイニ
テイクロマトグラフイ用として公知の担体を転用
する他はなかつた。
公知の担体としては、アガロース系担体、デキ
ストラン系担体、セルロース系担体等の天然高分
子系担体が知られている（たとえば商品名セフア
ローズ、フアルマシア社、スウエーデン）。しか
し、これらの天然高分子系担体は、以下の欠点を
有する。
(1) 機械的強度が不十分なために操作上の制約が
多い。たとえば活性化、固定化等の吸着体の調
製時に破壊されたり、輸送、使用時に担体のカ
ケ、クダケが生じる。
(2) 軟質ゲルであるため、カラムに充填し体液浄
化治療に用いる場合に、除去すべき物質を含む
体液を高流速で流すことができない。体液のよ
うな高粘度、高溶質濃度液を高流速で流すと、
軟質ゲルであるため、充填体積が減少し、目づ
まりと流量低下をおこし、ついには流れなくな
る場合もある。
(3) 軟質ゲルでありパーマネントボアーではない
ため、体液浄化用吸着材の必須要件である滅菌
操作も容易に行えない。たとえばエチレンオキ
サイドガス滅菌のように薬剤滅菌の場合、凍結
乾燥して滅菌されるが、凍結乾燥によつて細孔
が破壊され、再び水系媒体に分散しても元にも
どらない。凍結乾燥時その体積は約半量まで減
少し、再び水系媒体に分散しても元の体積のた
かだか80％程度にしかもどらず、吸着能力も減
少するのが常である。凍結乾燥時細孔を保護す
るため、添加剤を混入して行う方法もあるが、
添加剤が体液に入るのを防ぐため、使用前に徹
底的な洗浄を施さなければならない。
また高圧蒸気滅菌のような熱滅菌も、細孔を
破壊するので用いることができない。同様に放
射線滅菌も、その骨格および細孔を破壊するの
で用いることができない。
(4) さらには天然高分子系担体は体液浄化用に用
いる時、補体系の活性化、凝固系の活性化がお
こり、ロイコペニア、スロンボサイトペニア等
を生来するといわれ、あまり好ましくない。
本発明者らは、従来の担体の欠点を克服した体
液浄化用担体を鋭意研究した結果、担体として比
表面積が少なくとも５m2／ｇあるものが良い特性
を示し、また、ビニルアルコール単位を主構成々
分とする架橋合成高分子が優れた性能を持つこと
を見出し、先の発明（特願昭56−110817、特願昭
56−112919）をするに至つたのであるが、本発明
者らは、さらに物理的、化学的特性に優れた担体
を提供するために鋭意研究を重ねた。その結果、
カルボン酸のビニルエステルとトリアジン環構造
を有する架橋性単量体を共重合させた後、加水分
解して得られる架橋ポリビニルアルコールゲルに
おけるカルボン酸ビニルエステルと前記架橋性単
量体の量を、架橋度Ｘが0.35≦Ｘ≦0.8という比
較的架橋度の高い範囲になるように仕込んで製造
したものが、機械的強度において優れており、硬
く、変形し難く、乾燥による細孔破壊も少なく、
熱的にも安定していることを見出し、更に、ゲル
自身としては疎水的になるにもかかわらず、アル
ブミンのように生体にとつて有用な蛋白質の非特
異的吸着は少ないことを確認して、本発明を完成
するに至つた。
すなわち、本発明は、体液浄化用吸着材に用い
られる担体であつて、カルボン酸ビニルエステル
と下記トリアジン環構造を有する架橋性単量体(1)
または(2)
The present invention relates to a carrier used in an adsorbent for body fluid purification. More specifically, the present invention relates to a carrier used in an adsorbent that specifically removes substances harmful to living organisms expressed in body fluids. As is well known, malignant substances such as autoantibodies, immune complexes, protein degradation products, bilirubin, and certain medium molecular weight substances expressed in body fluids are associated with cancer, immunoproliferative syndrome, rheumatoid arthritis, systemic lupus erythematosus, etc. It is believed to be closely related to the causes or progression of diseases and phenomena such as autoimmune diseases, allergies, and rejection reactions during organ transplants, as well as diseases and phenomena such as hepatitis and nephritis. . Therefore, by specifically adsorbing and removing the above-mentioned malignant substances from body fluid components such as blood and plasma, it is possible to prevent the progression of the above-mentioned diseases, alleviate symptoms, and further accelerate healing. was expected. The present inventors have discovered that they can specifically adsorb malignant substances such as autoantibodies and immune complexes with high efficiency, have little nonspecific adsorption, are safe, can be easily sterilized, and can be used in body fluids. As a result of intensive research aimed at providing adsorbents suitable for purification or regeneration, we have developed various types of adsorbents in which the carrier holds a substance with a special chemical structure that selectively interacts with the adsorbed substance. He discovered an adsorbent and filed a patent application (Japanese Patent Application No. 7152, No. 1983, No. 18923, No. 1983).
76776, patent application No. 56-159444). In addition, various studies were conducted regarding the carrier, and it was found that a hard gel with a specific surface area of at least 5 m 2 /g is preferable as a carrier, and that a crosslinked synthetic polymer mainly composed of vinyl alcohol units has excellent performance. A patent application was previously filed for this heading (Japanese patent application No. 56-110817, Patent application No. 112919-1983). The present invention was made as a result of a more detailed study on a crosslinked synthetic polymer carrier mainly composed of vinyl alcohol units in connection with the previous invention, and relates to improvements to the above carrier. Hitherto, no carrier specifically designed for this purpose is known. Therefore, there was no choice but to repurpose a carrier that is generally known for use in affinity chromatography. As known carriers, natural polymer carriers such as agarose-based carriers, dextran-based carriers, and cellulose-based carriers are known (for example, trade name: Cepharose, Pharmacia, Sweden). However, these natural polymer carriers have the following drawbacks. (1) There are many operational restrictions due to insufficient mechanical strength. For example, the carrier may be destroyed during preparation of the adsorbent such as activation or immobilization, or the carrier may break or crumble during transportation or use. (2) Because it is a soft gel, when it is packed into a column and used for body fluid purification treatment, it is not possible to flow body fluids containing substances to be removed at a high flow rate. When a high viscosity, high solute concentration liquid such as body fluid flows at a high flow rate,
Since it is a soft gel, the filling volume decreases, causing clogging and a decrease in flow rate, which may eventually stop flowing. (3) Since it is a soft gel and does not have permanent bores, it cannot be easily sterilized, which is an essential requirement for an adsorbent for body fluid purification. For example, in the case of chemical sterilization such as ethylene oxide gas sterilization, the material is sterilized by freeze-drying, but the pores are destroyed by freeze-drying and cannot be restored to their original state even if they are re-dispersed in an aqueous medium. During freeze-drying, its volume decreases to about half, and even when it is redispersed in an aqueous medium, it only returns to about 80% of its original volume, and its adsorption capacity usually decreases. There is a method of mixing additives to protect the pores during freeze-drying, but
Thorough cleaning must be performed before use to prevent additives from entering body fluids. Furthermore, heat sterilization such as high-pressure steam sterilization cannot be used because it destroys the pores. Similarly, radiation sterilization cannot be used as it destroys the skeleton and pores. (4) Furthermore, when natural polymeric carriers are used for body fluid purification, they are said to activate the complement system and the coagulation system, resulting in leukopenia, thrombocytopenia, etc., and are therefore not very desirable. As a result of intensive research into carriers for body fluid purification that overcome the drawbacks of conventional carriers, the present inventors have found that carriers with a specific surface area of at least 5 m 2 /g exhibit good properties, and that they are mainly composed of vinyl alcohol units. It was discovered that cross-linked synthetic polymers with various components had excellent performance, and the earlier invention (Japanese Patent Application No. 56-110817;
56-112919), the present inventors conducted extensive research in order to provide a carrier with even better physical and chemical properties. the result,
After copolymerizing a carboxylic acid vinyl ester and a crosslinkable monomer having a triazine ring structure, the amounts of the carboxylic acid vinyl ester and the crosslinkable monomer in the crosslinked polyvinyl alcohol gel obtained by hydrolysis are adjusted to Products manufactured with a relatively high crosslinking degree of 0.35≦X≦0.8 have excellent mechanical strength, are hard, are difficult to deform, and have little pore destruction due to drying.
We found that it is thermally stable, and furthermore, we confirmed that although the gel itself is hydrophobic, there is little nonspecific adsorption of proteins that are useful to living organisms, such as albumin. , we have completed the present invention. That is, the present invention provides a carrier for use in an adsorbent for body fluid purification, which comprises a carboxylic acid vinyl ester and a crosslinkable monomer (1) having the following triazine ring structure.
or (2)
【式】
（R1、R2、R3は−CH2−CH＝CH2、−CH2−Ｃ
≡CHまたは[Formula] (R 1 , R 2 , R 3 are -CH 2 -CH=CH 2 , -CH 2 -C
≡CH or
【式】より選ばれた同一
もしくは異なる基）
とを下式で示される架橋度Ｘ
Ｘ＝W2／M2×n2／W1／M1×n1＋W2／M2×n2
M1：カルボン酸ビニルエステルの分子量
M2：架橋性単量体の分子量
W1：重合に用いたカルボン酸ビニルエステルの
重量
W2：重合に用いた架橋性単量体の重量
n1：カルボン酸ビニルエステル１分子が有するエ
チレン性二重結合の数
n2：架橋性単量体１分子が有するエチレン性二重
結合の数
を0.35≦Ｘ≦0.80の範囲にして重合した後、加水
分解して得られる体液浄化用吸着材担体である。
本発明の体液浄化用吸着材に適した担体は、カ
ルボン酸ビニルエステルと下記式(1)、(2)で示され
るトリアジン環を有する化合物を共重合して、該
共重合体をエステル交換またはケン化することに
よつて得ることができるが、カルボン酸ビニルエ
ステルとの共重合性および形成されたマトリツク
スの強度、微細孔構造、化学的安定性の面からト
リアリルイソシアヌレートが最も好ましい。(same or different groups selected from [Formula] ) and the degree of crosslinking shown by the following formula X 1 : Molecular weight of carboxylic acid vinyl ester M 2 : Molecular weight of crosslinkable monomer W 1 : Weight of carboxylic acid vinyl ester used in polymerization W 2 : Weight of crosslinkable monomer used in polymerization n 1 : Carboxylic acid Number of ethylenic double bonds in one molecule of vinyl ester n 2 : After polymerization with the number of ethylenic double bonds in one molecule of crosslinkable monomer in the range of 0.35≦X≦0.80, hydrolysis is performed. This is the obtained adsorbent carrier for body fluid purification. A carrier suitable for the body fluid purification adsorbent of the present invention is obtained by copolymerizing a carboxylic acid vinyl ester and a compound having a triazine ring represented by the following formulas (1) or (2), and transesterifying or transesterifying the copolymer. Although it can be obtained by saponification, triallylisocyanurate is most preferred from the viewpoints of copolymerizability with carboxylic acid vinyl ester, strength of the formed matrix, micropore structure, and chemical stability.
【式】
（ただし、R1、R2およびR3は、それぞれ独立に、
CH2＝CH−CH2−、CH≡Ｃ−CH2−および
[Formula] (However, R 1 , R 2 and R 3 are each independently,
CH 2 =CH−CH 2 −, CH≡C−CH 2 − and
【式】を示す）
カルボン酸ビニルエステルとは重合可能なカル
ボン酸ビニルエステル基を一つ以上有する化合物
のことで、たとえば、酢酸ビニル、プロピオン酸
ビニル等の脂肪酸ビニルをあげることができる。
本発明の体液浄化用吸着材の特性に影響を与えな
い重合性単量体、たとえばジエチレングリコー
ル、エチルビニルエーテル等を添加してもかまわ
ない。
本発明の担体においては、カルボン酸ビニルエ
ステルと架橋性単量体の量を下記（）式におい
てＸが0.35≦Ｘ≦0.8になるように選んで共重合
をおこなうのが好ましい。
Ｘ＝W2／M2×n2／W1／M1×n1＋W2／M2×n2…（）
（ただし
M1：カルボン酸ビニルエステルの分子量
M2：架橋性単量体の分子量
W1：重合に用いたカルボン酸ビニルエステルの
重量
W2：重合に用いた架橋性単量体の重量
n1：カルボン酸ビニルエステル１分子が有するエ
チレン性二重結合の数
n2：架橋性単量体１分子が有するエチレン性二重
結合の数）
Ｘが0.35より小さいと、吸着材の担体として
は、より親水的になり体液との親和性は良くなる
はずであるが、機械的な硬さがなくなる方向であ
り、カラムに詰めて高粘度の体液を流したとき
に、変形、目詰まりを起こし易くなる。また、乾
燥したときの収縮率が大きくなり、細孔の破壊が
起こり易くなる。
Ｘが0.8より大きくなると、非常に疎水的な吸
着材担体となつてくるため、体液との濡れが悪く
なるし、また、血液中の凝固線溶系、補体系を活
性化し易くなつたり、アルブミンのような有用蛋
白を非特易的に吸着し易くなつたりする。また、
リガンドの固定が可能な官能基密度が低くなるた
め、リガンドの高密度固定も不可能となる。
これに対してＸが0.35≦Ｘ≦0.8の範囲では、
水酸基密度の量、すなわち、リガンドを固定する
ことが可能な官能基を多数有し、かつ、適度な親
水性があり、また、機械的強度に優れ、乾燥時収
縮が少なく、細孔破壊が起り難い、熱滅菌可能
な、担体として非常に優れた特性を持つ。
本担体の形状としては、球状、粒状、糸状、中
空糸状、平膜状等いずれも有効に用いられるが、
その担体比表面積（吸着材としての吸着能力に相
当）および体外循環時の体液の流通面より、球状
または粒状が特に好ましく用いられる。したがつ
て、担体の合成法としては、公知の懸濁重合法が
特に有効に用いられる。
比表面積とは、乾燥ゲル単位重量当りに吸着し
た窒素ガスが占有する表面でもつて表示したもの
である。すなわち、比表面積は単位重量のゲルを
構成する物質が乾燥状態でいかに有効に表面を形
成しているかを表示している。
一般に高分子ゲルは、そのゲルと親和性のある
媒体中で膨潤し、乾燥すると収縮する。膨潤時に
媒体が満たされているポアーが架橋の網目のみで
維持されている軟質ゲルの場合は、乾燥すると網
目がつぶされてしまい、ポアーはほとんど消失す
る。この場合の比表面積は、ほとんど粒子の外側
だけの値になるため、一般に１m2／ｇ以下の低い
値を示す。従来アフイニテイクロマトグラフイ用
として知られているアガロースのようなものは軟
質ゲルであるため、乾燥によつてポアーが消失し
てしまう。したがつて、滅菌操作も容易に行え
ず、さらにはつぶれやすい軟質の網目を持つてい
るため、カラムに充填し体液浄化治療に用いる場
合にも、体液を長時間、高流速で流すことができ
ない。
一方、ポアーがしつかりした構造をもち、凍結
乾燥や熱滅菌に耐える硬質ゲルの場合には、乾燥
した際にポアーは多少収縮するものの膨潤時の状
態をほとんど維持する。すなわち、パーマネント
ポアーを有し、比表面積は軟質ゲルより高い値を
示す。本発明の担体は少なくとも５m2／ｇ以上の
値を示す。
比表面積の測定法はいろいろあるが、本発明で
は、最も一般的な窒素ガスによるBET法で求め
た。また比表面積測定に用いるサンプルは十分乾
燥しておかなければならないが、本発明の担体は
乾燥しにくいこともあり、水にぬれた担体をアセ
トンと平衡にした後、60℃以下で減圧乾燥して測
定用サンプルとした。
有効な吸着能力を維持しつつ、しかも血液、血
漿等の体液のような高粘度、高溶質濃度の液を高
流速で長時間安定に流通するには、さらに担体の
平均粒子径（DW）が一定の範囲にあることが好
ましい。平均粒子径は小さいほど吸着能力が高く
なり好ましいが、あまり小さ過ぎると体液を高流
速で長時間、安定に流通できなくなる。したがつ
て、平均粒子径は25〜2500μｍが好ましく、特に
全血用に用いる場合など、より好ましくは150〜
1500μｍである。
体液浄化用吸着材に用いる硬質ゲル担体の排除
限界分子量（Mlim）は、硬質ゲル担体に化学結
合により保持させる物質の分子量および目的吸着
物質の分子量を勘案して設定すればよい。本発明
の担体は、通常タンパク質Mlimで103ないし108、
ポリエチレングリコール、デキストランMlimで
３×102ないし３×107の範囲にある。タンパク質
Mlimはゲルのポアー内へ浸透できない分子の分
子量の下限を示す値である。Mlimはゲルをカラ
ムに充填して分子量既知の標準タンパク質を用い
て公知の方法で測定することができる。
体液浄化用吸着材に用いる担体の化学的特性と
しては、(1)被吸着物質に対し、例えば生物学的ま
たは／および化学的相互作用を示し、これと結合
しうる物質（リガンド）を高密度に化学結合でき
るように官能基の密度が高いこと、(2)目的とする
物質を選択的に吸着するように、担体の血漿タン
パク質等に対する非特異吸着が少ないこと、(3)補
体系、凝固系の活性化等の生体成分との反応が少
ないこと、(4)さらに全血用吸着材として用いる場
合には、血球成分との相互作用、すなわち、血栓
形成や血球成分の非特異粘着、残血等が少ないこ
と等の特性を備えたものが好ましい。したがつ
て、既に述べた物理的特性に加えて、以上の化学
的特性を満たす担体がより好ましく用いられる。
本発明の担体は、上記したような特性を良好に
満たすが、担体の水酸基密度として１〜15meq／
ｇの範囲が好ましい結果を与え、特に２〜
11meq／ｇの範囲にあるものがより好ましい結果
を与える。
通常架橋合成高分子は、線状ポリマーと架橋剤
で構成され、水酸基は線状ポリマー中に発現され
る。したがつて、水酸基の密度が高いほど親水性
が増加し、生体成分との相互作用が少なくなり、
リガンドの保持容量も向上して好ましいが、高す
ぎると架橋剤含量が低下して担体の強度が低下す
る。また水酸基の密度が低すぎると、非特異吸着
が生じて好ましくない。
水酸基の密度は、ゲルをピリジン溶媒中で無水
酢酸と反応させて、水酸基と反応して消費した無
水酢酸の量またはゲルの重量変化を測定し、これ
から求めることができる。乾燥ゲル１ｇが１ｍ
molの無水酢酸と反応したときの水酸基密度が
1meq／ｇである。
本発明の担体は、溶液重合、懸濁重合、エマル
ジヨン重合等で得ることができるが、体液浄化用
吸着材の形状は、球状または粒状が良いので懸濁
重合が好ましい。
懸濁重合は例えばカルボン酸ビニルエステルと
架橋性単量体を、これらの単量体を溶解するが水
に溶解しにくい溶媒の共存下に撹拌して小滴とな
し、重合することによつて行なわれる。単量体を
溶解するが水に溶解しにくい有機溶媒を単量体に
加えることにより、得られる共重合体にパーマネ
ントポアを形成させる。単量体を溶解するが水に
溶解しにくい有機溶媒とは、具体的にはトルエ
ン、キシレン等の芳香族炭化水素、ヘプタン、オ
クタン等の脂肪族炭化水素、酢酸エチル、酢酸ｎ
−ブチル、酢酸ｎ−ヘキシル等のエステル化合
物、ジブチルエーテル等のエーテル類あるいはメ
チルイソブチルケトン、ｎ−ヘプタノール等のこ
とである。有機溶媒は単量体100重量部に対して
20〜300重量部の範囲で用いるのが好ましい。
共重合体の孔径あるいは孔径分布を制御するた
めに、単量体混合物に溶解する線状重合体を前記
溶媒と併用してもよい。線状重合体としては、た
とえばポリ酢酸ビニル等を挙げることができる。
線状重合体は単量体100重量部に対して10重量部
以下で用いられる。かかる線状重合体を前記有機
溶媒と併用することによつて、より孔径の大きい
ゲルを得るのが容易になる。重合に際して用いら
れる開始剤は通常のラジカル重合開始剤でよく、
たとえば２，2′−アゾビスイソブチロニトリル
や、過酸化ベンゾイル等を用いることができる。
重合によつて得られた粒状重合体は、次にエス
テル交換またはケン化を行なう。
エステル交換反応またはケン化反応は、水やア
ルコールまたはその混合液を溶媒として、酸また
はアルカリを用いて行なわれる。反応の温度は５
〜55℃が好ましく、10〜50℃がさらに好ましく、
15〜45℃が特に好ましい。
エステル交換またはケン化によつて得られたゲ
ルは、たとえばエピクロルヒドリン、ブタンジオ
ールジグリシジルエーテル等で後架橋することも
できる。
リガンドを本発明の担体に結合する方法は、共
有結合、イオン結合、物理吸着、包埋あるいは重
合体表面への沈殿不溶化等あらゆる公知の方法を
用いることができるが、結合物の溶出し難さより
みて、共有結合により固定、不溶化して用いるこ
とが好ましい。そのためには通常固定化酵素、ア
フイニテイクロマトグラフイで用いられる公知の
担体の活性化方法およびリガンドの結合方法を用
いることができる。
活性化方法を例示すると、ハロゲン化シアン
法、エピクロルヒドリン法、ビスエポキシド法、
ハロゲン化トリアジン法、ブロモアセチルプロミ
ド法、エチルクロロホルマート法、１，1′−カル
ボニルジイミダゾール法等をあげることができ
る。本発明の活性化方法は、リガンドのアミノ
基、水酸基、カルボキシル基、チオール基等の活
性水素を有する求核反応基と置換および／または
付加反応できればよく、上記の例示に限定される
ものではないが、化学的安定性、熱的安定性等を
考慮するとエポキシドを用いる方法が好ましく、
特にエピクロルヒドリン法が推奨できる。また、
必要に応じて担体とリガンドの間に任意の長さの
分子（スペーサー）を導入してもよい。
本発明の担体に保持させるリガンドは、目的に
応じて自由に選べるが、その中の一部を例示す
る。
全身性エリテマトーデス治療用としては、抗核
抗体、抗DNA抗体の吸着除去用に、アデニン、
グアニン、シトシン、ウラシル、チミン等のモ
ノ、ジ、トリヌクレオチドのホモポリマー、また
はコポリマー、天然に存在するDNA、RNA等の
核酸を用いることができる。また血中に存在する
DNA、RNA、ENAの吸着除去用に、抗一本鎖
DNA抗体、抗二本鎖DNA抗体、抗RNA抗体、
抗ENA抗体等の抗核酸抗体、メチル化アルブミ
ンアクチノマイシンＤ等の塩基性化合物を用いる
ことができる。さらに血中の免疫複合体の吸着除
去用には、Clq等の補体成分、プロテインＡ等の
特異タンパク質、抗ヘビーチエイン不変部第２相
抗体等の免疫複合体に対する抗体を用いることが
できる。
慢性関節リウマチ、悪性関節リウマチ治療用と
しては、尿素、塩酸グアニジン、メルカプトエタ
ノール、界面活性剤、有機溶剤等の化学的変性
（凝集）方法、熱、超音波、ガスバブリング等の
物理的変性（凝集）方法により変性された変性γ
−グロブリン、変性イムノグロブリン、凝集γ−
グロブリン、凝集イムノグロブリン、イムノグロ
ブリンのFc部、イムノグロブリンのヘビーチエ
イン不変部第２相およびそれらの前記変性方法に
よる変性体等のリウマチ因子に対する抗原様物
質、および抗リウマチ因子抗体を用いることがで
きる。またリウマチの免疫複合体除去用には、
Clq等の補体成分、プロテインＡ等の特異タンパ
ク質、抗ヘビーチエイン不変部第２相抗体等の免
疫複合体に対する抗体を用いることができる。
橋本病治療用には、サイログロブリン、甲状線
のミクロソーム分画成分を用いることができる。
重症筋無力症治療用には、神経筋のアセチルコ
リンレセプター分画成分を用いることができる。
糸球体腎炎治療用には、糸球体基底膜成分、特
発性血小板減少性紫斑病治療用には、血小板膜成
分、血小板顆粒分画成分、クツシング症候群治療
用にはトランスコーチゾン、抗コーチゾン抗体を
用いることができる。
肝炎の予防、治療用には、Ａ型肝炎ウイルス、
Ｂ型肝炎ウイルス等のウイルス表面抗原に対する
抗体を用いることができる。
高血圧治療用には、抗アンジオテンシン抗
体、高脂血症治療用にはヘパリン、抗リボプロテ
イン抗体を用いることができる。
リンパ球異常に基づく免疫疾患治療用には、抗
Ｂセル抗体、抗サプレツサーＴ抗体、抗ヘルパー
Ｔ抗体等の抗リンパ球抗体を用いることができ
る。
乳ガン等のガン治療用には、プロテインＡ、抗
イムノグロブリン抗体を用いることができる。
本発明に用いることができるリガンドは、以上
の例示に限定されるものではなく、コングニチニ
ン、コンカナバリンＡ、フイトヘマアグルチニン
等のレクチン、核酸、アミノ酸、脂質、プロタミ
ン、ヘパリン、抗原、抗体、酵素、基質、補酵素
等の被吸着物質と結合可能な公知の物質を用いる
ことができる。
また、本発明の担体に２種以上のリガンドを保
持させて用いることもできる。さらにはリガンド
を保持した担体を２種以上併用して用いることも
できる。
以上述べてきたように、本発明の体液浄化用吸
着材に適した担体は、機械的強度が十分であるた
め、活性化、固定化等の吸着材の調製や輸送、体
外循環使用特に破壊されたり、カケやクダケを生
ずることが実質的になく、幅広い操作方法、条件
を選択することができる。また硬質ゲルであるた
め、カラムに充填し、体外循環に用いる場合に、
吸着、除去すべき物質を含む体液を高流速で長時
間、連続的に安定に通液することができる。さら
には硬質ゲルであり、パーマネントポアーを有す
るため、体外循環治療用吸着材の必須要件である
滅菌操作も容易に行えるものである。例えば吸着
材を凍結乾燥してエチレンオキサイドガス滅菌の
ような薬剤滅菌も、吸着材の吸着能力を損うこと
なく実施できる。
さらには、前記物理的特性に加えて好ましい化
学的特性を有し、次の効果を示した。
高い水酸基密度を有するため、リガンドを高密
度に化学結合できると共に、高親水性であるため
血漿タンパク質等に対する非特異吸着が少ない。
また補体系、凝固系の活性化等の生体成分との反
応が少なく、さらには全血用吸着材として用いる
場合にも、血球成分との相互作用、すなわち、血
栓形成や血球成分の非特異粘着、残血等が少な
く、好適に用いることができる。
本発明の担体は、自己血漿、自己血液等の体液
を浄化、再生する一般的な用法に適用可能であ
り、癌、免疫増殖性症候群、慢性関節リウマチ、
全身性エリテマトーデス等の膠原病、重症筋無力
症等の自己免疫疾患、気管支端息のようなアレル
ギー性疾患、臓器移殖時の拒絶反応等の生体免疫
機能に関係した疾患および現象、乾癬、白癬等の
皮膚疾患、あるいは腎炎等の腎臓病、肝炎等の肝
臓病などの体外循環治療に有効に利用できる。
また、アフイニテイ−クロマトグラフ用担体と
しても有効に利用できるものである。
以下実施例により、本発明の実施の態様をより
詳細に説明する。
実施例 １
酢酸ビニル100ｇ、トリアリルイソシアヌレー
ト64.3ｇ（Ｘ＝0.40）、酢酸エチル100ｇ、ヘプタ
ン100ｇ、ポリ酢酸ビニル（重合度500）7.5ｇお
よび２，2′−アゾビスイソブチロニトリル3.8ｇ
よりなる均一混合液と、ポリビニルアルコール１
重量％、リン酸二水素ナトリウム二水和物0.05重
量％およびリン酸水素二ナトリウム十二水和物
1.5重量％を溶解した水400mlとをフラスコに入
れ、十分撹拌したのち65℃で18時間、さらに75℃
で５時間加熱撹拌して懸濁重合を行ない、粒状共
重合体を得た。過水洗、ついでアセトン抽出
後、カセイソーダ46.5ｇおよびメタノール２よ
りなる溶液中で40℃で18時間、共重合体のエステ
ル交換反応を行なつた。
得られたゲルの平均粒径は150μｍ、前記方法
で求めた単位重量あたりの水酸基密度（qOH）
は9.0meq／ｇ、比表面積は60m2／ｇ、デキスト
ランによる排除限界分子量は６×105であつた。
このゲルを内径10mm、長さ50mmのカラム２本に
充填し、１本にはACD加健康人血漿を0.4ml／
minの流速で12ml、もう１本にはACD加健康人
血液を0.7ml／minの流速で20ml流した。いずれ
のカラムも充填体積の低下、目詰まり、流量低下
はみられず、カラム前後の圧力差も血漿で10mm
Hg以下、血液でも10〜20mmHgの範囲であつた。
カラム通過前後の血漿蛋白および血液血球成分
の変動を調べたところ、血漿ではアルブミンの吸
着はわずかであり、補体成分C3の減少も少なか
つた。すなわち、有用蛋白質の非特異吸着は少な
かつた。また血液では、カラム通過前後の赤血
球、白血球、血小板の濃度に有意な差は認められ
なかつた。すなわち、血球成分の粘着、溶血等は
殆んど認められなかつた。
次に、得られたゲル10ｇ（乾燥重量）をジメチ
ルスルホキシド120ml中に懸濁し、これにエピク
ロルヒドリン78.3ml、30％水酸化ナトリウム10ml
を加え、30℃で５時間振とう撹拌しながら活性化
反応を行なつた。反応終了後、ガラスフイルター
で集し、ジメチルスルホキシドで洗浄し、水洗
して活性化ゲルを得た。得られたゲルのエポキシ
基密度は1.1meq／ｇであつた（エポキシ基密度
の測定は、ゲルを水溶媒中でチオ硫酸ナトリウム
と反応させて、エポキシ基と反応して生成した水
酸化ナトリウムの量を測定し、これから求めた）。
この活性化ゲルをもとのゲル粒子と比較して光
学顕微鏡で観察したところ、カケ、クダケ等の破
壊はみられなかつた。
比較例 １
アフイニテイークロマトグラフ用の水不溶性担
体として市販されているアガロース系の担体であ
るセフアロース4B（フアルマシア・フアイン・ケ
ミカル社製）を実施例１と同様のカラム充填し、
実施例１と同様の条件で血漿を流した。その結
果、カラム中に占めるセフアロース4Bの体積が
約12％収縮し、圧力も20mmHg以上に上がつてし
まつた。
また、比表面積を測定するため、アセトンで溶
媒置換した後、60℃で乾燥したところ、ゲル同志
がお互に貼りついて収縮し、固まつてしまつた。
実施例 ２
実施例１で示した重合方法、ケン化方法と同様
の製造方法にて酢酸ビニルとトリアリルイソシア
ヌレートの仕込み比率を変えることにより、種々
の架橋度Ｘ＝0.05、0.25、0.35、0.50、0.80、0.9
を持つゲルを得た（このうち、Ｘ＝0.05、0.25お
よび0.9のゲルは、実施例２に対する比較例とし
て用いた）。
これらのゲルの物性値を下表に示す。[Formula]) A carboxylic acid vinyl ester is a compound having one or more polymerizable carboxylic acid vinyl ester groups, and includes, for example, fatty acid vinyl such as vinyl acetate and vinyl propionate.
Polymerizable monomers such as diethylene glycol, ethyl vinyl ether, etc., which do not affect the properties of the body fluid purifying adsorbent of the present invention, may be added. In the carrier of the present invention, it is preferable to carry out copolymerization by selecting the amounts of carboxylic acid vinyl ester and crosslinkable monomer such that in the following formula (), X satisfies 0.35≦X≦0.8. X=W 2 /M 2 ×n 2 /W 1 /M 1 ×n 1 +W 2 /M 2 ×n 2 … () (where M 1 : Molecular weight of carboxylic acid vinyl ester M 2 : Molecular weight of crosslinkable monomer Molecular weight W 1 : Weight of carboxylic acid vinyl ester used in polymerization W 2 : Weight of crosslinkable monomer used in polymerization n 1 : Number of ethylenic double bonds in one molecule of carboxylic acid vinyl ester n 2 : Crosslinking If X is smaller than 0.35 (the number of ethylenic double bonds that one molecule of the monomer has), it will become more hydrophilic as an adsorbent carrier and should have better affinity with body fluids, but mechanical This tends to cause the column to lose its hardness, making it susceptible to deformation and clogging when packed in a column and filled with highly viscous body fluids. In addition, the shrinkage rate upon drying increases, making pores more likely to be destroyed. When X is larger than 0.8, the adsorbent becomes a very hydrophobic carrier, which results in poor wettability with body fluids, and also makes it easier to activate the coagulation fibrinolytic system and complement system in the blood, and to inhibit albumin production. It becomes easier to adsorb useful proteins such as these in a non-specific manner. Also,
Since the density of functional groups capable of immobilizing a ligand becomes low, high-density immobilization of a ligand becomes impossible. On the other hand, when X is in the range of 0.35≦X≦0.8,
It has a large amount of hydroxyl group density, that is, a large number of functional groups capable of immobilizing ligands, has appropriate hydrophilicity, has excellent mechanical strength, has little shrinkage during drying, and has no pore destruction. It is difficult to heat, can be sterilized by heat, and has excellent properties as a carrier. As for the shape of the present carrier, any of the shapes such as spherical, granular, filamentous, hollow fiber, and flat membrane shapes can be effectively used.
A spherical or granular shape is particularly preferably used in view of the specific surface area of the carrier (corresponding to the adsorption capacity as an adsorbent) and the flow surface of body fluid during extracorporeal circulation. Therefore, the known suspension polymerization method is particularly effectively used as a method for synthesizing the carrier. The specific surface area is expressed as the surface occupied by nitrogen gas adsorbed per unit weight of dry gel. That is, the specific surface area indicates how effectively the substance constituting the gel per unit weight forms the surface in a dry state. Generally, polymer gels swell in a medium that has an affinity for the gel and shrink when dried. In the case of a soft gel in which the pores that are filled with the medium during swelling are maintained only by a network of crosslinks, when the gel dries, the network collapses and the pores almost disappear. In this case, the specific surface area is almost limited to the outside of the particle, so it generally shows a low value of 1 m 2 /g or less. Since agarose, which has been conventionally known for use in affixine chromatography, is a soft gel, its pores disappear when it dries. Therefore, it is not easy to sterilize, and it has a soft mesh that is easily crushed, so even when it is packed into a column and used for body fluid purification treatment, it is not possible to flow body fluids at a high flow rate for a long time. . On the other hand, in the case of a hard gel that has a firm pore structure and can withstand freeze-drying and heat sterilization, the pores will shrink somewhat when dried, but will maintain most of their swollen state. That is, it has permanent pores and has a higher specific surface area than soft gel. The carrier of the present invention exhibits a value of at least 5 m 2 /g or more. There are various methods for measuring the specific surface area, but in the present invention, it was determined by the most common BET method using nitrogen gas. In addition, the sample used for specific surface area measurement must be sufficiently dry, but since the carrier of the present invention is difficult to dry, the carrier wet with water is equilibrated with acetone and then dried under reduced pressure at 60°C or less. This was used as a sample for measurement. In order to maintain effective adsorption capacity and to stably flow liquids with high viscosity and high solute concentration, such as body fluids such as blood and plasma, at high flow rates for long periods of time, the average particle diameter (D W ) of the carrier must be adjusted. is preferably within a certain range. The smaller the average particle diameter, the higher the adsorption capacity, which is preferable, but if it is too small, body fluids cannot be stably distributed at a high flow rate for a long time. Therefore, the average particle diameter is preferably 25 to 2500 μm, more preferably 150 to 2500 μm, especially when used for whole blood.
It is 1500μm. The exclusion limit molecular weight (Mlim) of a hard gel carrier used as an adsorbent for body fluid purification may be set by taking into consideration the molecular weight of the substance to be held by the hard gel carrier through chemical bonds and the molecular weight of the target adsorbent. The carrier of the present invention is usually protein Mlim, with a concentration of 10 3 to 10 8 ,
Polyethylene glycol and dextran Mlim range from 3×10 2 to 3×10 7 . protein
Mlim is a value indicating the lower limit of the molecular weight of molecules that cannot penetrate into the pores of the gel. Mlim can be measured by a known method by packing a gel into a column and using a standard protein with a known molecular weight. The chemical properties of the carrier used in the adsorbent for body fluid purification include (1) a high density of substances (ligands) that exhibit biological and/or chemical interactions with and can bind to the adsorbed substance; (2) The carrier has low nonspecific adsorption to plasma proteins, etc. so that it selectively adsorbs the target substance, (3) Complement system, coagulation, etc. (4) Furthermore, when used as an adsorbent for whole blood, interactions with blood cell components, such as thrombus formation, nonspecific adhesion of blood cell components, and residual Those with characteristics such as less blood etc. are preferable. Therefore, in addition to the physical properties already mentioned, a carrier that satisfies the above chemical properties is more preferably used. The carrier of the present invention satisfies the above characteristics well, but the hydroxyl group density of the carrier is 1 to 15 meq/
A range of g gives preferable results, especially between 2 and
Those in the range of 11 meq/g give more favorable results. Generally, crosslinked synthetic polymers are composed of a linear polymer and a crosslinking agent, and hydroxyl groups are expressed in the linear polymer. Therefore, the higher the density of hydroxyl groups, the more hydrophilic it becomes and the less interaction with biological components.
It is preferable because it also improves the retention capacity of the ligand, but if it is too high, the content of the crosslinking agent decreases and the strength of the carrier decreases. Furthermore, if the density of hydroxyl groups is too low, non-specific adsorption will occur, which is not preferable. The density of hydroxyl groups can be determined by reacting the gel with acetic anhydride in a pyridine solvent and measuring the amount of acetic anhydride consumed by the reaction with the hydroxyl groups or the change in weight of the gel. 1g of dry gel is 1m
The hydroxyl group density when reacting with mol of acetic anhydride is
It is 1meq/g. The carrier of the present invention can be obtained by solution polymerization, suspension polymerization, emulsion polymerization, etc., but suspension polymerization is preferred because the shape of the adsorbent for body fluid purification is preferably spherical or granular. Suspension polymerization, for example, involves stirring a carboxylic acid vinyl ester and a crosslinking monomer in the coexistence of a solvent that dissolves these monomers but is difficult to dissolve in water to form small droplets, and polymerizing them. It is done. By adding an organic solvent that dissolves the monomer but is difficult to dissolve in water to the monomer, permanent pores are formed in the resulting copolymer. Organic solvents that dissolve monomers but are difficult to dissolve in water include aromatic hydrocarbons such as toluene and xylene, aliphatic hydrocarbons such as heptane and octane, ethyl acetate, and acetic acid.
-butyl, ester compounds such as n-hexyl acetate, ethers such as dibutyl ether, methyl isobutyl ketone, n-heptanol, etc. Organic solvent per 100 parts by weight of monomer
It is preferable to use it in a range of 20 to 300 parts by weight. A linear polymer soluble in the monomer mixture may be used in combination with the solvent to control the pore size or pore size distribution of the copolymer. Examples of linear polymers include polyvinyl acetate.
The linear polymer is used in an amount of 10 parts by weight or less per 100 parts by weight of the monomer. By using such a linear polymer in combination with the organic solvent, it becomes easy to obtain a gel with a larger pore size. The initiator used during polymerization may be a normal radical polymerization initiator,
For example, 2,2'-azobisisobutyronitrile, benzoyl peroxide, etc. can be used. The particulate polymer obtained by polymerization is then subjected to transesterification or saponification. The transesterification reaction or the saponification reaction is carried out using an acid or an alkali in water, alcohol, or a mixture thereof as a solvent. The temperature of the reaction is 5
-55°C is preferable, 10-50°C is more preferable,
Particularly preferred is 15-45°C. Gels obtained by transesterification or saponification can also be post-crosslinked, for example with epichlorohydrin, butanediol diglycidyl ether and the like. Any known method can be used to bind the ligand to the carrier of the present invention, such as covalent bonding, ionic bonding, physical adsorption, embedding, or precipitation insolubilization on the polymer surface. Therefore, it is preferable to use it by immobilizing it and making it insolubilized by covalent bonding. For this purpose, an immobilized enzyme, a known carrier activation method used in affinity chromatography, and a ligand binding method can be used. Examples of activation methods include cyanogen halide method, epichlorohydrin method, bisepoxide method,
Examples include the halogenated triazine method, the bromoacetyl bromide method, the ethyl chloroformate method, and the 1,1'-carbonyldiimidazole method. The activation method of the present invention is not limited to the above examples as long as it can perform a substitution and/or addition reaction with a nucleophilic reactive group having active hydrogen such as an amino group, a hydroxyl group, a carboxyl group, or a thiol group of the ligand. However, in consideration of chemical stability, thermal stability, etc., it is preferable to use epoxide.
In particular, the epichlorohydrin method is recommended. Also,
If necessary, a molecule (spacer) of arbitrary length may be introduced between the carrier and the ligand. The ligand to be retained on the carrier of the present invention can be freely selected depending on the purpose, and some of them are exemplified below. For the treatment of systemic lupus erythematosus, adenine,
Homopolymers or copolymers of mono-, di-, and trinucleotides such as guanine, cytosine, uracil, and thymine, and naturally occurring nucleic acids such as DNA and RNA can be used. also present in the blood
Anti-single-stranded for adsorption removal of DNA, RNA, and ENA.
DNA antibody, anti-double-stranded DNA antibody, anti-RNA antibody,
Anti-nucleic acid antibodies such as anti-ENA antibodies and basic compounds such as methylated albumin actinomycin D can be used. Furthermore, for adsorption and removal of immune complexes in blood, complement components such as Clq, specific proteins such as protein A, and antibodies against immune complexes such as anti-heavistein constant region 2 phase antibodies can be used. For the treatment of rheumatoid arthritis and malignant rheumatoid arthritis, chemical denaturation (coagulation) methods such as urea, guanidine hydrochloride, mercaptoethanol, surfactants, and organic solvents, physical denaturation (coagulation) methods such as heat, ultrasound, and gas bubbling are used. ) Modified γ modified by method
-Globulin, modified immunoglobulin, aggregated γ-
Antigen-like substances against rheumatoid factors such as globulin, aggregated immunoglobulin, Fc region of immunoglobulin, heavy chain constant region 2 of immunoglobulin, and modified products thereof by the above-mentioned modification method, and anti-rheumatoid factor antibodies can be used. . In addition, for the removal of rheumatoid immune complexes,
Antibodies against complement components such as Clq, specific proteins such as protein A, and immune complexes such as anti-heavichein constant region phase 2 antibodies can be used. For the treatment of Hashimoto's disease, thyroglobulin, a microsomal fraction component of thyroid gland, can be used. For the treatment of myasthenia gravis, neuromuscular acetylcholine receptor fraction components can be used. Glomerular basement membrane components are used to treat glomerulonephritis, platelet membrane components and platelet granule fraction components are used to treat idiopathic thrombocytopenic purpura, and transcortisone and anticortisone antibodies are used to treat Cushing syndrome. be able to. For the prevention and treatment of hepatitis, hepatitis A virus,
Antibodies against viral surface antigens such as hepatitis B virus can be used. Anti-angiotensin antibodies can be used to treat hypertension, and heparin and anti-riboprotein antibodies can be used to treat hyperlipidemia. For treatment of immune diseases based on lymphocyte abnormalities, anti-lymphocyte antibodies such as anti-B cell antibodies, anti-suppressor T antibodies, and anti-helper T antibodies can be used. Protein A and anti-immunoglobulin antibodies can be used to treat cancer such as breast cancer. Ligands that can be used in the present invention are not limited to the above examples, but include lectins such as congnitinin, concanavalin A, and phytohemaagglutinin, nucleic acids, amino acids, lipids, protamine, heparin, antigens, antibodies, enzymes, Known substances capable of binding to adsorbed substances such as substrates and coenzymes can be used. Furthermore, the carrier of the present invention can also be used with two or more types of ligands retained therein. Furthermore, two or more types of carriers holding ligands can be used in combination. As described above, the carrier suitable for the adsorbent for body fluid purification of the present invention has sufficient mechanical strength, so it is difficult to prepare the adsorbent through activation, immobilization, transportation, extracorporeal circulation, and especially destruction. There is virtually no possibility of chipping, chipping, or chipping, and a wide range of operating methods and conditions can be selected. In addition, since it is a hard gel, when packed in a column and used for extracorporeal circulation,
Body fluids containing substances to be adsorbed or removed can be stably passed continuously for a long time at a high flow rate. Furthermore, since it is a hard gel and has permanent pores, it can be easily sterilized, which is an essential requirement for an adsorbent for extracorporeal circulation therapy. For example, lyophilization of the adsorbent and chemical sterilization such as ethylene oxide gas sterilization can also be carried out without impairing the adsorption capacity of the adsorbent. Furthermore, in addition to the above-mentioned physical properties, it had favorable chemical properties and exhibited the following effects. Because it has a high hydroxyl group density, it is possible to chemically bond ligands at a high density, and because it is highly hydrophilic, there is little nonspecific adsorption to plasma proteins and the like.
In addition, there is little reaction with biological components such as activation of the complement system and coagulation system, and furthermore, when used as an adsorbent for whole blood, there is no interaction with blood cell components, such as thrombus formation and non-specific adhesion of blood cell components. , there is little residual blood, etc., and it can be used suitably. The carrier of the present invention is applicable to general usage for purifying and regenerating body fluids such as autologous plasma and autologous blood, and is applicable to cancer, immunoproliferative syndrome, rheumatoid arthritis,
Collagen diseases such as systemic lupus erythematosus, autoimmune diseases such as myasthenia gravis, allergic diseases such as bronchial asthma, diseases and phenomena related to the body's immune system such as rejection during organ transplantation, psoriasis, and ringworm. It can be effectively used for extracorporeal circulation treatment of skin diseases such as, kidney diseases such as nephritis, and liver diseases such as hepatitis. It can also be effectively used as a carrier for affinity chromatography. Embodiments of the present invention will be explained in more detail with reference to Examples below. Example 1 100 g of vinyl acetate, 64.3 g of triallyl isocyanurate (X = 0.40), 100 g of ethyl acetate, 100 g of heptane, 7.5 g of polyvinyl acetate (degree of polymerization 500) and 3.8 g of 2,2'-azobisisobutyronitrile
A homogeneous mixed liquid consisting of polyvinyl alcohol 1
wt%, sodium dihydrogen phosphate dihydrate 0.05 wt% and disodium hydrogen phosphate dodecahydrate
Add 400 ml of water in which 1.5% by weight was dissolved into a flask, stir thoroughly, and then heat at 65°C for 18 hours and then at 75°C.
Suspension polymerization was carried out by heating and stirring for 5 hours to obtain a granular copolymer. After washing with water and extraction with acetone, the copolymer was transesterified in a solution consisting of 46.5 g of caustic soda and 2 methanol at 40° C. for 18 hours. The average particle size of the obtained gel was 150 μm, and the hydroxyl group density (qOH) per unit weight determined by the above method.
The molecular weight was 9.0 meq/g, the specific surface area was 60 m 2 /g, and the exclusion limit molecular weight by dextran was 6×10 5 . This gel was packed into two columns with an inner diameter of 10 mm and a length of 50 mm, and each column was filled with 0.4 ml of ACD-added healthy human plasma.
12 ml of ACD-added healthy human blood was flowed into the other tube at a flow rate of 0.7 ml/min. No decrease in packing volume, clogging, or decrease in flow rate was observed in either column, and the pressure difference before and after the column was 10 mm for plasma.
It was less than Hg, and blood was in the range of 10 to 20 mmHg. When we examined changes in plasma protein and blood cell components before and after passing through the column, we found that albumin was only slightly adsorbed in plasma, and there was little decrease in complement component C3 . In other words, there was little non-specific adsorption of useful proteins. In addition, in blood, no significant difference was observed in the concentrations of red blood cells, white blood cells, and platelets before and after passing through the column. That is, almost no adhesion or hemolysis of blood cell components was observed. Next, 10 g (dry weight) of the obtained gel was suspended in 120 ml of dimethyl sulfoxide, and this was mixed with 78.3 ml of epichlorohydrin and 10 ml of 30% sodium hydroxide.
was added, and the activation reaction was carried out at 30°C for 5 hours with shaking and stirring. After the reaction was completed, it was collected with a glass filter, washed with dimethyl sulfoxide, and then washed with water to obtain an activated gel. The epoxy group density of the obtained gel was 1.1 meq/g (the epoxy group density was measured by reacting the gel with sodium thiosulfate in an aqueous solvent, and measuring the amount of sodium hydroxide produced by the reaction with the epoxy group). amount was measured and calculated from this). When this activated gel was compared with the original gel particles and observed under an optical microscope, no damage such as chipping or flaking was observed. Comparative Example 1 Sepharose 4B (manufactured by Pharmacia Huain Chemical Co., Ltd.), an agarose-based carrier commercially available as a water-insoluble carrier for affinity chromatography, was packed in the same column as in Example 1.
Plasma was run under the same conditions as in Example 1. As a result, the volume of Sepharose 4B in the column shrank by about 12%, and the pressure rose to over 20 mmHg. In addition, in order to measure the specific surface area, after replacing the solvent with acetone and drying at 60°C, the gels stuck to each other, contracted, and solidified. Example 2 Various crosslinking degrees X = 0.05, 0.25, 0.35, 0.50 were obtained by changing the charging ratio of vinyl acetate and triallyl isocyanurate using the same manufacturing method as the polymerization method and saponification method shown in Example 1. , 0.80, 0.9
(Among these, gels with X=0.05, 0.25 and 0.9 were used as comparative examples for Example 2). The physical properties of these gels are shown in the table below.
【表】
上の表から、Ｘが0.35より小さいと、乾燥時に
収縮するために比表面積が小さくなり、またＸが
0.8より大きいと、水酸基密度が非常に小さくな
つてしまうことがわかり、架橋度Ｘが0.35≦Ｘ≦
0.80の範囲にあるゲルは、大きな水酸基密度を持
ち、かつ比表面積も大きい。
これらのゲルを内径10mm、長さ50mmのカラムに
詰め、水を流しながらカラムの入口と出口間の差
圧を150mmHgにしたときのゲル体積（カラム容
量）の収縮率を測定した。その結果を第１図に示
す。
第１図から、架橋度Ｘが0.35より小さくなる
と、ゲルが柔らかくなり、ゲルの体積収縮率（カ
ラムが目詰りを起す度合に相当）が大きくなる。
次に、これらのゲル２ml（カラム容積）を三角
フラスコにとり、健康人血漿６mlを加え、37℃で
３時間振とうした。その後、血漿をゲルから分離
し、アルブミンと補体C3の分析を行なつた。評
価方法はアルブミンがブロムクレゾールグリーン
を用いる方法、補体C3がシングル・ラジアル・
イミユノ・デイフユージヨン法によつた。
結果を第２図および第３図に示すが、縦軸は処
理後の血漿の濃度（吸着材中の水分による希釈分
を補正後）を示し、破線は吸着実験に用いた血漿
の値を示す。
すなわち、架橋度Ｘが0.8より大きくなると、
生体にとつて有用なアルブミン、補体C3のよう
な蛋白の吸着が増加する。
以上の結果より、架橋度Ｘが0.35≦Ｘ≦0.8の
範囲においては、ゲルの比表面積が大きく、好ま
しい水酸基密度をもち、実用上充分な硬さ（応力
に対する変形のし難さ）があり、生体にとつて有
用な蛋白質の非特異的吸着が少ないことがわか
る。
実施例 ３
実施例１と同様にして得られたゲル（架橋度Ｘ
＝0.4）を湿潤状態で121℃、20分間オートクレー
ブ滅菌したが、吸着材の物性は殆んど変化しなか
つた。[Table] From the table above, when X is smaller than 0.35, the specific surface area becomes smaller due to shrinkage during drying, and
It can be seen that when it is larger than 0.8, the hydroxyl group density becomes very small, and the degree of crosslinking X is 0.35≦X≦
A gel in the range of 0.80 has a large hydroxyl group density and a large specific surface area. These gels were packed into a column with an inner diameter of 10 mm and a length of 50 mm, and the shrinkage rate of the gel volume (column capacity) was measured when the differential pressure between the inlet and outlet of the column was set to 150 mmHg while water was flowing. The results are shown in FIG. From FIG. 1, when the degree of crosslinking X becomes smaller than 0.35, the gel becomes soft and the volume shrinkage rate of the gel (corresponding to the degree to which the column becomes clogged) increases. Next, 2 ml of these gels (column volume) were placed in an Erlenmeyer flask, 6 ml of healthy human plasma was added, and the mixture was shaken at 37°C for 3 hours. Plasma was then separated from the gel and analyzed for albumin and complement C3 . The evaluation methods are: albumin using bromcresol green; complement C3 using single, radial,
It was based on the Imiyuno Diffusion Method. The results are shown in Figures 2 and 3, where the vertical axis shows the concentration of plasma after treatment (after correcting for dilution due to water in the adsorbent), and the broken line shows the value of the plasma used in the adsorption experiment. . That is, when the degree of crosslinking X is greater than 0.8,
Adsorption of proteins useful to living organisms such as albumin and complement C3 increases. From the above results, when the degree of crosslinking It can be seen that there is little non-specific adsorption of proteins useful to living organisms. Example 3 Gel obtained in the same manner as Example 1 (crosslinking degree
= 0.4) was sterilized in an autoclave at 121°C for 20 minutes in a wet state, but the physical properties of the adsorbent hardly changed.
第１図は実施例２におけるゲル体積の収縮率の
測定結果を示すグラフ、第２図は実施例２の吸着
実験におけるアルブンの分析結果を示すグラフ、
第３図は同じく補体C3の分析結果を示すグラフ
である。
FIG. 1 is a graph showing the measurement results of gel volume shrinkage in Example 2, FIG. 2 is a graph showing the results of Albun analysis in the adsorption experiment of Example 2,
FIG. 3 is a graph showing the results of analysis of complement C3 .
Claims (1)
て、カルボン酸ビニルエステルと下記トリアジン
環構造を有する架橋性単量体(1)または(2) 【式】【式】 （R1、R2、R3は−CH2−CH＝CH2、−CH2−Ｃ
≡CHまたは【式】より選ばれた同一 もしくは異なる基） とを下式で示される架橋度Ｘ Ｘ＝W2／M2×n2／W1／M1×n1＋W2／M2×n2 M1：カルボン酸ビニルエステルの分子量 M2：架橋性単量体の分子量 W1：重合に用いたカルボン酸ビニルエステルの
重量 W2：重合に用いた架橋性単量体の重量 n1：カルボン酸ビニルエステル１分子が有するエ
チレン性二重結合の数 n2：架橋性単量体１分子が有するエチレン性二重
結合の数 を0.35≦Ｘ≦0.80の範囲にして重合した後、加水
分解して得られる体液浄化用吸着材の担体。[Scope of Claims] 1. A carrier used in an adsorbent for body fluid purification, which comprises a carboxylic acid vinyl ester and a crosslinkable monomer (1) or (2) having the following triazine ring structure [Formula] [Formula] ( R 1 , R 2 , R 3 are −CH 2 −CH=CH 2 , −CH 2 −C
≡CH or the same or different groups selected from [Formula] ) and the degree of crosslinking shown by the following formula X n 2 M 1 : Molecular weight of carboxylic acid vinyl ester M 2 : Molecular weight of crosslinkable monomer W 1 : Weight of carboxylic acid vinyl ester used in polymerization W 2 : Weight of crosslinkable monomer used in polymerization n 1 : Number of ethylenic double bonds in one molecule of carboxylic acid vinyl ester n 2 : After polymerization with the number of ethylenic double bonds in one molecule of crosslinkable monomer in the range of 0.35≦X≦0.80, hydration Adsorbent carrier for body fluid purification obtained by decomposition.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP57048830A JPS58165860A (en) | 1982-03-29 | 1982-03-29 | Carrier of adsorbing material for purifying body liquid |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP57048830A JPS58165860A (en) | 1982-03-29 | 1982-03-29 | Carrier of adsorbing material for purifying body liquid |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS58165860A JPS58165860A (en) | 1983-09-30 |
| JPS6361024B2 true JPS6361024B2 (en) | 1988-11-28 |
Family
ID=12814146
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP57048830A Granted JPS58165860A (en) | 1982-03-29 | 1982-03-29 | Carrier of adsorbing material for purifying body liquid |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS58165860A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH0192064U (en) * | 1987-12-10 | 1989-06-16 | ||
| JPH03141416A (en) * | 1989-10-26 | 1991-06-17 | Mitsubishi Electric Corp | Memory card |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH0616842B2 (en) * | 1986-01-14 | 1994-03-09 | 鐘淵化学工業株式会社 | Adsorbent for activated complement components |
| JP5027591B2 (en) * | 2006-08-18 | 2012-09-19 | 株式会社カネカ | Crosslinked polymer particles and process for producing the same |
-
1982
- 1982-03-29 JP JP57048830A patent/JPS58165860A/en active Granted
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH0192064U (en) * | 1987-12-10 | 1989-06-16 | ||
| JPH03141416A (en) * | 1989-10-26 | 1991-06-17 | Mitsubishi Electric Corp | Memory card |
Also Published As
| Publication number | Publication date |
|---|---|
| JPS58165860A (en) | 1983-09-30 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP0143369B1 (en) | A porous adsorbent for adsorbing low density lipoproteins | |
| US4452918A (en) | Totally porous activated gel | |
| US4430229A (en) | Immune adsorbent and adsorbing device | |
| JP3901216B2 (en) | Tumor necrosis factor-α adsorbent, adsorption removal method, and adsorber using the adsorbent | |
| EP0819439B1 (en) | Apparatus comprising an adsorbent for adsorptive elimination of disease-related factors in body fluids | |
| JPH0323182B2 (en) | ||
| JPS6090039A (en) | Blood purifying adsorbing body | |
| JPS59193135A (en) | Adsorbing body | |
| JPS6361024B2 (en) | ||
| JP2543693B2 (en) | Adsorbent for low-density lipoprotein and method for producing the same | |
| JPH01181875A (en) | Adsorptive body of immune complex and removing device for immune complex with it | |
| JPH0424065B2 (en) | ||
| JPS59186558A (en) | Adsorbing material of self-antibody and/or immunological composite | |
| JPS6226073A (en) | Method and apparatus for direct infusion and adsorption of blood | |
| JPH0622632B2 (en) | Adsorbent and removal device | |
| JP3157026B2 (en) | Adsorbent for blood purification | |
| JPH0771632B2 (en) | Adsorbent and removal device using the same | |
| JP3084436B2 (en) | Anti-DNA antibody removal device | |
| JPS6259975B2 (en) | ||
| JPS6090038A (en) | Blood compatible carrier | |
| JP2726662B2 (en) | Adsorbent and removal device using the same | |
| JPH0341210B2 (en) | ||
| JPS60126165A (en) | Blood compatible adsorbing material | |
| JPH01315338A (en) | Adsorbent for lipoprotein having low specific gravity | |
| JPS59139937A (en) | Adsorbent for lipoprotein with low specific gravity |