CN101810854A - 新的无白蛋白的因子viii制剂 - Google Patents
新的无白蛋白的因子viii制剂 Download PDFInfo
- Publication number
- CN101810854A CN101810854A CN200910171121A CN200910171121A CN101810854A CN 101810854 A CN101810854 A CN 101810854A CN 200910171121 A CN200910171121 A CN 200910171121A CN 200910171121 A CN200910171121 A CN 200910171121A CN 101810854 A CN101810854 A CN 101810854A
- Authority
- CN
- China
- Prior art keywords
- preparation
- factor viii
- factor
- nacl
- temperature
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 239000000203 mixture Substances 0.000 title claims abstract description 67
- 238000009472 formulation Methods 0.000 title claims abstract description 52
- 229960000301 factor viii Drugs 0.000 title claims abstract description 50
- 108010054218 Factor VIII Proteins 0.000 title claims abstract description 48
- 102000001690 Factor VIII Human genes 0.000 title claims abstract description 48
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims abstract description 114
- 239000011780 sodium chloride Substances 0.000 claims abstract description 57
- 229930006000 Sucrose Natural products 0.000 claims abstract description 25
- 239000005720 sucrose Substances 0.000 claims abstract description 25
- 239000003381 stabilizer Substances 0.000 claims abstract description 21
- HDTRYLNUVZCQOY-UHFFFAOYSA-N α-D-glucopyranosyl-α-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OC1C(O)C(O)C(O)C(CO)O1 HDTRYLNUVZCQOY-UHFFFAOYSA-N 0.000 claims abstract description 15
- HDTRYLNUVZCQOY-WSWWMNSNSA-N Trehalose Natural products O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-WSWWMNSNSA-N 0.000 claims abstract description 15
- HDTRYLNUVZCQOY-LIZSDCNHSA-N alpha,alpha-trehalose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-LIZSDCNHSA-N 0.000 claims abstract description 15
- 102000009027 Albumins Human genes 0.000 claims abstract description 13
- 108010088751 Albumins Proteins 0.000 claims abstract description 13
- 159000000007 calcium salts Chemical class 0.000 claims abstract description 12
- 239000000546 pharmaceutical excipient Substances 0.000 claims abstract description 11
- 239000004475 Arginine Substances 0.000 claims abstract description 9
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 claims abstract description 9
- 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 claims abstract description 8
- 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 claims abstract description 8
- 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 claims abstract description 8
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 claims abstract description 6
- 238000002360 preparation method Methods 0.000 claims description 85
- 102100022641 Coagulation factor IX Human genes 0.000 claims description 47
- 108010076282 Factor IX Proteins 0.000 claims description 47
- 229960004222 factor ix Drugs 0.000 claims description 47
- 238000000034 method Methods 0.000 claims description 42
- 239000000945 filler Substances 0.000 claims description 26
- 238000007710 freezing Methods 0.000 claims description 20
- 230000008014 freezing Effects 0.000 claims description 20
- 239000003795 chemical substances by application Substances 0.000 claims description 17
- 239000000872 buffer Substances 0.000 claims description 16
- 230000002829 reductive effect Effects 0.000 claims description 12
- 239000008194 pharmaceutical composition Substances 0.000 claims description 8
- 239000003814 drug Substances 0.000 claims description 6
- 229940079593 drug Drugs 0.000 claims description 4
- 125000000185 sucrose group Chemical group 0.000 claims 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 abstract description 24
- 239000006172 buffering agent Substances 0.000 abstract 1
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 64
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 34
- 239000004471 Glycine Substances 0.000 description 32
- 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 30
- 229930195725 Mannitol Natural products 0.000 description 30
- 239000000594 mannitol Substances 0.000 description 30
- 235000010355 mannitol Nutrition 0.000 description 30
- 238000004108 freeze drying Methods 0.000 description 26
- 238000002425 crystallisation Methods 0.000 description 23
- 230000008025 crystallization Effects 0.000 description 23
- 230000008569 process Effects 0.000 description 22
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 17
- 229920000053 polysorbate 80 Polymers 0.000 description 17
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 16
- 239000001110 calcium chloride Substances 0.000 description 16
- 229910001628 calcium chloride Inorganic materials 0.000 description 16
- RWSXRVCMGQZWBV-WDSKDSINSA-N glutathione Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-WDSKDSINSA-N 0.000 description 14
- 239000007983 Tris buffer Substances 0.000 description 13
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 12
- 239000003963 antioxidant agent Substances 0.000 description 10
- 230000000694 effects Effects 0.000 description 10
- 230000009477 glass transition Effects 0.000 description 10
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 9
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 9
- 239000007995 HEPES buffer Substances 0.000 description 9
- 229920001612 Hydroxyethyl starch Polymers 0.000 description 9
- 238000000137 annealing Methods 0.000 description 9
- 235000006708 antioxidants Nutrition 0.000 description 9
- 235000003969 glutathione Nutrition 0.000 description 9
- 229960003180 glutathione Drugs 0.000 description 9
- 229940027278 hetastarch Drugs 0.000 description 9
- 238000011160 research Methods 0.000 description 9
- 230000003078 antioxidant effect Effects 0.000 description 8
- 210000002381 plasma Anatomy 0.000 description 8
- 108090000623 proteins and genes Proteins 0.000 description 7
- 108010047303 von Willebrand Factor Proteins 0.000 description 7
- 230000003647 oxidation Effects 0.000 description 6
- 238000007254 oxidation reaction Methods 0.000 description 6
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 6
- 229940068968 polysorbate 80 Drugs 0.000 description 6
- 235000018102 proteins Nutrition 0.000 description 6
- 102000004169 proteins and genes Human genes 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 239000004094 surface-active agent Substances 0.000 description 6
- 108010024636 Glutathione Proteins 0.000 description 5
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 5
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 5
- 235000004279 alanine Nutrition 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- IHPYMWDTONKSCO-UHFFFAOYSA-N 2,2'-piperazine-1,4-diylbisethanesulfonic acid Chemical compound OS(=O)(=O)CCN1CCN(CCS(O)(=O)=O)CC1 IHPYMWDTONKSCO-UHFFFAOYSA-N 0.000 description 4
- DVLFYONBTKHTER-UHFFFAOYSA-N 3-(N-morpholino)propanesulfonic acid Chemical compound OS(=O)(=O)CCCN1CCOCC1 DVLFYONBTKHTER-UHFFFAOYSA-N 0.000 description 4
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 4
- 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 4
- 101000911390 Homo sapiens Coagulation factor VIII Proteins 0.000 description 4
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 4
- 239000004472 Lysine Substances 0.000 description 4
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 4
- 229920001213 Polysorbate 20 Polymers 0.000 description 4
- 239000011575 calcium Substances 0.000 description 4
- 229960005069 calcium Drugs 0.000 description 4
- 229910052791 calcium Inorganic materials 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 229960003646 lysine Drugs 0.000 description 4
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 4
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 4
- 229940068977 polysorbate 20 Drugs 0.000 description 4
- 238000012545 processing Methods 0.000 description 4
- 239000000600 sorbitol Substances 0.000 description 4
- 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 3
- 239000007991 ACES buffer Substances 0.000 description 3
- 239000007989 BIS-Tris Propane buffer Substances 0.000 description 3
- 241000699802 Cricetulus griseus Species 0.000 description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 3
- 239000007993 MOPS buffer Substances 0.000 description 3
- 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 3
- 239000007990 PIPES buffer Substances 0.000 description 3
- HHKZCCWKTZRCCL-UHFFFAOYSA-N bis-tris propane Chemical compound OCC(CO)(CO)NCCCNC(CO)(CO)CO HHKZCCWKTZRCCL-UHFFFAOYSA-N 0.000 description 3
- 210000004027 cell Anatomy 0.000 description 3
- 238000005660 chlorination reaction Methods 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 230000006872 improvement Effects 0.000 description 3
- 238000007689 inspection Methods 0.000 description 3
- 229910052751 metal Inorganic materials 0.000 description 3
- 239000002184 metal Substances 0.000 description 3
- 210000001672 ovary Anatomy 0.000 description 3
- -1 polyoxyethylene Polymers 0.000 description 3
- 229920000136 polysorbate Polymers 0.000 description 3
- 230000009467 reduction Effects 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 238000003860 storage Methods 0.000 description 3
- 150000005846 sugar alcohols Polymers 0.000 description 3
- DWNBOPVKNPVNQG-LURJTMIESA-N (2s)-4-hydroxy-2-(propylamino)butanoic acid Chemical compound CCCN[C@H](C(O)=O)CCO DWNBOPVKNPVNQG-LURJTMIESA-N 0.000 description 2
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 2
- 101100230376 Acetivibrio thermocellus (strain ATCC 27405 / DSM 1237 / JCM 9322 / NBRC 103400 / NCIMB 10682 / NRRL B-4536 / VPI 7372) celI gene Proteins 0.000 description 2
- 239000004322 Butylated hydroxytoluene Substances 0.000 description 2
- NLZUEZXRPGMBCV-UHFFFAOYSA-N Butylhydroxytoluene Chemical compound CC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 NLZUEZXRPGMBCV-UHFFFAOYSA-N 0.000 description 2
- 102100026735 Coagulation factor VIII Human genes 0.000 description 2
- 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 2
- 201000003542 Factor VIII deficiency Diseases 0.000 description 2
- 208000009292 Hemophilia A Diseases 0.000 description 2
- 208000032843 Hemorrhage Diseases 0.000 description 2
- 239000007987 MES buffer Substances 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- UBQYURCVBFRUQT-UHFFFAOYSA-N N-benzoyl-Ferrioxamine B Chemical compound CC(=O)N(O)CCCCCNC(=O)CCC(=O)N(O)CCCCCNC(=O)CCC(=O)N(O)CCCCCN UBQYURCVBFRUQT-UHFFFAOYSA-N 0.000 description 2
- 102000005877 Peptide Initiation Factors Human genes 0.000 description 2
- 108010044843 Peptide Initiation Factors Proteins 0.000 description 2
- 108020004511 Recombinant DNA Proteins 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 235000001014 amino acid Nutrition 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 230000023555 blood coagulation Effects 0.000 description 2
- 235000010354 butylated hydroxytoluene Nutrition 0.000 description 2
- 229940095259 butylated hydroxytoluene Drugs 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 229960000958 deferoxamine Drugs 0.000 description 2
- 239000003599 detergent Substances 0.000 description 2
- 230000008034 disappearance Effects 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- FCZCIXQGZOUIDN-UHFFFAOYSA-N ethyl 2-diethoxyphosphinothioyloxyacetate Chemical compound CCOC(=O)COP(=S)(OCC)OCC FCZCIXQGZOUIDN-UHFFFAOYSA-N 0.000 description 2
- 230000005496 eutectics Effects 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- 102000057593 human F8 Human genes 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000012423 maintenance Methods 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 229910021645 metal ion Inorganic materials 0.000 description 2
- 229920001184 polypeptide Polymers 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 238000004321 preservation Methods 0.000 description 2
- 230000000630 rising effect Effects 0.000 description 2
- 230000000087 stabilizing effect Effects 0.000 description 2
- XOAAWQZATWQOTB-UHFFFAOYSA-N taurine Chemical compound NCCS(O)(=O)=O XOAAWQZATWQOTB-UHFFFAOYSA-N 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 238000001890 transfection Methods 0.000 description 2
- 238000010792 warming Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- AGBQKNBQESQNJD-SSDOTTSWSA-N (R)-lipoic acid Chemical compound OC(=O)CCCC[C@@H]1CCSS1 AGBQKNBQESQNJD-SSDOTTSWSA-N 0.000 description 1
- CMCBDXRRFKYBDG-UHFFFAOYSA-N 1-dodecoxydodecane Chemical class CCCCCCCCCCCCOCCCCCCCCCCCC CMCBDXRRFKYBDG-UHFFFAOYSA-N 0.000 description 1
- IEQAICDLOKRSRL-UHFFFAOYSA-N 2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-(2-dodecoxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethanol Chemical compound CCCCCCCCCCCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCO IEQAICDLOKRSRL-UHFFFAOYSA-N 0.000 description 1
- XIRIZNCOALEZIK-XRIGFGBMSA-N 2-aminoacetic acid;(2s)-2-amino-3-(1h-imidazol-5-yl)propanoic acid Chemical compound NCC(O)=O.NCC(O)=O.OC(=O)[C@@H](N)CC1=CNC=N1 XIRIZNCOALEZIK-XRIGFGBMSA-N 0.000 description 1
- 102000004506 Blood Proteins Human genes 0.000 description 1
- 108010017384 Blood Proteins Proteins 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 241000699800 Cricetinae Species 0.000 description 1
- YPZMPEPLWKRVLD-PJEQPVAWSA-N D-Glycero-D-gulo-Heptose Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)[C@@H](O)C=O YPZMPEPLWKRVLD-PJEQPVAWSA-N 0.000 description 1
- DSLZVSRJTYRBFB-LLEIAEIESA-N D-glucaric acid Chemical compound OC(=O)[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O DSLZVSRJTYRBFB-LLEIAEIESA-N 0.000 description 1
- 108020004414 DNA Proteins 0.000 description 1
- 239000004201 L-cysteine Substances 0.000 description 1
- FFFHZYDWPBMWHY-VKHMYHEASA-N L-homocysteine Chemical compound OC(=O)[C@@H](N)CCS FFFHZYDWPBMWHY-VKHMYHEASA-N 0.000 description 1
- BVHLGVCQOALMSV-JEDNCBNOSA-N L-lysine hydrochloride Chemical compound Cl.NCCCC[C@H](N)C(O)=O BVHLGVCQOALMSV-JEDNCBNOSA-N 0.000 description 1
- JLVVSXFLKOJNIY-UHFFFAOYSA-N Magnesium ion Chemical compound [Mg+2] JLVVSXFLKOJNIY-UHFFFAOYSA-N 0.000 description 1
- DBXNUXBLKRLWFA-UHFFFAOYSA-N N-(2-acetamido)-2-aminoethanesulfonic acid Chemical compound NC(=O)CNCCS(O)(=O)=O DBXNUXBLKRLWFA-UHFFFAOYSA-N 0.000 description 1
- 125000003047 N-acetyl group Chemical group 0.000 description 1
- 241001597008 Nomeidae Species 0.000 description 1
- IVXIDMMTUHCNBC-LOLRQIBTSA-N OC=1C(=C2CCC(OC2=C(C1C)C)(C(=O)O)C)C.N[C@H](C(=O)O)CCC(=O)N[C@@H](CS)C(=O)NCC(=O)O Chemical compound OC=1C(=C2CCC(OC2=C(C1C)C)(C(=O)O)C)C.N[C@H](C(=O)O)CCC(=O)N[C@@H](CS)C(=O)NCC(=O)O IVXIDMMTUHCNBC-LOLRQIBTSA-N 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 229920001030 Polyethylene Glycol 4000 Polymers 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- GLEVLJDDWXEYCO-UHFFFAOYSA-N Trolox Chemical compound O1C(C)(C(O)=O)CCC2=C1C(C)=C(C)C(O)=C2C GLEVLJDDWXEYCO-UHFFFAOYSA-N 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 238000002441 X-ray diffraction Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000004520 agglutination Effects 0.000 description 1
- AGBQKNBQESQNJD-UHFFFAOYSA-N alpha-Lipoic acid Natural products OC(=O)CCCCC1CCSS1 AGBQKNBQESQNJD-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical group [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000003064 anti-oxidating effect Effects 0.000 description 1
- 238000013096 assay test Methods 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
- 229960000074 biopharmaceutical Drugs 0.000 description 1
- 208000015294 blood coagulation disease Diseases 0.000 description 1
- 239000004227 calcium gluconate Substances 0.000 description 1
- 229960004494 calcium gluconate Drugs 0.000 description 1
- 235000013927 calcium gluconate Nutrition 0.000 description 1
- NEEHYRZPVYRGPP-UHFFFAOYSA-L calcium;2,3,4,5,6-pentahydroxyhexanoate Chemical compound [Ca+2].OCC(O)C(O)C(O)C(O)C([O-])=O.OCC(O)C(O)C(O)C(O)C([O-])=O NEEHYRZPVYRGPP-UHFFFAOYSA-L 0.000 description 1
- 238000010523 cascade reaction Methods 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 239000002738 chelating agent Substances 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 230000008602 contraction Effects 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 238000002447 crystallographic data Methods 0.000 description 1
- 230000009849 deactivation Effects 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 150000002016 disaccharides Chemical class 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-N ethanesulfonic acid Chemical compound CCS(O)(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-N 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 229960001731 gluceptate Drugs 0.000 description 1
- KWMLJOLKUYYJFJ-VFUOTHLCSA-N glucoheptonic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)[C@@H](O)C(O)=O KWMLJOLKUYYJFJ-VFUOTHLCSA-N 0.000 description 1
- 230000009931 harmful effect Effects 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 229940027029 hemofil Drugs 0.000 description 1
- 125000000487 histidyl group Chemical group [H]N([H])C(C(=O)O*)C([H])([H])C1=C([H])N([H])C([H])=N1 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 235000019136 lipoic acid Nutrition 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229960005337 lysine hydrochloride Drugs 0.000 description 1
- 229910001425 magnesium ion Inorganic materials 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Substances [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 1
- 229920001983 poloxamer Polymers 0.000 description 1
- 229920001993 poloxamer 188 Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229950008882 polysorbate Drugs 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 239000001294 propane Substances 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 229940047431 recombinate Drugs 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000004153 renaturation Methods 0.000 description 1
- 230000008521 reorganization Effects 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- 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 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- IREPZTZSVPKCAR-WCCKRBBISA-M sodium;(2s)-2-amino-4-methylsulfanylbutanoate Chemical compound [Na+].CSCC[C@H](N)C([O-])=O IREPZTZSVPKCAR-WCCKRBBISA-M 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 238000007655 standard test method Methods 0.000 description 1
- 229960002663 thioctic acid Drugs 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 230000001131 transforming effect Effects 0.000 description 1
- 230000007704 transition Effects 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
- A61K38/36—Blood coagulation or fibrinolysis factors
- A61K38/37—Factors VIII
-
- 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
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- 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
-
- 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
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/38—Cellulose; Derivatives thereof
-
- 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
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
-
- 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
- A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10S530/00—Chemistry: natural resins or derivatives; peptides or proteins; lignins or reaction products thereof
- Y10S530/827—Proteins from mammals or birds
- Y10S530/829—Blood
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Inorganic Chemistry (AREA)
- Hematology (AREA)
- Zoology (AREA)
- Gastroenterology & Hepatology (AREA)
- Immunology (AREA)
- Molecular Biology (AREA)
- Biochemistry (AREA)
- Dermatology (AREA)
- Diabetes (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicinal Preparation (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Peptides Or Proteins (AREA)
Abstract
一种因子VIII组合物,所述组合物在配制时不加入白蛋白,除因子VIII外,还包括下列制剂赋形剂:300mM至500mM NaCl;1%至4%重量/体积的稳定剂,其选自蔗糖、海藻糖、棉子糖和精氨酸;1mM至5mM的钙盐;和维持pH在6和8之间的缓冲剂。
Description
本申请是申请日为2000年2月22日、申请号为008063044(国际申请号为PCT/US00/40068)、名称为新的无白蛋白的因子VIII制剂的发明专利申请的分案申请。
本发明背景
因子VIII是在血浆中发现的导致凝血的级联反应中的辅助因子。血液中因子VIII活性量的缺乏可导致称为甲型血友病的凝血障碍,一种主要影响男性的遗传病。目前甲型血友病以因子VIII的疗效性制剂治疗,所述因子VIII制剂来源于人血浆或采用重组DNA技术制备。这些制剂或者针对急性出血(需要治疗)给药或者经常性间隔给药以防止失控性出血(预防)。
已知因子VIII在疗效性制剂中相对不稳定。在血浆中,因子VIII通常与另一种血浆蛋白,维勒布兰得(von Willebrand)因子(vWF)形成复合体,后者以大于因子VIII的摩尔量存在于血浆并且被认为可防止因子VIII的早熟降解。另一种循环血浆蛋白,白蛋白,可能也在体内起到稳定因子VIII的作用。因此目前市售的因子VIII组合物主要依靠采用白蛋白和/或vWF使因子VIII在制备过程和贮藏过程中保持稳定。
目前应用于市售的因子VIII组合物中的白蛋白和/或vWF来源于人血浆,然而,这些物质的采用存在某些缺点。由于通常加入比因子VIII大的摩尔量的白蛋白以增加因子VIII在这些制剂中的稳定性,因而这些制剂中因子VIII蛋白难以体现其自身特性。对重组制备的因子VIII组合物来说加入来源于人的白蛋白到因子VIII中也发现是有缺陷的。这是因为没有这些另加的白蛋白时,重组来源的因子VIII组合物不会含有来源于人的蛋白,因此理论上的传播病毒的危险应当会减少。
配制不含白蛋白或vWF(或使用相对低水平的这些赋形剂)的因子VIII的几种尝试已有描述。例如,Freudenberg的美国专利No.5565427(EP 508194)(转让至Behringwerke)中描述的因子VIII组合物中,除赋形剂如氯化钠和蔗糖外,还含有去污剂和氨基酸的特殊组合,特别是精氨酸和甘氨酸。所描述的去污剂,聚山梨醇酯20或聚山梨醇酯80,以0.001至0.5%(v/v)间的量存在,而精氨酸和甘氨酸的存在量在0.01至1mol/L之间。所描述的蔗糖存在量在0.1至10%之间。该专利的实施例2提出了溶液中稳定性不超过16小时的溶液(1)0.75%蔗糖、0.4M甘氨酸、和0.15M NaCl,和(2)0.01M柠檬酸钠、0.08M甘氨酸、0.016M赖氨酸、0.0025M氯化钙、和0.4M氯化钠,而溶液(3)1%蔗糖、0.14M精氨酸、0.1M氯化钠以及(4)1%蔗糖、0.4M甘氨酸、0.14M精氨酸、0.1M氯化钠、和0.05%吐温80则呈现出稳定性。
Nayer的美国专利No.5763401(欧洲专利818204)(转让至Bayer)也描述了不含白蛋白的治疗用因子VIII制剂,其包括15-60mM蔗糖、最多50mM的NaCl、最多5mM的氯化钙、65-400mM甘氨酸、以及最多50mM的组氨酸。下列特定制剂经检测是稳定的:(1)150mMNaCl、2.5mM氯化钙、和165mM甘露醇;和(2)1%蔗糖、30mM氯化钠、2.5mM氯化钙、20mM组氨酸、和290mM甘氨酸。发现一种糖含量较高的制剂(10%麦芽糖、50mM NaCl、2.5mM氯化钙、和5mM组氨酸)在冷冻干燥状态下与制剂(2)相比呈现出较差的稳定性。
Osterberg的美国专利No.5733873(欧洲专利627924)(转让至Pharmacia & Upjohn)公开的制剂中含有0.01-1mg/ml的表面活性剂。该专利公开的制剂中含有下列范围内的赋形剂:至少0.01mg/ml量的聚山梨醇酯20或80,优选0.02-1.0mg/ml;至少0.1M NaCl;至少0.5mM钙盐;和至少1mM组氨酸。更特殊地,下列特别实施例被公开:(1)14.7-50-65mM组氨酸、0.31-0.6M NaCl、4mM氯化钙、0.001-0.02-0.025%聚山梨醇酯80、有或无0.1%PEG 4000或19.9mM蔗糖;以及(2)20mg/ml甘露醇、2.67mg/ml组氨酸、18mg/ml NaCl、3.7mM氯化钙、和0.23mg/ml聚山梨醇酯80。
其它采用低或高浓度氯化钠的尝试也被描述。Lee的美国专利No.4877608(欧洲专利315968)(转让至Rhone-Poulenc Rorer)指出含相对低浓度氯化钠的制剂,即制剂含有0.5mM-15mM NaCl、5mM氯化钙、0.2mM-5mM组氨酸、0.01-10mM赖氨酸盐酸盐和最多10%的糖。该“糖”可以是最多10%的麦芽糖、10%蔗糖、或5%甘露醇。
Lee的美国专利5605884(欧洲专利0314095)(转让至Rhone-Poulenc Rorer)指出含有相对高浓度氯化钠的制剂。这些制剂包括0.35M-1.2M NaCl、1.5-40mM氯化钙、1mM-50mM组氨酸、和最多10%的“糖”如甘露醇、蔗糖或麦芽糖。作为实例的一种制剂中含有0.45M NaCl、2.3mM氯化钙、和1.4mM组氨酸。
Roser的国际专利申请书WO 96/22107(转让至Quadrant HoldingsCambridge Limited)描述了含有海藻糖的制剂。这些制剂包括:(1)0.1MNaCl、15mM氯化钙、15nM组氨酸、和1.27M(48%)海藻糖;或(2)0.011%氯化钙、0.12%组氨酸、0.002%Tris、0.002%吐温80、0.004%PEG 3350、7.5%海藻糖、和0.13%或1.03%NaCl。
已有技术中的其它治疗用因子VIII组合物一般包含为使因子VIII稳定的白蛋白和/或vWF,因而与本发明无关。例如,Schwinn的美国专利No.5328694(EP 511234)(转让至Octapharma AG)描述的制剂中包括100-650mM二糖和100mM-1.0M氨基酸。特别是,公开了下列制剂:(1)0.9M蔗糖、0.25M甘氨酸、0.25M赖氨酸、和3mM氯化钙;以及(2)0.7M蔗糖、0.5M甘氨酸、和5mM氯化钙。
尽管已经进行了几项配制不含白蛋白或vWF的因子VIII的尝试,但对在不含白蛋白或其它蛋白下稳定的治疗用因子VIII制剂的需求仍然存在。
本发明概述
本发明涉及在不含白蛋白条件下的稳定的治疗用因子VIII组合物。特别地,本发明包括因子VIII组合物,除因子VIII外,还包含:4%至10%的选自甘露醇、甘氨酸和丙氨酸的填充剂;1%至4%的选自蔗糖、海藻糖、棉子糖、精氨酸的稳定剂;1mM至5mM钙盐;100mM至300mM NaCl;以及使pH保持在约6和8之间的缓冲剂。该组合物还可含表面活性剂如聚山梨醇酯20、聚山梨醇酯80、普卢兰尼克(Pluronic)F68、或玻雷吉(Brij)35。当表面活性剂为聚山梨醇酯80时,其存在量应低于0.1%。
根据本发明的因子VIII组合物的缓冲剂优选以10mM至50mM的浓度存在,并优选选自组氨酸、Tris、BIS-Tris丙烷、PIPES、MOPS、HEPES和ACES。缓冲剂最好是组氨酸或Tris。本发明的因子VIII组合物还可以包含抗氧化剂。
本发明的因子VIII组合物同时包括填充剂和稳定剂。填充剂的存在量可以从约6%至约8%,优选约8%。稳定剂的存在量优选约2%,氯化钠也存在于这些组合物中,优选量是从150至350mM,并且更优选的量为约225mM。该组合物的钙盐也优选氯化钙,并且该组合物自身优选为冻干形式。
在另一种实施方案中,本发明可包括不含白蛋白的配制的因子VIII组合物,其除因子VIII外还包含下列赋形剂:2%至6%羟乙基淀粉;1%至4%的选自蔗糖、海藻糖、棉子糖、精氨酸的稳定剂;1mM至5mM钙盐;100mM至300mM NaCl;以及使pH保持在约6至8之间的缓冲剂。该组合物优选含有约4%羟乙基淀粉,且NaCl的存在量为200mM。还优选稳定剂的存在量为约2%。
在又一种实施方案中,本发明包括不含白蛋白的配制的因子VIII组合物,其包含:300mM至500mM NaCl;1%至4%的选自蔗糖、海藻糖、棉子糖、精氨酸的稳定剂;1mM至5mM钙盐;和保持pH约6至8之间的缓冲剂。NaCl优选以约400mM的量存在。
另一种实施方案中,本发明包括采用冷冻干燥机在容器中将含水因子VIII组合物冷冻干燥的方法,其中该方法包括初次冷冻步骤,且该初次冷冻步骤进一步包括下列步骤:(a)使冻干机冻干室温度降低至至少-45℃;(b)使冻干室的温度上升至约-15℃至-25℃;随后(c)使冻干室温度降低至至少-45℃。在该方法中,冻干室温度上升或下降的速率优选在每分钟约0.5℃至约1.0℃之间。在步骤(a)中,其温度优选保持约1小时,再降低到约-55℃。在步骤(b)中,温度优选在-15℃至-25℃之间,且更优选在-22℃保持约1至3小时,并且步骤(c)中的温度优选保持约1小时。在该方法中采用的因子VIII组合物优选含有4%至10%的选自甘露醇、甘氨酸和丙氨酸的试剂,还优选含有1%至4%的选自蔗糖、海藻糖、棉子糖和精氨酸的试剂。此外,在该方法中使用的因子VIII组合物还优选含有约100mM至300mMNaCl。
本发明详述
定义
除非另有说明外,用于本文时,下列术语及其变化形式应作如下定义:
因子VIII-天然存在的以及在治疗用制剂中作为非均质分布的多肽(来源于单一基因产品)的因子VIII分子(参见,例如,Andersson等,Proc.Natl.Acad.Sci.USA,83,2979-2983,1986年5月)。术语“因子VIII”用于本文时指所有这些多肽,不论是来源于血浆或是采用重组DNA技术制备。商业上可以获得的含因子VIII的治疗用制剂实例包括以商品名HEMOFIL M和RECOMBINATE销售的那些制剂(可以从美国伊利诺斯州Deerfield的Baxter Healthcare Corporation获得)。目前在开发中的其它制剂主要含单一亚型的因子VIII分子,其分子缺少B结构域蛋白。
国际单位,IU-国际单位,或IU,是一种以标准测定法测定因子VIII血液凝集活性的度量单位,例如下列方法之一:
一步测定法。一步测定法在本领域内是已知的,例如Lee,MartinL等,在An Effect of Predilution on Potency Assays of Factor VIIIConcentrates(预先稀释对因子浓度效力分析的影响),ThrombosisResearch(血栓形成研究)(Pergamon Press Ltd.)30,511-519(1983)中描述的方法。
显色测定法。显色测定试剂盒可以从商业上购得,例如CoatestFactor VIII,可以从瑞典Molndal的Chromogenix AB获得。
退火-术语退火用于表示进行药用制剂冷冻干燥的冻干过程中的一个步骤,在制剂的冷冻-干燥之前,其制剂温度由较低温度上升至较高温度然后在一段时间后再次冷却。
填充剂-在本申请的目的中,填充剂是这样的化学物,它使药用制剂冻干后形成“饼状物”或残余固态团块的结构并且防止它塌陷。可结晶的填充剂应当指所述填充剂可以在冻干过程中结晶,氯化钠除外。HES不包括在这组可结晶填充剂之内。
冷冻-干燥、冷冻、冻干-“冷冻-干燥”,除非通过其出现的上下文而另有说明外,应当用于表示冻干过程中的药用制剂的温度被升高以除去制剂中的水分的这一部分。冻干过程中的“冷冻”步骤是发生在冷冻干燥之前的那些步骤。除另有说明外,“冻干”应指冻干全过程,包括冷冻步骤和冷冻-干燥步骤。
除另有说明外,术语百分比表示重量/体积百分比并且温度是摄氏温度。
制剂组分
本发明的因子VIII组合物包括填充剂、稳定剂、缓冲剂、氯化钠、钙盐、以及,最好含有其它赋形剂。选择这些赋形剂目的是获得因子VIII在冻干制剂中的最大限度的稳定性。而且,本发明的VIII组合物在液体状态下也呈现出稳定性。
本发明制剂中所采用的填充剂,其形成冻干产品中的晶体部分(HES情况下除外),选自甘露醇、甘氨酸、丙氨酸、和羟乙基淀粉(HES)。甘露醇、甘氨酸或丙氨酸以4-10%,优选6-9%,且更优选约8%的量存在。当采用HES作为填充剂时,其存在量为2-6%,优选3-5%,且更优选约4%。
用于本发明制剂中的稳定剂选自蔗糖、海藻糖、棉子糖和精氨酸。这些物质在本发明制剂中的存在量在1-4%之间,优选2-3%,更优选约2%。山梨糖醇和甘油被认为是可能的稳定剂,但发现在本发明制剂中是较差的稳定剂。
本发明制剂中含氯化钠的量为100-300mM,优选150-250mM,且最优选约225mM。在本发明的一种实施方案中,氯化钠自身可以被使用而没有任何上述填充剂,在此情况下制剂的NaCl含量应当在300mM和500mM之间,优选350至450mM NaCl,且更优选约400mMNaCl。
此外,在这些制剂中存在缓冲剂,因为一般认为冻干过程中的pH改变可能对因子VIII的分子产生不利影响。在冻干过程中pH优选保持在6至8的范围之内,且更优选pH约为7。缓冲剂可以是任何生理学上可接受的能够充当缓冲剂的化学物或化学物的组合,包括组氨酸、Tris、BIS-Tris丙烷、PIPES、MOPS、HEPES、MES和ACES。所有这些缓冲剂的化学名列于下表1中。这些缓冲剂的标准含量浓度为10-50mM。当制剂中加入组氨酸,其单独或与其它缓冲剂例如Tris一起时,采用超过20mM的浓度并优选约25mM。特别优选组氨酸用于本发明组合物,这在下文中将更详细地叙述。
表1-缓冲剂
Tris | 三-(羟甲基)-氨基甲烷 |
BIS-Tris丙烷 | 1,3-双-[三-(羟基-甲基)-甲氨基]-丙烷 |
PIPES | 哌嗪-N,N’-双-(2-乙磺酸) |
MOPS | 3-(N-吗啉代)丙磺酸 |
HEPES | N-2-羟乙基-哌嗪-N’-2-乙磺酸 |
MES | 2-(N-吗啉代)乙磺酸 |
ACES | N-2-乙酰氨基-2-氨基乙磺酸 |
为保护因子VIII的活性,本发明制剂还含有可以与因子VIII相互作用并维持其活性的钙或另一种二价阳离子是十分重要的,推测这是通过维持因子VIII的重链和轻链的联系实现的。可以采用1mM至5mM的钙盐,更优选3-4mM,并最优选约4mM。钙盐优选氯化钙,但也可以是其它的钙盐如葡萄糖酸钙、葡萄糖二酸(glubinate)钙、葡庚酸(gluceptate)钙。
本发明因子VIII组合物还优选含有表面活性剂,优选量为0.1%或更低,且更优选的量约为0.03%。其表面活性剂可以,例如,选自聚山梨醇酯20、聚山梨醇酯80、普卢尼克多元醇类、和玻雷吉35(聚氧乙烯23十二烷基醚)。可以得到几个等级的普卢尼克多元醇(以商品名普卢尼克出售,BASF Wyandotte公司制造)。这些分子量(从1000到大于16000)以及理化性质不同的多元醇被用作表面活性剂。分子量为5000的普卢尼克F-38,和分子量为9000的普卢尼克F-68,都含有80%(重量比)的亲水性的聚氧乙烯基团和20%疏水性的聚氧丙烯基团。然而,本发明制剂中优选吐温-80,一种商品化的聚山梨醇酯,尤其是来源于植物的吐温-80。
本发明因子VIII组合物还优选含有抗氧化剂。已发现向本发明冻干制剂中加入抗氧化剂可以改善这些制剂的稳定性,并且延长其贮存期。所采用的抗氧化剂对于所采用的药用制剂必须是相容性的,此外还优选是水溶的。当制剂中加入抗氧化剂时,优选在冻干之前的过程中尽可能晚地加入这些抗氧化剂,以避免抗氧化剂的迅速氧化。下表2列举了合适的抗氧化剂,其可以在商业上从一些公司如Calbiochem及Sigma获得。
表2-抗氧化剂
N-乙酰基-L-半胱氨酸/高半胱氨酸 |
谷胱甘肽 |
6-羟基-2,5,7,8-四甲基色满-2-羧酸(Trolox) |
硫辛酸 |
甲硫氨酸 |
硫代硫酸钠 |
铂 |
甘氨酸-甘氨酸-组氨酸(三肽) |
丁化羟基甲苯(BHT) |
在上述抗氧化剂中,优选谷胱甘肽。已发现浓度在约0.05mg/ml至1.0mg/ml以上的范围都能够增加因子VIII组合物的稳定性,并且相信更高的浓度也应该是有用的(直至达到任何毒性作用或对制备有不良影响,例如降低冻干产品玻璃化转变温度)。
特别是发现组氨酸与谷胱甘肽组合对因子VIII组合物的稳定性产生有益的协同作用。组氨酸,当被用作缓冲剂时,也可以充当金属螯合剂。对于因金属诱导的氧化作用导致的因子VIII失活程度,组氨酸可以通过结合这些氧化的金属离子从而使因子VIII稳定。一般认为通过结合这些金属,谷胱甘肽(或存在的其它任何氧化剂)能够由此进一步发挥抗氧化保护作用,因为组氨酸已经限制了金属离子的氧化作用。
其它螯合剂也可以用于本发明组合物。如果钙盐被用于组合物时,这些螯合剂应当以大于对钙的亲和力优先结合金属如铜和铁。这些螯合剂的其中之一是去铁敏(deferoxamine),一种轻易除去Al++和铁的螯合剂。甲磺酸去铁敏,C25H48N6O8*CH4O3S,可以从Sigma(Sigma产品No.D9533)获得。它是铝和铁(II)螯合剂,其仅螯合+3价氧化态的铁(为1∶1螯合复合物),而非+2价氧化态,并且还可以结合镁离子和其它金属。去铁敏的使用量最好为0.25mg/l。
本发明的制剂中所用的因子VIII可以是高度纯化的来源于人血浆的因子VIII也可以是更加优选的重组产品因子VIII。重组因子VIII可以由携带因子VIII分子DNA序列密码的介导物转染的中国仓鼠卵巢(CHO)细胞生产。建立这种转染的CHO细胞的方法被特别描述于Toole,Jr.的美国专利No.4757006中,尽管其它方法也为本领域内所已知(见,例如,也属于Toole,Jr.的美国专利No.4868112,以及PCT国际专利申请WO-A-91/09122)。用于培养这些CHO细胞以产生因子VIII的方法也为本领域内所已知,例如Genetics Institute的欧洲专利申请No.0362218,标题为“改进的制备因子VIII的方法:C-型蛋白”。而且,重组因子VIII也可以在其它细胞系中产生,例如,幼年仓鼠肾(BHK)细胞。因子VIII分子自身,如果是重组产物,可以是全长因子VIII或者是其缺失衍生物,例如B结构域缺失的因子VIII分子。
尽管本申请中所述的因子VIII组合物可以冻干并以指定的浓度重配,但是本领域内的技术人员应当理解这些制剂也可以以更加稀释的形式重新配制。例如,被冻干且/或通常重配成2ml的溶液的本发明制剂也可以重配成更大体积的稀释液,例如5ml。这特别适用于当因子VIII制剂快速注射给患者时,因为此时因子VIII失活的可能性更小,因子VIII溶液越稀释其注射就可以越快。
制剂及冻干过程的改进
为获得最佳稳定性,本发明的因子VIII组合物优选被冻干。在冻干过程中,因子VIII由含水相转变成无定形相,这被认为能够保护蛋白质以避免化学和/或结构的不稳定性。该冻干制剂不仅含有无定形相,而且还含有在冻干过程中结晶的组分。这被认为能使因子VIII组合物快速冻干以及形成更加精致的饼状物(即,饼状物从冻干容器壁上的收缩尽可能小)。在本发明制剂中,稳定剂被选择存在于冻干产品的初始无定形分散相中,而填充剂(HES除外)被选择在冷冻过程中结晶。
因子VIII和稳定剂都优选分散于无定形相的冻干饼状物中。稳定剂质量也优选比无定形形式中的其它赋形剂大。此外,无定型相的表观玻璃化转变温度(Tg’)优选在冷冻-干燥过程中相对较高,而固体的玻璃化转变温度(Tg)同样优选在储存期间较高。已发现产品中氯化钠的结晶是合乎需要的,因为无定形氯化钠可降低无定形相的Tg’。
为避免特定组合物的饼状物的坍塌,初次干燥优选在产品温度低于冷冻浓缩物的表观玻璃化转变温度下进行。还可能需要增加干燥时间以补偿下降的Tg’。其它关于冻干的资料可以见于Carpenter,J.F.和Chang,B.S.著,蛋白质药物的冻干(Lyophilization of ProteinPharmaceuticals),K.E.Avis和V.L.Wu主编:生物技术与生物药生产,加工及保存(Biotechnology and Biopharmaceutical Manufacturing,Processing and Preservation),(Buffalo Grove,IL;Interpharm Press,Inc.),199-264页(1996)。
实施例1
在数项研究中调查了因子VIII的浓度以及添加稳定剂对因子VIII复性的影响。采用甘露醇作为标准填充剂及蔗糖作为标准稳定剂进行这些研究。下表3所示三种制剂样品在这些研究中被采用。这些研究中的所有制剂都含有10mM Tris,200mM NaCl,8%甘露醇,4mMCaCl2,及0.02%吐温-80并在pH7.0下进行。
样品代码 | 起始因子VIII (IU/ml) | 蔗糖% |
IA IB IC | 600 60 60 | - - 2 |
这些样品采用下表4所示的冻干周期进行冻干以维持产品温度低于表观玻璃化转变温度(Tg’)。差示扫描量热仪(DSC)研究表明甘露醇制剂约在-40℃出现转化。为维持产品温度低于此值,在初次干燥过程中将支架温度设定在-32℃。在这些条件下初次干燥进行约55小时,其整个周期时间约为80小时。
冷冻/工艺方法 | 说明 |
I (冷冻) | 冷却至+5℃; 以1℃/分钟速度冷却至-5℃,保持20分钟; 以1℃/分钟速度冷却至-20±5℃,保持1小时(最 多3小时); 以0.5℃/分钟速度冷却至-45℃,保持1小时; |
II | 一次方法I的冷冻(Freeze per method I) 于-35℃下保持48小时; |
III | 一次方法I的冷冻 于-35℃下保持48小时; 于-20℃下保持48小时; |
IV (冷冻-干燥) | 在首次冷冻约55小时(最多100小时)期间支架温 度-32℃; 在初次干燥期间产品温度<-40℃; 以0.2℃/分钟速度由-32℃上升至+40℃; 在二次干燥3小时期间支架温度为+40℃ |
这些样品的因子VIII的活性,如由一步凝血检测法测定的,与保持-45℃的对照组比较。检测结果见下表5所示。
这些结果表明蛋白质浓度对冷冻期间的因子VIII的恢复有影响。含60IU/ml的制剂在冷冻步骤中失去起始因子VIII活性的37-42%,而含600IU/ml的制剂则失去6.7%的因子VIII活性。这些结果表明较高的蛋白质浓度在冷冻期间具有保护性作用。尽管蔗糖在保持中间温度期间以及冷冻-干燥期间对因子VIII提供了一定的保护作用,但在初次冷却步骤中不能保护蛋白质。
实施例2
随着实施例1所述冻干过程的改进,进一步进行了该步骤的优化。已发现可以如下制备具有较高玻璃化转变温度的冻干组合物(而且,在理论上,因子VIII的稳定性更好):(1)首先降低冷冻温度至-45℃或更低(例如降低到约-50℃或-55℃);(2)升温至-20℃或-22℃(±5℃);然后(3)再次降低温度至-45℃或更低。在条件可能时,温度以约每分钟0.5℃至约1.0℃之间的速率升高或降低。当达到所需温度时,组合物在此温度下保持1至3小时。这种改进的冷冻周期见下表6所示。
表6
冷冻方法 | 说明 |
I | 冷却至+5℃; 以0.5-1℃/分钟的速率冷却至-5℃,保持20分钟; 以0.5-1℃/分钟的速率冷却至-55℃和-45℃之间,保持 约1小时; 以0.5-1℃/分钟的速率升温至-22℃(±5℃),保持1至3 小时; 以0.5-1℃/分钟的速率冷却至-45℃,保持约1小时。 |
除另有说明外,在该实施例中以及其它实施例中涉及的温度是指冻干机冻干架温度而实际上不是指产品本身温度。根据改进的冷冻周期,其余冻干步骤可以按照上述实施例1所述、或另外按照本文进一步描述或按照本领域内技术人员决定进行。
已发现这种改进的冻干方法对那些含甘氨酸作为填充剂以及那些采用甘露醇的制剂是有用的。它还被认为也适用于那些利用本发明其它填充剂的制剂。
实施例3
一般认为为了生产出具有可接受的饼状物外形以及玻璃化转变温度的冻干产品,含有氯化钠的冻干药用制剂的填充剂,如甘氨酸或甘露醇,可能需要被结晶。因此发展了下列适合可结晶填充剂的改进的冻干方法。
表7a--冷冻步骤
加工步骤 | 温度 | 步骤时程 |
初次冷冻 | -40℃或更低 | 1小时 |
首次退火 | -23℃至-27℃之间 | 3小时 |
再次冷冻 | -55℃ | 1小时 |
再次退火 | -36℃ | 4小时 |
第三次冷冻 | -50℃ | 1小时 |
表7b--冷冻步骤
加工步骤 | 温度 | 步骤时程 |
首次干燥 | -35℃ | 最多100小时 |
二次干燥:第一步 | 40℃ | 3小时 |
二次干燥:第二步 | 45℃ | 3小时 |
二次干燥:第三步 | 50℃ | 3小时 |
在冷冻步骤中,温度的改变以约0.5℃/分钟至1℃/分钟的速率进行。一般认为步骤的时程较长也有效。
首次冷冻步骤之前,使温度在约2℃至8℃之间保持约1小时,目的是使所有管形瓶达到大约相同的温度。此后使冻干机冷冻至-5℃。首次冷冻步骤应在低于-30℃的温度下进行,优选低于-35℃,并且更优选在约-40℃。在此之后,首次退火步骤应在-30℃和-19℃之间进行,更优选在约-25℃和-28℃之间(如果甘氨酸是填充剂)或在-21℃和-24℃之间(如果甘露醇是填充剂),最优选的温度是在-23℃和-26℃之间,一般认为可结晶填充剂在此温度下结晶,至少部分结晶。无论如何,对于含有甘露醇和精氨酸的制剂不推荐低于约-27℃的范围。该步骤优选进行约3小时。
首次退火步骤之后,温度被降低,优选至低于-50℃并且更优选低于-55℃,持续约1小时。一般认为制剂中的氯化钠在这时形成核晶。
二次退火步骤中,药用制剂的温度上升至约-30℃和-39℃之间,并且对于含甘露醇的组合物优选至约-33℃而对于含甘氨酸的组合物优选-36℃。相信在这时出现NaCl晶体的生长,至少是部分晶体生长。这个步骤优选进行约4小时。在此之后,冻干机温度降低至约-50℃,优选持续约1小时,以便降低制剂的温度。
在随后的冷冻-干燥步骤中,温度的改变以约0.1℃/min至0.5℃/min的速度发生。当冻干机压力降低至约65mTorr后,温度上升至约-32℃和-35℃之间进行初次干燥。制剂中冰晶在此温度下升华。这个步骤进行最多约100小时,或直到绝大部分的冰已经从制剂中升华。绝大部分的冰已经升华的时间点可以,例如,采用露点传感器检测,当其读数降低时(回折点)表明冰升华的终止。
初次干燥后,温度上升至+40℃,优选速率约为0.2℃/min,开始二次干燥以进一步从制剂中除去水分。此温度优选保持约3小时。在第一步之后进行第二步和第三步的二次干燥步骤,其温度上升到约+45℃保持约3小时再到约+50℃保持3小时以上,以使冻干饼的水分减少到2%以下(w/w)。
实施例4
为特别考察组氨酸对于含甘氨酸或甘露醇作为填充剂的冻干因子VIII组合物的影响而进行另一项研究。采用非转向热流(Non-reversing heat flow)(改进的DSC,mDSC)检测这些填充剂在冷冻期间的结晶过程。测定结晶温度以及从结晶放热反应测定总结晶热。升温过程中NaCl低共熔体熔化的吸热表现被用于确定NaCl结晶过程。在mDSC中,结晶程度采用全热流信号由制剂熔化的焓对纯NaCl溶液熔化的焓的比率确定。此外,进行X-光衍射分析以测定冻干制剂中的结晶程度。
当组氨酸浓度低于20mM时对甘氨酸的结晶没有显著影响,50mM组氨酸降低甘氨酸的结晶程度。精制的NaCl结晶放热在含甘氨酸制剂的冷却过程中没有被发现。然而,加热过程中低共熔体熔化吸热表明在冷却至-50℃以下以及在-30℃、-35℃和-40℃下退火之后NaCl被结晶(>50%)。在含甘氨酸的制剂中,含50mM组氨酸可阻碍NaCl结晶。其后,为达到相应的结晶度,这些制剂的退火时间增加了3倍。
然而,20mM组氨酸对含甘氨酸制剂中的NaCl的结晶影响极小。在冷冻-干燥研究中,视觉观察到含有50mM组氨酸的含甘氨酸制剂中冻干饼的坍塌。X-光粉末衍射数据表明含组氨酸样品中NaCl结晶度减低。含甘露醇制剂中,一般有83%-90%的在-40℃和-45℃间的冷却期间结晶且无须退火。而含20mM组氨酸的制剂在冷冻过程中受到抑制的NaCl结晶,退火可以产生约40%的NaCl结晶。
因此,在含可结晶填充剂,如甘氨酸或甘露醇,以及NaCl的制剂中,含有组氨酸可能降低NaCl的结晶程度。尽管这在某些情况下导致冻干过程中形成的饼状物的坍塌,但在这些制剂中使用相对较低浓度的组氨酸可以减少这种影响。不过,含35mM和50mM浓度的组氨酸能够形成可接受的饼状物。在基于甘露醇和甘氨酸的制剂中,组氨酸作为缓冲剂还可能优于HEPES,因为已经观察到采用HEPES比类似量的组氨酸使Tg’降低程度更大。
实施例5
在另一项研究中评价了一些活性因子VIII制剂的物理性质,其含有七种侯选的稳定剂和五种填充剂。除填充剂和稳定剂外,下表8中列举的所有制剂(制剂11除外)含有10mM Tris·HCl、200mM NaCl、0.02%吐温-80、4mM CaCl2且pH为7.0。制剂11含有10mM Tris·HCl、0.02%吐温-80,及4mM CaCl2,并且pH也是在7.0。pH测定全部在环境温度下进行。
表8
通过冷冻-干燥显微镜检测定的坍塌温度以及DSC测定的热转变(transition)被用于预测冷冻-干燥的行为。DSC、X-光粉末衍射以及偏振光显微术也被用于测定冻干样品的结晶度。还评价了重新配制时间以及样品外观。所有这些测定的结果概括在下表9中。
表9
样品 代码 | Tpe (℃) | Te (℃) | Tg (℃) | 重配时间 (秒) | 含水量 (%) | 外观 |
1 2 3 4 5 6 7 8 9 10 11 12 | -14 -20 -15 - - n/c - - - - - - | -10 -15 -10 - - n/c - - - - - - | 54 53 54 - - <10℃* <10℃* 86 54 63 66 - | 64 62 77 - - 63 - 49 22 18 11 57 | n/c 1.4 1.7 - - 0.6 - 0.7 0.8 - 0.4 0.5 | 精致 顶部部分坍塌 精致 部分坍塌 坍塌 精致 精致 精致但从侧面收缩 精致 精致 精致(铺于底层) 精致 |
*山梨糖醇和甘氨酸的玻璃化转变温度<10℃。DSC扫描范围不包括此范围内的温度。
n/c=不清楚
Tpc=冷冻-干燥显微镜检中发生部分坍塌的温度
Tc=冷冻-干燥显微镜检中发生完全坍塌的温度
Tg=玻璃化转变温度
除甘露醇:赖氨酸外,所有制剂均呈现出适当的物理学外观。赖氨酸干扰甘露醇及甘氨酸的结晶,这导致玻璃化转变温度降低和冻干饼的坍塌。
实施例6
上述表8中描述的因子VIII组合物被放置在-70℃、25℃、40℃和50℃下贮存不同时间长度以评价它们的稳定性。因子VIII的活性水平在2周、1月、2月、和3月后评价,而此结果被概括在下表10中。其中两种样品,一种采用甘露醇作为填充剂和山梨糖醇作为稳定剂,而另一种采用甘露醇作为填充剂和甘油作为稳定剂,呈现出较差的稳定性。其余制剂都呈现出稳定因子VIII的能力。
表10
25 | 100.00 | 83.13 | ||||
40 | 100.00 | 81.09 | 73.61 | 67.16 | ||
50 | 100.00 | 71.69 | 68.52 | 54.25 | 47.11 | |
甘露醇:甘油 | -70 | |||||
25 | ||||||
40 | ||||||
50 | ||||||
甘露醇:山梨糖醇 | -70 | 100.00 | 104.06 | |||
25 | 100.00 | |||||
40 | 100.00 | |||||
50 | 100.00 | 32.73 | ||||
HES:蔗糖 | -70 | 100.00 | 102.74 | 103.03 | 100.90 | |
25 | 100.00 | |||||
40 | 100.00 | 76.89 | 77.47 | |||
50 | 100.00 | 71.47 | 67.40 | 30.02 | ||
NaCl:蔗糖 | -70 | 100.00 | 88.54 | 88.44 | 95.58 | |
25 | 100.00 | |||||
40 | 100.00 | 71.56 | 58.30 | |||
50 | 100.00 | 52.71 | 37.90 | 30.34 | ||
丙氨酸:蔗糖 | -70 | 100.00 | 109.78 | 109.67 | 108.96 | |
25 | 100.00 | |||||
40 | 100.00 | 92.99 | 73.03 | |||
50 | 100.00 | 83.25 | 74.91 | 57.65 | ||
甘氨酸:棉子糖 | -70 | 100.00 | 111.57 | 114.51 | 105.25 | |
25 | 100.00 | |||||
40 | 100.00 | 89.20 | 82.10 | |||
50 | 100.00 | 93.21 | 72.22 | 53.24 |
实施例7
基于在实施例5和实施例6所述研究过程中获得的资料判定,包含下表11所示赋形剂的侯选制剂应当有进一步的改善。
表11
赋形剂 | 浓度 |
甘露醇或甘氨酸 | 6-9% |
精氨酸或海藻糖 | 1-3% |
吐温-80 | 0.005-0.04% |
NaCl | 200-250mM |
CaCl2 | 3-5mM |
TRIS | 20-30mM |
组氨酸或HEPES | 10-50mM |
谷胱甘肽 | 0.15-0.25mg/ml |
以这些参数为基础,开发下列特定制剂:
表12
制剂#1 | 制剂#2 | 制剂#3 |
10mM HEPES 20mM Tris 225mM NaCl 0.03%(v/v)吐温-80 8%(w/v)甘露醇 2%(w/v)海藻糖 0.2mg/ml还原性 谷胱甘肽 4mM CaCl2 | 10mM HEPES 20mM Tris 225mM NaCl 0.03%(v/v)吐温-80 8%(w/v)甘氨酸 2%(w/v)海藻糖 0.2mg/ml还原性 谷胱甘肽 4mM CaCl2 | 10mM HEPES 20mM Tris 225mM NaCl 0.03%(v/v)吐温-80 8%(w/v)甘露醇 2%(w/v)精氨酸 0.2mg/ml还原性 谷胱甘肽 4mM CaCl2 |
制剂#4 | 制剂#5 |
25mM组氨酸 20mM Tris 225mM NaCl 0.03%(v/v)吐温-80 8%(w/v)甘露醇 2%(w/v)海藻糖 0.2mg/ml还原性谷胱甘肽 4mM CaCl2 | 25mM组氨酸 20mM Tris 225mM NaCl 0.03%(v/v)吐温-80 8%(w/v)甘氨酸 2%(w/v)海藻糖 0.2mg/ml还原性谷胱甘肽 4mM CaCl2 |
Claims (4)
1.一种因子VIII组合物,所述组合物在配制时不加入白蛋白,除因子VIII外,还包括下列制剂赋形剂:
300mM至500mM NaCl;
1%至4%重量/体积的稳定剂,其选自蔗糖、海藻糖、棉子糖和精氨酸;
1mM至5mM的钙盐;和
维持pH在6和8之间的缓冲剂。
2.根据权利要求1的因子VIII组合物,其中NaCl的存在量为400mM。
3.根据权利要求1或2的因子VIII组合物在制备治疗血友病的药物中的用途。
4.一种改进的冻干根据权利要求1或2的因子VIII组合物的方法,其中所述因子VIII组合物为含可结晶填充剂和NaCl的含水药用制剂,其中所述方法包括下列步骤:
(a)在低于-35℃的温度下冷冻含水药用制剂;
(b)使药用制剂在-30℃至-19℃之间退火;
(c)使药用制剂的温度降低到-50℃以下;
(d)使药用制剂在-30℃至-39℃之间退火;然后
(e)冷冻-干燥该药用制剂。
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US25527999A | 1999-02-22 | 1999-02-22 | |
US09/255,279 | 1999-02-22 | ||
US45275299A | 1999-12-01 | 1999-12-01 | |
US09/452,752 | 1999-12-01 |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CNB008063044A Division CN100553678C (zh) | 1999-02-22 | 2000-02-22 | 新的无白蛋白的因子ⅷ制剂 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN101810854A true CN101810854A (zh) | 2010-08-25 |
Family
ID=26944588
Family Applications (3)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN200910171121A Pending CN101810854A (zh) | 1999-02-22 | 2000-02-22 | 新的无白蛋白的因子viii制剂 |
CNB008063044A Expired - Lifetime CN100553678C (zh) | 1999-02-22 | 2000-02-22 | 新的无白蛋白的因子ⅷ制剂 |
CN2009101711245A Expired - Lifetime CN101683522B (zh) | 1999-02-22 | 2000-02-22 | 新的无白蛋白的因子ⅷ制剂 |
Family Applications After (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CNB008063044A Expired - Lifetime CN100553678C (zh) | 1999-02-22 | 2000-02-22 | 新的无白蛋白的因子ⅷ制剂 |
CN2009101711245A Expired - Lifetime CN101683522B (zh) | 1999-02-22 | 2000-02-22 | 新的无白蛋白的因子ⅷ制剂 |
Country Status (19)
Country | Link |
---|---|
US (8) | US6586573B1 (zh) |
EP (5) | EP1154796B1 (zh) |
JP (9) | JP5149470B2 (zh) |
CN (3) | CN101810854A (zh) |
AT (1) | ATE365052T1 (zh) |
AU (1) | AU777972B2 (zh) |
BR (1) | BR0008405B1 (zh) |
CA (4) | CA2362927C (zh) |
CY (2) | CY1108030T1 (zh) |
CZ (3) | CZ307715B6 (zh) |
DE (1) | DE60035260T2 (zh) |
DK (4) | DK1154796T3 (zh) |
ES (4) | ES2394755T3 (zh) |
HK (4) | HK1139862A1 (zh) |
MX (1) | MXPA01008515A (zh) |
PL (4) | PL204701B1 (zh) |
PT (4) | PT1820516E (zh) |
RU (1) | RU2244556C2 (zh) |
WO (1) | WO2000048635A1 (zh) |
Families Citing this family (126)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB9501040D0 (en) * | 1995-01-19 | 1995-03-08 | Quadrant Holdings Cambridge | Dried composition |
US7244824B2 (en) * | 1995-01-19 | 2007-07-17 | Quadrant Drug Delivery Limited | Dried blood factor composition comprising trehalose |
US7253262B2 (en) * | 1995-01-19 | 2007-08-07 | Quandrant Drug Delivery Limited | Dried blood factor composition comprising trehalose |
US6214054B1 (en) | 1998-09-21 | 2001-04-10 | Edwards Lifesciences Corporation | Method for fixation of biological tissues having mitigated propensity for post-implantation calcification and thrombosis and bioprosthetic devices prepared thereby |
CN101810854A (zh) * | 1999-02-22 | 2010-08-25 | 巴克斯特国际公司 | 新的无白蛋白的因子viii制剂 |
US6830917B2 (en) * | 2001-12-10 | 2004-12-14 | Baxter Healthcare S.A. | Method of isolation and purification of trypsin from pronase protease and use thereof |
AU2002351756A1 (en) | 2001-12-21 | 2003-07-15 | Novo Nordisk Health Care Ag | Liquid composition of factor vii polypeptides |
KR20040065278A (ko) * | 2001-12-21 | 2004-07-21 | 노보 노르디스크 에이/에스 | 변경된 인자 ⅶ 폴리펩티드의 액체 조성물 |
US6878168B2 (en) | 2002-01-03 | 2005-04-12 | Edwards Lifesciences Corporation | Treatment of bioprosthetic tissues to mitigate post implantation calcification |
US6982080B2 (en) * | 2002-03-15 | 2006-01-03 | Wyeth | Hydroxyethyl starch—containing polypeptide compositions |
GB0207092D0 (en) * | 2002-03-26 | 2002-05-08 | Sod Conseils Rech Applic | Stable pharmaceutical composition containing factor VIII |
US20040009918A1 (en) * | 2002-05-03 | 2004-01-15 | Hanne Nedergaard | Stabilised solid compositions of modified factor VII |
CA2490342C (en) | 2002-06-21 | 2015-06-16 | Novo Nordisk A/S | Stabilised solid compositions of factor vii polypeptides |
GB0304636D0 (en) * | 2003-02-28 | 2003-04-02 | Britannia Pharmaceuticals Ltd | Pharmaceutical composition for nasal delivery |
MXPA05009914A (es) * | 2003-03-18 | 2006-01-09 | Novo Nordisk Healthcare Ag | Composiciones farmaceuticas acuosas, liquidas de polipeptidos del factor vii. |
US7897734B2 (en) * | 2003-03-26 | 2011-03-01 | Novo Nordisk Healthcare Ag | Method for the production of proteins |
CA2525224A1 (en) * | 2003-05-23 | 2004-12-02 | Michael Bech Jensen | Protein stabilization in solution |
EP1641487B1 (en) * | 2003-06-25 | 2012-02-29 | Novo Nordisk Health Care AG | Liquid composition of factor vii polypeptides |
DE602004023848D1 (de) * | 2003-07-01 | 2009-12-10 | Novo Nordisk Healthcare Ag | Von factor vii polypeptiden |
DE10333317A1 (de) * | 2003-07-22 | 2005-02-17 | Biotecon Therapeutics Gmbh | Formulierung für Proteinarzneimittel ohne Zusatz von humanem Serumalbumin (HSA) |
EP2107069B1 (en) * | 2003-08-05 | 2013-01-16 | Novo Nordisk A/S | Novel insulin derivatives |
KR100560697B1 (ko) * | 2003-08-06 | 2006-03-16 | 씨제이 주식회사 | 알부민을 함유하지 않는 에리스로포이에틴 제제 |
BRPI0413518A (pt) | 2003-08-14 | 2006-10-10 | Novo Nordisk Healthcare Ag | composição farmacêutica lìquida aquosa, método para preparar e uso da mesma, método para tratar uma sìndrome responsiva ao fator vii, e, recipiente hermético |
WO2005028496A2 (en) * | 2003-09-12 | 2005-03-31 | Antigenics, Inc. | Vaccine for treatment and prevention of herpes simplex virus infection |
DK2298287T3 (en) * | 2003-12-19 | 2018-07-23 | Novo Nordisk Healthcare Ag | Stabilized compositions of factor VII polypeptides |
GB0404586D0 (en) * | 2004-03-01 | 2004-04-07 | Britannia Pharmaceuticals Ltd | Improvements in or relating to organic materials |
WO2005089712A1 (en) * | 2004-03-04 | 2005-09-29 | Wyeth | Lyophilization method to improve excipient crystallization |
CA2557061C (en) * | 2004-03-19 | 2013-08-20 | Baxter International Inc. | Factor ixa for the treatment of bleeding disorders |
US7319032B2 (en) * | 2004-04-22 | 2008-01-15 | Medtox | Non-sugar sweeteners for use in test devices |
KR100624013B1 (ko) * | 2004-06-25 | 2006-09-19 | 주식회사 녹십자홀딩스 | 동결건조된 알부민 비함유 재조합 사람 혈액응고 제 8인자 제제 |
DK1835938T3 (da) | 2004-12-27 | 2013-11-04 | Baxter Int | Polymer-von Willebrand-faktor-konjugater |
FR2881139A1 (fr) * | 2005-01-26 | 2006-07-28 | Agronomique Inst Nat Rech | Composition pour la lyophilisation de proteines |
US7956160B2 (en) * | 2005-07-22 | 2011-06-07 | Amgen Inc. | Concentrated protein lyophilates, methods, and uses |
NO347263B1 (no) | 2005-11-01 | 2023-08-14 | Wyeth Llc | Fremgangsmåte for fremstilling av en Faktor IX formulering for intravenøs injeksjon |
WO2007055388A2 (en) | 2005-11-09 | 2007-05-18 | Ajinomoto Co., Inc. | Calcium receptor activator |
EP2175273B1 (en) * | 2005-11-09 | 2013-09-04 | Ajinomoto Co., Inc. | Kokumi-imparting agent |
US8420144B2 (en) * | 2005-11-09 | 2013-04-16 | Ajinomoto Co., Inc. | Kokumi-imparting agent, method of using, and compositions containing same |
AU2006318583A1 (en) * | 2005-11-22 | 2007-05-31 | Wyeth | Immunoglobulin fusion protein formulations |
PT1969004E (pt) | 2005-12-28 | 2011-11-25 | Novo Nordisk As | Composições que compreendem uma insulina acilada e zinco e método para criar tais composições |
US7645860B2 (en) | 2006-03-31 | 2010-01-12 | Baxter Healthcare S.A. | Factor VIII polymer conjugates |
US7985839B2 (en) | 2006-03-31 | 2011-07-26 | Baxter International Inc. | Factor VIII polymer conjugates |
US7982010B2 (en) | 2006-03-31 | 2011-07-19 | Baxter International Inc. | Factor VIII polymer conjugates |
WO2007126808A1 (en) * | 2006-03-31 | 2007-11-08 | Baxter International Inc | Pegylated factor viii |
ES2386972T3 (es) * | 2006-05-31 | 2012-09-10 | Genzyme Corporation | Uso de polisacáridos para la estimulación de la actividad enzimática |
CN101626682B (zh) | 2006-10-27 | 2014-04-16 | 爱德华兹生命科学公司 | 用于外科植入的生物组织 |
AR063606A1 (es) * | 2006-11-07 | 2009-02-04 | Acambis Inc | Estabilizacion de vacunas mediante liofilizacion |
BRPI0720282B8 (pt) | 2006-12-15 | 2021-05-25 | Baxalta GmbH | construção proteica, composição farmacêutica, e, kit |
FR2913020B1 (fr) | 2007-02-23 | 2012-11-23 | Biomethodes | Nouveaux facteurs viii pour le traitement des hemophiles de type a |
JP5179521B2 (ja) * | 2007-03-05 | 2013-04-10 | カディラ・ヘルスケア・リミテッド | ペグ‐インターフェロンアルファ接合体および凍結保護剤としてラフィノースを含む組成物 |
AU2013204652B2 (en) * | 2007-04-26 | 2015-06-18 | Bayer Healthcare Llc | Stabilization of liquid solutions of recombinant protein for frozen storage |
JP5401446B2 (ja) * | 2007-04-26 | 2014-01-29 | バイエル ヘルスケア エルエルシー | 凍結貯蔵を目的とした、組み換えタンパク質溶液の安定化 |
AU2008249287C1 (en) * | 2007-05-08 | 2015-06-04 | Ajinomoto Co., Inc. | Low-fat food |
US9101691B2 (en) | 2007-06-11 | 2015-08-11 | Edwards Lifesciences Corporation | Methods for pre-stressing and capping bioprosthetic tissue |
JP5552046B2 (ja) * | 2007-06-13 | 2014-07-16 | ノボ・ノルデイスク・エー/エス | インスリン誘導体を含有する薬学的製剤 |
GB0715285D0 (en) * | 2007-08-06 | 2007-09-12 | Britannia Pharmaceuticals Ltd | Improvements in or relating to powdered medicaments for nasal delivery |
CN101376022B (zh) * | 2007-08-31 | 2011-11-30 | 上海医药工业研究院 | 含聚乙二醇降纤酶的药物组合物 |
EP2222315B1 (en) * | 2007-12-21 | 2013-04-24 | Inspiration Biopharmaceuticals, Inc. | Stabilized factor ix formulations containing trehalose |
US8357387B2 (en) | 2007-12-21 | 2013-01-22 | Edwards Lifesciences Corporation | Capping bioprosthetic tissue to reduce calcification |
SG10201503304RA (en) * | 2007-12-27 | 2015-06-29 | Baxter Int | Cell culture processes |
EP2113564A1 (en) * | 2008-05-01 | 2009-11-04 | Arecor Limited | Protein formulation |
ES2968301T3 (es) * | 2008-08-05 | 2024-05-08 | Wyeth Llc | Liofilización por encima del colapso |
JP2012500250A (ja) | 2008-08-21 | 2012-01-05 | オクタファルマ アクチェン ゲゼルシャフト | 組換えにより産生したヒト第viii及び第ix因子 |
CA2734919C (en) * | 2008-08-27 | 2016-08-16 | Schering Corporation | Lyophilized formulations of engineered anti-il-23p19 antibodies |
JP5960990B2 (ja) * | 2008-09-03 | 2016-08-02 | オクタファルマ アクチェン ゲゼルシャフト | 組み換え技術によって製造された第viii因子のための新規な保護組成物 |
US20100068210A1 (en) * | 2008-09-10 | 2010-03-18 | Ji Junyan A | Compositions and methods for the prevention of oxidative degradation of proteins |
EP2352513B1 (en) * | 2008-10-30 | 2016-09-14 | Novo Nordisk A/S | Treating diabetes melitus using insulin injections with less than daily injection frequency |
JP5779780B2 (ja) | 2008-11-07 | 2015-09-16 | バクスター・インターナショナル・インコーポレイテッドBaxter International Incorp0Rated | 第viii因子製剤 |
EP2248518B1 (en) * | 2009-04-17 | 2013-01-16 | Merz Pharma GmbH & Co. KGaA | Formulation for stabilizing proteins, peptides or mixtures thereof. |
US8809501B2 (en) | 2009-07-27 | 2014-08-19 | Baxter International Inc. | Nucleophilic catalysts for oxime linkage |
PL2459224T3 (pl) | 2009-07-27 | 2017-08-31 | Baxalta GmbH | Koniugaty białka związanego z krzepnięciem krwi |
US8642737B2 (en) | 2010-07-26 | 2014-02-04 | Baxter International Inc. | Nucleophilic catalysts for oxime linkage |
CA2769326A1 (en) | 2009-07-27 | 2011-02-10 | Baxter International Inc. | Blood coagulation protein conjugates |
RU2533619C2 (ru) | 2009-07-27 | 2014-11-20 | Лайпоксен Текнолоджиз Лимитед | Гликополисиалирование белков, не являющихся белками свертывания крови |
GB0915480D0 (en) * | 2009-09-04 | 2009-10-07 | Arecor Ltd | Stable formulation of factor viii |
ES2948612T3 (es) | 2009-09-21 | 2023-09-14 | Takeda Pharmaceuticals Co | Formulaciones de ADAMTS13 líquidas y liofilizadas estabilizadas |
EP2496246B1 (en) | 2009-11-03 | 2018-06-27 | Grifols Therapeutics LLC | Composition, method, and kit for alpha-1 proteinase inhibitor |
WO2011066291A2 (en) * | 2009-11-24 | 2011-06-03 | Talecris Biotherapeutics, Inc. | Lyophilization methods, compositions, and kits |
EP2525779B1 (en) * | 2010-01-19 | 2018-09-05 | Hanmi Science Co., Ltd. | Liquid formulations for long-acting erythropoietin conjugate |
NZ602066A (en) | 2010-03-23 | 2013-09-27 | Edwards Lifesciences Corp | Methods of conditioning sheet bioprosthetic tissue |
US8906601B2 (en) | 2010-06-17 | 2014-12-09 | Edwardss Lifesciences Corporation | Methods for stabilizing a bioprosthetic tissue by chemical modification of antigenic carbohydrates |
PL2616090T3 (pl) * | 2010-09-17 | 2023-12-18 | Takeda Pharmaceutical Company Limited | Stabilizowanie immunoglobulin poprzez wodną formulację z histydyną o ph od słabo kwaśnego do obojętnego |
AU2011316111B2 (en) | 2010-10-12 | 2015-05-28 | Merz Pharma Gmbh & Co. Kgaa | Formulation suitable for stabilizing proteins, which is free of mammalian excipients |
RU2013123515A (ru) | 2010-10-27 | 2014-12-10 | Ново Нордиск А/С | Лечение сахарного диабета с помощью инъекций инсулина, вводимых с различными интервалами |
AU2011323236B2 (en) | 2010-11-05 | 2017-03-30 | Takeda Pharmaceutical Company Limited | A new variant of antihemophilic factor VIII having increased specific activity |
US9351829B2 (en) | 2010-11-17 | 2016-05-31 | Edwards Lifesciences Corporation | Double cross-linkage process to enhance post-implantation bioprosthetic tissue durability |
KR20130125789A (ko) * | 2010-12-16 | 2013-11-19 | 노보 노르디스크 에이/에스 | 수성 인자ⅷ 용액 |
CA2822591C (en) | 2010-12-22 | 2020-12-29 | Baxter International Inc. | Materials and methods for conjugating a water soluble fatty acid derivative to a protein |
BRPI1105317A2 (pt) | 2011-01-24 | 2013-04-30 | Fundacco Hemoct De Ribeirco Preto | produÇço estÁvel e em larga escala de fviii humano em linhagem celular humana sk-hep-1 |
JP6014116B2 (ja) | 2011-03-31 | 2016-10-25 | メルク・シャープ・アンド・ドーム・コーポレーションMerck Sharp & Dohme Corp. | ヒト・プログラム死受容体pd−1に対する抗体の安定製剤および関連治療 |
US8916352B2 (en) | 2011-04-08 | 2014-12-23 | Bio-Rad Laboratories, Inc. | PCR reaction mixtures with decreased non-specific activity |
SG194032A1 (en) | 2011-04-08 | 2013-11-29 | Bio Rad Laboratories | Sso7-polymerase conjugates with decreased non-specific activity |
WO2014031718A1 (en) | 2012-08-23 | 2014-02-27 | Merck Sharp & Dohme Corp. | Stable formulations of antibodies to tslp |
US10238771B2 (en) | 2012-11-08 | 2019-03-26 | Edwards Lifesciences Corporation | Methods for treating bioprosthetic tissue using a nucleophile/electrophile in a catalytic system |
EP2970430A4 (en) * | 2013-03-15 | 2017-01-11 | Bayer HealthCare LLC | Recombinant factor viii formulations |
PL3666283T3 (pl) * | 2013-03-15 | 2022-10-03 | Bioverativ Therapeutics Inc. | Formulacje polipeptydu czynnika viii |
US9839579B2 (en) | 2013-04-24 | 2017-12-12 | Corning Incorporated | Delamination resistant pharmaceutical glass containers containing active pharmaceutical ingredients |
US9700486B2 (en) | 2013-04-24 | 2017-07-11 | Corning Incorporated | Delamination resistant pharmaceutical glass containers containing active pharmaceutical ingredients |
US10137172B2 (en) | 2013-04-30 | 2018-11-27 | Novo Nordisk A/S | Administration regime |
KR102058864B1 (ko) * | 2013-12-16 | 2019-12-24 | 주식회사 티움바이오 | 인자 vii의 융합 단백질을 포함하는 안정성이 개선된 약학적 조성물 |
JP2017509659A (ja) * | 2014-04-01 | 2017-04-06 | アドヴァンテック・バイオサイエンス・ファルマスーティカ・リミターダ | 低糖−低グリシンの安定な第viii因子製剤 |
MX2016012869A (es) * | 2014-04-01 | 2017-05-12 | Advantech Bioscience Farmacêutica Ltda | Estabilizacion del factor viii sin calcio como un excipiente. |
BR112017002090B1 (pt) * | 2014-08-04 | 2021-06-01 | Csl Limited | Composição aquosa de fator viii de coagulação e método de estabilizar uma molécula de fviii |
EP3750556A1 (en) * | 2014-08-20 | 2020-12-16 | Portola Pharmaceuticals, Inc. | Lyophilized formulations for factor xa antidote |
SG11201702757YA (en) * | 2014-10-23 | 2017-05-30 | Ngm Biopharmaceuticals Inc | Pharmaceutical compositions comprising peptide variants and methods of use thereof |
CN107660149B (zh) | 2015-04-21 | 2021-04-27 | 舒泰神(北京)生物制药股份有限公司 | 一种神经生长因子组合物及注射粉剂 |
DK3287139T3 (da) | 2015-04-21 | 2021-09-13 | Beijing Staidson Medical Tech Co Ltd | Nervevækstfaktorsammensætning og injektionspulver |
EP3319930A4 (en) * | 2015-07-07 | 2019-04-10 | NanoBio Corporation | METHOD AND COMPOSITIONS FOR STABILIZING PROTEINS |
GB2556002B (en) | 2015-07-07 | 2020-12-16 | Bluewillow Biologics Inc | Methods and compositions for nanoemulsion vaccine formulations |
WO2017011275A1 (en) * | 2015-07-10 | 2017-01-19 | Nersissian Aram M | Factor viii protein compositions and methods of treating hemophilia a |
EP3167877A1 (en) * | 2015-11-12 | 2017-05-17 | Bayer Pharma Aktiengesellschaft | Method for the production of freeze-dried pellets comprising factor viii |
CN108883160B (zh) | 2016-02-24 | 2022-06-28 | 博尔托拉制药公司 | 因子xa解毒剂的冻干制剂 |
RU2758796C2 (ru) * | 2016-06-01 | 2021-11-01 | Сервье Ип Юк Лимитед | Препараты полиалкиленоксид-аспарагиназы и способы их получения и применение |
WO2018112780A1 (en) * | 2016-12-21 | 2018-06-28 | Chung Chin Sun | Novel method for blood plasma protein activity preservation |
JOP20190260A1 (ar) | 2017-05-02 | 2019-10-31 | Merck Sharp & Dohme | صيغ ثابتة لأجسام مضادة لمستقبل الموت المبرمج 1 (pd-1) وطرق استخدامها |
CA3060581A1 (en) | 2017-05-02 | 2018-11-08 | Merck Sharp & Dohme Corp. | Formulations of anti-lag3 antibodies and co-formulations of anti-lag3 antibodies and anti-pd-1 antibodies |
JP6630315B2 (ja) | 2017-06-27 | 2020-01-15 | 矢崎総業株式会社 | ノイズ低減ユニット |
US10335464B1 (en) | 2018-06-26 | 2019-07-02 | Novo Nordisk A/S | Device for titrating basal insulin |
KR20210113271A (ko) * | 2019-01-06 | 2021-09-15 | 엔도 글로벌 에스테틱스 리미티드 | 콜라게나제 제형 및 이의 제조 방법 |
JP2022538357A (ja) | 2019-07-04 | 2022-09-01 | ツェー・エス・エル・ベーリング・レングナウ・アクチエンゲゼルシャフト | 第VIII凝固因子のin vitroでの安定性を向上させるための切断型フォン・ヴィレブランド因子(VWF) |
CN110772487B (zh) * | 2019-12-09 | 2021-09-21 | 湖南科伦制药有限公司 | 一种二乙酰氨乙酸乙二胺的冻干方法 |
CN112121009B (zh) * | 2020-09-24 | 2022-12-02 | 科兴生物制药股份有限公司 | 一种聚乙二醇修饰重组人粒细胞刺激因子新制剂 |
JP2023545926A (ja) | 2020-09-24 | 2023-11-01 | メルク・シャープ・アンド・ドーム・エルエルシー | プログラム死受容体1(pd-1)抗体とヒアルロニダーゼ変異体とそれらのフラグメントとの安定製剤およびその使用方法 |
WO2022099223A2 (en) | 2020-11-09 | 2022-05-12 | Takeda Pharmaceutical Company Limited | Purification of fviii from plasma using silicon oxide adsorption |
WO2022217041A1 (en) * | 2021-04-09 | 2022-10-13 | Hyalo Technologies, LLC | Method of sterilization of biologics |
CN117813107A (zh) * | 2021-08-11 | 2024-04-02 | 基立福环球运营有限公司 | 用于产生人血浆来源的因子viii/冯·维勒布兰德因子的方法和获得的组合物 |
CN114015758B (zh) * | 2021-10-15 | 2022-06-24 | 无锡百泰克生物技术有限公司 | 一种冻干保护剂、荧光pcr检测试剂盒及冻干工艺 |
Family Cites Families (177)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB941019A (en) | 1961-04-27 | 1963-11-06 | Crookes Lab Ltd | Improvements in and relating to the stability of anti-haemophilic globulin (factor viii) |
US3389314A (en) | 1962-05-07 | 1968-06-18 | Penn Controls | Proportional silicon controlled rectifier driven system for a heat motor |
US3681126A (en) | 1969-11-25 | 1972-08-01 | Monsanto Co | Flame retardant article containing tris-(3 - halo - 2-hydroxypropyl)-hydroxymethylphosphonium chloride |
US3839314A (en) | 1971-06-29 | 1974-10-01 | Baxter Laboratories Inc | Clarification of blood serum and plasma using block copolymers of ethylene oxide and polyoxypropylene |
US3770631A (en) | 1971-06-29 | 1973-11-06 | Baxter Laboratories Inc | Clarification of blood serum and plasma |
US4073886A (en) | 1973-01-30 | 1978-02-14 | Baxter Travenol Laboratories, Inc. | Blood fractionation process using block copolymers of ethylene oxide and polyoxypropylene |
US3980432A (en) | 1973-04-02 | 1976-09-14 | Behringwerke Aktiengesellschaft | Partial thromboplastin, its use as diagnostic agent and process for preparing it |
US3893991A (en) | 1973-04-05 | 1975-07-08 | Baxter Laboratories Inc | Clarification of blood serum and plasma using block copolymers of ethylene oxide and polyoxypropylene |
US3893990A (en) | 1973-04-05 | 1975-07-08 | Baxter Laboratories Inc | Clarification of blood serum and plasma using a block copolymer of ethylene oxide and polyoxypropylene |
US4189425A (en) | 1975-04-11 | 1980-02-19 | Edward Shanbrom, Inc. | Method of preserving blood plasma I |
US4105650A (en) | 1975-04-11 | 1978-08-08 | Edward Shanbrom, Inc. | Method of preserving blood plasma i |
US4069216A (en) | 1975-06-16 | 1978-01-17 | Edward Shanbrom, Inc. | Simplified methods for preparation of very high purity Factor VIII concentrate |
US4089944A (en) | 1975-12-22 | 1978-05-16 | Baxter Travenol Laboratories, Inc. | Rapidly solubilized AHF composition and process for preparing same |
US4027013A (en) | 1976-01-22 | 1977-05-31 | William L. Wilson | Clottable fibrinogen free factor VIII and albumin product and process |
SU663404A1 (ru) | 1976-12-30 | 1979-05-25 | Московский Ордена Ленина И Ордена Трудового Красного Знамени Государственный Университет Им. М.В.Ломоносова | Способ получени фибрин-мономера |
US4137223A (en) | 1977-05-16 | 1979-01-30 | Edward Shanbrom, Inc. | Method of preserving blood plasma II |
SE443293B (sv) | 1978-01-25 | 1986-02-24 | Blombaeck E G B | Blodfraktionsframstellning |
DE2916711A1 (de) | 1979-04-25 | 1980-11-06 | Behringwerke Ag | Blutgerinnungsfaktoren und verfahren zu ihrer herstellung |
US4783441A (en) | 1979-04-30 | 1988-11-08 | Hoechst Aktiengesellschaft | Aqueous protein solutions stable to denaturation |
FR2460305A2 (fr) | 1979-06-29 | 1981-01-23 | Merieux Inst | Procede de preparation d'un concentre de facteur viii |
US4386068A (en) | 1980-02-26 | 1983-05-31 | Cutter Laboratories, Inc. | Antihemophilic factor concentrate and method for preparation |
US4341764A (en) | 1980-03-05 | 1982-07-27 | Cutter Laboratories, Inc. | Method of preparing fibronectin and antihemophilic factor |
US4440679A (en) | 1980-03-05 | 1984-04-03 | Cutter Laboratories, Inc. | Pasteurized therapeutically active protein compositions |
US4623717A (en) | 1980-03-05 | 1986-11-18 | Miles Laboratories, Inc. | Pasteurized therapeutically active protein compositions |
EP0035204B2 (en) | 1980-03-05 | 1991-05-22 | Miles Inc. | Pasteurized therapeutically active protein compositions |
JPS56127308A (en) | 1980-03-11 | 1981-10-06 | Green Cross Corp:The | Blood-coagulation factor 8 pharmaceutical |
JPS56135418A (en) | 1980-03-27 | 1981-10-22 | Green Cross Corp:The | Heat treatment of aqueous solution containing 8 factor of coagulation of blood derived from human |
AT369263B (de) | 1980-08-27 | 1982-12-27 | Immuno Ag | Verfahren zur herstellung eines faktor viii(ahf) -hochkonzentrates |
DE3033932C2 (de) | 1980-09-10 | 1984-05-24 | Biotest-Serum-Institut Gmbh, 6000 Frankfurt | Verfahren zur Kaltsterilisation von Blutgerinnungsfaktor VIII enthaltenden Präparaten |
JPS5770814A (en) | 1980-10-17 | 1982-05-01 | Isamu Horikoshi | Oral preparation of blood clotting eighth factor |
US4495278A (en) | 1981-04-27 | 1985-01-22 | Baxter Travenol Laboratories, Inc. | Process for making novel blood clotting enzyme compositions |
US4382083A (en) | 1981-06-25 | 1983-05-03 | Baxter Travenol Laboratories, Inc. | Therapeutic method for treating blood-clotting defects with factor VIIa |
US4479938A (en) | 1981-06-25 | 1984-10-30 | Baxter Travenol Laboratories, Inc. | Therapeutic composition containing factor VIIa |
JPS5874617A (ja) | 1981-10-28 | 1983-05-06 | Green Cross Corp:The | 人由来血液凝固第7因子含有水溶液の加熱処理方法 |
US4456590B2 (en) | 1981-11-02 | 1989-05-30 | Heat treatment of lyphilized blood clotting factor viii concentrate | |
US4481189A (en) | 1982-04-14 | 1984-11-06 | New York Blood Center Inc. | Process for preparing sterilized plasma and plasma derivatives |
US4591505A (en) | 1982-04-14 | 1986-05-27 | New York Blood Center, Inc. | Process for inactivating hepatitis B virus |
US4495175A (en) | 1982-08-05 | 1985-01-22 | University Of Rochester | Preparation of highly purified human antihemophilic factor |
DE3230849A1 (de) | 1982-08-19 | 1984-02-23 | Behringwerke Ag, 3550 Marburg | Pasteurisiertes human-fibrinogen (hf) und verfahren zu dessen herstellung |
DE3237512A1 (de) | 1982-10-09 | 1984-04-12 | Behringwerke Ag, 3550 Marburg | Verfahren zur pasteurisierung von antihaemophilem kryopraezipitat (ahk) und danach hergestelltes antihaemophiles kryopraezipitat |
GB2129685B (en) | 1982-11-11 | 1985-11-13 | Nat Biolog Standards Board | Anti-haemophilic compositions |
JPS59134730A (ja) | 1983-01-20 | 1984-08-02 | Green Cross Corp:The | 血液凝固第8因子の加熱処理法 |
EP0148843B2 (en) | 1983-03-21 | 1994-05-04 | Novo Nordisk A/S | A concentrate of the antihemophilic factor viii and a process for producing it |
FI841281A (fi) | 1983-03-31 | 1984-10-01 | Scripps Clinic Res | Ny faktor foer viii koagulenta polypeptider och deras monoklonala antikroppar. |
US4748120A (en) | 1983-05-02 | 1988-05-31 | Diamond Scientific Co. | Photochemical decontamination treatment of whole blood or blood components |
US4727027A (en) | 1983-05-02 | 1988-02-23 | Diamond Scientific Co. | Photochemical decontamination treatment of whole blood or blood components |
AT379510B (de) | 1983-05-20 | 1986-01-27 | Immuno Ag | Verfahren zur herstellung einer faktor viii (ahf) -haeltigen praeparation |
DE3318521A1 (de) | 1983-05-20 | 1984-11-22 | Lentia GmbH Chem. u. pharm. Erzeugnisse - Industriebedarf, 8000 München | Verfahren zur herstellung eines antihaemophiliefaktor-konzentrats |
US4540573A (en) | 1983-07-14 | 1985-09-10 | New York Blood Center, Inc. | Undenatured virus-free biologically active protein derivatives |
DE3336631A1 (de) | 1983-10-08 | 1985-04-18 | Behringwerke Ag, 3550 Marburg | Verfahren zur pasteurisierung von plasma oder von konzentraten der blutgerinnungsfaktoren ii, vii, ix und x |
US4757006A (en) | 1983-10-28 | 1988-07-12 | Genetics Institute, Inc. | Human factor VIII:C gene and recombinant methods for production |
US4693981A (en) | 1983-12-20 | 1987-09-15 | Advanced Genetics Research Institute | Preparation of inactivated viral vaccines |
JPS6122022A (ja) | 1983-12-28 | 1986-01-30 | Green Cross Corp:The | 血漿蛋白の加熱処理方法 |
DK165506C (da) | 1984-01-12 | 1993-04-19 | Chiron Corp | Proteinpraeparat med koagulationsaktivitet samt fremgangsmaade til fremstilling deraf |
AT389815B (de) | 1984-03-09 | 1990-02-12 | Immuno Ag | Verfahren zur inaktivierung von vermehrungsfaehigen filtrierbaren krankheitserregern in blutprodukten |
US4831012A (en) | 1984-03-23 | 1989-05-16 | Baxter International Inc. | Purified hemoglobin solutions and method for making same |
JPS60199829A (ja) | 1984-03-24 | 1985-10-09 | Nippon Sekijiyuujishiya | 高純度抗血友病グロブリンの製造方法 |
US5043428A (en) | 1984-08-31 | 1991-08-27 | Behringwerke Aktiengesellschaft | Pasteurized, isoagglutinin-free factor VIII preparation and a process for its production |
US4543210A (en) | 1984-10-04 | 1985-09-24 | Miles Laboratories, Inc. | Process for producing a high purity antihemophilic factor concentrate |
US4613501A (en) | 1984-12-21 | 1986-09-23 | New York Blood Center, Inc. | Inactivation of viruses in labile blood derivatives |
JPS61271222A (ja) * | 1985-05-24 | 1986-12-01 | Dainippon Pharmaceut Co Ltd | ヒトインターロイキン1ポリペプチド及びその製造法 |
US4847362A (en) | 1985-02-01 | 1989-07-11 | New York University | Method for purifying antihemophilic factor |
US4952675A (en) | 1985-02-01 | 1990-08-28 | New York University | Method for purifying antihemophilic factor |
US4743680A (en) | 1985-02-01 | 1988-05-10 | New York University | Method for purifying antihemophilic factor |
CA1341174C (en) | 1985-04-12 | 2001-01-30 | John J. Toole Jr. | Procoagulant proteins derived from factor viii: c |
EP0229810B1 (en) | 1985-07-09 | 1991-10-16 | Quadrant Bioresources Limited | Protection of proteins and the like |
US4758657A (en) | 1985-07-11 | 1988-07-19 | Armour Pharmaceutical Company | Method of purifying Factor VIII:C |
ATE52922T1 (de) | 1985-08-05 | 1990-06-15 | Immuno Ag | Verfahren zur herstellung von praeparationen auf basis von blutgerinnungsfaktoren. |
AU6487286A (en) | 1985-11-08 | 1987-05-14 | Baxter Travenol Laboratories Inc. | Antihemophilic factor by cold precipitation |
US5180583A (en) | 1985-11-26 | 1993-01-19 | Hedner Ulla K E | Method for the treatment of bleeding disorders |
JPS62195331A (ja) | 1986-02-24 | 1987-08-28 | Nippon Sekijiyuujishiya | 血液凝固第8因子製剤の製法 |
AT390374B (de) | 1986-03-18 | 1990-04-25 | Schwab & Co Gmbh | Verfahren zum pasteurisieren von plasmaprotein und plasmaproteinfraktionen |
DE3609431A1 (de) | 1986-03-20 | 1987-09-24 | Biotest Pharma Gmbh | Verfahren zur herstellung eines den blutgerinnungsfaktor viii enthaltenden, sterilen praeparates |
US4841023A (en) | 1986-06-25 | 1989-06-20 | New York Blood Center, Inc. | Inactivation of viruses in labile protein-containing compositions using fatty acids |
AT391808B (de) | 1986-11-03 | 1990-12-10 | Immuno Ag | Verfahren zur herstellung einer faktor viii (ahf)-haeltigen fraktion |
GB8628104D0 (en) | 1986-11-25 | 1986-12-31 | Connaught Lab | Pasteurization of immunoglobin solutions |
CA1331157C (en) | 1987-04-06 | 1994-08-02 | Randal J. Kaufman | Method for producing factor viii:c-type proteins |
ES2006632A6 (es) | 1987-04-21 | 1989-05-01 | Green Cross Corp | Procedimiento de tratamiento termico de fibrinogeno. |
IL86417A (en) | 1987-05-22 | 1992-09-06 | Armour Pharma | Process for the inactivation of pathogens in biological or pharmaceutical material by mixing with aqueous solution containing a sugar(alcohol)and neutral salts as stabilizers |
US4876241A (en) | 1987-05-22 | 1989-10-24 | Armour Pharmaceutical Company | Stabilization of biological and pharmaceutical products during thermal inactivation of viral and bacterial contaminants |
US4795806A (en) | 1987-07-16 | 1989-01-03 | Miles Laboratories, Inc. | Phospholipid affinity purification of Factor VIII:C |
JPH0387173A (ja) | 1987-09-10 | 1991-04-11 | Teijin Ltd | ヒト活性化天然型ファクター8cの製造方法及びそれに用いる形質転換体 |
DE3730533A1 (de) | 1987-09-11 | 1989-03-30 | Biotest Pharma Gmbh | Verfahren zur sterilisation von plasma oder plasmafraktionen |
KR890004724A (ko) * | 1987-09-17 | 1989-05-09 | 히사시 미하라 | 신규 프로테아제 제제(製劑) |
CA1329760C (en) | 1987-10-29 | 1994-05-24 | Ted C. K. Lee | Plasma and recombinant protein formulations in high ionic strength media |
US5605884A (en) | 1987-10-29 | 1997-02-25 | Rhone-Poulenc Rorer Pharmaceuticals Inc. | Factor VIII formulations in high ionic strength media |
US4877608A (en) | 1987-11-09 | 1989-10-31 | Rorer Pharmaceutical Corporation | Pharmaceutical plasma protein formulations in low ionic strength media |
US5177191A (en) | 1987-12-21 | 1993-01-05 | Miles, Inc. | Gel filtration of factor VIII |
DK18288D0 (da) | 1988-01-15 | 1988-01-15 | Nordisk Gentofte | Fremgangsmaade til pasteurisering af vandige oploesninger af faktor viii |
WO1989009784A1 (en) | 1988-04-08 | 1989-10-19 | Commonwealth Serum Laboratories Commission | Production of heat-stable factor viii concentrate |
US4981951A (en) | 1988-04-14 | 1991-01-01 | Miles Inc. | Lectin affinity chromatography of factor VIII |
FR2632309B1 (fr) | 1988-06-07 | 1990-08-24 | Lille Transfusion Sanguine | Procede de purification par voie chromatographique de proteines, notamment de facteur viii, et les produits obtenus |
US5047249A (en) | 1988-07-22 | 1991-09-10 | John Morris Co., Inc. | Compositions and methods for treating skin conditions and promoting wound healing |
US5051353A (en) | 1988-08-09 | 1991-09-24 | The United States Of America As Represented By The Secretary Of The Navy | Preservation and restoration of hemoglobin in blood substitutes |
JPH02157231A (ja) * | 1988-12-07 | 1990-06-18 | Bio Kagaku Kenkyusho:Kk | 細胞増殖抑制剤 |
DE3904354A1 (de) | 1989-02-14 | 1990-08-16 | Behringwerke Ag | Pasteurisiertes, gereinigtes von willebrand-faktor-konzentrat und verfahren zu seiner herstellung |
US5760183A (en) | 1989-02-17 | 1998-06-02 | Association D'aquitaine Pour De Developpment De La Transfusion Sanguine Et Des Recherches Hematologiques | Process for the manufacture of very high-purity antithaemophilic factor (FVIIIC), and von Willebrand factor, and pharmaceutical compositions containing same |
FR2665449B1 (fr) | 1990-08-02 | 1995-04-14 | Aquitaine Developp Transf Sang | Procede de fabrication de facteur von willebrand ayant une tres haute purete, depourvu en majeure partie de facteur antihemophilique (fviiic), et facteur von willebrand ainsi obtenu, ainsi qu'une composition pharmaceutique le contenant. |
CN1047342A (zh) | 1989-05-13 | 1990-11-28 | 杭州市中心血站 | 因子viii的生产及其病毒灭活方法 |
DE69002033T2 (de) | 1989-05-24 | 1993-09-30 | Miles Inc | Gelfiltration von wärmebehandeltem Faktor VIII. |
GB8913183D0 (en) * | 1989-06-08 | 1989-07-26 | Central Blood Lab Authority | Chemical products |
US5138034A (en) | 1989-07-12 | 1992-08-11 | The Green Cross Corporation | Method of fractionating plasma proteins |
US5062498A (en) | 1989-07-18 | 1991-11-05 | Jaromir Tobias | Hydrostatic power transfer system with isolating accumulator |
ES2097120T3 (es) | 1989-07-24 | 1997-04-01 | Bayer Ag | Estabilizacion de proteinas altamente purificadas. |
DE3926034C3 (de) | 1989-08-07 | 1996-11-21 | Behringwerke Ag | Verfahren zur Herstellung eines stabilen Faktors VIII |
FR2651437A1 (fr) | 1989-09-05 | 1991-03-08 | Lille Transfusion Sanguine | Procede de preparation de concentre du complexe facteur viii-facteur von willebrand de la coagulation sanguine a partir de plasma total. |
DK162233C (da) | 1989-11-09 | 1992-03-16 | Novo Nordisk As | Fremgangsmaade til isolering af faktor viii fra blodplasma og pharmaceutisk praeparat indeholdende den saaledes isolerede fator viii |
SE465222C5 (sv) | 1989-12-15 | 1998-02-10 | Pharmacia & Upjohn Ab | Ett rekombinant, humant faktor VIII-derivat och förfarande för dess framställning |
US5439882A (en) | 1989-12-29 | 1995-08-08 | Texas Tech University Health Sciences Center | Blood substitute |
DE4001451A1 (de) | 1990-01-19 | 1991-08-01 | Octapharma Ag | Stabile injizierbare loesungen von faktor viii und faktor ix |
US5418130A (en) | 1990-04-16 | 1995-05-23 | Cryopharm Corporation | Method of inactivation of viral and bacterial blood contaminants |
US5798238A (en) | 1990-04-16 | 1998-08-25 | Baxter International Inc. | Method of inactivation of viral and bacterial blood contaminants with quinolines as photosensitizer |
US5587490A (en) | 1990-04-16 | 1996-12-24 | Credit Managers Association Of California | Method of inactivation of viral and bacterial blood contaminants |
WO1991017194A1 (en) * | 1990-05-07 | 1991-11-14 | Exxon Chemical Patents Inc. | UNSATURATED α-OLEFIN COPOLYMERS AND METHOD FOR PREPARATION THEREOF |
US5378612A (en) | 1990-05-11 | 1995-01-03 | Juridical Foundation The Chemo-Sero-Therapeutic Research Institute | Culture medium for production of recombinant protein |
US5712086A (en) | 1990-05-15 | 1998-01-27 | New York Blood Center, Inc. | Process for transfusing cell containing fractions sterilized with radiation and a quencher of type I and type II photodynamic reactions |
US5232844A (en) | 1990-05-15 | 1993-08-03 | New York Blood Center | Photodynamic inactivation of viruses in cell-containing compositions |
FR2662166A1 (fr) | 1990-05-18 | 1991-11-22 | Fondation Nale Transfusion San | Procede de preparation de facteur viii de tres haute purete comprenant une etape rapide d'immunoadsorption. |
IT1248723B (it) | 1990-06-12 | 1995-01-26 | Scalvo S P A | Processo per la purificazione del fattore viii e fattore viii ottenuto con tale processo |
AU654962B2 (en) | 1990-07-12 | 1994-12-01 | Dade Produktions Ag | Factor VIII:Ca chromogenic assay |
AU650045B2 (en) | 1990-09-12 | 1994-06-09 | Lifecell Corporation | Method and apparatus for cryopreparation dry stabilization and rehydration of biological suspensions |
US5272135A (en) | 1991-03-01 | 1993-12-21 | Chiron Ophthalmics, Inc. | Method for the stabilization of methionine-containing polypeptides |
FR2673632A1 (fr) | 1991-03-08 | 1992-09-11 | Lille Transfusion Sanguine | Procede de preparation de concentre de facteur von willebrand humain de tres haute purete, approprie a un usage therapeutique. |
DE4111393A1 (de) | 1991-04-09 | 1992-10-15 | Behringwerke Ag | Stabilisierte faktor viii-praeparationen |
SE468480B (sv) | 1991-05-24 | 1993-01-25 | Arne Holmgren | Modifierat tioredoxin och dess anvaendning |
AU2309692A (en) | 1991-07-03 | 1993-02-11 | Cryolife, Inc. | Method for stabilization of biomaterials |
US5254350A (en) | 1991-07-22 | 1993-10-19 | Helena Laboratories Corporation | Method of preparing a thromboplastin extract |
CA2078721A1 (en) | 1991-09-24 | 1993-03-25 | Hiroshi Yonemura | Process for preparing human coagulation factor viii protein complex |
FR2681867B1 (fr) | 1991-09-26 | 1993-12-31 | Pasteur Merieux Serums Vaccins | Procede de purification du facteur viii et preparations obtenues. |
US5278289A (en) | 1991-11-12 | 1994-01-11 | Johnson Alan J | Antihemophilic factor stabilization |
US5192743A (en) | 1992-01-16 | 1993-03-09 | Genentech, Inc. | Reconstitutable lyophilized protein formulation |
JPH05331071A (ja) * | 1992-01-17 | 1993-12-14 | Asahi Chem Ind Co Ltd | カルシトニン遺伝子関連ペプチド類の凍結乾燥組成物および安定化法 |
AT399818B (de) | 1992-04-24 | 1995-07-25 | Immuno Ag | Verfahren zur herstellung einer hochgereinigten virussicheren faktor viii-präparation |
US5288853A (en) | 1992-04-30 | 1994-02-22 | Alpha Therapeutic Corporation | Factor viii purification process |
US5399670A (en) | 1992-04-30 | 1995-03-21 | Alpha Therapeutic Corporation | Solubilization and stabilization of factor VIII complex |
US5378601A (en) | 1992-07-24 | 1995-01-03 | Montefiore Medical Center | Method of preserving platelets with apyrase and an antioxidant |
US5424471A (en) * | 1992-07-31 | 1995-06-13 | U.S. Bioscience, Inc. | Crystalline amifostine compositions and methods of the preparation and use of same |
SK282483B6 (sk) * | 1992-10-02 | 2002-02-05 | Genetics Institute, Inc. | Stabilná kompozícia koagulačného faktora VIII, spôsob jej prípravy a stabilizácie |
IT1256622B (it) | 1992-12-04 | 1995-12-12 | Sclavo Spa | Processo per l'estrazione del complesso fattore viii-fattore von willebrand (fviii:c-fvw) da plasma umano totale. |
DE4242863A1 (de) * | 1992-12-18 | 1994-06-23 | Boehringer Mannheim Gmbh | Stabile lyophilisierte pharmazeutische Zubereitungen von G-CSF |
ES2118386T3 (es) | 1993-02-09 | 1998-09-16 | Octapharma Ag | Procedimiento para la inactivacion de virus que no estan provistos de envolventes lipidicas. |
SE9301581D0 (sv) * | 1993-05-07 | 1993-05-07 | Kabi Pharmacia Ab | Protein formulation |
SE504074C2 (sv) | 1993-07-05 | 1996-11-04 | Pharmacia Ab | Proteinberedning för subkutan, intramuskulär eller intradermal administrering |
US5576291A (en) | 1993-09-13 | 1996-11-19 | Baxter International Inc. | Activated factor VIII as a therapeutic agent and method of treating factor VIII deficiency |
US5353835A (en) | 1993-09-23 | 1994-10-11 | Ingersoll-Rand Company | Air tank drain |
IT1268920B1 (it) | 1994-03-29 | 1997-03-13 | Syfal Srl | Macchina rotativa per la decorazione-smaltatura in particolare dipiastrelle ceramiche. |
IL113010A (en) | 1994-03-31 | 1999-10-28 | Pharmacia & Upjohn Ab | Pharmaceutical formulation comprising factor viii with an activity of at least 500iu/ml and an enhancer for improved subcutaneous intramuscular or intradermal administration |
US5514781A (en) | 1994-04-11 | 1996-05-07 | Bayer Corporation | Use of azoles as virucidal agents in solutions of biologically active proteins |
US5955448A (en) | 1994-08-19 | 1999-09-21 | Quadrant Holdings Cambridge Limited | Method for stabilization of biological substances during drying and subsequent storage and compositions thereof |
FR2719479B1 (fr) * | 1994-05-04 | 1996-07-26 | Sanofi Elf | Formulation stable lyophilisée comprenant une protéine: kit de dosage. |
DE69530196T2 (de) | 1994-06-02 | 2003-11-20 | Elan Drug Delivery Ltd | Methode zum verhindern der aggregation von proteinen/peptiden bei rehydratation oder auftauen |
US5580856A (en) | 1994-07-15 | 1996-12-03 | Prestrelski; Steven J. | Formulation of a reconstituted protein, and method and kit for the production thereof |
DE4431833C1 (de) | 1994-09-07 | 1995-05-18 | Blutspendedienst Der Drk Lande | Verfahren zur Herstellung eines AHF-Konzentrates |
GB2293100A (en) | 1994-09-15 | 1996-03-20 | Medeva Europ Ltd | Pharmaceutical compositions with deuterium oxide |
SE503424C2 (sv) | 1994-11-14 | 1996-06-10 | Pharmacia Ab | Process för rening av rekombinant koagulationsfaktor VIII |
SE9403915D0 (sv) | 1994-11-14 | 1994-11-14 | Annelie Almstedt | Process A |
WO1996019918A1 (en) * | 1994-12-28 | 1996-07-04 | Biotime, Inc. | Plasma expanders and blood substitutes |
GB9501040D0 (en) * | 1995-01-19 | 1995-03-08 | Quadrant Holdings Cambridge | Dried composition |
SE9501189D0 (sv) * | 1995-03-31 | 1995-03-31 | Pharmacia Ab | Protein formulation |
US5679549A (en) | 1995-05-04 | 1997-10-21 | Bayer Corporation | Production of recombinant factor VIII in the presence of liposome-like substances of mixed composition |
JP3927248B2 (ja) * | 1995-07-11 | 2007-06-06 | 第一製薬株式会社 | Hgf凍結乾燥製剤 |
KR0167677B1 (ko) * | 1995-08-31 | 1999-02-01 | 김광호 | 다중 비트 테스트를 위한 패턴 발생기를 가지는 메모리 테스트 시스템 |
SE9503380D0 (sv) | 1995-09-29 | 1995-09-29 | Pharmacia Ab | Protein derivatives |
ES2099678B1 (es) | 1995-11-03 | 1998-02-16 | Grifols Grupo Sa | Procedimiento para la inactivacion de virus en proteinas. |
WO1997016966A1 (en) | 1995-11-06 | 1997-05-15 | New York Blood Center, Inc. | Viral inactivation treatment of red blood cells using phthalocyanines and red light |
US5659017A (en) | 1995-11-07 | 1997-08-19 | Alpha Therapeutic Corporation | Anion exchange process for the purification of Factor VIII |
US5925738A (en) | 1995-12-01 | 1999-07-20 | The American National Red Cross | Methods of production and use of liquid formulations of plasma proteins |
US6632648B1 (en) | 1996-05-14 | 2003-10-14 | Elan Drug Delivery Limited | Methods of terminal sterilization of fibrinogen |
US5851800A (en) | 1996-05-14 | 1998-12-22 | Pharmacia & Upjohn Ab | Process for producing a protein |
US5763401A (en) * | 1996-07-12 | 1998-06-09 | Bayer Corporation | Stabilized albumin-free recombinant factor VIII preparation having a low sugar content |
CN101810854A (zh) * | 1999-02-22 | 2010-08-25 | 巴克斯特国际公司 | 新的无白蛋白的因子viii制剂 |
CA2378751C (en) | 1999-07-13 | 2012-11-06 | Biovitrum Ab | Stable factor viii compositions |
US6440414B1 (en) * | 1999-10-01 | 2002-08-27 | Amgen Inc. | Pharmaceutical compositions of fibrinolytic agent |
DK2298287T3 (en) | 2003-12-19 | 2018-07-23 | Novo Nordisk Healthcare Ag | Stabilized compositions of factor VII polypeptides |
JP5231810B2 (ja) | 2005-12-28 | 2013-07-10 | 中外製薬株式会社 | 抗体含有安定化製剤 |
JO3324B1 (ar) | 2006-04-21 | 2019-03-13 | Amgen Inc | مركبات علاجية مجففة بالتبريد تتعلق بالعصارة الهضمية |
JP5960990B2 (ja) | 2008-09-03 | 2016-08-02 | オクタファルマ アクチェン ゲゼルシャフト | 組み換え技術によって製造された第viii因子のための新規な保護組成物 |
-
2000
- 2000-02-22 CN CN200910171121A patent/CN101810854A/zh active Pending
- 2000-02-22 CA CA2362927A patent/CA2362927C/en not_active Expired - Lifetime
- 2000-02-22 EP EP00907322A patent/EP1154796B1/en not_active Expired - Lifetime
- 2000-02-22 PL PL382300A patent/PL204701B1/pl unknown
- 2000-02-22 US US09/507,011 patent/US6586573B1/en not_active Expired - Lifetime
- 2000-02-22 CA CA002634674A patent/CA2634674A1/en not_active Abandoned
- 2000-02-22 CZ CZ2008-828A patent/CZ307715B6/cs not_active IP Right Cessation
- 2000-02-22 AU AU28843/00A patent/AU777972B2/en not_active Expired
- 2000-02-22 PT PT60772290T patent/PT1820516E/pt unknown
- 2000-02-22 CZ CZ20012996A patent/CZ300547B6/cs not_active IP Right Cessation
- 2000-02-22 DK DK00907322T patent/DK1154796T3/da active
- 2000-02-22 DK DK10075019.9T patent/DK2193809T3/en active
- 2000-02-22 ES ES09075396T patent/ES2394755T3/es not_active Expired - Lifetime
- 2000-02-22 DK DK06077229.0T patent/DK1820516T3/da active
- 2000-02-22 CZ CZ2008-827A patent/CZ307322B6/cs not_active IP Right Cessation
- 2000-02-22 CN CNB008063044A patent/CN100553678C/zh not_active Expired - Lifetime
- 2000-02-22 EP EP15154020.0A patent/EP2921180B1/en not_active Expired - Lifetime
- 2000-02-22 PL PL356453A patent/PL198123B1/pl unknown
- 2000-02-22 CA CA002634663A patent/CA2634663C/en not_active Expired - Lifetime
- 2000-02-22 PT PT100750199T patent/PT2193809E/pt unknown
- 2000-02-22 CA CA2634664A patent/CA2634664C/en not_active Expired - Lifetime
- 2000-02-22 PL PL382299A patent/PL203893B1/pl unknown
- 2000-02-22 ES ES06077229T patent/ES2435141T3/es not_active Expired - Lifetime
- 2000-02-22 MX MXPA01008515A patent/MXPA01008515A/es active IP Right Grant
- 2000-02-22 PT PT09075396T patent/PT2130554E/pt unknown
- 2000-02-22 ES ES10075019.9T patent/ES2541470T3/es not_active Expired - Lifetime
- 2000-02-22 DE DE60035260T patent/DE60035260T2/de not_active Expired - Lifetime
- 2000-02-22 PL PL382288A patent/PL203177B1/pl unknown
- 2000-02-22 EP EP06077229.0A patent/EP1820516B1/en not_active Expired - Lifetime
- 2000-02-22 AT AT00907322T patent/ATE365052T1/de active
- 2000-02-22 CN CN2009101711245A patent/CN101683522B/zh not_active Expired - Lifetime
- 2000-02-22 WO PCT/US2000/040068 patent/WO2000048635A1/en active Application Filing
- 2000-02-22 EP EP09075396A patent/EP2130554B1/en not_active Revoked
- 2000-02-22 JP JP2000599425A patent/JP5149470B2/ja not_active Expired - Lifetime
- 2000-02-22 PT PT00907322T patent/PT1154796E/pt unknown
- 2000-02-22 ES ES00907322T patent/ES2288843T3/es not_active Expired - Lifetime
- 2000-02-22 DK DK09075396.3T patent/DK2130554T3/da active
- 2000-02-22 BR BRPI0008405-0B1A patent/BR0008405B1/pt not_active IP Right Cessation
- 2000-02-22 RU RU2001125929/15A patent/RU2244556C2/ru active
- 2000-02-22 EP EP10075019.9A patent/EP2193809B1/en not_active Expired - Lifetime
-
2003
- 2003-07-01 US US10/610,723 patent/US7087723B2/en not_active Expired - Lifetime
-
2006
- 2006-05-15 US US11/434,634 patent/US7247707B2/en not_active Expired - Lifetime
-
2007
- 2007-06-18 US US11/764,770 patent/US8058226B2/en not_active Expired - Lifetime
- 2007-08-07 CY CY20071101050T patent/CY1108030T1/el unknown
- 2007-12-07 HK HK10106491.9A patent/HK1139862A1/zh not_active IP Right Cessation
- 2007-12-07 HK HK07113386.8A patent/HK1106705A1/xx not_active IP Right Cessation
- 2007-12-07 HK HK10100752.6A patent/HK1133583A1/ not_active IP Right Cessation
-
2008
- 2008-05-01 JP JP2008120035A patent/JP5006832B2/ja not_active Expired - Lifetime
- 2008-09-30 JP JP2008255510A patent/JP5140539B2/ja not_active Expired - Lifetime
-
2011
- 2011-09-30 US US13/250,789 patent/US8372800B2/en not_active Expired - Lifetime
-
2012
- 2012-01-20 JP JP2012009767A patent/JP5596064B2/ja not_active Expired - Lifetime
- 2012-12-04 CY CY20121101185T patent/CY1113969T1/el unknown
-
2013
- 2013-02-06 US US13/760,900 patent/US8765665B2/en not_active Expired - Lifetime
- 2013-11-01 JP JP2013227977A patent/JP6038003B2/ja not_active Expired - Lifetime
-
2014
- 2014-05-23 US US14/286,391 patent/US9352027B2/en not_active Expired - Fee Related
-
2015
- 2015-02-20 JP JP2015031316A patent/JP6155442B2/ja not_active Expired - Lifetime
- 2015-11-11 JP JP2015220875A patent/JP6253627B2/ja not_active Expired - Lifetime
-
2016
- 2016-02-18 HK HK16101857.2A patent/HK1213801A1/zh unknown
- 2016-05-04 US US15/146,835 patent/US9669076B2/en not_active Expired - Lifetime
-
2017
- 2017-04-27 JP JP2017088289A patent/JP2017125076A/ja not_active Withdrawn
-
2018
- 2018-07-02 JP JP2018125917A patent/JP2018172413A/ja active Pending
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN100553678C (zh) | 新的无白蛋白的因子ⅷ制剂 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
C12 | Rejection of a patent application after its publication | ||
RJ01 | Rejection of invention patent application after publication |
Application publication date: 20100825 |