WO2001017542A1 - Preparation de solution de proteines et procede de stabilisation associe - Google Patents
Preparation de solution de proteines et procede de stabilisation associe Download PDFInfo
- Publication number
- WO2001017542A1 WO2001017542A1 PCT/JP2000/006144 JP0006144W WO0117542A1 WO 2001017542 A1 WO2001017542 A1 WO 2001017542A1 JP 0006144 W JP0006144 W JP 0006144W WO 0117542 A1 WO0117542 A1 WO 0117542A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- solution preparation
- protein solution
- protein
- container
- resin
- Prior art date
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 107
- 239000012460 protein solution Substances 0.000 title claims abstract description 70
- 238000000034 method Methods 0.000 title claims description 21
- 230000000087 stabilizing effect Effects 0.000 title claims description 6
- 229920005989 resin Polymers 0.000 claims abstract description 42
- 239000011347 resin Substances 0.000 claims abstract description 42
- 230000002209 hydrophobic effect Effects 0.000 claims abstract description 9
- OXCMYAYHXIHQOA-UHFFFAOYSA-N potassium;[2-butyl-5-chloro-3-[[4-[2-(1,2,4-triaza-3-azanidacyclopenta-1,4-dien-5-yl)phenyl]phenyl]methyl]imidazol-4-yl]methanol Chemical compound [K+].CCCCC1=NC(Cl)=C(CO)N1CC1=CC=C(C=2C(=CC=CC=2)C2=N[N-]N=N2)C=C1 OXCMYAYHXIHQOA-UHFFFAOYSA-N 0.000 claims description 50
- 108090000623 proteins and genes Proteins 0.000 claims description 50
- 239000000243 solution Substances 0.000 claims description 50
- 102000003951 Erythropoietin Human genes 0.000 claims description 49
- 108090000394 Erythropoietin Proteins 0.000 claims description 49
- 229940105423 erythropoietin Drugs 0.000 claims description 49
- 102000004169 proteins and genes Human genes 0.000 claims description 47
- -1 polyethylene Polymers 0.000 claims description 39
- 239000000203 mixture Substances 0.000 claims description 26
- 229920000642 polymer Polymers 0.000 claims description 25
- 238000009472 formulation Methods 0.000 claims description 24
- 102000004269 Granulocyte Colony-Stimulating Factor Human genes 0.000 claims description 23
- 108010017080 Granulocyte Colony-Stimulating Factor Proteins 0.000 claims description 23
- 229920001577 copolymer Polymers 0.000 claims description 20
- XBFJAVXCNXDMBH-UHFFFAOYSA-N tetracyclo[6.2.1.1(3,6).0(2,7)]dodec-4-ene Chemical compound C1C(C23)C=CC1C3C1CC2CC1 XBFJAVXCNXDMBH-UHFFFAOYSA-N 0.000 claims description 17
- 238000011049 filling Methods 0.000 claims description 14
- 238000007142 ring opening reaction Methods 0.000 claims description 14
- 235000000346 sugar Nutrition 0.000 claims description 14
- JFNLZVQOOSMTJK-KNVOCYPGSA-N norbornene Chemical compound C1[C@@H]2CC[C@H]1C=C2 JFNLZVQOOSMTJK-KNVOCYPGSA-N 0.000 claims description 12
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 claims description 9
- 239000005977 Ethylene Substances 0.000 claims description 9
- 150000001336 alkenes Chemical class 0.000 claims description 9
- 229920001169 thermoplastic Polymers 0.000 claims description 9
- 239000004416 thermosoftening plastic Substances 0.000 claims description 9
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 claims description 8
- 150000001925 cycloalkenes Chemical class 0.000 claims description 7
- 239000004698 Polyethylene Substances 0.000 claims description 4
- 239000004743 Polypropylene Substances 0.000 claims description 4
- 102000007056 Recombinant Fusion Proteins Human genes 0.000 claims description 4
- 108010008281 Recombinant Fusion Proteins Proteins 0.000 claims description 4
- 239000012611 container material Substances 0.000 claims description 4
- 229920000573 polyethylene Polymers 0.000 claims description 4
- 229920000139 polyethylene terephthalate Polymers 0.000 claims description 4
- 239000005020 polyethylene terephthalate Substances 0.000 claims description 4
- 229920001155 polypropylene Polymers 0.000 claims description 4
- 229920000515 polycarbonate Polymers 0.000 claims description 3
- 239000004417 polycarbonate Substances 0.000 claims description 3
- QQONPFPTGQHPMA-UHFFFAOYSA-N propylene Natural products CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 claims description 3
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 claims description 3
- 229940071643 prefilled syringe Drugs 0.000 claims description 2
- 229920003229 poly(methyl methacrylate) Polymers 0.000 claims 1
- 239000004926 polymethyl methacrylate Substances 0.000 claims 1
- 235000018102 proteins Nutrition 0.000 description 42
- 239000011521 glass Substances 0.000 description 37
- 238000012360 testing method Methods 0.000 description 31
- 229920000089 Cyclic olefin copolymer Polymers 0.000 description 27
- 230000001133 acceleration Effects 0.000 description 14
- 210000004027 cell Anatomy 0.000 description 11
- 235000002639 sodium chloride Nutrition 0.000 description 11
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 10
- 235000014113 dietary fatty acids Nutrition 0.000 description 10
- 239000000194 fatty acid Substances 0.000 description 10
- 229930195729 fatty acid Natural products 0.000 description 10
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 9
- 230000007774 longterm Effects 0.000 description 9
- 229910052710 silicon Inorganic materials 0.000 description 9
- 239000010703 silicon Substances 0.000 description 9
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 8
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 8
- 210000004978 chinese hamster ovary cell Anatomy 0.000 description 8
- 238000013112 stability test Methods 0.000 description 8
- 239000004480 active ingredient Substances 0.000 description 7
- 239000000126 substance Substances 0.000 description 7
- 239000000178 monomer Substances 0.000 description 6
- 229920001223 polyethylene glycol Polymers 0.000 description 6
- 230000006798 recombination Effects 0.000 description 6
- 150000003839 salts Chemical class 0.000 description 6
- 150000001413 amino acids Chemical group 0.000 description 5
- 230000000975 bioactive effect Effects 0.000 description 5
- 229960002885 histidine Drugs 0.000 description 5
- 239000012535 impurity Substances 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 5
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 5
- 229920000053 polysorbate 80 Polymers 0.000 description 5
- 239000011780 sodium chloride Substances 0.000 description 5
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 4
- 239000003963 antioxidant agent Substances 0.000 description 4
- 235000006708 antioxidants Nutrition 0.000 description 4
- 239000000872 buffer Substances 0.000 description 4
- 239000003638 chemical reducing agent Substances 0.000 description 4
- 239000003085 diluting agent Substances 0.000 description 4
- 229940068968 polysorbate 80 Drugs 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- 238000005215 recombination Methods 0.000 description 4
- 238000003860 storage Methods 0.000 description 4
- 239000011593 sulfur Substances 0.000 description 4
- 229910052717 sulfur Inorganic materials 0.000 description 4
- CWERGRDVMFNCDR-UHFFFAOYSA-N thioglycolic acid Chemical compound OC(=O)CS CWERGRDVMFNCDR-UHFFFAOYSA-N 0.000 description 4
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 3
- 241000894006 Bacteria Species 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerol Natural products OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 3
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 3
- 229920001213 Polysorbate 20 Polymers 0.000 description 3
- 230000004071 biological effect Effects 0.000 description 3
- 150000001720 carbohydrates Chemical group 0.000 description 3
- 239000011248 coating agent Substances 0.000 description 3
- 238000000576 coating method Methods 0.000 description 3
- 239000004615 ingredient Substances 0.000 description 3
- 239000002736 nonionic surfactant Substances 0.000 description 3
- 239000003921 oil Substances 0.000 description 3
- 239000000546 pharmaceutical excipient Substances 0.000 description 3
- 238000006116 polymerization reaction Methods 0.000 description 3
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 3
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 3
- 229940068977 polysorbate 20 Drugs 0.000 description 3
- 238000011084 recovery Methods 0.000 description 3
- 238000004007 reversed phase HPLC Methods 0.000 description 3
- 229920002545 silicone oil Polymers 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 238000001179 sorption measurement Methods 0.000 description 3
- 239000003381 stabilizer Substances 0.000 description 3
- 239000012929 tonicity agent Substances 0.000 description 3
- CRSBERNSMYQZNG-UHFFFAOYSA-N 1 -dodecene Natural products CCCCCCCCCCC=C CRSBERNSMYQZNG-UHFFFAOYSA-N 0.000 description 2
- 108010047041 Complementarity Determining Regions Proteins 0.000 description 2
- SRBFZHDQGSBBOR-IOVATXLUSA-N D-xylopyranose Chemical compound O[C@@H]1COC(O)[C@H](O)[C@H]1O SRBFZHDQGSBBOR-IOVATXLUSA-N 0.000 description 2
- SNRUBQQJIBEYMU-UHFFFAOYSA-N Dodecane Natural products CCCCCCCCCCCC SNRUBQQJIBEYMU-UHFFFAOYSA-N 0.000 description 2
- 241000588724 Escherichia coli Species 0.000 description 2
- 102000004457 Granulocyte-Macrophage Colony-Stimulating Factor Human genes 0.000 description 2
- 108010017213 Granulocyte-Macrophage Colony-Stimulating Factor Proteins 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 239000004472 Lysine Substances 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- 229920001214 Polysorbate 60 Polymers 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- 102000003978 Tissue Plasminogen Activator Human genes 0.000 description 2
- 108090000373 Tissue Plasminogen Activator Proteins 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 230000002776 aggregation Effects 0.000 description 2
- 238000004220 aggregation Methods 0.000 description 2
- 150000005215 alkyl ethers Chemical class 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 229940024606 amino acid Drugs 0.000 description 2
- 235000001014 amino acid Nutrition 0.000 description 2
- 230000003078 antioxidant effect Effects 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
- 238000000354 decomposition reaction Methods 0.000 description 2
- 230000036425 denaturation Effects 0.000 description 2
- 238000004925 denaturation Methods 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 238000007922 dissolution test Methods 0.000 description 2
- 229940069096 dodecene Drugs 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 235000011187 glycerol Nutrition 0.000 description 2
- 230000003394 haemopoietic effect Effects 0.000 description 2
- 238000005984 hydrogenation reaction Methods 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 2
- 239000007951 isotonicity adjuster Substances 0.000 description 2
- 229960003136 leucine Drugs 0.000 description 2
- 210000004962 mammalian cell Anatomy 0.000 description 2
- 239000003002 pH adjusting agent Substances 0.000 description 2
- 239000008363 phosphate buffer Substances 0.000 description 2
- 239000008055 phosphate buffer solution Substances 0.000 description 2
- 229920001483 poly(ethyl methacrylate) polymer Polymers 0.000 description 2
- 239000001509 sodium citrate Substances 0.000 description 2
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 2
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
- 230000006641 stabilisation Effects 0.000 description 2
- 238000011105 stabilization Methods 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 239000004094 surface-active agent Substances 0.000 description 2
- 238000010998 test method Methods 0.000 description 2
- 229960000187 tissue plasminogen activator Drugs 0.000 description 2
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 2
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 1
- PBTPTBMYJPCXRQ-MGMRMFRLSA-N (2r)-2-[(1s)-1,2-dihydroxyethyl]-3,4-dihydroxy-2h-furan-5-one;hexadecanoic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O.CCCCCCCCCCCCCCCC(O)=O PBTPTBMYJPCXRQ-MGMRMFRLSA-N 0.000 description 1
- CSTRPYAGFNTOEQ-MGMRMFRLSA-N (2r)-2-[(1s)-1,2-dihydroxyethyl]-3,4-dihydroxy-2h-furan-5-one;octadecanoic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O.CCCCCCCCCCCCCCCCCC(O)=O CSTRPYAGFNTOEQ-MGMRMFRLSA-N 0.000 description 1
- REYLLNRLWCBKCM-YFKPBYRVSA-N (2s)-2-acetamido-4-sulfanylbutanoic acid Chemical compound CC(=O)N[C@H](C(O)=O)CCS REYLLNRLWCBKCM-YFKPBYRVSA-N 0.000 description 1
- AGBQKNBQESQNJD-SSDOTTSWSA-N (R)-lipoic acid Chemical compound OC(=O)CCCC[C@@H]1CCSS1 AGBQKNBQESQNJD-SSDOTTSWSA-N 0.000 description 1
- 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 description 1
- SPSPIUSUWPLVKD-UHFFFAOYSA-N 2,3-dibutyl-6-methylphenol Chemical compound CCCCC1=CC=C(C)C(O)=C1CCCC SPSPIUSUWPLVKD-UHFFFAOYSA-N 0.000 description 1
- MOMKYJPSVWEWPM-UHFFFAOYSA-N 4-(chloromethyl)-2-(4-methylphenyl)-1,3-thiazole Chemical compound C1=CC(C)=CC=C1C1=NC(CCl)=CS1 MOMKYJPSVWEWPM-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- 102100032528 C-type lectin domain family 11 member A Human genes 0.000 description 1
- 101710167766 C-type lectin domain family 11 member A Proteins 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- 241000699802 Cricetulus griseus Species 0.000 description 1
- 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 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- ZAKOWWREFLAJOT-CEFNRUSXSA-N D-alpha-tocopherylacetate Chemical compound CC(=O)OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C ZAKOWWREFLAJOT-CEFNRUSXSA-N 0.000 description 1
- CIWBSHSKHKDKBQ-DUZGATOHSA-N D-araboascorbic acid Natural products OC[C@@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-DUZGATOHSA-N 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
- WQZGKKKJIJFFOK-QTVWNMPRSA-N D-mannopyranose Chemical compound OC[C@H]1OC(O)[C@@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-QTVWNMPRSA-N 0.000 description 1
- 229920002307 Dextran Polymers 0.000 description 1
- 239000003109 Disodium ethylene diamine tetraacetate Substances 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- ZGTMUACCHSMWAC-UHFFFAOYSA-L EDTA disodium salt (anhydrous) Chemical compound [Na+].[Na+].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O ZGTMUACCHSMWAC-UHFFFAOYSA-L 0.000 description 1
- 102000001690 Factor VIII Human genes 0.000 description 1
- 108010054218 Factor VIII Proteins 0.000 description 1
- 229930091371 Fructose Natural products 0.000 description 1
- 239000005715 Fructose Substances 0.000 description 1
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 description 1
- 230000005526 G1 to G0 transition Effects 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
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- SQUHHTBVTRBESD-UHFFFAOYSA-N Hexa-Ac-myo-Inositol Natural products CC(=O)OC1C(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C1OC(C)=O SQUHHTBVTRBESD-UHFFFAOYSA-N 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 102000004877 Insulin Human genes 0.000 description 1
- 108090001061 Insulin Proteins 0.000 description 1
- 102000014150 Interferons Human genes 0.000 description 1
- 108010050904 Interferons Proteins 0.000 description 1
- 108010002352 Interleukin-1 Proteins 0.000 description 1
- 108090001005 Interleukin-6 Proteins 0.000 description 1
- 235000019766 L-Lysine Nutrition 0.000 description 1
- PWKSKIMOESPYIA-BYPYZUCNSA-N L-N-acetyl-Cysteine Chemical compound CC(=O)N[C@@H](CS)C(O)=O PWKSKIMOESPYIA-BYPYZUCNSA-N 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-N L-arginine Chemical compound OC(=O)[C@@H](N)CCCN=C(N)N ODKSFYDXXFIFQN-BYPYZUCNSA-N 0.000 description 1
- 229930064664 L-arginine Natural products 0.000 description 1
- 235000014852 L-arginine Nutrition 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- 239000002211 L-ascorbic acid Substances 0.000 description 1
- 235000000069 L-ascorbic acid Nutrition 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- 239000004395 L-leucine Substances 0.000 description 1
- 235000019454 L-leucine Nutrition 0.000 description 1
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 1
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 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
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 239000004166 Lanolin Substances 0.000 description 1
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 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 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- MUPFEKGTMRGPLJ-RMMQSMQOSA-N Raffinose Natural products O(C[C@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@@H](O[C@@]2(CO)[C@H](O)[C@@H](O)[C@@H](CO)O2)O1)[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 MUPFEKGTMRGPLJ-RMMQSMQOSA-N 0.000 description 1
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 1
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 1
- 102000007562 Serum Albumin Human genes 0.000 description 1
- 108010071390 Serum Albumin Proteins 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-N Sulfurous acid Chemical compound OS(O)=O LSNNMFCWUKXFEE-UHFFFAOYSA-N 0.000 description 1
- 239000004098 Tetracycline Substances 0.000 description 1
- 241001061127 Thione Species 0.000 description 1
- 102000036693 Thrombopoietin Human genes 0.000 description 1
- 108010041111 Thrombopoietin 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
- MUPFEKGTMRGPLJ-UHFFFAOYSA-N UNPD196149 Natural products OC1C(O)C(CO)OC1(CO)OC1C(O)C(O)C(O)C(COC2C(C(O)C(O)C(CO)O2)O)O1 MUPFEKGTMRGPLJ-UHFFFAOYSA-N 0.000 description 1
- 229960004308 acetylcysteine Drugs 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 150000008051 alkyl sulfates Chemical class 0.000 description 1
- AGBQKNBQESQNJD-UHFFFAOYSA-N alpha-Lipoic acid Natural products OC(=O)CCCCC1CCSS1 AGBQKNBQESQNJD-UHFFFAOYSA-N 0.000 description 1
- 229920006127 amorphous resin Polymers 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 239000003945 anionic surfactant Substances 0.000 description 1
- 210000000628 antibody-producing cell Anatomy 0.000 description 1
- 239000000427 antigen Substances 0.000 description 1
- 102000036639 antigens Human genes 0.000 description 1
- 108091007433 antigens Proteins 0.000 description 1
- 239000012062 aqueous buffer Substances 0.000 description 1
- PYMYPHUHKUWMLA-UHFFFAOYSA-N arabinose Natural products OCC(O)C(O)C(O)C=O PYMYPHUHKUWMLA-UHFFFAOYSA-N 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 235000009697 arginine Nutrition 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 235000013871 bee wax Nutrition 0.000 description 1
- 239000012166 beeswax Substances 0.000 description 1
- SRBFZHDQGSBBOR-UHFFFAOYSA-N beta-D-Pyranose-Lyxose Natural products OC1COC(O)C(O)C1O SRBFZHDQGSBBOR-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- SQVRNKJHWKZAKO-UHFFFAOYSA-N beta-N-Acetyl-D-neuraminic acid Natural products CC(=O)NC1C(O)CC(O)(C(O)=O)OC1C(O)C(O)CO SQVRNKJHWKZAKO-UHFFFAOYSA-N 0.000 description 1
- 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
- CZBZUDVBLSSABA-UHFFFAOYSA-N butylated hydroxyanisole Chemical compound COC1=CC=C(O)C(C(C)(C)C)=C1.COC1=CC=C(O)C=C1C(C)(C)C CZBZUDVBLSSABA-UHFFFAOYSA-N 0.000 description 1
- 235000010354 butylated hydroxytoluene Nutrition 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- 235000011148 calcium chloride Nutrition 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 239000004359 castor oil Substances 0.000 description 1
- 235000019438 castor oil Nutrition 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 238000003163 cell fusion method Methods 0.000 description 1
- 239000002738 chelating agent Substances 0.000 description 1
- 239000007979 citrate buffer Substances 0.000 description 1
- 238000004581 coalescence Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000013256 coordination polymer Substances 0.000 description 1
- 210000004748 cultured cell Anatomy 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 230000001351 cycling effect Effects 0.000 description 1
- UFULAYFCSOUIOV-UHFFFAOYSA-N cysteamine Chemical compound NCCS UFULAYFCSOUIOV-UHFFFAOYSA-N 0.000 description 1
- GVJHHUAWPYXKBD-UHFFFAOYSA-N d-alpha-tocopherol Natural products OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 235000019301 disodium ethylene diamine tetraacetate Nutrition 0.000 description 1
- CSVGEMRSDNSWRF-UHFFFAOYSA-L disodium;dihydrogen phosphate Chemical group [Na+].[Na+].OP(O)([O-])=O.OP(O)([O-])=O CSVGEMRSDNSWRF-UHFFFAOYSA-L 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000012407 engineering method Methods 0.000 description 1
- 239000004318 erythorbic acid Substances 0.000 description 1
- 235000010350 erythorbic acid Nutrition 0.000 description 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 1
- 229940071106 ethylenediaminetetraacetate Drugs 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- ZTHYODDOHIVTJV-UHFFFAOYSA-N gallic acid propyl ester Natural products CCCOC(=O)C1=CC(O)=C(O)C(O)=C1 ZTHYODDOHIVTJV-UHFFFAOYSA-N 0.000 description 1
- 238000010353 genetic engineering Methods 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 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 description 1
- 230000013595 glycosylation Effects 0.000 description 1
- 238000006206 glycosylation reaction Methods 0.000 description 1
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 1
- 235000014304 histidine Nutrition 0.000 description 1
- 210000004408 hybridoma Anatomy 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 238000002649 immunization Methods 0.000 description 1
- 230000003053 immunization Effects 0.000 description 1
- CDAISMWEOUEBRE-GPIVLXJGSA-N inositol Chemical compound O[C@H]1[C@H](O)[C@@H](O)[C@H](O)[C@H](O)[C@@H]1O CDAISMWEOUEBRE-GPIVLXJGSA-N 0.000 description 1
- 229960000367 inositol Drugs 0.000 description 1
- 229940125396 insulin Drugs 0.000 description 1
- 229940079322 interferon Drugs 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 229940026239 isoascorbic acid Drugs 0.000 description 1
- FZWBNHMXJMCXLU-BLAUPYHCSA-N isomaltotriose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1OC[C@@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@@H](OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O)O1 FZWBNHMXJMCXLU-BLAUPYHCSA-N 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 235000019388 lanolin Nutrition 0.000 description 1
- 229940039717 lanolin Drugs 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 235000019136 lipoic acid Nutrition 0.000 description 1
- 235000018977 lysine Nutrition 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000000873 masking effect Effects 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 229960003151 mercaptamine Drugs 0.000 description 1
- 229930182817 methionine Natural products 0.000 description 1
- 235000006109 methionine Nutrition 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- XONPDZSGENTBNJ-UHFFFAOYSA-N molecular hydrogen;sodium Chemical compound [Na].[H][H] XONPDZSGENTBNJ-UHFFFAOYSA-N 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- PJUIMOJAAPLTRJ-UHFFFAOYSA-N monothioglycerol Chemical compound OCC(O)CS PJUIMOJAAPLTRJ-UHFFFAOYSA-N 0.000 description 1
- 150000002848 norbornenes Chemical class 0.000 description 1
- 125000003518 norbornenyl group Chemical group C12(C=CC(CC1)C2)* 0.000 description 1
- 210000001672 ovary Anatomy 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 1
- 235000008729 phenylalanine Nutrition 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 239000007981 phosphate-citrate buffer Substances 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 229910021420 polycrystalline silicon Inorganic materials 0.000 description 1
- 125000003367 polycyclic group Chemical group 0.000 description 1
- 229920005672 polyolefin resin Polymers 0.000 description 1
- 229920002503 polyoxyethylene-polyoxypropylene Polymers 0.000 description 1
- 229920005591 polysilicon Polymers 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 239000001508 potassium citrate Substances 0.000 description 1
- 229960002635 potassium citrate Drugs 0.000 description 1
- QEEAPRPFLLJWCF-UHFFFAOYSA-K potassium citrate (anhydrous) Chemical compound [K+].[K+].[K+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O QEEAPRPFLLJWCF-UHFFFAOYSA-K 0.000 description 1
- 235000011082 potassium citrates Nutrition 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 239000000473 propyl gallate Substances 0.000 description 1
- 235000010388 propyl gallate Nutrition 0.000 description 1
- 229940075579 propyl gallate Drugs 0.000 description 1
- 235000004252 protein component Nutrition 0.000 description 1
- MUPFEKGTMRGPLJ-ZQSKZDJDSA-N raffinose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO[C@@H]2[C@@H]([C@@H](O)[C@@H](O)[C@@H](CO)O2)O)O1 MUPFEKGTMRGPLJ-ZQSKZDJDSA-N 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 238000010188 recombinant method Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 238000007151 ring opening polymerisation reaction Methods 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- CDAISMWEOUEBRE-UHFFFAOYSA-N scyllo-inosotol Natural products OC1C(O)C(O)C(O)C(O)C1O CDAISMWEOUEBRE-UHFFFAOYSA-N 0.000 description 1
- 230000001235 sensitizing effect Effects 0.000 description 1
- 235000004400 serine Nutrition 0.000 description 1
- SQVRNKJHWKZAKO-OQPLDHBCSA-N sialic acid Chemical compound CC(=O)N[C@@H]1[C@@H](O)C[C@@](O)(C(O)=O)OC1[C@H](O)[C@H](O)CO SQVRNKJHWKZAKO-OQPLDHBCSA-N 0.000 description 1
- SCPYDCQAZCOKTP-UHFFFAOYSA-N silanol Chemical compound [SiH3]O SCPYDCQAZCOKTP-UHFFFAOYSA-N 0.000 description 1
- 125000005372 silanol group Chemical group 0.000 description 1
- 125000004469 siloxy group Chemical group [SiH3]O* 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000011083 sodium citrates Nutrition 0.000 description 1
- FQENQNTWSFEDLI-UHFFFAOYSA-J sodium diphosphate Chemical compound [Na+].[Na+].[Na+].[Na+].[O-]P([O-])(=O)OP([O-])([O-])=O FQENQNTWSFEDLI-UHFFFAOYSA-J 0.000 description 1
- 235000019983 sodium metaphosphate Nutrition 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 235000011008 sodium phosphates Nutrition 0.000 description 1
- 229940048086 sodium pyrophosphate Drugs 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 150000003408 sphingolipids Chemical class 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 239000012756 surface treatment agent Substances 0.000 description 1
- 229960002180 tetracycline Drugs 0.000 description 1
- 229930101283 tetracycline Natural products 0.000 description 1
- 235000019364 tetracycline Nutrition 0.000 description 1
- 150000003522 tetracyclines Chemical class 0.000 description 1
- 235000019818 tetrasodium diphosphate Nutrition 0.000 description 1
- 239000001577 tetrasodium phosphonato phosphate Substances 0.000 description 1
- 238000003856 thermoforming Methods 0.000 description 1
- 229960002663 thioctic acid Drugs 0.000 description 1
- YODZTKMDCQEPHD-UHFFFAOYSA-N thiodiglycol Chemical compound OCCSCCO YODZTKMDCQEPHD-UHFFFAOYSA-N 0.000 description 1
- 229950006389 thiodiglycol Drugs 0.000 description 1
- 229940035024 thioglycerol Drugs 0.000 description 1
- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
- 235000010384 tocopherol Nutrition 0.000 description 1
- 229960001295 tocopherol Drugs 0.000 description 1
- 229930003799 tocopherol Natural products 0.000 description 1
- 239000011732 tocopherol Substances 0.000 description 1
- 229940042585 tocopherol acetate Drugs 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/02—Inorganic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
- A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
Definitions
- the present invention relates to a long-term stable protein solution preparation which is easy to handle. More specifically, the present invention relates to a stable protein solution formulation pre-filled in a resin container. The invention further relates to a method for stabilizing a protein solution formulation. Background art
- protein solution preparations contain diluents, solubilizers, isotonic agents, excipients, pH adjusters, buffers, sulfur-containing reducing agents, antioxidants, etc., in addition to the active ingredient protein. It is offered to the market in containers such as vials, ampoules or disposable syringes.
- Such containers should satisfy the following conditions: (1) the protein preparation is stable under long-term storage; (2) heat resistance and pressure resistance that can withstand the conditions used for sterilization; (4) that the container fragments do not mix into the solution preparation during use; (5) if the container is a syringe, the plunger has good sliding properties; (6) the solution It must be transparent so that it can detect turbidity and foreign substances, (7) it is convenient for transportation, and (8) there is little eluate from containers.
- Glass containers are excellent in terms of heat resistance, pressure resistance, chemical resistance, and transparency, but the work of applying or baking a surface treatment agent such as silicon is complicated and costly. In addition, there is a possibility that a drug derived from glass There are also problems in terms of transportation, as there are boil-offs and the glass containers are heavy and fragile.
- the protein when the protein is prepared as a solution, there is a problem in that the content is reduced due to aggregation, denaturation, and decomposition of the protein, especially when long-term storage at room temperature is desired.
- the present inventors have examined the reactivity between proteins and glass surfaces, and found that polar residues such as silanol and silyloxy, which are originally present on the surface of glass materials, are the main causes of the degradation and association of proteins having biological activity.
- Conventional methods for reducing the effects of these polar residues include the application of polysilicon or alkyl silicon to the glass surface, or the chemical masking of silanol residues. However, it was not an essential means of improving stability.
- the present inventors have found that, particularly when the protein is erythropoietin (EPO), the affinity of the protein solution with the container surface comes into contact, and the pure phase on the glass surface, that is, the stationary phase is a hydrophilic group. If filled, the hydrophilic part of the protein would be distributed more, and this would lead to a decrease in stability. Based on this hypothesis, if the surface of the container is different from the glass surface, and if it is a reversed phase with no polar residues, the lipid-soluble residues of the protein will be more distributed, and the It was expected that the polarity of the protein, which causes the protein, would be opposite to the surface of the container, which would greatly contribute to the improvement of protein stability.
- EPO erythropoietin
- proteins with sugar chains tend to be easily adsorbed to the container, and it was expected that the present invention could greatly contribute to the improvement of the stability of protein solutions with sugar chains.
- the present inventors have discovered that by selecting a container having a reversed phase of hydrophobicity, protein stability can be ensured without treating the surface of the container. That is, the book The present inventors have completed the present invention by finding that, when a protein solution preparation is filled in a resin container of a specific material, aggregation, denaturation, and decomposition can be suppressed over a long period of time and a high content of protein can be retained.
- the present invention provides a stable protein solution preparation, in which at least a part of the container for storing the protein solution preparation, which is in direct contact with the preparation, is made of a hydrophobic resin.
- the present invention provides the above protein solution preparation, wherein the container is a resin container.
- the present invention provides the above-mentioned protein solution preparation, wherein the resin is selected from the group consisting of polyethylene, polypropylene, polyethylene terephthalate, polycarbonate, polyethyl methacrylate, and a copolymer of these resins and cycling olefins. I will provide a.
- the present invention provides the above-mentioned protein solution preparation, wherein the resin is selected from ring-opened polymers of cycloolefins.
- the present invention provides the above protein solution preparation, wherein the resin is selected from hydrogenated cycloolefins ring-opening polymers.
- the present invention provides the above protein solution preparation, wherein the cycloopenfin ring-opening polymer is a norbornene or tetracycline dodecene ring-opening polymer.
- the present invention provides the above protein solution preparation, wherein the hydrogenated product of the cycloopenfin ring-opening polymer is a hydrogenated product of a noropennene or tetracyclododecene ring-opening polymer.
- the present invention provides the above protein solution preparation, wherein the resin is a cycloolefin copolymer which is a copolymer of cyclic olefin and olefin.
- the present invention provides the above protein solution preparation, which is a copolymer of dodecene or a derivative thereof and ethylene or propylene.
- the present invention provides the above protein solution preparation, wherein the cycloolefin copolymer is a copolymer of norpolene or tetracyclododecene and ethylene.
- the present invention provides the above protein solution preparation, wherein the resin is a thermoplastic norpolene-based resin or a thermoplastic tetracyclododecene-based resin.
- the present invention provides the above protein solution preparation, wherein the container shape is selected from the group consisting of vials, ampoules, syringes and bottles.
- the present invention provides the above protein solution preparation, wherein the protein is a recombinant protein.
- the present invention provides the above protein solution preparation, wherein the protein is erythropoietin.
- the present invention provides the above protein solution preparation, wherein the protein is a granulocyte colony stimulating factor.
- the present invention provides the above protein solution preparation, wherein the protein is a protein having a sugar chain.
- the present invention provides a method for stabilizing a protein solution preparation, comprising filling and storing the protein solution preparation in a container in which at least a portion of the material in contact with the preparation is a hydrophobic resin.
- Resins suitable for the material of the container used in the present invention include known medical container materials such as polyethylene (PE), polypropylene (PP), polyethylene terephthalate (PET), polycarbonate, and polyethyl methacrylate, and are preferable.
- a cycloolefin ring-opening polymer such as norportene or tetracyclododecene or a derivative thereof and a hydrogenated product thereof, a cycloolefin such as norbornene or tetracyclododecene or a derivative thereof, and a molecule obtained by polymerization of ethylene or propylene.
- thermoplastic norbornene-based resins and thermoplastic tetracyclododecene-based resins.
- thermoplastic norbornene-based resin include a ring-opened polymer of a norbornene-based monomer, a hydrogenated product thereof, an addition-type polymer of a norbornene-based monomer, and an addition-type polymer of a norbornene-based monomer and an olefin.
- thermoplastic tetracyclododecene resin examples include a ring-opened polymer of a tetracyclododecene monomer, a hydrogenated product thereof, and a tetracyclododecene monomer. Addition polymers, addition polymers of tetracyclododecene-based monomers and olefins, and the like are included.
- Thermoplastic norbornene resins are described in, for example, JP-A-3-14882, JP-A-3-122137, JP-A-4-63807, and the like.
- a copolymer using norbornene and an olefin such as ethylene as a raw material and a cycloolefin copolymer (COC) which is a copolymer using a raw material such as tetracyclododecene and an olefin such as ethylene as a raw material, and norbornene.
- COCs and COPs are described in, for example, JP-A-5-300939 or JP-A-5-317411. Preferred structures of C ⁇ C and C ⁇ P are shown below.
- n degree of polymerization
- m, m ' copolymer content molar ratio
- R lower alkyl group
- R ', R " same or different lower alkyl group
- the COC is commercially available, for example, as Abel (registered trademark) manufactured by Mitsui Chemicals, and the COP is, for example, manufactured by Zeon, Zenex (registered trademark) or Zeonoa (registered trademark). (Registered trademark) ⁇ Daikyo Resin CZ (registered trademark).
- COC and COP are characterized by heat resistance, chemical properties such as light resistance, and chemical resistance as characteristics of a polyolefin resin.Physical properties such as mechanical properties, melting, flow properties, and dimensional accuracy are as amorphous resins. It is the most preferable material because it shows the characteristics of
- the protein solution preparation of the present invention means that a solution preparation containing a physiologically active protein is pre-filled in a container in which at least a part of the container in direct contact with the preparation is made of a hydrophobic resin, so that it can be stored for a long period of time. Refers to a preparation.
- the container for filling the protein solution preparation in the present invention can be selected according to the purpose of use, but it has a predetermined capacity such as a vial, an ampoule or a syringe, and a large capacity such as a bottle. Including shapes. Most preferred are syringes, especially disposable syringes.
- the bioactive protein used as an active ingredient in the present invention includes, for example, hematopoietic factors such as granulocyte colony stimulating factor (G-CSF), granulocyte macrophage colony stimulating factor (GM-CSF), erythropoietin (EPII), and tropopoietin; Interferon, cytodynamics such as IL-1 and IL-6, monoclonal antibody, tissue plasminogen activator (TPA), perokinase, serum albumin, blood coagulation factor VIII, lebutin, insulin, stem cell growth factor ( SCF) and the like, but are not limited thereto.
- hematopoietic factors such as EPO, G—CSF, and thrombopoietin, and monoclonal antibodies are preferable, and EP is more preferable.
- the biologically active protein used as the active ingredient in the present invention is a protein having substantially the same biological activity as that of a mammal, particularly a human biologically active protein, and is derived from a natural source or a recombinant method. Among them, those obtained by the gene recombination method are preferable. Proteins obtained by the genetic recombination method are those having the same amino acid sequence as the natural protein, or those having one or more of the amino acid sequences deleted, substituted or added and having the biological activity described above. Including. Furthermore, bioactive proteins are chemically modified with PEG or the like. Also included.
- a protein having a sugar chain is particularly preferable.
- the origin of the sugar chain is not particularly limited, but a sugar chain added to a mammalian cell is preferable.
- Mammalian cells include, for example, Chinese hamster ovary cells (CHO cells), BHK cells, COS cells, human-derived cells, etc. Among them, CHO cells are most preferred.
- EPO may be produced by any method, extracted from human urine by various methods, and separated and purified. It was produced in Chinese hamster ovary cells (CHO), BHK cells, C ⁇ S cells, human-derived cells, etc. by engineering methods (eg, JP-A-61-12288), and extracted, separated and purified by various methods. Is used. Furthermore, it includes EPO chemically modified with PEG or the like (see International Patent Application Publication No. WO 90/12874). Furthermore, it also includes those obtained by chemically modifying EP ⁇ without a sugar chain with PEG or the like.
- EPO analogs modified to increase the number of one or more glycosylation sites at the N-linked carbohydrate chain binding site or the O-linked carbohydrate chain binding site in the amino acid sequence of EPO (for example, 8 _ 151398, Tokuhyohei 8-506023). Furthermore, the number of sugar chains may be increased by increasing the content of sialic acid or the like without changing the number of sugar chain binding sites.
- any G_CSF can be used as long as it is highly purified G-CSF.
- the G-CSF in the present invention may be produced by any method, such as those obtained by culturing a cell line of human tumor cells and extracting and separating and purifying it from various cells, or E. coli or the like by genetic engineering techniques.
- Bacteria Yeast bacteria; Chinese hamster ovary (CHO) cells, cultured cells derived from animals such as C127 cells, C ⁇ S cells, etc., extracted and separated and purified by various methods are used.
- it is produced by a gene recombination method using Escherichia coli, a bacterium or a CHO cell. Most preferably, it is produced by a CHO cell using a genetic recombination method. Furthermore, G—CS chemically modified with PEG etc. F (see International Patent Application Publication No. WO90 / 128874).
- the monoclonal antibody may be produced by any method.
- Monoclonal antibodies are basically immunized with a sensitizing antigen according to a usual immunization method using a known technique, and the obtained immunocytes are fused with a known parent cell by a usual cell fusion method. Thus, it can be prepared by screening monoclonal antibody-producing cells.
- the monoclonal antibody is not limited to the monoclonal antibody produced by the hybridoma, but includes a chimeric antibody artificially modified for the purpose of, for example, reducing the xenoantigenicity to humans.
- a reshaped (reshaped) human antibody can also be used in the present invention. This is obtained by replacing the complementarity-determining region of a human antibody with the complementarity-determining region of a non-human mammal, for example, a mouse antibody, and a general gene recombination technique is also known. Using the known method, a reshaped humanized antibody useful in the present invention can be obtained.
- the protein solution preparation of the present invention contains a diluent, a solubilizing agent, a tonicity agent, an excipient, a pH adjusting agent, a soothing agent, a buffer, a sulfur-containing reducing agent, an antioxidant, and the like. Is also good.
- sugars such as polyethylene glycol; dextran, mannitol, sorbitol, inositol, glucose, fructose, lactose, xylose, mannose, maltose, sucrose, and raffinose can be used as the tonicity agent.
- sulfur-containing reducing agent examples include N-acetyl cysteine, N-acetyl homocysteine, thioctic acid, thiodiglycol, thioethanolamine, thioglycerol, thiosorby] yl, thioglycolic acid and salts thereof, and thioglycolic acid.
- sulfur-containing reducing agent examples include those having a sulfhydryl group such as sodium sulfate, dalban thione, and thioalkanoic acid having 1 to 7 carbon atoms.
- antioxidants include erythorbic acid, dibutylhydroxytoluene, butylhydroxyanisole, heart tocopherol, tocopherol acetate, L-ascorbic acid and salts thereof, L-ascorbic acid palmitate, L-ascorbic acid stearate, and sulfurous acid.
- erythorbic acid dibutylhydroxytoluene, butylhydroxyanisole
- heart tocopherol tocopherol acetate
- L-ascorbic acid and salts thereof L-ascorbic acid palmitate, L-ascorbic acid stearate
- sulfurous acid e.g., sulfurous acid.
- EDTA disodium ethylenediaminetetraacetate
- Chelating agents such as sodium metaphosphate are exemplified.
- inorganic salts such as sodium chloride, potassium chloride, calcium chloride, sodium phosphate, potassium phosphate, and sodium hydrogen carbonate
- solution preparations such as organic salts such as sodium citrate, potassium citrate, and sodium acetate
- the protein solution preparation of the present invention may further contain an appropriate stabilizer for each protein, and the stabilizer includes a surfactant (for example, sorbitan fatty acid ester or glycerin fatty acid ester which is a nonionic surfactant).
- the stable protein solution preparation of the present invention is usually administered by parenteral administration route, for example, injection (subcutaneous or intravenous injection), transdermal, transmucosal, nasal, etc., but oral administration is also possible.
- parenteral administration route for example, injection (subcutaneous or intravenous injection), transdermal, transmucosal, nasal, etc., but oral administration is also possible.
- the amount of protein contained in the stable protein solution preparation of the present invention depends on the protein used, the type of disease to be treated, the severity of the disease, the age of the patient, etc. Can be determined.
- the amount of EPO in the solution formulation is generally 100-5000001 U / m 1 (about 0.5-3000 z gZm 1), preferably 200-: L 00000 I UZm 1 (About 1 to 600 ⁇ g / 1), and more preferably 750 to 72000 1 U / m1 (about 4 to 400 gZm1).
- the final administration concentration is generally 1 to 1000 gZm, preferably 10 to 800 gZm1, and more preferably 50 to 500 gZml.
- it is an antibody, it is generally 0.1 to 200 mgZm at the final administration concentration, preferably 1 to 12 Omg / m1.
- the solution formulation of the present invention can be prepared by dissolving these components in an aqueous buffer known in the field of solution formulation such as phosphate and phosphate buffers or citrate buffers.
- aqueous buffer known in the field of solution formulation
- phosphate and phosphate buffers or citrate buffers preferably a sodium monohydrogen phosphate monosodium dihydrogen phosphate system
- citrate buffer is preferably a sodium citrate buffer.
- the protein solution preparation of the present invention is an erythropoietin solution preparation
- it includes EPO, nonionic surfactants (eg, polysorbate 80, polysorbate 20), isotonic agents (eg, sodium chloride) and optionally Accordingly, it preferably contains a stabilizer (eg, an amino acid, preferably L-histidine), and has a pH of 5.0-8.0, preferably 5.5-7.0.
- a stabilizer eg, an amino acid, preferably L-histidine
- the protein solution preparation of the present invention is a G-CSF solution preparation
- it contains G-CSF, a nonionic surfactant (for example, polysorbate 80, polysorbate 20), and if necessary, Includes diluent, solubilizer, tonicity agent, excipient, pH adjuster, soothing agent, buffer, sulfur-containing reducing agent, antioxidant, etc., with a pH of 5.0-8.0, preferably Is preferably 6.0-7.0.
- the stable protein solution preparation pre-filled in the hydrophobic resin container of the present invention was subjected to an accelerated test at 40 ° C. for 4 months, as shown in the examples described below, which were tested using EPO and G-CSF. Even after the test, it shows an extremely good residual ratio of EPO compared to a glass container.
- the present invention also provides a method for stabilizing a protein solution preparation, which comprises filling and storing the protein solution preparation in the above-mentioned resin container.
- the stabilization in the present invention differs depending on the type of protein to be packed.
- the stabilization is performed, for example, at 10 ° C for 2 years or more, or at 25 ° C for 6 months or more, It is preferably stored for 1 year or more, more preferably for 2 years or more, or for 2 weeks or more at 40 ° C.
- the residual ratio of erythropoietin is 90% or more, preferably 95% or more, and more preferably 98% or more. It means to keep it above%.
- the protein solution preparation pre-filled in the hydrophobic resin container of the present invention does not decrease the physiologically active content of the protein over a long period of time, and is more stable than the conventional solution preparation pre-filled in a glass container.
- a protein solution preparation conventionally stored at a low temperature can be stably stored at room temperature for a long period of time. Since the production of the resin container of the present invention is thermoforming, there is an advantage that the process is simplified. Furthermore, resin containers are lighter in weight and less susceptible to breakage than glass containers, so they are suitable for transportation, and the industrial utility of the present invention is extremely large.
- EPO erythropoietin
- G-CSF granulocyte colony stimulating factor
- the evaluation of the preparation was performed by determining the content of EPO or G-CSF using the RP-HPLC analysis method.
- Example 1 Long-term stability test of a £? 0 solution formulation at 10 ° C and 25 ° C storage
- erythropoietin solution preparation prepared as described above was used in a glass container coated with silicon on the surface and a COP container (manufactured from COP, which is a hydrogenated product of the ring-opening polymer of norpolene: Daikyosei Into Daikyo Resin CZ (registered trademark)) to prepare EPO solution formulations for 3 months and 9 months at 10 ° C, and 3 months, 6 months, 12 months and 24 months at 25 ° C. A monthly stability test was performed.
- EP ⁇ used in this example is a recombinant protein having a sugar chain produced in CHO cells.
- Table 1 Long-term stability test results at 10 ° C
- EPO solution preparations prepared by filling glass and COP containers in the same manner as in Example 1 were stored in an accelerated test at 40 ° C for 2, 4 and 6 months.
- EPO solution preparations prepared by filling glass and C ⁇ P containers in the same manner as in Example 1 were stored for one month, two months and three months in an accelerated test at 50.
- EPO solution preparations prepared by filling in glass and COP containers in the same manner as in Example 1 were stored in an accelerated test at 60 ° C for 1, 2 and 3 weeks.
- G-CSF solution preparation 0.5 mL of the G-CSF solution prepared as described above was placed in a glass container not coated with silicone oil on its surface, a glass container coated with silicon oil, and a C0P container (ring opening weight of norbornene).
- a hydrogenated product of the coalescence Daikyo Resin CZ (registered trademark) manufactured by Daikyo Seie Co., Ltd.)
- G-CSF solution preparation is prepared and stored for 2 weeks in accelerated test at 40 ° C did.
- G-CSF used in this example is a recombinant protein having a sugar chain produced in CHO cells.
- the results obtained are shown in Table 6 below.
- the numbers indicate the content of G-CSF measured by the RP-HPLC analysis method, and the numbers in force indicate the remaining rates when the filling rate (Initial) is 100%.
- a erythropoietin solution formulation was prepared containing 1500 IU or 4800 IU of EPO in 1 ml of the preparation solution. Formulations containing 1500 international units are described in Example 1. It was prepared as described. A preparation containing 48,000 IU was prepared as follows.
- EPO solution preparation was prepared by filling into glass ampoules without silicon coating on the surface and glass vials without silicon coating on the surface .
- Preparation solution Erythropoietin solution formulation containing 1500 IPO of EPO in lm1 (prepared in the same manner as in Example 1) 0.5 ml of glass container, COP container (hydrogenated ring-opening polymer of norbornene Manufactured from a certain COP: Daikyo Resin CZ (registered trademark) manufactured by Daikyo Seiji Co., Ltd .; COC container (copolymer using tetracyclododecene and olefin such as ethylene as raw materials: manufactured by Mitsui Chemicals, Abel (registered trademark) ) To prepare EPO solution formulations.
- Stability tests were conducted at 25 ° C for 2 months, 3 months and 6 months, and for EPO solution preparations filled in glass containers and COC containers, (2) Acceleration test for 2 months, 4 months and 6 months at 40, (3) Acceleration test for 1 month, 2 months and 3 months at 50 ° C, (4) 1 week and 2 weeks at 60 ° ⁇ And a three-week acceleration test.
- the results obtained are shown in Tables 8, 9, 10, and 11, respectively.
- the figures show the residual ratio when the residual ratio at the time of filling (Initial) is 100%.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Inorganic Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Dermatology (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicinal Preparation (AREA)
- Medical Preparation Storing Or Oral Administration Devices (AREA)
- Infusion, Injection, And Reservoir Apparatuses (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Peptides Or Proteins (AREA)
- Distillation Of Fermentation Liquor, Processing Of Alcohols, Vinegar And Beer (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Non-Alcoholic Beverages (AREA)
- Physical Or Chemical Processes And Apparatus (AREA)
Description
Claims
Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP00957046A EP1232753B1 (en) | 1999-09-08 | 2000-09-08 | Stable protein solution filled in a container made from a hydrophobic resin and method of stabilizing the same |
AU68759/00A AU6875900A (en) | 1999-09-08 | 2000-09-08 | Protein solution preparation and method of stabilizing the same |
US09/720,757 US7253142B1 (en) | 1999-09-08 | 2000-09-08 | Protein solution preparation and method of stabilizing the same |
DE60038386T DE60038386T2 (de) | 1999-09-08 | 2000-09-08 | Stabile proteinlösung abgefüllt in einem behältnis aus hydrophobem harz und eine methode zur stabilisierung derselben |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP25489699 | 1999-09-08 | ||
JP11/254896 | 1999-09-08 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2001017542A1 true WO2001017542A1 (fr) | 2001-03-15 |
Family
ID=17271358
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/JP2000/006144 WO2001017542A1 (fr) | 1999-09-08 | 2000-09-08 | Preparation de solution de proteines et procede de stabilisation associe |
Country Status (8)
Country | Link |
---|---|
US (1) | US7253142B1 (ja) |
EP (1) | EP1232753B1 (ja) |
JP (3) | JP5450508B2 (ja) |
AT (1) | ATE389414T1 (ja) |
AU (1) | AU6875900A (ja) |
DE (1) | DE60038386T2 (ja) |
TW (1) | TWI245645B (ja) |
WO (1) | WO2001017542A1 (ja) |
Cited By (14)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2004019966A1 (ja) * | 2002-08-27 | 2004-03-11 | Chugai Seiyaku Kabushiki Kaisha | タンパク質溶液製剤の安定化方法 |
JP2006182960A (ja) * | 2004-12-28 | 2006-07-13 | Nipro Corp | 医療用潤滑剤およびこれを塗布したシリンジ |
JP2007502310A (ja) * | 2003-05-23 | 2007-02-08 | ノボ ノルディスク ヘルス ケア アクチェンゲゼルシャフト | 溶液中におけるタンパク質の安定化 |
JP2007508235A (ja) * | 2003-06-25 | 2007-04-05 | ノボ ノルディスク ヘルス ケア アクチェンゲゼルシャフト | Vii因子ポリペプチドの液体組成物 |
JP2007528842A (ja) * | 2003-06-10 | 2007-10-18 | エルジー ライフサイエンス リミテッド | 血清アルブミンを含まない、安定なヒトエリスロポエチン水溶液 |
JP2011519347A (ja) * | 2008-02-07 | 2011-07-07 | アムジエン・インコーポレーテツド | 安定化されたタンパク質組成物 |
US8461116B2 (en) | 2001-12-21 | 2013-06-11 | Novo Nordisk Healthcare Ag | Liquid composition of factor VII polypeptides |
US8729022B2 (en) | 2002-06-21 | 2014-05-20 | Novo Nordisk Healthcare Ag | Stabilised solid compositions of factor VII polypeptides |
US20150071945A1 (en) * | 2001-06-08 | 2015-03-12 | Abbvie Biotechnology Ltd. | Methods of administering anti-tnfalpha antibodies |
JP2016506409A (ja) * | 2012-12-20 | 2016-03-03 | メディミューン,エルエルシー | 凝集プロファイルが改善されている液状抗体製剤 |
JP2020535181A (ja) * | 2017-09-29 | 2020-12-03 | ヤンセン バイオテツク,インコーポレーテツド | 低用量抗体組成物を安定化する新規製剤 |
US10914720B2 (en) | 2016-02-10 | 2021-02-09 | Becton Dickinson France | Method to evaluate the stability of a protein-based formulation |
WO2021153511A1 (ja) * | 2020-01-28 | 2021-08-05 | 日本ゼオン株式会社 | プレフィルド薬剤パッケージ及びプレフィルド薬剤パッケージの製造方法 |
US11844830B2 (en) | 2013-03-12 | 2023-12-19 | The Trustees Of The University Of Pennsylvania | Vaccines for human papilloma virus and methods for using the same |
Families Citing this family (20)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
TWI245645B (en) * | 1999-09-08 | 2005-12-21 | Chugai Pharmaceutical Co Ltd | Protein solution formulations and stabilization methods thereof |
ES2237574T5 (es) † | 2000-05-15 | 2017-08-09 | F. Hoffmann-La Roche Ag | Composición farmacéutica líquida que contiene un derivado de eritropoyetina |
JP2006524195A (ja) * | 2003-03-18 | 2006-10-26 | ノボ ノルディスク ヘルス ケア アクチェンゲゼルシャフト | Vii因子ポリペプチドの液状水性医薬組成物 |
US7897734B2 (en) | 2003-03-26 | 2011-03-01 | Novo Nordisk Healthcare Ag | Method for the production of proteins |
KR101293503B1 (ko) | 2003-08-14 | 2013-08-07 | 노보 노르디스크 헬스 케어 악티엔게젤샤프트 | 인자 vii 폴리펩티드의 액상 수성 약학적 조성물 |
BRPI0417721B8 (pt) | 2003-12-19 | 2021-05-25 | Novo Nordisk Healthcare Ag | kit contendo um medicamento farmacêutico, método para preparar uma formulação líquida de um fator recombinante viia, composição e métodos para preparar as composições |
TWI556829B (zh) | 2004-04-09 | 2016-11-11 | 艾伯維生物技術有限責任公司 | 用於治療TNFα相關失調症之多重可變劑量療法 |
BRPI0610058A2 (pt) | 2005-05-16 | 2010-05-25 | Abbott Biotech Ltd | uso de inibidor de tnf para tratamento da poliartrite erosiva |
US9605064B2 (en) | 2006-04-10 | 2017-03-28 | Abbvie Biotechnology Ltd | Methods and compositions for treatment of skin disorders |
CN107106409A (zh) * | 2014-10-02 | 2017-08-29 | 泰尔茂株式会社 | 用于容纳蛋白质溶液制剂的医疗用容器 |
EP3240630A1 (en) * | 2014-12-31 | 2017-11-08 | Koninklijke Philips N.V. | Modified oligonucleotide immobilization onto polymer substrate via physisorption |
EP3434251B1 (en) | 2016-03-24 | 2023-08-16 | Terumo Kabushiki Kaisha | Drug container |
JP7153999B2 (ja) * | 2016-04-22 | 2022-10-17 | ロート製薬株式会社 | 水性組成物 |
JP7155003B2 (ja) * | 2016-04-25 | 2022-10-18 | テルモ株式会社 | シリンジ用バレル及びプレフィルドシリンジ |
JP7024730B2 (ja) | 2016-12-22 | 2022-02-24 | 日本ゼオン株式会社 | オリゴペプチドの探索方法、オリゴペプチド、修飾ペプチド、及び免疫測定方法 |
JPWO2019225568A1 (ja) * | 2018-05-21 | 2021-07-01 | 中外製薬株式会社 | ガラス容器に封入された凍結乾燥製剤 |
CN112243423B (zh) | 2018-05-28 | 2022-11-04 | 中外制药株式会社 | 填充喷嘴 |
US20210292402A1 (en) * | 2018-07-31 | 2021-09-23 | Zeon Corporation | Pre-filled syringe and method of producing pre-filled syringe |
WO2020026926A1 (ja) | 2018-07-31 | 2020-02-06 | 日本ゼオン株式会社 | プレフィルドシリンジおよびプレフィルドシリンジの製造方法 |
WO2021006057A1 (ja) | 2019-07-05 | 2021-01-14 | テルモ株式会社 | タンパク質製剤を収納するための医薬品容器 |
Citations (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS54135215A (en) * | 1978-04-10 | 1979-10-20 | Ss Pharmaceutical Co | Stable aqueous lisozyme solution |
GB2193631A (en) * | 1986-07-18 | 1988-02-17 | Chugai Pharmaceutical Co Ltd | Stable granulocyte colony stimulating factor composition |
WO1989001791A1 (en) * | 1987-08-26 | 1989-03-09 | Astra Meditec Ab | Articles exhibiting a blood-compatible surface layer and process for providing articles with such a surface layer |
JPH0296533A (ja) * | 1988-09-30 | 1990-04-09 | Toyo Jozo Co Ltd | ポリペプタイド類の吸着防止剤 |
US4992419A (en) * | 1987-05-09 | 1991-02-12 | Boehringer Mannheim Gmbh | Stabilized erythropoietin preparations |
EP0490549A1 (en) * | 1990-12-11 | 1992-06-17 | Ciba-Geigy Ag | Stabilisation of pharmaceutical compositions comprising calcitonin |
EP0556034A1 (en) * | 1992-02-12 | 1993-08-18 | Daikyo Gomu Seiko Ltd. | A medical instrument |
EP0559146A1 (en) * | 1992-03-03 | 1993-09-08 | Nippon Zeon Co., Ltd. | Medical implement, polymer composition and optical material |
EP0576294A2 (en) * | 1992-06-26 | 1993-12-29 | Seikagaku Kogyo Kabushiki Kaisha (Seikagaku Corporation) | Chondroitinase, process for preparing the same, and pharmaceutical composition comprising the same |
WO1996038503A1 (fr) * | 1995-06-02 | 1996-12-05 | Solvay (Societe Anonyme) | Composition souple a base de polymere de chlorure de vinyle, utilisation de cette composition pour la fabrication d'un article et article comprenant cette composition |
JPH11146910A (ja) * | 1997-04-25 | 1999-06-02 | Minoru Terano | 生体適合性ポリオレフィン成形品、及び生体適合性高分子材料 |
JP2000044487A (ja) * | 1998-05-29 | 2000-02-15 | Taiyo Yakuhin Kogyo Kk | カルシトニン類のプレフィルドシリンジ製剤 |
Family Cites Families (28)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3788319A (en) * | 1971-07-30 | 1974-01-29 | Univ Iowa State Res Found Inc | System for exchanging blood ultrafiltrate |
US4732889A (en) | 1985-02-06 | 1988-03-22 | Chugai Seiyaku Kabushiki Kaisha | Pharmaceutical composition for the treatment of the anemia of rheumatoid arthritis |
DE3777845D1 (de) | 1986-01-22 | 1992-05-07 | Chugai Pharmaceutical Co Ltd | Pharmazeutischer stoff fuer die behandlung von myelogener leukaemie. |
US4838861A (en) * | 1986-05-02 | 1989-06-13 | Sharp David E | Blood preservation by ultrahemodilution |
JP2629000B2 (ja) * | 1986-07-18 | 1997-07-09 | 中外製薬株式会社 | 安定な顆粒球コロニー刺激因子含有製剤 |
US4810249A (en) * | 1987-03-12 | 1989-03-07 | Habley Medical Technology Corp. | Linear and Vernier-type syringe |
US5728437A (en) | 1987-08-26 | 1998-03-17 | Astra Meditec Aktiebolag | Articles exhibiting a blood-compatible surface layer and process for providing articles with such a surface layer |
ES2008948A6 (es) * | 1988-01-07 | 1989-08-16 | Martinez Gimeno Carlos Vicente | Jeringa de un solo uso auto-inutilizable. |
US5213814A (en) * | 1989-04-10 | 1993-05-25 | Cryopharm Corporation | Lyophilized and reconstituted blood platelet compositions |
ATE145661T1 (de) | 1991-07-22 | 1996-12-15 | Daikyo Gomu Seiko Kk | Behälter für hygienische artikel |
US5571788A (en) | 1991-12-09 | 1996-11-05 | Ciba-Geigy Corporation | Stable calcitonin pharmaceutical compositions |
US6007520A (en) | 1992-02-12 | 1999-12-28 | Daikyo Gomu Seiko, Ltd. | Medical instrument |
JP3666884B2 (ja) * | 1992-05-21 | 2005-06-29 | 日本ゼオン株式会社 | 医療用器材 |
DE69333924T2 (de) * | 1992-05-29 | 2006-08-17 | University Of North Carolina At Chapel Hill | Im immobilisierten Zustand getrocknete pharmazeutisch verträgliche menschliche Blutplättchen |
JP3895782B2 (ja) * | 1992-10-26 | 2007-03-22 | 生化学工業株式会社 | コンドロイチナーゼ組成物およびそれを含有する注射用製剤 |
US5661125A (en) | 1992-08-06 | 1997-08-26 | Amgen, Inc. | Stable and preserved erythropoietin compositions |
NZ260909A (en) | 1993-07-05 | 1995-04-27 | Takeda Chemical Industries Ltd | Production of sustained release preparation by allowing a water-soluble polypeptide to permeate into a biodegradable matrix in an aqueous solution |
JP2747979B2 (ja) * | 1994-08-19 | 1998-05-06 | 雪印乳業株式会社 | ヒト由来の糖蛋白質からなる生理活性因子を有効成分とする医薬 |
JPH08155007A (ja) * | 1994-12-02 | 1996-06-18 | Mitsui Petrochem Ind Ltd | 薬剤充填容器製剤及びこれに用いる容器 |
TW434020B (en) | 1995-03-15 | 2001-05-16 | Kirin Brewery | Methods for preventing adsorption of thrombopoietin (TPO), and stable top-containing compositions |
TWI240627B (en) | 1996-04-26 | 2005-10-01 | Chugai Pharmaceutical Co Ltd | Erythropoietin solution preparation |
PT954272E (pt) * | 1996-12-23 | 2002-09-30 | Novo Nordisk As | Recipiente em polimere de hidrocarboneto ciclico para armazenagem de medicamento liquido |
JP3387775B2 (ja) * | 1997-05-22 | 2003-03-17 | 株式会社大協精工 | 注射器用密封栓及びプレフィルド注射器 |
JP3568398B2 (ja) * | 1997-09-11 | 2004-09-22 | 中外製薬株式会社 | アポトーシスを誘起するモノクローナル抗体 |
WO2000015241A1 (fr) | 1998-09-11 | 2000-03-23 | Chugai Seiyaku Kabushiki Kaisha | Preparation d'une solution proteinique et son procede de stabilisation |
JP5271481B2 (ja) * | 1999-09-08 | 2013-08-21 | 中外製薬株式会社 | タンパク質溶液製剤およびその安定化方法 |
TWI245645B (en) * | 1999-09-08 | 2005-12-21 | Chugai Pharmaceutical Co Ltd | Protein solution formulations and stabilization methods thereof |
JP5765281B2 (ja) * | 2012-03-27 | 2015-08-19 | 株式会社Jvcケンウッド | 復号装置、復号方法、及び、プログラム |
-
2000
- 2000-09-08 TW TW089118513A patent/TWI245645B/zh not_active IP Right Cessation
- 2000-09-08 AU AU68759/00A patent/AU6875900A/en not_active Abandoned
- 2000-09-08 WO PCT/JP2000/006144 patent/WO2001017542A1/ja active IP Right Grant
- 2000-09-08 EP EP00957046A patent/EP1232753B1/en not_active Expired - Lifetime
- 2000-09-08 DE DE60038386T patent/DE60038386T2/de not_active Expired - Lifetime
- 2000-09-08 AT AT00957046T patent/ATE389414T1/de not_active IP Right Cessation
- 2000-09-08 US US09/720,757 patent/US7253142B1/en not_active Expired - Lifetime
-
2011
- 2011-05-13 JP JP2011108579A patent/JP5450508B2/ja not_active Expired - Lifetime
-
2013
- 2013-10-02 JP JP2013207358A patent/JP6076226B2/ja not_active Expired - Lifetime
-
2015
- 2015-11-04 JP JP2015216695A patent/JP6134370B2/ja not_active Expired - Lifetime
Patent Citations (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS54135215A (en) * | 1978-04-10 | 1979-10-20 | Ss Pharmaceutical Co | Stable aqueous lisozyme solution |
GB2193631A (en) * | 1986-07-18 | 1988-02-17 | Chugai Pharmaceutical Co Ltd | Stable granulocyte colony stimulating factor composition |
US4992419A (en) * | 1987-05-09 | 1991-02-12 | Boehringer Mannheim Gmbh | Stabilized erythropoietin preparations |
WO1989001791A1 (en) * | 1987-08-26 | 1989-03-09 | Astra Meditec Ab | Articles exhibiting a blood-compatible surface layer and process for providing articles with such a surface layer |
JPH0296533A (ja) * | 1988-09-30 | 1990-04-09 | Toyo Jozo Co Ltd | ポリペプタイド類の吸着防止剤 |
EP0490549A1 (en) * | 1990-12-11 | 1992-06-17 | Ciba-Geigy Ag | Stabilisation of pharmaceutical compositions comprising calcitonin |
EP0556034A1 (en) * | 1992-02-12 | 1993-08-18 | Daikyo Gomu Seiko Ltd. | A medical instrument |
EP0559146A1 (en) * | 1992-03-03 | 1993-09-08 | Nippon Zeon Co., Ltd. | Medical implement, polymer composition and optical material |
EP0576294A2 (en) * | 1992-06-26 | 1993-12-29 | Seikagaku Kogyo Kabushiki Kaisha (Seikagaku Corporation) | Chondroitinase, process for preparing the same, and pharmaceutical composition comprising the same |
WO1996038503A1 (fr) * | 1995-06-02 | 1996-12-05 | Solvay (Societe Anonyme) | Composition souple a base de polymere de chlorure de vinyle, utilisation de cette composition pour la fabrication d'un article et article comprenant cette composition |
JPH11146910A (ja) * | 1997-04-25 | 1999-06-02 | Minoru Terano | 生体適合性ポリオレフィン成形品、及び生体適合性高分子材料 |
JP2000044487A (ja) * | 1998-05-29 | 2000-02-15 | Taiyo Yakuhin Kogyo Kk | カルシトニン類のプレフィルドシリンジ製剤 |
Cited By (20)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20150079101A1 (en) * | 2001-06-08 | 2015-03-19 | Abbvie Biotechnology Ltd. | Methods of administering anti-tnfalpha antibodies |
US20150071945A1 (en) * | 2001-06-08 | 2015-03-12 | Abbvie Biotechnology Ltd. | Methods of administering anti-tnfalpha antibodies |
US8461116B2 (en) | 2001-12-21 | 2013-06-11 | Novo Nordisk Healthcare Ag | Liquid composition of factor VII polypeptides |
US8729022B2 (en) | 2002-06-21 | 2014-05-20 | Novo Nordisk Healthcare Ag | Stabilised solid compositions of factor VII polypeptides |
JPWO2004019966A1 (ja) * | 2002-08-27 | 2005-12-15 | 中外製薬株式会社 | タンパク質溶液製剤の安定化方法 |
WO2004019966A1 (ja) * | 2002-08-27 | 2004-03-11 | Chugai Seiyaku Kabushiki Kaisha | タンパク質溶液製剤の安定化方法 |
JP4489591B2 (ja) * | 2002-08-27 | 2010-06-23 | 中外製薬株式会社 | タンパク質溶液製剤の安定化方法 |
JP2007502310A (ja) * | 2003-05-23 | 2007-02-08 | ノボ ノルディスク ヘルス ケア アクチェンゲゼルシャフト | 溶液中におけるタンパク質の安定化 |
US8536127B2 (en) * | 2003-05-23 | 2013-09-17 | Novo Nordisk Healthcare Ag | Protein stabilization in solution |
JP2007528842A (ja) * | 2003-06-10 | 2007-10-18 | エルジー ライフサイエンス リミテッド | 血清アルブミンを含まない、安定なヒトエリスロポエチン水溶液 |
JP4871720B2 (ja) * | 2003-06-10 | 2012-02-08 | エルジー ライフサイエンス リミテッド | 血清アルブミンを含まない、安定なヒトエリスロポエチン水溶液 |
JP4658041B2 (ja) * | 2003-06-25 | 2011-03-23 | ノボ ノルディスク ヘルス ケア アクチェンゲゼルシャフト | Vii因子ポリペプチドの液体組成物 |
JP2007508235A (ja) * | 2003-06-25 | 2007-04-05 | ノボ ノルディスク ヘルス ケア アクチェンゲゼルシャフト | Vii因子ポリペプチドの液体組成物 |
JP2006182960A (ja) * | 2004-12-28 | 2006-07-13 | Nipro Corp | 医療用潤滑剤およびこれを塗布したシリンジ |
JP2011519347A (ja) * | 2008-02-07 | 2011-07-07 | アムジエン・インコーポレーテツド | 安定化されたタンパク質組成物 |
JP2016506409A (ja) * | 2012-12-20 | 2016-03-03 | メディミューン,エルエルシー | 凝集プロファイルが改善されている液状抗体製剤 |
US11844830B2 (en) | 2013-03-12 | 2023-12-19 | The Trustees Of The University Of Pennsylvania | Vaccines for human papilloma virus and methods for using the same |
US10914720B2 (en) | 2016-02-10 | 2021-02-09 | Becton Dickinson France | Method to evaluate the stability of a protein-based formulation |
JP2020535181A (ja) * | 2017-09-29 | 2020-12-03 | ヤンセン バイオテツク,インコーポレーテツド | 低用量抗体組成物を安定化する新規製剤 |
WO2021153511A1 (ja) * | 2020-01-28 | 2021-08-05 | 日本ゼオン株式会社 | プレフィルド薬剤パッケージ及びプレフィルド薬剤パッケージの製造方法 |
Also Published As
Publication number | Publication date |
---|---|
JP2014051502A (ja) | 2014-03-20 |
US7253142B1 (en) | 2007-08-07 |
EP1232753A1 (en) | 2002-08-21 |
EP1232753A4 (en) | 2004-08-11 |
ATE389414T1 (de) | 2008-04-15 |
TWI245645B (en) | 2005-12-21 |
EP1232753B1 (en) | 2008-03-19 |
JP2016056176A (ja) | 2016-04-21 |
JP6076226B2 (ja) | 2017-02-08 |
JP2011168610A (ja) | 2011-09-01 |
DE60038386D1 (de) | 2008-04-30 |
DE60038386T2 (de) | 2009-04-23 |
JP6134370B2 (ja) | 2017-05-24 |
AU6875900A (en) | 2001-04-10 |
JP5450508B2 (ja) | 2014-03-26 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP6134370B2 (ja) | タンパク質溶液製剤およびその安定化方法 | |
JP5490972B2 (ja) | タンパク質注射製剤 | |
JP4607336B2 (ja) | 長期安定化製剤 | |
US7163671B2 (en) | Long-term stabilized formulations | |
AU2006235962A1 (en) | Solution formulations having long-term stability | |
JP4607010B2 (ja) | タンパク質含有安定化製剤 | |
JP2007204498A (ja) | 長期安定化製剤 | |
JP3895109B2 (ja) | 蛋白非添加製剤 | |
JP5271481B2 (ja) | タンパク質溶液製剤およびその安定化方法 | |
JP3479082B2 (ja) | トロンボポイエチン組成物 | |
WO2000015241A1 (fr) | Preparation d'une solution proteinique et son procede de stabilisation | |
US10052361B2 (en) | Liquid pharmaceutical composition of conjugated erythropoietin | |
CN114746439A (zh) | 整合蛋白抗体的稳定制剂 | |
JP2017528526A (ja) | α型インターフェロンを含有する安定したベンジルアルコールフリーの水溶液製剤 | |
JP4454571B2 (ja) | 蛋白非添加製剤 | |
WO2001047544A1 (fr) | Preparation de seringue prealablement remplie de proteine et procede de stabilisation | |
CN117355321A (zh) | 增强性能的赋形剂以及降低生物制剂的粘度和提高生物制剂的稳定性的方法 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
ENP | Entry into the national phase |
Ref country code: JP Ref document number: 2001 521332 Kind code of ref document: A Format of ref document f/p: F |
|
WWE | Wipo information: entry into national phase |
Ref document number: 09720757 Country of ref document: US |
|
AK | Designated states |
Kind code of ref document: A1 Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CR CU CZ DE DK DM DZ EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT TZ UA UG US UZ VN YU ZA ZW |
|
AL | Designated countries for regional patents |
Kind code of ref document: A1 Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG |
|
DFPE | Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101) | ||
121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
WWE | Wipo information: entry into national phase |
Ref document number: 2000957046 Country of ref document: EP |
|
REG | Reference to national code |
Ref country code: DE Ref legal event code: 8642 |
|
WWP | Wipo information: published in national office |
Ref document number: 2000957046 Country of ref document: EP |
|
WWG | Wipo information: grant in national office |
Ref document number: 2000957046 Country of ref document: EP |