ZA200506452B - Albumin solution and method for the production thereof - Google Patents
Albumin solution and method for the production thereof Download PDFInfo
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- ZA200506452B ZA200506452B ZA200506452A ZA200506452A ZA200506452B ZA 200506452 B ZA200506452 B ZA 200506452B ZA 200506452 A ZA200506452 A ZA 200506452A ZA 200506452 A ZA200506452 A ZA 200506452A ZA 200506452 B ZA200506452 B ZA 200506452B
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- albumin
- process according
- virus
- albumin solution
- solution
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- 102000009027 Albumins Human genes 0.000 title claims abstract description 112
- 108010088751 Albumins Proteins 0.000 title claims abstract description 112
- 238000000034 method Methods 0.000 title claims abstract description 47
- 238000004519 manufacturing process Methods 0.000 title abstract 2
- 230000008569 process Effects 0.000 claims abstract description 35
- 239000003381 stabilizer Substances 0.000 claims abstract description 27
- 239000011159 matrix material Substances 0.000 claims abstract description 19
- 230000002209 hydrophobic effect Effects 0.000 claims abstract description 11
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 claims abstract description 10
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 10
- 241000700605 Viruses Species 0.000 claims abstract description 9
- 230000002779 inactivation Effects 0.000 claims abstract description 9
- 125000001931 aliphatic group Chemical group 0.000 claims abstract description 6
- 238000004587 chromatography analysis Methods 0.000 claims abstract description 6
- 238000000605 extraction Methods 0.000 claims abstract description 6
- 125000001165 hydrophobic group Chemical group 0.000 claims abstract description 5
- 238000004191 hydrophobic interaction chromatography Methods 0.000 claims abstract description 5
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 claims abstract description 5
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 claims abstract description 5
- 150000001413 amino acids Chemical class 0.000 claims abstract description 4
- 235000014113 dietary fatty acids Nutrition 0.000 claims abstract description 4
- 229930195729 fatty acid Natural products 0.000 claims abstract description 4
- 239000000194 fatty acid Substances 0.000 claims abstract description 4
- 150000004665 fatty acids Chemical class 0.000 claims abstract description 4
- 235000000346 sugar Nutrition 0.000 claims abstract description 4
- 150000005846 sugar alcohols Chemical class 0.000 claims abstract description 4
- 108010071241 Factor XIIa Proteins 0.000 claims description 20
- 239000000126 substance Substances 0.000 claims description 19
- 238000002360 preparation method Methods 0.000 claims description 14
- 239000013543 active substance Substances 0.000 claims description 8
- 239000003610 charcoal Substances 0.000 claims description 8
- 238000009928 pasteurization Methods 0.000 claims description 8
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims description 6
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 6
- 230000000694 effects Effects 0.000 claims description 6
- 239000003921 oil Substances 0.000 claims description 6
- 229920000642 polymer Polymers 0.000 claims description 6
- 239000001632 sodium acetate Substances 0.000 claims description 6
- 235000017281 sodium acetate Nutrition 0.000 claims description 6
- 125000004432 carbon atom Chemical group C* 0.000 claims description 5
- 238000004255 ion exchange chromatography Methods 0.000 claims description 5
- 238000011146 sterile filtration Methods 0.000 claims description 5
- 229920003053 polystyrene-divinylbenzene Polymers 0.000 claims description 4
- 239000004471 Glycine Substances 0.000 claims description 3
- 235000001014 amino acid Nutrition 0.000 claims description 3
- 239000004359 castor oil Substances 0.000 claims description 3
- 235000019438 castor oil Nutrition 0.000 claims description 3
- 150000001768 cations Chemical group 0.000 claims description 3
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 claims description 3
- 238000004806 packaging method and process Methods 0.000 claims description 3
- 150000008163 sugars Chemical class 0.000 claims description 3
- OWEGMIWEEQEYGQ-UHFFFAOYSA-N 100676-05-9 Natural products OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(OC2C(OC(O)C(O)C2O)CO)O1 OWEGMIWEEQEYGQ-UHFFFAOYSA-N 0.000 claims description 2
- 239000004475 Arginine Substances 0.000 claims description 2
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 claims description 2
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 claims description 2
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 claims description 2
- GUBGYTABKSRVRQ-PICCSMPSSA-N Maltose Natural products O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-PICCSMPSSA-N 0.000 claims description 2
- CERQOIWHTDAKMF-UHFFFAOYSA-M Methacrylate Chemical compound CC(=C)C([O-])=O CERQOIWHTDAKMF-UHFFFAOYSA-M 0.000 claims description 2
- 150000001450 anions Chemical group 0.000 claims description 2
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 claims description 2
- 229930195712 glutamate Natural products 0.000 claims description 2
- 239000006193 liquid solution Substances 0.000 claims description 2
- 102000039446 nucleic acids Human genes 0.000 claims description 2
- 108020004707 nucleic acids Proteins 0.000 claims description 2
- 150000007523 nucleic acids Chemical class 0.000 claims description 2
- 229920001184 polypeptide Polymers 0.000 claims description 2
- 102000004196 processed proteins & peptides Human genes 0.000 claims description 2
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 2
- 239000007787 solid Substances 0.000 claims description 2
- 239000000600 sorbitol Substances 0.000 claims description 2
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 claims 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 claims 1
- 239000004472 Lysine Substances 0.000 claims 1
- 238000001914 filtration Methods 0.000 abstract description 3
- 239000000243 solution Substances 0.000 description 31
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- 108090000623 proteins and genes Proteins 0.000 description 8
- 230000009102 absorption Effects 0.000 description 7
- 239000003446 ligand Substances 0.000 description 6
- 229960002895 phenylbutazone Drugs 0.000 description 6
- VYMDGNCVAMGZFE-UHFFFAOYSA-N phenylbutazonum Chemical compound O=C1C(CCCC)C(=O)N(C=2C=CC=CC=2)N1C1=CC=CC=C1 VYMDGNCVAMGZFE-UHFFFAOYSA-N 0.000 description 6
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- PJVWKTKQMONHTI-UHFFFAOYSA-N warfarin Chemical compound OC=1C2=CC=CC=C2OC(=O)C=1C(CC(=O)C)C1=CC=CC=C1 PJVWKTKQMONHTI-UHFFFAOYSA-N 0.000 description 5
- 229960005080 warfarin Drugs 0.000 description 5
- 108010062466 Enzyme Precursors Proteins 0.000 description 3
- 102000010911 Enzyme Precursors Human genes 0.000 description 3
- 102100035792 Kininogen-1 Human genes 0.000 description 3
- DZTHIGRZJZPRDV-LBPRGKRZSA-N N-acetyl-L-tryptophan Chemical compound C1=CC=C2C(C[C@H](NC(=O)C)C(O)=O)=CNC2=C1 DZTHIGRZJZPRDV-LBPRGKRZSA-N 0.000 description 3
- DZTHIGRZJZPRDV-UHFFFAOYSA-N Nalpha-Acetyltryptophan Natural products C1=CC=C2C(CC(NC(=O)C)C(O)=O)=CNC2=C1 DZTHIGRZJZPRDV-UHFFFAOYSA-N 0.000 description 3
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- 229940116191 n-acetyltryptophan Drugs 0.000 description 3
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- 210000002381 plasma Anatomy 0.000 description 3
- 239000011148 porous material Substances 0.000 description 3
- 238000001542 size-exclusion chromatography Methods 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- STCOOQWBFONSKY-UHFFFAOYSA-N tributyl phosphate Chemical compound CCCCOP(=O)(OCCCC)OCCCC STCOOQWBFONSKY-UHFFFAOYSA-N 0.000 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 2
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- 102000004506 Blood Proteins Human genes 0.000 description 2
- 108010000487 High-Molecular-Weight Kininogen Proteins 0.000 description 2
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- 229920002684 Sepharose Polymers 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 239000003599 detergent Substances 0.000 description 2
- 239000006167 equilibration buffer Substances 0.000 description 2
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- 238000005194 fractionation Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000002243 precursor Substances 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- BYKRNSHANADUFY-UHFFFAOYSA-M sodium octanoate Chemical compound [Na+].CCCCCCCC([O-])=O BYKRNSHANADUFY-UHFFFAOYSA-M 0.000 description 2
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- 108091006522 Anion exchangers Proteins 0.000 description 1
- 101800004538 Bradykinin Proteins 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- XUIIKFGFIJCVMT-GFCCVEGCSA-N D-thyroxine Chemical compound IC1=CC(C[C@@H](N)C(O)=O)=CC(I)=C1OC1=CC(I)=C(O)C(I)=C1 XUIIKFGFIJCVMT-GFCCVEGCSA-N 0.000 description 1
- 229920002271 DEAE-Sepharose Polymers 0.000 description 1
- WDJUZGPOPHTGOT-OAXVISGBSA-N Digitoxin Natural products O([C@H]1[C@@H](C)O[C@@H](O[C@@H]2C[C@@H]3[C@@](C)([C@@H]4[C@H]([C@]5(O)[C@@](C)([C@H](C6=CC(=O)OC6)CC5)CC4)CC3)CC2)C[C@H]1O)[C@H]1O[C@@H](C)[C@H](O[C@H]2O[C@@H](C)[C@@H](O)[C@@H](O)C2)[C@@H](O)C1 WDJUZGPOPHTGOT-OAXVISGBSA-N 0.000 description 1
- 102000001690 Factor VIII Human genes 0.000 description 1
- 108010054218 Factor VIII Proteins 0.000 description 1
- 108010080865 Factor XII Proteins 0.000 description 1
- 102000000429 Factor XII Human genes 0.000 description 1
- QXZGBUJJYSLZLT-UHFFFAOYSA-N H-Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg-OH Natural products NC(N)=NCCCC(N)C(=O)N1CCCC1C(=O)N1C(C(=O)NCC(=O)NC(CC=2C=CC=CC=2)C(=O)NC(CO)C(=O)N2C(CCC2)C(=O)NC(CC=2C=CC=CC=2)C(=O)NC(CCCN=C(N)N)C(O)=O)CCC1 QXZGBUJJYSLZLT-UHFFFAOYSA-N 0.000 description 1
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 1
- 108060005987 Kallikrein Proteins 0.000 description 1
- 102000001399 Kallikrein Human genes 0.000 description 1
- 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 1
- CMWTZPSULFXXJA-UHFFFAOYSA-N Naproxen Natural products C1=C(C(C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-UHFFFAOYSA-N 0.000 description 1
- 241001306288 Ophrys fuciflora Species 0.000 description 1
- 108090000113 Plasma Kallikrein Proteins 0.000 description 1
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 description 1
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- GUBGYTABKSRVRQ-QUYVBRFLSA-N beta-maltose Chemical compound OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O GUBGYTABKSRVRQ-QUYVBRFLSA-N 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- QXZGBUJJYSLZLT-FDISYFBBSA-N bradykinin Chemical compound NC(=N)NCCC[C@H](N)C(=O)N1CCC[C@H]1C(=O)N1[C@H](C(=O)NCC(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CO)C(=O)N2[C@@H](CCC2)C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)CCC1 QXZGBUJJYSLZLT-FDISYFBBSA-N 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 238000013375 chromatographic separation Methods 0.000 description 1
- 238000005345 coagulation Methods 0.000 description 1
- 230000015271 coagulation Effects 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 239000012228 culture supernatant Substances 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 229960000633 dextran sulfate Drugs 0.000 description 1
- 238000011026 diafiltration Methods 0.000 description 1
- WDJUZGPOPHTGOT-XUDUSOBPSA-N digitoxin Chemical compound C1[C@H](O)[C@H](O)[C@@H](C)O[C@H]1O[C@@H]1[C@@H](C)O[C@@H](O[C@@H]2[C@H](O[C@@H](O[C@@H]3C[C@@H]4[C@]([C@@H]5[C@H]([C@]6(CC[C@@H]([C@@]6(C)CC5)C=5COC(=O)C=5)O)CC4)(C)CC3)C[C@@H]2O)C)C[C@@H]1O WDJUZGPOPHTGOT-XUDUSOBPSA-N 0.000 description 1
- 229960000648 digitoxin Drugs 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 229960000301 factor viii Drugs 0.000 description 1
- 239000013020 final formulation Substances 0.000 description 1
- -1 for example Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 229960002897 heparin Drugs 0.000 description 1
- 229920000669 heparin Polymers 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000009434 installation Methods 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 150000004668 long chain fatty acids Chemical class 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 229910021645 metal ion Inorganic materials 0.000 description 1
- 235000013336 milk Nutrition 0.000 description 1
- 239000008267 milk Substances 0.000 description 1
- 210000004080 milk Anatomy 0.000 description 1
- 229960002009 naproxen Drugs 0.000 description 1
- CMWTZPSULFXXJA-VIFPVBQESA-N naproxen Chemical compound C1=C([C@H](C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-VIFPVBQESA-N 0.000 description 1
- 238000002414 normal-phase solid-phase extraction Methods 0.000 description 1
- WWZKQHOCKIZLMA-UHFFFAOYSA-M octanoate Chemical compound CCCCCCCC([O-])=O WWZKQHOCKIZLMA-UHFFFAOYSA-M 0.000 description 1
- 229920002113 octoxynol Polymers 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 239000008057 potassium phosphate buffer Substances 0.000 description 1
- 238000010926 purge Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 229960005480 sodium caprylate Drugs 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 238000010257 thawing Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 229940034208 thyroxine Drugs 0.000 description 1
- XUIIKFGFIJCVMT-UHFFFAOYSA-N thyroxine-binding globulin Natural products IC1=CC(CC([NH3+])C([O-])=O)=CC(I)=C1OC1=CC(I)=C(O)C(I)=C1 XUIIKFGFIJCVMT-UHFFFAOYSA-N 0.000 description 1
- GPRLSGONYQIRFK-MNYXATJNSA-N triton Chemical compound [3H+] GPRLSGONYQIRFK-MNYXATJNSA-N 0.000 description 1
- 238000000108 ultra-filtration Methods 0.000 description 1
- 239000002550 vasoactive agent Substances 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/38—Albumins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/08—Plasma substitutes; Perfusion solutions; Dialytics or haemodialytics; Drugs for electrolytic or acid-base disorders, e.g. hypovolemic shock
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Epidemiology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Zoology (AREA)
- Gastroenterology & Hepatology (AREA)
- Immunology (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention relates to a therapeutically usable virus-inactivated albumin and a method for producing a therapeutically usable virus-inactivated albumin, which is characterized by a combination of the following steps: (a) a first aqueous albumin solution is subjected to a virus inactivation treatment according to the SD method by contacting said aqueous albumin solution with SD reagents at a temperature of less than 45 DEG C; (b) the SD reagents are at least essentially removed by means of oil extraction and subsequent hydrophobic interaction chromatography, a hydrophobic matrix, especially a matrix to which optional hydrophobic groups can be bonded, being used for the chromatography process provided that said groups are aliphatic groups wherein C > 24, and a second albumin solution is obtained to which (c) one or several stabilizers from the group comprising sugar, amino acids, and sugar alcohols is/are optionally added provided that no indole stabilizer and no C6-C10 fatty acid are used as stabilizers; whereupon (d) the second albumin solution, to which stabilizer has been optionally added, is finished and sterilized by filtration and optionally filled into final containers.
Description
SMB
Albumin Solution and Process for the Preparation Thereof
The invention relates to a therapeutically usable virus-inactivated albumin, and to a process for the preparation thereof.
Albumin is the plasma protein with the highest proportion in blood plasma.
Albumin can bind many endogenous and exogenous substances to its molecule.
This binding capacity is also the basis of one of its main functions: the transport of the substances bound to albumin.
Due to this binding capacity, albumin is also an important depot for a wide variety of compounds, such as long-chain fatty acids, bilirubin, tryptophan, thyroxine or metal ions. Administered pharmaceutically active substances, such as warfarin, digitoxin or naproxen, are aiso bound to albumin and transported.
However, in this connection, it is critical to know that only the free fraction of the respective pharmaceutically active substance, i.e., that which is not bound to albumin, is the one that displays the pharmacological action. A reduction of the portion bound to albumin increases the free fraction and thus the pharmacological activity.
All commercially available albumin preparations are prepared by means of a modified Cohn fractionation, a method which usually consists of several fractiona- tion steps. Pasteurization (10 hours at 60 °C) of the albumin concentrate has been employed as the virus-inactivation step for decades. To avoid the denaturing of albumin during this step, stabilizers are employed. According to the European
Pharmacopoeia, sodium caprylate (sodium octanoate) or N-acetyltryptophan or a combination of both is used as a stabilizer.
To obtain virus-inactivated factor VIII preparations or other plasma proteins, the so-called SD method is employed, as described, for example, in EP-A-0 131 740.
This laid-open specification is included herein by reference.
From his own studies, Applicant knows that the binding capacity of commercially available albumin is considerably reduced as compared to natural albumin. This is explained by the fact that the stabilizers used in the pasteurization are bound by albumin and thus occupy important transport sites, whereby the binding capacity is decreased. This means that patients which obtain such albumin preparations are exposed to a significantly increased concentration of free active substance, i.e., one which is not bound to albumin, when pharmaceutically active substances are administered, which naturally means an increased risk of exceeding pharmacologi- cal effects and side effects for the patient.
A need exists to provide an albumin preparation which does not have this disad- vantage.
Figure 1 shows the ultraviolet absorption behavior of albumins from different sources as a function of the elution time during the chromatographic separation.
Figure 2 illustrates the binding behavior of albumins from different sources in the presence of different concentrations of phenylbutazone.
Figure 3 illustrates the binding behavior of albumins from different sources in the presence of different concentrations of warfarin.
This need is fulfilled by a therapeutically usable virus-inactivated albumin having an increased binding capacity for substances as compared to albumin virus-in- activated by pasteurization. In particular, the albumin according to the invention has a binding capacity which is increased by at least 10% over that of albumin virus-inactivated by pasteurization, typically a binding capacity which is increased by from 20 to 500%, especially one which is increased by from 100 to 500%. In singular cases, even higher values are possible, depending on the substance to be bound.
AMENDED SHEET
= 3 = ~ P)
The substances are especially those which are bound and/or transported by native albumin, particularly including low-molecular weight active substances. In particu- lar, the low-molecular weight active substances are organic or inorganic sub- stances, nucleic acids, polypeptides, which typically have a molecular weight of < 10000 Da.
For the therapeutical uses mentioned above, the albumin according to the inven- tion can be in the form of a liquid solution or in a solid state, especially in a lyophilized form.
The albumin according to the invention can also be obtained by a process which is characterized by the combination of the following steps: (a) subjecting a first aqueous albumin solution to a treatment for virus inactiva- tion by the SD method by contacting it with SD reagents at a temperature of below 45 °C; (b) removing, at least substantially, the SD reagents by oil extraction followed by hydrophobic interaction chromatography, wherein a hydrophobic matrix, especially a matrix to which hydrophobic groups may optionally be bound, is used for said chromatography, with the proviso that said groups are ali- phatic groups with more than 24 carbon atoms, to obtain a second albumin solution to which (©) optionally one or more stabilizers selected from the group of sugars, amino acids and sugar alcohols are added, with the proviso that no indole stabilizer and no Cg-Cy, fatty acid is employed as said stabilizer, whereupon (d) said second albumin solution to which a stabilizer has optionally been added is subjected to final packaging and sterile filtration and optionally filled into final containers.
The term "indole stabilizer" shall comprise all stabilizers which have an indole skeleton, such as N-acetyitryptophan.
The SD (= solvent/detergent) method for the inactivation of viruses has been known from EP-A-0 131 740. This specification also mentioned albumin, among other proteins.
It is true, from EP-A-0 366 946, it is known that the SD reagents can be removed with vegetable oils, for example, soybean oil, followed by hydrophobic interaction chromatography. Thus, as far as it overlaps with the process according to EP-A- 0 366 946, the process according to claim 8 is to be considered as an analogous process for the preparation of the albumin according to the invention in one aspect. However, for chromatography, the above patent preferably proposes a matrix, for example, a silica matrix, to which hydrophobic side chains, i.e., branched or unbranched Cs-Cy4 alkyl chains, are bound.
Surprisingly, it has been found that the use of a hydrophobic matrix instead of a matrix which bears C18 alkyl chains, for example, as hydrophobic side chains results in a higher binding capacity for the adsorption of detergents. Accordingly, no further hydrophobic groups need to be bound to the matrix employed according to the invention. Therefore, the invention also relates to a process in which such a matrix is used.
The virus inactivation is advantageously effected at a temperature within a range of from 25 to 40 °C.
In a preferred embodiment of the process according to the invention, the virus inactivation is effected during a period of time within a range of from 4 to 6 hours.
Glycine is very suitable as a stabilizer.
Castor oil is very suitable for oil extraction.
It has been found of particular advantage to the purification effect if a polystyrene- divinylbenzene polymer or a methacrylate-based polymer is used as said hydro- phobic matrix.
The hydrophobic matrices employed according to the invention can bear branched or linear aliphatic groups with more than 24 carbon atoms.
Depending on the starting material employed, a step for depletion of the so-called prekallikrein activator (PKA) activity may be required. PKA is known to cause the drop of blood pressure after the administration of PKA-containing preparations by releasing the vaso-active substance bradykinin from high molecular weight kininogen (HMWK).
PKA is usually inactivated during the pasteurization of protein preparations. Since a heat treatment, by which PKA is at least partially inactivated as known from former experience, is disadvantageous to the albumin prepared according to the invention for the reasons mentioned above, PKA can be removed by special measures, if required. These include incubation with active charcoal followed by filtration, preferably with deep filters, or direct filtration through filters containing active charcoal.
Further, ion-exchangers, such as cation or anion exchangers, are very suitable for removing PKA. This may be effected by contacting the albumin-containing solution with the matrix in columns, or by batch processes known to the skilled person.
Alternatively, dextran sulfate or heparin matrices may be employed for the reduction of PKA.
In the albumin-containing solution obtained, PKA is reduced, and no longer detectable in the optimum case. According to the current state of the art, PKA is identical with the activated (coagulation) factor XII (FXIla), which is generated from its pro-enzyme form (FXII). This can occur on surfaces by autocatalysis or by enzymatic action, for example, of kallikrein. Accordingly, depletion of FXII (the pro-enzyme), being a precursor of PKA, is also recommendable, but not necessar- ily required. However, to prevent the renewed generation of PKA from the pro- enzyme form, the latter may also be removed by ion-exchange chromatography.
The depletion of the FXII may optionally be performed in order to enable the long- term storage of albumin in a liquid state. This is also important after the thawing of an albumin solution which may have been stored in a frozen state. Accordingly, the albumin solution may be deep-frozen after being filled into the final containers, but it may also be cooled in a liquid or freeze-dried state and stored at a temperature of up to 40 °C.
Thus, to remove PKA or PKA-precursor substances, any prekallikrein activator (PKA) activity which may be present before or after steps (a), (b) or (c) can be removed in a per se known manner, in particular wherein the albumin solution is
A) contacted with active charcoal, followed by removing the active charcoal from the albumin solution; or
B) subjected to ion-exchange chromatography.
Step (A) is effected at an albumin concentration of from 1 to 25% by weight, especially from 5 to 10% by weight.
Step (B) is performed, in particular, at an albumin concentration of from 5 to 10% by weight.
In a further embodiment of the process according to the invention, the ion- exchanger is an anion-exchanger, and the albumin solution is buffered with sodium acetate within a range of from 100 to 150 mmol/l, and the pH is within a range of from 5.0 to 6.0, especially < 5.5.
Further, a process is described which is characterized in that said ion-exchanger is a cation exchanger, and the albumin solution is buffered with sodium acetate within a range of from 20 to 30 mmol/l, and the pH value is within a range of from 4.8 to 6.0, especially within a range of from 4.8 to 5.2.
The invention further relates to an albumin solution which can be obtained by the process according to the invention. This process can be applied to albumin solutions obtained from different sources, for example, from blood plasma or serum, from albumin-containing fractions of plasma fractioning, from albumin recovered from the culture supernatant after recombinant preparation, or from transgenically prepared albumin, or from a medium containing the albumin, such as milk.
A preferred embodiment of the invention is further described by means of the following Example.
To 1000 g of an aqueous albumin solution obtained by the Cohn method (after dia- filtration/ultrafiltration) and having a protein content of about 23% are added
Triton X-100 and tri-n-butylphosphate (TNBP) up to a concentration of 1% each.
Subsequently, the albumin solution is stirred at 30 °C for 4 hours.
To remove the SD reagents, castor oil is first added with stirring up to a concentra- tion of 5% while the solution is brought to a temperature within a range of from 20 to 25°C. Thereafter, the mixture is stirred for 30 minutes. After the stirring, the mixture is allowed to stand for 60 minutes to form a heavy aqueous and a light phase. The heavy phase is separated off and filtered through a filter having membranes with a pore size of < 1 ym and < 0.45 pm. The light phase (oil phase) contains the TNBP and is discarded.
To separate off the Triton X-100, the filtered solution is passed through a solid- phase extraction column. A polystyrene-divinylbenzene polymer (Amberchrome CG 161) without hydrophobic side chains is used as the hydrophobic matrix. Water for injection is used for purging the column, which process is monitored by measuring the ultraviolet absorption at 280 nm. After use, the column is regenerated.
The following can be added as stabilizers: glycine, glutamate, arginine, maltose, sorbitol or mixtures of these substances.
The solution obtained is brought to pH 7.0, and the protein content is adjusted to 200 g/l, and the sodium content to 80 mmol/l Na*. Then, the solution is subjected to sterile filtration through a membrane filter having a pore size of < 0.2 pm.
The sterile-filtered solution is filled into sterile and pyrogen-free PVC bags under aseptic conditions, and the bags are labeled.
The labeled bags are deep-frozen at a temperature of < -60°C so that the temperature within the bags reaches < -30 °C. At this temperature (< -30 °C), the bags are stored.
Prekallikrein depletion
When PKA is to be depleted, the following procedure variants can be used: a) An albumin solution having a protein concentration of from 1 to 25% by weight, especially from 5 to 10 % by weight, is stirred for one hour with 3-10% by weight, especially 5% by weight, of active charcoal at pH = 5.
Subsequently, the active charcoal is filtered off. b) An albumin solution having a protein concentration of from 5 to 10% by weight is subjected to ion-exchange chromatography (DEAE Sepharose,
Q Sepharose) at pH 5-6, especially < 5.5, in a system buffered with 100-150 mM sodium acetate. Due to the high ion strength, a PKA-free al- bumin solution is obtained in the filtrate.
Cc) An albumin solution having a protein concentration of from 5 to 10% by weight is subjected to ion-exchange chromatography (SP Toyopearl, CM
Sepharose) at pH 5-6, preferably 4.8-5.2, in a system buffered with 20-30 mmol/l sodium acetate. A PKA-free albumin solution is obtained in the filtrate.
Final formulation
The solutions obtained are brought to pH = 7.0 each, and the protein content is adjusted to 200 g/l, and the sodium content to 80 mmol/I Na*. Then, the solution is subjected to sterile filtration through a membrane filter having a pore size of < 0.2 ym.
The sterile-filtered solutions are filled into sterile and pyrogen-free PVC bags under aseptic conditions, and the bags are labeled.
The labeled bags are deep-frozen at a temperature of < -60°C so that the temperature within the bags reaches < -30 °C. At this temperature (< -30 °C), the bags are stored.
Measurement of the binding of substances to different albumin preparations
A direct method for determining the binding properties of substances to albumin is the size-exclusion chromatography (SEC) according to Hummel and Dreyer (Biochim Biophys Acta 1962; 63: 530-532).
Thus, an SEC column is equilibrated with a buffer solution containing the binding ligand (e.g., phenylbutazone or warfarin). The absorption in the ultraviolet region is continuously monitored. The protein is applied to the column and eluted in the equilibration buffer. Bound ligand becomes eluted together with the albumin, while the non-bound ligand, which is smaller in most cases, becomes eluted correspond- ingly later. The absorption of the bound ligand mostly interferes with the absorp- tion of the albumin and possible accompanying substances, such as stabilizers. The later eluting "negative" or so-called "vacancy" peak is caused by the depletion of the ligand in the subsequent buffer, which occupies the larger a surface area, the more binding to the previously eluted albumin occurred. Koizumi et al. (Biomed
Chromatogr 1998; 12: 203-210) used this method in a slightly modified form to examine the binding capacities of substances to albumin or their affinities, for example, by adding increasing amounts of the ligand to constant concentrations of albumin in separate runs, whereby the binding capacity could be established in the form of albumin-to-substance ratios.
For these examinations, a Biosep-SEC-s 4000 column, 300 x 4.6 mm micron (Phenomenenx) on a Shimadzu HPLC installation was used. The buffer flow rate was 0.35 ml/min, the column having been equilibrated with 50 mM of potassium phosphate buffer, pH 7.4. The protein concentration was 50 pM, and the injection volume was 80 ul. Phenylbutazone was monitored at 263 nm, and warfarin at 308 nm. The regions of linear absorption had been determined beforehand.
The albumin as described in this application (1) as well as two commercially obtainable (stabilized) albumin preparations (2, 3) were used. They were 20% albumin solutions.
Figure 1 shows a superposition of four different chromatograms, the column having been equilibrated in 50 uM phenylbutazone (in phosphate buffer). At a retention time of 11 minutes, the albumin became eluted first, the peak indicating the sum of protein absorption and that of the bound substance. At 14.5 min, an
N-acetyltryptophan (stabilizer) peak is usually found in the case of a commercial albumin. After 18.5 min, the "vacancy" peak appears in the form of a "negative" representation of the absorption relative to the level of the equilibration buffer including the substance. The higher (in a negative sense) this peak or the larger the peak area, the more substance has bound to the previously eluted albumin.
Figure 2 shows the ultraviolet absorptions of three concentrations of phenylbuta- zone bound to albumin (after subtraction of the buffer peak). Thus, two commer- cially available albumins (containing caprylate and N-acetyltryptophan) and the albumin prepared by the process described in the present application were subjected to chromatography, and the binding qualities compared. For comparable molar concentrations of phenylbutazone to albumin, it is clearly found that the peaks are significantly larger in terms of height and area in the case of the novel albumin. This similarly holds for the second example, namely warfarin, as shown in
Figure 3.
These results underscore that the commercial albumin is inferior to the albumin described herein with respect to binding property.
Comparison of the binding capacity of RP-18 columns as compared to polystyrene- divinylbenzene polymers (Amberchrome 161 M).
Test system: column volume: 44 ml!
Flow rate: 4 ml/min
The column was charged with 1% Triton X-100 solution. The Triton X content in the eluate was measured after each column volume by means of reverse-phase
HPLC. If Triton could be detected in the eluate, the capacity of the gel was exhausted.
Result:
The RP-18 gel binds 140 mg of Triton X-100/ml of gel, and the Amberchrome gel binds 160 mg of Triton X-100/ml of gel.
Claims (26)
1. A therapeutically usable virus-inactivated albumin having an increased binding capacity for substances as compared to albumin virus-inactivated by pasteurization.
2. The albumin according to claim 1, wherein the binding capacity is increased by at least 10% as compared to albumin virus-inactivated by pasteurization.
3. The albumin according to claim 1 and/or 2, wherein the binding capacity is increased by at least 20 to 500% as compared to albumin virus-inactivated by pasteurization.
4, The albumin according to at least one of claims 1 to 3, wherein said substances are low-molecular weight active substances.
5. The albumin according to at least one of claims 1 to 4, wherein said low- molecular weight active substances are organic substances, nucleic acids, polypeptides, which have a molecular weight of at most 10 000 Da.
6. The albumin according to at least one of claims 1 to 5 in the form of a liquid solution or in a solid state.
7. The albumin according to claim 6 in a lyophilized form.
8. A process for the preparation of albumin, characterized by the combination of the foilowing steps: (a) subjecting a first aqueous albumin solution to a treatment for virus inactivation by the SD method by contacting it with SD reagents at a temperature of below 45 °C; (b) removing, at least substantially, the SD reagents by oil extraction followed by hydrophobic interaction chromatography, wherein a hy- drophobic matrix, especially a matrix to which hydrophobic groups may optionally be bound, is used for said chromatography, with the proviso that said groups are aliphatic groups with more than 24 car- bon atoms, to obtain a second albumin solution to which (c) optionally one or more stabilizers selected from the group of sugars, amino acids and sugar alcohols are added, with the proviso that no indole stabilizer and no C¢-Cy fatty acid is employed as said stabi- lizer, whereupon (d) said second albumin solution to which a stabilizer has optionally been added is subjected to final packaging and sterile filtration and option- ally filled into final containers.
9. The process according to claim 8, characterized in that said virus inactiva- tion is effected at a temperature within a range of from 25 to 40 °C.
10. The process according to any of claims 8 and/or 9, characterized in that said virus inactivation is effected during a period of time within a range of from 4 to 6 hours.
11. The process according to any of claims 8 to 10, characterized in that glycine, glutamate, arginine or lysine or a combination thereof is employed as said stabilizer.
12. The process according to any of claims 8 to 10, characterized in that maltose and/or sorbitol is employed as said stabilizer.
13. The process according to any of claims 8 to 12, characterized in that castor oil is employed for oil extraction.
14. The process according to any of claims 8 to 13, characterized in that a polystyrene-divinylbenzene polymer or a methacrylate-based polymer is used as said hydrophobic matrix.
15. The process according to any of claims 8 to 14, characterized in that branched or linear aliphatic groups with more than 24 carbon atoms are bound to the matrix.
16. The process according to any of claims 8 to 15, characterized in that the albumin solution is deep-frozen after being filled into the final containers.
17. The process according to any of claims 8 to 16, characterized in that any prekallikrein activator (PKA) activity which may be present before or after steps (a), (b) or (c) is removed in a per se known manner.
18. The process according to claim 17, characterized in that said albumin solution is a) contacted with active charcoal, followed by removing the active charcoal from the albumin solution; or b) subjected to ion-exchange chromatography; to remove said prekallikrein activator activity which may be present.
19. The process according to claim 18, characterized in that step a) is per- formed at an albumin concentration of from 1 to 25% by weight.
20. The process according to claim 19, characterized in that said albumin concentration is from 5 to 10% by weight.
21. The process according to claim 18, characterized in that step b) is per- formed at an albumin concentration of from 5 to 10% by weight.
22. The process according to either of claims 18 or 21, characterized in that said ion-exchanger is an anion exchanger, and the albumin solution is buffered with sodium acetate within a range of from 100 to 150 mmol/l, and the pH is within a range of from 5.0 to 6.0.
23. The process according to claim 22, characterized in that the pH is < 5.5.
24. The process according to either of claims 18 or 21, characterized in that said ion-exchanger is a cation exchanger, and the albumin solution is buffered with sodium acetate within a range of from 20 to 30 mmol/l, and the pH value is within a range of from 4.8 to 6.0.
25. The process according to claim 24, characterized in that the pH is within a range of from 4.8 to 5.2.
26. An albumin solution obtainable by the process according to any of claims 1 to 25.
Abstract
The invention relates to a therapeutically usable virus-inactivated albumin, and to a process for the preparation of a therapeutically usable virus-inactivated albumin,
characterized by the combination of the following steps:
(a) subjecting a first aqueous albumin solution to a treatment for virus inactiva- tion by the SD method by contacting it with SD reagents at a temperature of below 45°C;
(b) removing, at least substantially, the SD reagents by oil extraction followed by hydrophobic interaction chromatography, wherein a hydrophobic matrix, especially a matrix to which hydrophobic groups may optionally be bound, is used for said chromatography, with the proviso that said groups are ali- phatic groups with more than 24 carbon atoms, to obtain a second albumin solution to which
(c) optionally one or more stabilizers selected from the group of sugars, amino acids and sugar alcohols are added, with the proviso that no indole stabilizer and no C¢-C, fatty acid is employed as said stabilizer, whereupon
(d) said second albumin solution to which a stabilizer has optionally been added is subjected to final packaging and sterile filtration and optionally filled into final containers.
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JP (1) | JP2006517938A (en) |
KR (1) | KR20050103292A (en) |
CN (1) | CN100384471C (en) |
AT (1) | ATE362376T1 (en) |
AU (1) | AU2004212324B2 (en) |
BR (1) | BRPI0407458A (en) |
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DE (1) | DE502004003834D1 (en) |
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DE102005023155A1 (en) | 2005-05-13 | 2006-11-16 | Albutec Gmbh | albumin solution |
US20100168000A1 (en) * | 2005-12-22 | 2010-07-01 | Peter Kiessling | Octanoate-Reduced Human Albumin |
ES2332846B1 (en) | 2007-10-26 | 2010-07-08 | Grifols, S.A. | USE OF THERAPEUTIC HUMAN ALBUMIN FOR THE PREPARATION OF A MEDICINAL PRODUCT FOR THE TREATMENT OF PATIENTS AFFECTED BY COGNITIVE DISORDERS. |
ES2294976B1 (en) | 2007-11-12 | 2008-12-16 | Grifols, S.A. | "HIGH EFFECTIVE HUMAN ALBUMIN OBTAINING PROCEDURE FOR USE IN DETOXIFICATION THERAPY". |
EP2382993A1 (en) | 2010-04-19 | 2011-11-02 | KTB Tumorforschungsgesellschaft mbH | Combination of drugs with protein-binding prodrugs |
CN111195351A (en) * | 2020-01-20 | 2020-05-26 | 华兰生物工程重庆有限公司 | Preparation method of 5% low-concentration human serum albumin |
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JPH0669961B2 (en) * | 1984-09-25 | 1994-09-07 | 株式会社ミドリ十字 | Immunoglobulin heat treatment method |
US5094960A (en) * | 1988-10-07 | 1992-03-10 | New York Blood Center, Inc. | Removal of process chemicals from labile biological mixtures by hydrophobic interaction chromatography |
US5250662A (en) * | 1989-10-05 | 1993-10-05 | Alpha Therapeutic Corporation | Albumin purification |
DE19729778A1 (en) * | 1997-07-11 | 1999-01-21 | Blutspendedienst Der Drk Lande | Process for the preparation of virus-inactivated biological fluids |
US5919907A (en) * | 1997-12-22 | 1999-07-06 | Shanbrom Technologies Llc | Preparation and utilization of a novel sterile albumin |
IL136552A (en) * | 2000-06-05 | 2005-05-17 | Omrix Biopharmaceuticals Ltd | Method for the inactivation of viruses by a solvent - detergent combination and by nanofiltration |
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EP1592439A1 (en) | 2005-11-09 |
AU2004212324A1 (en) | 2004-08-26 |
NO20053677L (en) | 2005-10-31 |
RS20050624A (en) | 2007-06-04 |
PT1592439E (en) | 2007-06-22 |
ES2285427T3 (en) | 2007-11-16 |
UA80469C2 (en) | 2007-09-25 |
DE502004003834D1 (en) | 2007-06-28 |
MXPA05008276A (en) | 2006-03-21 |
RU2305556C2 (en) | 2007-09-10 |
EP1592439B1 (en) | 2007-05-16 |
BRPI0407458A (en) | 2006-01-31 |
RU2005128507A (en) | 2006-01-20 |
DK1592439T3 (en) | 2007-09-10 |
WO2004071524A1 (en) | 2004-08-26 |
AU2004212324B2 (en) | 2009-05-07 |
JP2006517938A (en) | 2006-08-03 |
PL376644A1 (en) | 2006-01-09 |
CY1106793T1 (en) | 2012-05-23 |
NO20053677D0 (en) | 2005-07-29 |
KR20050103292A (en) | 2005-10-28 |
IL169828A0 (en) | 2011-08-01 |
CN100384471C (en) | 2008-04-30 |
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