CN101274096B - 一种稳定的巴曲酶药物组合物 - Google Patents
一种稳定的巴曲酶药物组合物 Download PDFInfo
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- CN101274096B CN101274096B CN200710038676XA CN200710038676A CN101274096B CN 101274096 B CN101274096 B CN 101274096B CN 200710038676X A CN200710038676X A CN 200710038676XA CN 200710038676 A CN200710038676 A CN 200710038676A CN 101274096 B CN101274096 B CN 101274096B
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- batroxobin
- described compositions
- stabilizing agent
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- 239000000203 mixture Substances 0.000 title claims abstract description 88
- 108010027612 Batroxobin Proteins 0.000 title claims abstract description 78
- 229960002210 batroxobin Drugs 0.000 title claims abstract description 76
- 239000003814 drug Substances 0.000 title claims description 7
- 108010010803 Gelatin Proteins 0.000 claims abstract description 22
- 229920000159 gelatin Polymers 0.000 claims abstract description 22
- 239000008273 gelatin Substances 0.000 claims abstract description 22
- 235000019322 gelatine Nutrition 0.000 claims abstract description 22
- 235000011852 gelatine desserts Nutrition 0.000 claims abstract description 22
- 239000007788 liquid Substances 0.000 claims abstract description 13
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 22
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims description 20
- 239000007864 aqueous solution Substances 0.000 claims description 17
- 238000002360 preparation method Methods 0.000 claims description 17
- 229960003180 glutathione Drugs 0.000 claims description 15
- 210000002381 plasma Anatomy 0.000 claims description 15
- 239000003381 stabilizer Substances 0.000 claims description 14
- 239000003146 anticoagulant agent Substances 0.000 claims description 13
- 229940127219 anticoagulant drug Drugs 0.000 claims description 13
- 239000000843 powder Substances 0.000 claims description 12
- 239000000413 hydrolysate Substances 0.000 claims description 11
- 238000002347 injection Methods 0.000 claims description 11
- 239000007924 injection Substances 0.000 claims description 11
- 239000011780 sodium chloride Substances 0.000 claims description 11
- 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 description 10
- 239000004471 Glycine Substances 0.000 claims description 10
- 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 description 10
- 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 description 10
- OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 claims description 10
- 238000000034 method Methods 0.000 claims description 9
- 230000000295 complement effect Effects 0.000 claims description 7
- 230000007062 hydrolysis Effects 0.000 claims description 7
- 238000006460 hydrolysis reaction Methods 0.000 claims description 7
- 229960004926 chlorobutanol Drugs 0.000 claims description 5
- 238000001694 spray drying Methods 0.000 claims description 5
- 108010009736 Protein Hydrolysates Proteins 0.000 claims description 3
- 230000002439 hemostatic effect Effects 0.000 claims description 2
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- YRWWOAFMPXPHEJ-OFBPEYICSA-K sodium L-ascorbic acid 2-phosphate Chemical compound [Na+].[Na+].[Na+].OC[C@H](O)[C@H]1OC(=O)C(OP([O-])([O-])=O)=C1[O-] YRWWOAFMPXPHEJ-OFBPEYICSA-K 0.000 claims 2
- 229940048058 sodium ascorbyl phosphate Drugs 0.000 claims 2
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- 229910019142 PO4 Inorganic materials 0.000 description 10
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- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- LVZIWKFQFKNSMO-UHFFFAOYSA-N 1-chlorobutan-1-ol Chemical class CCCC(O)Cl LVZIWKFQFKNSMO-UHFFFAOYSA-N 0.000 description 5
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 5
- 239000003223 protective agent Substances 0.000 description 5
- 229910052708 sodium Inorganic materials 0.000 description 5
- 239000000463 material Substances 0.000 description 4
- -1 sodium ascorbyl phosphates Chemical class 0.000 description 4
- 239000008215 water for injection Substances 0.000 description 4
- 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 3
- 102000008100 Human Serum Albumin Human genes 0.000 description 3
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- 230000023555 blood coagulation Effects 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 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 3
- 239000000138 intercalating agent Substances 0.000 description 3
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- 238000013112 stability test Methods 0.000 description 3
- 239000011550 stock solution Substances 0.000 description 3
- 239000004094 surface-active agent Substances 0.000 description 3
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- 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 2
- 208000032843 Hemorrhage Diseases 0.000 description 2
- 229930195725 Mannitol Natural products 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- 108010008281 Recombinant Fusion Proteins Proteins 0.000 description 2
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 2
- 208000019802 Sexually transmitted disease Diseases 0.000 description 2
- 159000000021 acetate salts Chemical class 0.000 description 2
- 230000002744 anti-aggregatory effect Effects 0.000 description 2
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- 239000003638 chemical reducing agent Substances 0.000 description 2
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- 238000007865 diluting Methods 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 235000003969 glutathione Nutrition 0.000 description 2
- 239000000594 mannitol Substances 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- QVLTXCYWHPZMCA-UHFFFAOYSA-N po4-po4 Chemical compound OP(O)(O)=O.OP(O)(O)=O QVLTXCYWHPZMCA-UHFFFAOYSA-N 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
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- 238000005215 recombination Methods 0.000 description 2
- 230000006798 recombination Effects 0.000 description 2
- 238000012216 screening Methods 0.000 description 2
- DAEPDZWVDSPTHF-UHFFFAOYSA-M sodium pyruvate Chemical compound [Na+].CC(=O)C([O-])=O DAEPDZWVDSPTHF-UHFFFAOYSA-M 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- OWEGMIWEEQEYGQ-UHFFFAOYSA-N 100676-05-9 Natural products OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(OC2C(OC(O)C(O)C2O)CO)O1 OWEGMIWEEQEYGQ-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 108010088751 Albumins Proteins 0.000 description 1
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- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 241000271511 Bothrops atrox Species 0.000 description 1
- QFOHBWFCKVYLES-UHFFFAOYSA-N Butylparaben Chemical compound CCCCOC(=O)C1=CC=C(O)C=C1 QFOHBWFCKVYLES-UHFFFAOYSA-N 0.000 description 1
- ZZZCUOFIHGPKAK-UHFFFAOYSA-N D-erythro-ascorbic acid Natural products OCC1OC(=O)C(O)=C1O ZZZCUOFIHGPKAK-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 1
- 102000007625 Hirudins Human genes 0.000 description 1
- 108010007267 Hirudins Proteins 0.000 description 1
- 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 1
- 241000235058 Komagataella pastoris Species 0.000 description 1
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- GUBGYTABKSRVRQ-PICCSMPSSA-N Maltose Natural products O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-PICCSMPSSA-N 0.000 description 1
- 229920001213 Polysorbate 20 Polymers 0.000 description 1
- 102000007056 Recombinant Fusion Proteins Human genes 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 229930003268 Vitamin C Natural products 0.000 description 1
- QCGGXGCODUUTLZ-UHFFFAOYSA-N [Na].[Na].[Na].[Na] Chemical compound [Na].[Na].[Na].[Na] QCGGXGCODUUTLZ-UHFFFAOYSA-N 0.000 description 1
- YBCVMFKXIKNREZ-UHFFFAOYSA-N acoh acetic acid Chemical compound CC(O)=O.CC(O)=O YBCVMFKXIKNREZ-UHFFFAOYSA-N 0.000 description 1
- 230000008485 antagonism Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
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- JEIPFZHSYJVQDO-UHFFFAOYSA-N ferric oxide Chemical compound O=[Fe]O[Fe]=O JEIPFZHSYJVQDO-UHFFFAOYSA-N 0.000 description 1
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- 229960002897 heparin Drugs 0.000 description 1
- 229920000669 heparin Polymers 0.000 description 1
- 229940006607 hirudin Drugs 0.000 description 1
- WQPDUTSPKFMPDP-OUMQNGNKSA-N hirudin Chemical compound C([C@@H](C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C=CC(OS(O)(=O)=O)=CC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCCN)NC(=O)[C@H]1N(CCC1)C(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)CNC(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@H]1NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCC(O)=O)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)CNC(=O)[C@H](CC(C)C)NC(=O)[C@H]([C@@H](C)CC)NC(=O)[C@@H]2CSSC[C@@H](C(=O)N[C@@H](CCC(O)=O)C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@H](C(=O)N[C@H](C(NCC(=O)N[C@@H](CCC(N)=O)C(=O)NCC(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)N2)=O)CSSC1)C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H]1NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CO)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=2C=CC(O)=CC=2)NC(=O)[C@@H](NC(=O)[C@@H](N)C(C)C)C(C)C)[C@@H](C)O)CSSC1)C(C)C)[C@@H](C)O)[C@@H](C)O)C1=CC=CC=C1 WQPDUTSPKFMPDP-OUMQNGNKSA-N 0.000 description 1
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- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 1
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- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
- 231100000614 poison Toxicity 0.000 description 1
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- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 1
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
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- 230000003248 secreting effect Effects 0.000 description 1
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- 229940054269 sodium pyruvate Drugs 0.000 description 1
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- 238000012430 stability testing Methods 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- RTKIYNMVFMVABJ-UHFFFAOYSA-L thimerosal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 description 1
- 239000002435 venom Substances 0.000 description 1
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Landscapes
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicinal Preparation (AREA)
Abstract
Description
辅料 | 配方1 | 配方2 | 配方3 | 配方4 | 配方5 | 配方6 | 配方7 |
甘露醇 | — | √ | √ | √ | √ | √ | √ |
醋酸盐缓冲pH5.0 | √ | √ | √ | — | — | — | — |
磷酸盐缓冲pH6.0 | — | — | — | — | — | √ | √ |
Tris-HCl缓冲pH7.4 | — | — | — | √ | √ | — | — |
人血白蛋白 | — | — | √ | — | √ | — | √ |
37℃存放天数 | 0 | 7 | 14 | 21 | 28 | 60 | 90 | 120 | 150 | 180 |
稀释2000X倍的凝血时间 | 62.0 | 61.9 | 67.6 | 63.2 | 59.8 | 65.0 | 66.3 | 68.8 | 69.0 | 67.6 |
Claims (9)
Priority Applications (1)
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CN200710038676XA CN101274096B (zh) | 2007-03-29 | 2007-03-29 | 一种稳定的巴曲酶药物组合物 |
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CN200710038676XA CN101274096B (zh) | 2007-03-29 | 2007-03-29 | 一种稳定的巴曲酶药物组合物 |
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CN101274096A CN101274096A (zh) | 2008-10-01 |
CN101274096B true CN101274096B (zh) | 2011-04-27 |
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CN200710038676XA Active CN101274096B (zh) | 2007-03-29 | 2007-03-29 | 一种稳定的巴曲酶药物组合物 |
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CN (1) | CN101274096B (zh) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
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EP2672986B1 (en) * | 2011-02-09 | 2020-03-18 | GlaxoSmithKline LLC | Lyophilized formulations |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1179980A (zh) * | 1996-08-29 | 1998-04-29 | 东菱药品工业株式会社 | 与细胞凋亡有关的疾病的预防和/或治疗药剂 |
CN1534093A (zh) * | 2003-03-28 | 2004-10-06 | 上海万兴生物制药有限公司 | 巴曲酶基因的合成及其表达产物的纯化制备 |
CN1187087C (zh) * | 1995-06-28 | 2005-02-02 | 东菱药品工业株式会社 | 巴曲酶在制备治疗或预防缺血-再灌注损伤的药物中的用途 |
-
2007
- 2007-03-29 CN CN200710038676XA patent/CN101274096B/zh active Active
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1187087C (zh) * | 1995-06-28 | 2005-02-02 | 东菱药品工业株式会社 | 巴曲酶在制备治疗或预防缺血-再灌注损伤的药物中的用途 |
CN1179980A (zh) * | 1996-08-29 | 1998-04-29 | 东菱药品工业株式会社 | 与细胞凋亡有关的疾病的预防和/或治疗药剂 |
CN1534093A (zh) * | 2003-03-28 | 2004-10-06 | 上海万兴生物制药有限公司 | 巴曲酶基因的合成及其表达产物的纯化制备 |
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CN101274096A (zh) | 2008-10-01 |
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