JP5546554B2 - タンパク質結合物質を除去するための収着剤 - Google Patents
タンパク質結合物質を除去するための収着剤 Download PDFInfo
- Publication number
- JP5546554B2 JP5546554B2 JP2011546521A JP2011546521A JP5546554B2 JP 5546554 B2 JP5546554 B2 JP 5546554B2 JP 2011546521 A JP2011546521 A JP 2011546521A JP 2011546521 A JP2011546521 A JP 2011546521A JP 5546554 B2 JP5546554 B2 JP 5546554B2
- Authority
- JP
- Japan
- Prior art keywords
- protein
- adsorption
- sorbent
- albumin
- polypeptide
- 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 - Fee Related
Links
- 102000004169 proteins and genes Human genes 0.000 title claims description 61
- 108090000623 proteins and genes Proteins 0.000 title claims description 61
- 239000002594 sorbent Substances 0.000 title claims description 58
- 239000000126 substance Substances 0.000 title claims description 42
- 238000001179 sorption measurement Methods 0.000 claims description 90
- 239000011148 porous material Substances 0.000 claims description 69
- 102000008100 Human Serum Albumin Human genes 0.000 claims description 36
- 108091006905 Human Serum Albumin Proteins 0.000 claims description 36
- 229920001577 copolymer Polymers 0.000 claims description 34
- 238000000576 coating method Methods 0.000 claims description 26
- 239000011248 coating agent Substances 0.000 claims description 25
- 239000013060 biological fluid Substances 0.000 claims description 24
- 238000000034 method Methods 0.000 claims description 16
- 239000002245 particle Substances 0.000 claims description 15
- 238000010521 absorption reaction Methods 0.000 claims description 12
- 239000010419 fine particle Substances 0.000 claims description 8
- 238000004519 manufacturing process Methods 0.000 claims description 7
- 238000001784 detoxification Methods 0.000 claims description 6
- 239000004005 microsphere Substances 0.000 claims description 5
- 230000004087 circulation Effects 0.000 claims description 4
- 239000000725 suspension Substances 0.000 claims description 3
- 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 76
- 108090000765 processed proteins & peptides Proteins 0.000 description 62
- 229920001184 polypeptide Polymers 0.000 description 61
- 102000004196 processed proteins & peptides Human genes 0.000 description 61
- 239000003463 adsorbent Substances 0.000 description 53
- 101800004937 Protein C Proteins 0.000 description 48
- 102000017975 Protein C Human genes 0.000 description 48
- 101800001700 Saposin-D Proteins 0.000 description 48
- 229960000856 protein c Drugs 0.000 description 48
- 102000009027 Albumins Human genes 0.000 description 44
- 108010088751 Albumins Proteins 0.000 description 44
- 239000000243 solution Substances 0.000 description 43
- 229920000642 polymer Polymers 0.000 description 42
- 230000007935 neutral effect Effects 0.000 description 40
- 210000004369 blood Anatomy 0.000 description 28
- 239000008280 blood Substances 0.000 description 28
- 210000004185 liver Anatomy 0.000 description 27
- 229920001600 hydrophobic polymer Polymers 0.000 description 26
- 229920005989 resin Polymers 0.000 description 25
- 239000011347 resin Substances 0.000 description 25
- 238000012360 testing method Methods 0.000 description 23
- 239000010410 layer Substances 0.000 description 22
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 20
- 206010019663 Hepatic failure Diseases 0.000 description 18
- 208000007903 liver failure Diseases 0.000 description 18
- 231100000835 liver failure Toxicity 0.000 description 18
- 239000003053 toxin Substances 0.000 description 17
- 231100000765 toxin Toxicity 0.000 description 16
- 108700012359 toxins Proteins 0.000 description 16
- 229920001429 chelating resin Polymers 0.000 description 15
- 210000000056 organ Anatomy 0.000 description 15
- 239000006228 supernatant Substances 0.000 description 13
- 230000002209 hydrophobic effect Effects 0.000 description 12
- 230000002829 reductive effect Effects 0.000 description 12
- BHQCQFFYRZLCQQ-UHFFFAOYSA-N (3alpha,5alpha,7alpha,12alpha)-3,7,12-trihydroxy-cholan-24-oic acid Natural products OC1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)C(O)C2 BHQCQFFYRZLCQQ-UHFFFAOYSA-N 0.000 description 9
- 239000004380 Cholic acid Substances 0.000 description 9
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 description 9
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 description 9
- BHQCQFFYRZLCQQ-OELDTZBJSA-N cholic acid Chemical compound C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 BHQCQFFYRZLCQQ-OELDTZBJSA-N 0.000 description 9
- 229960002471 cholic acid Drugs 0.000 description 9
- 235000019416 cholic acid Nutrition 0.000 description 9
- KXGVEGMKQFWNSR-UHFFFAOYSA-N deoxycholic acid Natural products C1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)C(O)C2 KXGVEGMKQFWNSR-UHFFFAOYSA-N 0.000 description 9
- 150000001450 anions Chemical class 0.000 description 8
- 239000003795 chemical substances by application Substances 0.000 description 8
- 231100000614 poison Toxicity 0.000 description 8
- 239000003440 toxic substance Substances 0.000 description 8
- 208000007788 Acute Liver Failure Diseases 0.000 description 7
- 206010000804 Acute hepatic failure Diseases 0.000 description 7
- 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 7
- 231100000836 acute liver failure Toxicity 0.000 description 7
- 230000007423 decrease Effects 0.000 description 7
- 229960002897 heparin Drugs 0.000 description 7
- 229920000669 heparin Polymers 0.000 description 7
- 229940096437 Protein S Drugs 0.000 description 6
- 102000029301 Protein S Human genes 0.000 description 6
- 108010066124 Protein S Proteins 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 230000008901 benefit Effects 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 230000005661 hydrophobic surface Effects 0.000 description 6
- 206010053567 Coagulopathies Diseases 0.000 description 5
- 230000023555 blood coagulation Effects 0.000 description 5
- 230000008081 blood perfusion Effects 0.000 description 5
- 230000015271 coagulation Effects 0.000 description 5
- 238000005345 coagulation Methods 0.000 description 5
- 230000006870 function Effects 0.000 description 5
- 230000003993 interaction Effects 0.000 description 5
- 102000004506 Blood Proteins Human genes 0.000 description 4
- 108010017384 Blood Proteins Proteins 0.000 description 4
- 208000010378 Pulmonary Embolism Diseases 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 4
- 239000003130 blood coagulation factor inhibitor Substances 0.000 description 4
- 230000035602 clotting Effects 0.000 description 4
- 230000001951 hemoperfusion Effects 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 239000012528 membrane Substances 0.000 description 4
- 239000013642 negative control Substances 0.000 description 4
- 238000005457 optimization Methods 0.000 description 4
- 239000002952 polymeric resin Substances 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 229920003002 synthetic resin Polymers 0.000 description 4
- 108010049003 Fibrinogen Proteins 0.000 description 3
- 102000008946 Fibrinogen Human genes 0.000 description 3
- 206010019670 Hepatic function abnormal Diseases 0.000 description 3
- 208000001647 Renal Insufficiency Diseases 0.000 description 3
- 150000001413 amino acids Chemical class 0.000 description 3
- 239000003146 anticoagulant agent Substances 0.000 description 3
- 229940127219 anticoagulant drug Drugs 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 230000003247 decreasing effect Effects 0.000 description 3
- 238000009792 diffusion process Methods 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 238000011156 evaluation Methods 0.000 description 3
- 229940012952 fibrinogen Drugs 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 238000011534 incubation Methods 0.000 description 3
- 210000003734 kidney Anatomy 0.000 description 3
- 201000006370 kidney failure Diseases 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 208000019423 liver disease Diseases 0.000 description 3
- 230000003908 liver function Effects 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 239000002356 single layer Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 108010039209 Blood Coagulation Factors Proteins 0.000 description 2
- 102000015081 Blood Coagulation Factors Human genes 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 206010051055 Deep vein thrombosis Diseases 0.000 description 2
- 206010040047 Sepsis Diseases 0.000 description 2
- PPBRXRYQALVLMV-UHFFFAOYSA-N Styrene Chemical compound C=CC1=CC=CC=C1 PPBRXRYQALVLMV-UHFFFAOYSA-N 0.000 description 2
- 206010047249 Venous thrombosis Diseases 0.000 description 2
- 239000006096 absorbing agent Substances 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- -1 aliphatic ester Chemical class 0.000 description 2
- 230000010100 anticoagulation Effects 0.000 description 2
- 239000003613 bile acid Substances 0.000 description 2
- 230000017531 blood circulation Effects 0.000 description 2
- 230000007196 blood circulation pathway Effects 0.000 description 2
- 239000003114 blood coagulation factor Substances 0.000 description 2
- 238000000502 dialysis Methods 0.000 description 2
- 238000009826 distribution Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000012530 fluid Substances 0.000 description 2
- 230000005976 liver dysfunction Effects 0.000 description 2
- 230000004060 metabolic process Effects 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 229930014626 natural product Natural products 0.000 description 2
- 229920003053 polystyrene-divinylbenzene Polymers 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 230000004083 survival effect Effects 0.000 description 2
- HSINOMROUCMIEA-FGVHQWLLSA-N (2s,4r)-4-[(3r,5s,6r,7r,8s,9s,10s,13r,14s,17r)-6-ethyl-3,7-dihydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-17-yl]-2-methylpentanoic acid Chemical compound C([C@@]12C)C[C@@H](O)C[C@H]1[C@@H](CC)[C@@H](O)[C@@H]1[C@@H]2CC[C@]2(C)[C@@H]([C@H](C)C[C@H](C)C(O)=O)CC[C@H]21 HSINOMROUCMIEA-FGVHQWLLSA-N 0.000 description 1
- 208000010444 Acidosis Diseases 0.000 description 1
- 208000005223 Alkalosis Diseases 0.000 description 1
- VYZAMTAEIAYCRO-UHFFFAOYSA-N Chromium Chemical compound [Cr] VYZAMTAEIAYCRO-UHFFFAOYSA-N 0.000 description 1
- 208000017667 Chronic Disease Diseases 0.000 description 1
- 102100022641 Coagulation factor IX Human genes 0.000 description 1
- 102100023804 Coagulation factor VII Human genes 0.000 description 1
- 102000018832 Cytochromes Human genes 0.000 description 1
- 108010052832 Cytochromes Proteins 0.000 description 1
- AEMOLEFTQBMNLQ-AQKNRBDQSA-N D-glucopyranuronic acid Chemical compound OC1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O AEMOLEFTQBMNLQ-AQKNRBDQSA-N 0.000 description 1
- 238000008157 ELISA kit Methods 0.000 description 1
- 108010076282 Factor IX Proteins 0.000 description 1
- 108010023321 Factor VII Proteins 0.000 description 1
- 108010014173 Factor X Proteins 0.000 description 1
- IAJILQKETJEXLJ-UHFFFAOYSA-N Galacturonsaeure Natural products O=CC(O)C(O)C(O)C(O)C(O)=O IAJILQKETJEXLJ-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 102000001554 Hemoglobins Human genes 0.000 description 1
- 108010054147 Hemoglobins Proteins 0.000 description 1
- 206010023126 Jaundice Diseases 0.000 description 1
- 102000002397 Kinins Human genes 0.000 description 1
- 108010093008 Kinins Proteins 0.000 description 1
- LSDPWZHWYPCBBB-UHFFFAOYSA-N Methanethiol Chemical compound SC LSDPWZHWYPCBBB-UHFFFAOYSA-N 0.000 description 1
- 102000036675 Myoglobin Human genes 0.000 description 1
- 108010062374 Myoglobin Proteins 0.000 description 1
- 101000882917 Penaeus paulensis Hemolymph clottable protein Proteins 0.000 description 1
- 102000007584 Prealbumin Human genes 0.000 description 1
- 108010071690 Prealbumin Proteins 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- 108091005605 Vitamin K-dependent proteins Proteins 0.000 description 1
- 230000007950 acidosis Effects 0.000 description 1
- 208000026545 acidosis disease Diseases 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 230000002340 alkalosis Effects 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 238000005349 anion exchange Methods 0.000 description 1
- 230000002429 anti-coagulating effect Effects 0.000 description 1
- 108010072035 antithrombin III-protease complex Proteins 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 210000000941 bile Anatomy 0.000 description 1
- 208000015294 blood coagulation disease Diseases 0.000 description 1
- 229940019700 blood coagulation factors Drugs 0.000 description 1
- 210000001124 body fluid Anatomy 0.000 description 1
- 239000010839 body fluid Substances 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 230000009852 coagulant defect Effects 0.000 description 1
- 229920001688 coating polymer Polymers 0.000 description 1
- 230000004154 complement system Effects 0.000 description 1
- 230000006735 deficit Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 238000003795 desorption Methods 0.000 description 1
- 230000008034 disappearance Effects 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003792 electrolyte Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 229960004222 factor ix Drugs 0.000 description 1
- 229940012413 factor vii Drugs 0.000 description 1
- 229940012426 factor x Drugs 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 229940097043 glucuronic acid Drugs 0.000 description 1
- 231100000784 hepatotoxin Toxicity 0.000 description 1
- 229920000140 heteropolymer Polymers 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 229920001519 homopolymer Polymers 0.000 description 1
- 230000003100 immobilizing effect Effects 0.000 description 1
- 230000007124 immune defense Effects 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 239000003550 marker Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- QSHDDOUJBYECFT-UHFFFAOYSA-N mercury Chemical compound [Hg] QSHDDOUJBYECFT-UHFFFAOYSA-N 0.000 description 1
- 229910052753 mercury Inorganic materials 0.000 description 1
- 239000003607 modifier Substances 0.000 description 1
- 239000000178 monomer Substances 0.000 description 1
- 239000000025 natural resin Substances 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 150000002989 phenols Chemical class 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 239000003805 procoagulant Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000005215 recombination Methods 0.000 description 1
- 230000006798 recombination Effects 0.000 description 1
- 230000008085 renal dysfunction Effects 0.000 description 1
- 230000002940 repellent Effects 0.000 description 1
- 239000005871 repellent Substances 0.000 description 1
- 210000003786 sclera Anatomy 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- KAKZBPTYRLMSJV-UHFFFAOYSA-N vinyl-ethylene Natural products C=CC=C KAKZBPTYRLMSJV-UHFFFAOYSA-N 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 150000003722 vitamin derivatives Chemical class 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M1/00—Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
- A61M1/36—Other treatment of blood in a by-pass of the natural circulatory system, e.g. temperature adaptation, irradiation ; Extra-corporeal blood circuits
- A61M1/3679—Other treatment of blood in a by-pass of the natural circulatory system, e.g. temperature adaptation, irradiation ; Extra-corporeal blood circuits by absorption
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D15/00—Separating processes involving the treatment of liquids with solid sorbents; Apparatus therefor
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D15/00—Separating processes involving the treatment of liquids with solid sorbents; Apparatus therefor
- B01D15/08—Selective adsorption, e.g. chromatography
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
- B01J20/22—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof comprising organic material
- B01J20/26—Synthetic macromolecular compounds
- B01J20/264—Synthetic macromolecular compounds derived from different types of monomers, e.g. linear or branched copolymers, block copolymers, graft copolymers
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
- B01J20/22—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof comprising organic material
- B01J20/26—Synthetic macromolecular compounds
- B01J20/265—Synthetic macromolecular compounds modified or post-treated polymers
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
- B01J20/28—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof characterised by their form or physical properties
- B01J20/28002—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof characterised by their form or physical properties characterised by their physical properties
- B01J20/28004—Sorbent size or size distribution, e.g. particle size
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
- B01J20/28—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof characterised by their form or physical properties
- B01J20/28054—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof characterised by their form or physical properties characterised by their surface properties or porosity
- B01J20/28078—Pore diameter
- B01J20/28083—Pore diameter being in the range 2-50 nm, i.e. mesopores
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
- B01J20/281—Sorbents specially adapted for preparative, analytical or investigative chromatography
- B01J20/282—Porous sorbents
- B01J20/285—Porous sorbents based on polymers
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
- B01J20/30—Processes for preparing, regenerating, or reactivating
- B01J20/32—Impregnating or coating ; Solid sorbent compositions obtained from processes involving impregnating or coating
- B01J20/3202—Impregnating or coating ; Solid sorbent compositions obtained from processes involving impregnating or coating characterised by the carrier, support or substrate used for impregnation or coating
- B01J20/3206—Organic carriers, supports or substrates
- B01J20/3208—Polymeric carriers, supports or substrates
- B01J20/321—Polymeric carriers, supports or substrates consisting of a polymer obtained by reactions involving only carbon to carbon unsaturated bonds
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
- B01J20/30—Processes for preparing, regenerating, or reactivating
- B01J20/32—Impregnating or coating ; Solid sorbent compositions obtained from processes involving impregnating or coating
- B01J20/3231—Impregnating or coating ; Solid sorbent compositions obtained from processes involving impregnating or coating characterised by the coating or impregnating layer
- B01J20/3242—Layers with a functional group, e.g. an affinity material, a ligand, a reactant or a complexing group
- B01J20/3244—Non-macromolecular compounds
- B01J20/3246—Non-macromolecular compounds having a well defined chemical structure
- B01J20/3248—Non-macromolecular compounds having a well defined chemical structure the functional group or the linking, spacer or anchoring group as a whole comprising at least one type of heteroatom selected from a nitrogen, oxygen or sulfur, these atoms not being part of the carrier as such
- B01J20/3253—Non-macromolecular compounds having a well defined chemical structure the functional group or the linking, spacer or anchoring group as a whole comprising at least one type of heteroatom selected from a nitrogen, oxygen or sulfur, these atoms not being part of the carrier as such comprising a cyclic structure not containing any of the heteroatoms nitrogen, oxygen or sulfur, e.g. aromatic structures
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
- B01J20/30—Processes for preparing, regenerating, or reactivating
- B01J20/32—Impregnating or coating ; Solid sorbent compositions obtained from processes involving impregnating or coating
- B01J20/3231—Impregnating or coating ; Solid sorbent compositions obtained from processes involving impregnating or coating characterised by the coating or impregnating layer
- B01J20/3242—Layers with a functional group, e.g. an affinity material, a ligand, a reactant or a complexing group
- B01J20/3244—Non-macromolecular compounds
- B01J20/3246—Non-macromolecular compounds having a well defined chemical structure
- B01J20/3248—Non-macromolecular compounds having a well defined chemical structure the functional group or the linking, spacer or anchoring group as a whole comprising at least one type of heteroatom selected from a nitrogen, oxygen or sulfur, these atoms not being part of the carrier as such
- B01J20/3255—Non-macromolecular compounds having a well defined chemical structure the functional group or the linking, spacer or anchoring group as a whole comprising at least one type of heteroatom selected from a nitrogen, oxygen or sulfur, these atoms not being part of the carrier as such comprising a cyclic structure containing at least one of the heteroatoms nitrogen, oxygen or sulfur, e.g. heterocyclic or heteroaromatic structures
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
- B01J20/30—Processes for preparing, regenerating, or reactivating
- B01J20/32—Impregnating or coating ; Solid sorbent compositions obtained from processes involving impregnating or coating
- B01J20/3231—Impregnating or coating ; Solid sorbent compositions obtained from processes involving impregnating or coating characterised by the coating or impregnating layer
- B01J20/3242—Layers with a functional group, e.g. an affinity material, a ligand, a reactant or a complexing group
- B01J20/3268—Macromolecular compounds
- B01J20/3272—Polymers obtained by reactions otherwise than involving only carbon to carbon unsaturated bonds
- B01J20/3274—Proteins, nucleic acids, polysaccharides, antibodies or antigens
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
- B01J20/28—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof characterised by their form or physical properties
- B01J20/28014—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof characterised by their form or physical properties characterised by their form
- B01J20/28023—Fibres or filaments
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
- B01J20/28—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof characterised by their form or physical properties
- B01J20/28054—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof characterised by their form or physical properties characterised by their surface properties or porosity
- B01J20/28078—Pore diameter
- B01J20/28085—Pore diameter being more than 50 nm, i.e. macropores
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2220/00—Aspects relating to sorbent materials
- B01J2220/50—Aspects relating to the use of sorbent or filter aid materials
- B01J2220/58—Use in a single column
Landscapes
- Chemical & Material Sciences (AREA)
- Analytical Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Heart & Thoracic Surgery (AREA)
- General Health & Medical Sciences (AREA)
- Vascular Medicine (AREA)
- Engineering & Computer Science (AREA)
- Nanotechnology (AREA)
- Cardiology (AREA)
- Molecular Biology (AREA)
- Biochemistry (AREA)
- Anesthesiology (AREA)
- Biomedical Technology (AREA)
- Hematology (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- External Artificial Organs (AREA)
- Solid-Sorbent Or Filter-Aiding Compositions (AREA)
Description
被覆に用いたいろいろな平均孔径のスチレン−ジビニルベンゼンコポリマーを表1に示す。粒度は、5μm±3〜4μmであった。
2.1.吸着剤
まず、いろいろな孔径のスチレン/ジビニルベンゼンコポリマーを準備した。これらのスチレン/ジビニルベンゼンコポリマーの粒度は、5μm±3〜4μmであった。次いで実施例1の製造手順により、これらのスチレン/ジビニルベンゼンコポリマーを、10%ヒトアルブミン溶液(HSA)を用いて被覆させた。吸着剤を表2に示す。
上に示した吸着剤のタンパク質結合物質の吸着とヒト血漿からのプロテインCの吸着についての性質を、バッチ試験で検討した。これらの試験のために、吸着剤をスパイク血漿(2.2.1節を参照)で被覆した。
血漿スパイクの製造のために、健康な供与者からの血漿を、明確な濃度の肝臓毒素を用いてスパイクした。100mLの肝臓毒素を含むスパイク後の血漿は、300μMのビリルビンと、100μMのコール酸、100μMのトリプトファン、2mMフェノールを含んでいた。
5分、15分、30分、60分後に、各試験管から1mLを抜き出し、直ちに11,000gで10分間遠心分離した。上澄液を直ちにエッペンドルフ反応容器に移した。吸着剤を含まない負のコントロール(「コントロール血漿」と呼ぶ)を、0分の時点での測定に用いた。試料は−20℃で保存し、分析までは光から保護した。
加えた肝臓毒素(ビリルビン、コール酸、トリプトファン、フェノール)と血漿中に存在するタンパク質(アルブミンとプロテインC)の吸着の両方を分析した。
ビリルビン、キットロット:14652700 (ロシュ社)
コール酸、ロット:R284067 (ロシュ社)
トリプトファンキットロット:685125−01 (ロシュ社)
フェノール:HPLCクロマトグラフィー
アルブミンキットロット:688271−01 (ロシュ社)
プロテインC ELISAキットロット:12021228 (テクノクローン社)
分析は、日立902(VT)で行った。
試験結果を、グラフの形式で数字で示す。
2.4.バッチ試験からの結果の要約
バッチ試験の結果より、吸着剤のアルブミン被覆で生体親和性をかなり改善できること、特に天然の抗凝固剤であるプロテインCの吸着が阻害されるか大きく低下することがわかる。したがって、これがプロテインSにも当てはまると考えるべきである。これは、敗血症または肝不全の患者に大きな意味を持つ。これらの患者の血液の凝固能力が攪乱されており、さらにこれを悪化させてはならないからである。また、肝不全と腎不全の主たる毒素の吸着に対する吸着剤の特性(図1A、図1B、図2A、図2B、図3A、図3B、図4A、および図4Bを参照)がHSAタンパク質の被覆により影響を受けず、それらの吸着容量と吸着速度がほぼ維持されている。
タンパク質結合物質とプロテインCの吸着への、中性で疎水性のスチレン/ジビニルコポリマーの被覆に用いられるヒトアルブミン溶液(実施例1の手順を参照)の濃度の影響を調べた。この試験の目的は、コポリマーの被覆のために理想的なヒトアルブミン溶液の濃度を試験することである。
バッチ試験の結果の要約
HSA溶液の濃度は、ビリルビン、コール酸、アルブミンおよびフェノールの吸着に影響を及ぼさない。これらの曲線は、実質的に同じである。
Claims (10)
- 生体液からタンパク質結合物質を除去するための収着剤、即ち(a)多孔性のスチレン/ジビニルベンゼンコポリマーと(b)前記コポリマー上に吸着されたヒト血清アルブミン(HSA)層からなる収着剤であって、前記コポリマーの平均孔径が30〜40nmであることを特徴とする収着剤。
- 前記収着剤が前記コポリマーの微粒子を含み、前記微粒子の粒度が20μm以下であることを特徴とする請求項1に記載の収着剤。
- 前記微粒子の粒度が8μm以下であることを特徴とする請求項2に記載の収着剤。
- 前記微粒子の粒度が5μm以下であることを特徴とする請求項2に記載の収着剤。
- 請求項1〜4の一項に記載の収着剤を含む吸収装置。
- 請求項1〜4の一項に記載の収着剤の懸濁液を含む血漿循環経路。
- 最高で10%のヒト血清アルブミン溶液を、前記コポリマーの吸着被覆に用いることを特徴とする請求項1〜4の一項に記載の収着剤の製造方法。
- 前記コポリマーの吸着被覆に1%のヒト血清アルブミン溶液を用いることを特徴とする請求項7に記載の方法。
- 前記コポリマーの吸着被覆に10%のヒト血清アルブミン溶液を用いることを特徴とする請求項7に記載の方法。
- 請求項1〜4の一項に記載の収着剤を含むMDS(マイクロスフェアー系無害化システム)。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
ATA112/2009 | 2009-01-22 | ||
AT0011209A AT507847B1 (de) | 2009-01-22 | 2009-01-22 | Sorptionsmittel zum entfernen proteingebundener substanzen |
PCT/AT2010/000016 WO2010083544A1 (de) | 2009-01-22 | 2010-01-20 | Sorptionsmittel zum entfernen proteingebundener substanzen |
Publications (2)
Publication Number | Publication Date |
---|---|
JP2012515640A JP2012515640A (ja) | 2012-07-12 |
JP5546554B2 true JP5546554B2 (ja) | 2014-07-09 |
Family
ID=42199560
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2011546521A Expired - Fee Related JP5546554B2 (ja) | 2009-01-22 | 2010-01-20 | タンパク質結合物質を除去するための収着剤 |
Country Status (6)
Country | Link |
---|---|
US (1) | US9320845B2 (ja) |
EP (1) | EP2389206B1 (ja) |
JP (1) | JP5546554B2 (ja) |
CN (1) | CN102361658B (ja) |
AT (1) | AT507847B1 (ja) |
WO (1) | WO2010083544A1 (ja) |
Families Citing this family (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN104415739A (zh) * | 2013-08-28 | 2015-03-18 | 天津市阳权医疗器械有限公司 | 苯乙烯-二乙烯苯医用树脂的应用 |
WO2016017811A1 (ja) * | 2014-08-01 | 2016-02-04 | 日本化成株式会社 | 生体物質の選択的吸・脱着材 |
JPWO2018181925A1 (ja) * | 2017-03-30 | 2020-03-05 | 日立化成株式会社 | ゲルろ過用分離材及び水溶性高分子物質の精製方法 |
DE102018104177A1 (de) * | 2018-02-23 | 2019-08-29 | B. Braun Avitum Ag | Vorrichtung zur Entfernung von Noxen aus Blut, extrakorporales Perfusionssystem mit einer solchen Vorrichtung sowie Verfahren zur Herstellung einer solchen Vorrichtung |
DE102019109646A1 (de) * | 2019-04-11 | 2020-10-15 | B.Braun Avitum Ag | Verfahren und Vorrichtung zur Reinigung von Blut |
Family Cites Families (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS5415381A (en) * | 1977-07-05 | 1979-02-05 | Asahi Chemical Ind | Adsorbent for purifying blood |
DE2827109C2 (de) * | 1977-06-24 | 1986-10-30 | Asahi Kasei Kogyo K.K., Osaka | Verfahren und Vorrichtung zur Abtrennung von organischen Verbindungen von Plasmaproteinen des Blutes |
JPS5836624B2 (ja) * | 1978-04-05 | 1983-08-10 | 旭化成株式会社 | 血液処理用吸着剤 |
JPS55125872A (en) * | 1979-03-22 | 1980-09-29 | Asahi Chemical Ind | Blood purifier |
DD249274B5 (de) * | 1986-05-26 | 1993-11-04 | Bitterfeld Wolfen Chemie | Verfahren zur herstellung von adsorberpolymeren fuer die haemoperfusion |
US5536412A (en) * | 1992-02-06 | 1996-07-16 | Hemocleanse, Inc. | Hemofiltration and plasmafiltration devices and methods |
ATA159993A (de) | 1993-08-10 | 1995-09-15 | Dieter Dr Falkenhagen | Anordnung zur elimination von substanzen aus flüssigkeiten |
ITMO970044U1 (it) * | 1997-10-16 | 1999-04-16 | Braun Carex Spa | Utilizzo di una resina assorbente non ionica in accoppiamento al siste ma denominato fegato bioartificiale. |
US20040228829A1 (en) | 2003-03-11 | 2004-11-18 | Roberts Craig P. | Plasma detoxification system and methods of use |
US8038638B2 (en) * | 2004-02-23 | 2011-10-18 | Hemolife Medical, Inc. | Plasma detoxification and volume control system and methods of use |
JP2008503273A (ja) * | 2004-06-21 | 2008-02-07 | ヘモライフ メディカル, インコーポレイテッド | 血漿無毒化および体積制御システムならびに使用方法 |
-
2009
- 2009-01-22 AT AT0011209A patent/AT507847B1/de not_active IP Right Cessation
-
2010
- 2010-01-20 CN CN201080013198.7A patent/CN102361658B/zh not_active Expired - Fee Related
- 2010-01-20 US US13/146,003 patent/US9320845B2/en not_active Expired - Fee Related
- 2010-01-20 JP JP2011546521A patent/JP5546554B2/ja not_active Expired - Fee Related
- 2010-01-20 EP EP10705777.0A patent/EP2389206B1/de not_active Not-in-force
- 2010-01-20 WO PCT/AT2010/000016 patent/WO2010083544A1/de active Application Filing
Also Published As
Publication number | Publication date |
---|---|
US20120125857A1 (en) | 2012-05-24 |
CN102361658B (zh) | 2016-03-30 |
WO2010083544A1 (de) | 2010-07-29 |
US9320845B2 (en) | 2016-04-26 |
EP2389206B1 (de) | 2016-07-06 |
JP2012515640A (ja) | 2012-07-12 |
EP2389206A1 (de) | 2011-11-30 |
AT507847A1 (de) | 2010-08-15 |
CN102361658A (zh) | 2012-02-22 |
AT507847B1 (de) | 2011-12-15 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US9440019B2 (en) | Sorbent for endotoxins | |
US3725113A (en) | Blood compatible microencapsulated detoxicants and method for making | |
US7311845B2 (en) | Adsorbing material for blood and plasma cleaning method and for albumin purification | |
KR101036995B1 (ko) | 중합체 친화성 기질과 이의 제조 방법 및 용도 | |
JP5656871B2 (ja) | エンドトキシン用着収剤 | |
JP5546554B2 (ja) | タンパク質結合物質を除去するための収着剤 | |
JP2008503273A (ja) | 血漿無毒化および体積制御システムならびに使用方法 | |
WO2006106972A1 (ja) | 吸着材および体外循環用カラム | |
US6090292A (en) | Device for purifying solutions containing proteins and use of the device | |
JP4578405B2 (ja) | 全血処理が可能な低密度リポ蛋白およびフィブリノーゲンの吸着材、及び吸着器 | |
JP2019005569A (ja) | タンパク質結合尿毒症性毒素の透析のための血液適合性吸着体 | |
JP2006312804A (ja) | 吸着材および体外循環用カラム | |
JP2001299904A (ja) | フィブリノーゲンおよび/またはフィブリンの濃度を減少させるための吸着剤、吸着装置の製造のための吸着剤の使用、および吸着剤を有する吸着装置 | |
JPH01171638A (ja) | 血清アミロイドa蛋白用吸着体 | |
JPH0667472B2 (ja) | 血清アミロイドp蛋白用吸着体 | |
Wang et al. | Macroporous poly (vinyl alcohol) microspheres bearing phosphate groups as a new adsorbent for low-density lipoprotein apheresis | |
JP4402236B2 (ja) | リポ蛋白質の吸着除去方法 | |
JPH0258939B2 (ja) | ||
JP4443309B2 (ja) | フィブリノゲン吸着剤iii | |
Gu et al. | Hemoperfusion | |
JPH05285381A (ja) | 低比重リポタンパク質吸着材 | |
Davankov et al. | Hypercrosslinked Polystyrene as Hemosorbents | |
JPH05176994A (ja) | 低比重リポ蛋白吸着材 | |
JPH02286173A (ja) | ビリルビン吸着剤および吸着装置 | |
JP2011139805A (ja) | 生体内塩基性物質を利用した体液浄化装置 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20111014 |
|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20110915 |
|
A977 | Report on retrieval |
Free format text: JAPANESE INTERMEDIATE CODE: A971007 Effective date: 20121109 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20121120 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20130111 |
|
A602 | Written permission of extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A602 Effective date: 20130121 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20130315 |
|
A602 | Written permission of extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A602 Effective date: 20130325 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20130422 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20130910 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20131205 |
|
A602 | Written permission of extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A602 Effective date: 20131212 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20140109 |
|
A602 | Written permission of extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A602 Effective date: 20140117 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20140123 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20140225 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20140303 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20140408 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20140409 |
|
TRDD | Decision of grant or rejection written | ||
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20140430 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20140513 |
|
R150 | Certificate of patent or registration of utility model |
Ref document number: 5546554 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
LAPS | Cancellation because of no payment of annual fees |