CN1053101C - 杂泡脂质体的制备方法 - Google Patents
杂泡脂质体的制备方法 Download PDFInfo
- Publication number
- CN1053101C CN1053101C CN91102478A CN91102478A CN1053101C CN 1053101 C CN1053101 C CN 1053101C CN 91102478 A CN91102478 A CN 91102478A CN 91102478 A CN91102478 A CN 91102478A CN 1053101 C CN1053101 C CN 1053101C
- Authority
- CN
- China
- Prior art keywords
- water
- group
- lipid
- substance
- forming
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- 239000002502 liposome Substances 0.000 title claims abstract description 71
- 238000000034 method Methods 0.000 claims abstract description 38
- 239000000203 mixture Substances 0.000 claims abstract description 21
- 239000000126 substance Substances 0.000 claims abstract description 21
- 150000002632 lipids Chemical class 0.000 claims description 41
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 31
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical group ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 30
- 239000000463 material Substances 0.000 claims description 30
- 239000000839 emulsion Substances 0.000 claims description 26
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 24
- 239000007762 w/o emulsion Substances 0.000 claims description 23
- -1 butyl Amikacin Chemical compound 0.000 claims description 15
- 239000003960 organic solvent Substances 0.000 claims description 15
- 239000002904 solvent Substances 0.000 claims description 14
- 230000000975 bioactive effect Effects 0.000 claims description 13
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 claims description 13
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 10
- 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 claims description 9
- 102000000588 Interleukin-2 Human genes 0.000 claims description 9
- 108010002350 Interleukin-2 Proteins 0.000 claims description 9
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 claims description 9
- 239000004472 Lysine Substances 0.000 claims description 9
- 239000008103 glucose Substances 0.000 claims description 9
- 229960003646 lysine Drugs 0.000 claims description 9
- WTJKGGKOPKCXLL-RRHRGVEJSA-N phosphatidylcholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCC=CCCCCCCCC WTJKGGKOPKCXLL-RRHRGVEJSA-N 0.000 claims description 7
- SNKAWJBJQDLSFF-NVKMUCNASA-N 1,2-dioleoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCC\C=C/CCCCCCCC SNKAWJBJQDLSFF-NVKMUCNASA-N 0.000 claims description 6
- 235000012000 cholesterol Nutrition 0.000 claims description 6
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 claims description 6
- TZCPCKNHXULUIY-RGULYWFUSA-N 1,2-distearoyl-sn-glycero-3-phosphoserine Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(=O)OC[C@H](N)C(O)=O)OC(=O)CCCCCCCCCCCCCCCCC TZCPCKNHXULUIY-RGULYWFUSA-N 0.000 claims description 5
- ZWZWYGMENQVNFU-UHFFFAOYSA-N Glycerophosphorylserin Natural products OC(=O)C(N)COP(O)(=O)OCC(O)CO ZWZWYGMENQVNFU-UHFFFAOYSA-N 0.000 claims description 5
- 239000007864 aqueous solution Substances 0.000 claims description 5
- 230000007935 neutral effect Effects 0.000 claims description 5
- 229910052757 nitrogen Inorganic materials 0.000 claims description 5
- 102000004169 proteins and genes Human genes 0.000 claims description 5
- 108090000623 proteins and genes Proteins 0.000 claims description 5
- UHDGCWIWMRVCDJ-CCXZUQQUSA-N Cytarabine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 UHDGCWIWMRVCDJ-CCXZUQQUSA-N 0.000 claims description 4
- JZNWSCPGTDBMEW-UHFFFAOYSA-N Glycerophosphorylethanolamin Natural products NCCOP(O)(=O)OCC(O)CO JZNWSCPGTDBMEW-UHFFFAOYSA-N 0.000 claims description 4
- BVHLGVCQOALMSV-JEDNCBNOSA-N L-lysine hydrochloride Chemical compound Cl.NCCCC[C@H](N)C(O)=O BVHLGVCQOALMSV-JEDNCBNOSA-N 0.000 claims description 4
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 claims description 4
- 229960005337 lysine hydrochloride Drugs 0.000 claims description 4
- GLVAUDGFNGKCSF-UHFFFAOYSA-N mercaptopurine Chemical compound S=C1NC=NC2=C1NC=N2 GLVAUDGFNGKCSF-UHFFFAOYSA-N 0.000 claims description 4
- 150000008104 phosphatidylethanolamines Chemical class 0.000 claims description 4
- ZFXYFBGIUFBOJW-UHFFFAOYSA-N theophylline Chemical compound O=C1N(C)C(=O)N(C)C2=C1NC=N2 ZFXYFBGIUFBOJW-UHFFFAOYSA-N 0.000 claims description 4
- WYWHKKSPHMUBEB-UHFFFAOYSA-N 6-Mercaptoguanine Natural products N1C(N)=NC(=S)C2=C1N=CN2 WYWHKKSPHMUBEB-UHFFFAOYSA-N 0.000 claims description 3
- 108010001857 Cell Surface Receptors Proteins 0.000 claims description 3
- 102000000844 Cell Surface Receptors Human genes 0.000 claims description 3
- 102000018233 Fibroblast Growth Factor Human genes 0.000 claims description 3
- 108050007372 Fibroblast Growth Factor Proteins 0.000 claims description 3
- 108010017213 Granulocyte-Macrophage Colony-Stimulating Factor Proteins 0.000 claims description 3
- 102000004877 Insulin Human genes 0.000 claims description 3
- 108090001061 Insulin Proteins 0.000 claims description 3
- 108010025020 Nerve Growth Factor Proteins 0.000 claims description 3
- 102000015336 Nerve Growth Factor Human genes 0.000 claims description 3
- 150000001875 compounds Chemical class 0.000 claims description 3
- 238000004945 emulsification Methods 0.000 claims description 3
- 238000005516 engineering process Methods 0.000 claims description 3
- 229940126864 fibroblast growth factor Drugs 0.000 claims description 3
- 239000012458 free base Substances 0.000 claims description 3
- 239000000893 inhibin Substances 0.000 claims description 3
- ZPNFWUPYTFPOJU-LPYSRVMUSA-N iniprol Chemical compound C([C@H]1C(=O)NCC(=O)NCC(=O)N[C@H]2CSSC[C@H]3C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@H](C(N[C@H](C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=4C=CC(O)=CC=4)C(=O)N[C@@H](CC=4C=CC=CC=4)C(=O)N[C@@H](CC=4C=CC(O)=CC=4)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CC=4C=CC=CC=4)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](CCCNC(N)=N)NC2=O)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](CC=2C=CC=CC=2)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H]2N(CCC2)C(=O)[C@@H](N)CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N2[C@@H](CCC2)C(=O)N2[C@@H](CCC2)C(=O)N[C@@H](CC=2C=CC(O)=CC=2)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N2[C@@H](CCC2)C(=O)N3)C(=O)NCC(=O)NCC(=O)N[C@@H](C)C(O)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@H](C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@H](C(=O)N1)C(C)C)[C@@H](C)O)[C@@H](C)CC)=O)[C@@H](C)CC)C1=CC=C(O)C=C1 ZPNFWUPYTFPOJU-LPYSRVMUSA-N 0.000 claims description 3
- 229940125396 insulin Drugs 0.000 claims description 3
- 229940053128 nerve growth factor Drugs 0.000 claims description 3
- 108020004707 nucleic acids Proteins 0.000 claims description 3
- 102000039446 nucleic acids Human genes 0.000 claims description 3
- 150000007523 nucleic acids Chemical class 0.000 claims description 3
- 238000005507 spraying Methods 0.000 claims description 3
- KISWVXRQTGLFGD-UHFFFAOYSA-N 2-[[2-[[6-amino-2-[[2-[[2-[[5-amino-2-[[2-[[1-[2-[[6-amino-2-[(2,5-diamino-5-oxopentanoyl)amino]hexanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]pyrrolidine-2-carbonyl]amino]-3-hydroxypropanoyl]amino]-5-oxopentanoyl]amino]-5-(diaminomethylideneamino)p Chemical compound C1CCN(C(=O)C(CCCN=C(N)N)NC(=O)C(CCCCN)NC(=O)C(N)CCC(N)=O)C1C(=O)NC(CO)C(=O)NC(CCC(N)=O)C(=O)NC(CCCN=C(N)N)C(=O)NC(CO)C(=O)NC(CCCCN)C(=O)NC(C(=O)NC(CC(C)C)C(O)=O)CC1=CC=C(O)C=C1 KISWVXRQTGLFGD-UHFFFAOYSA-N 0.000 claims description 2
- 108010005853 Anti-Mullerian Hormone Proteins 0.000 claims description 2
- RKWGIWYCVPQPMF-UHFFFAOYSA-N Chloropropamide Chemical compound CCCNC(=O)NS(=O)(=O)C1=CC=C(Cl)C=C1 RKWGIWYCVPQPMF-UHFFFAOYSA-N 0.000 claims description 2
- 102000008186 Collagen Human genes 0.000 claims description 2
- 108010035532 Collagen Proteins 0.000 claims description 2
- 102000016359 Fibronectins Human genes 0.000 claims description 2
- 108010067306 Fibronectins Proteins 0.000 claims description 2
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 claims description 2
- 102000047918 Myelin Basic Human genes 0.000 claims description 2
- 101710107068 Myelin basic protein Proteins 0.000 claims description 2
- 108010038512 Platelet-Derived Growth Factor Proteins 0.000 claims description 2
- 102000010780 Platelet-Derived Growth Factor Human genes 0.000 claims description 2
- 229930006000 Sucrose Natural products 0.000 claims description 2
- 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 claims description 2
- 108010009583 Transforming Growth Factors Proteins 0.000 claims description 2
- 102000009618 Transforming Growth Factors Human genes 0.000 claims description 2
- 229960003556 aminophylline Drugs 0.000 claims description 2
- 230000001088 anti-asthma Effects 0.000 claims description 2
- 239000000868 anti-mullerian hormone Substances 0.000 claims description 2
- 239000000924 antiasthmatic agent Substances 0.000 claims description 2
- 239000000427 antigen Substances 0.000 claims description 2
- 102000036639 antigens Human genes 0.000 claims description 2
- 108091007433 antigens Proteins 0.000 claims description 2
- 229920001436 collagen Polymers 0.000 claims description 2
- 229960000258 corticotropin Drugs 0.000 claims description 2
- IDLFZVILOHSSID-OVLDLUHVSA-N corticotropin Chemical compound C([C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](C(C)C)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC(N)=O)C(=O)NCC(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)NC(=O)[C@@H](N)CO)C1=CC=C(O)C=C1 IDLFZVILOHSSID-OVLDLUHVSA-N 0.000 claims description 2
- VJJPUSNTGOMMGY-MRVIYFEKSA-N etoposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 VJJPUSNTGOMMGY-MRVIYFEKSA-N 0.000 claims description 2
- 229960005420 etoposide Drugs 0.000 claims description 2
- 229940088597 hormone Drugs 0.000 claims description 2
- 239000005556 hormone Substances 0.000 claims description 2
- 229930195733 hydrocarbon Natural products 0.000 claims description 2
- 150000002430 hydrocarbons Chemical class 0.000 claims description 2
- 229960000485 methotrexate Drugs 0.000 claims description 2
- 239000003921 oil Substances 0.000 claims description 2
- 239000005720 sucrose Substances 0.000 claims description 2
- NRUKOCRGYNPUPR-QBPJDGROSA-N teniposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@@H](OC[C@H]4O3)C=3SC=CC=3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 NRUKOCRGYNPUPR-QBPJDGROSA-N 0.000 claims description 2
- 229960000278 theophylline Drugs 0.000 claims description 2
- 229930003799 tocopherol Natural products 0.000 claims description 2
- 239000011732 tocopherol Substances 0.000 claims description 2
- 150000003626 triacylglycerols Chemical class 0.000 claims description 2
- 235000015112 vegetable and seed oil Nutrition 0.000 claims description 2
- 239000008158 vegetable oil Substances 0.000 claims description 2
- 150000003904 phospholipids Chemical class 0.000 claims 6
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 claims 4
- AQHHHDLHHXJYJD-UHFFFAOYSA-N propranolol Chemical compound C1=CC=C2C(OCC(O)CNC(C)C)=CC=CC2=C1 AQHHHDLHHXJYJD-UHFFFAOYSA-N 0.000 claims 4
- 229940088623 biologically active substance Drugs 0.000 claims 3
- 229960001031 glucose Drugs 0.000 claims 3
- KWGRBVOPPLSCSI-WPRPVWTQSA-N (-)-ephedrine Chemical compound CN[C@@H](C)[C@H](O)C1=CC=CC=C1 KWGRBVOPPLSCSI-WPRPVWTQSA-N 0.000 claims 2
- OZSITQMWYBNPMW-GDLZYMKVSA-N 1,2-ditetradecanoyl-sn-glycerol-3-phosphate Chemical compound CCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(O)=O)OC(=O)CCCCCCCCCCCCC OZSITQMWYBNPMW-GDLZYMKVSA-N 0.000 claims 2
- HNXQXTQTPAJEJL-UHFFFAOYSA-N 2-aminopteridin-4-ol Chemical compound C1=CN=C2NC(N)=NC(=O)C2=N1 HNXQXTQTPAJEJL-UHFFFAOYSA-N 0.000 claims 2
- STQGQHZAVUOBTE-UHFFFAOYSA-N 7-Cyan-hept-2t-en-4,6-diinsaeure Natural products C1=2C(O)=C3C(=O)C=4C(OC)=CC=CC=4C(=O)C3=C(O)C=2CC(O)(C(C)=O)CC1OC1CC(N)C(O)C(C)O1 STQGQHZAVUOBTE-UHFFFAOYSA-N 0.000 claims 2
- 108010006654 Bleomycin Proteins 0.000 claims 2
- 102000055006 Calcitonin Human genes 0.000 claims 2
- 108060001064 Calcitonin Proteins 0.000 claims 2
- SHIBSTMRCDJXLN-UHFFFAOYSA-N Digoxigenin Natural products C1CC(C2C(C3(C)CCC(O)CC3CC2)CC2O)(O)C2(C)C1C1=CC(=O)OC1 SHIBSTMRCDJXLN-UHFFFAOYSA-N 0.000 claims 2
- ULGZDMOVFRHVEP-RWJQBGPGSA-N Erythromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 ULGZDMOVFRHVEP-RWJQBGPGSA-N 0.000 claims 2
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 claims 2
- RPTUSVTUFVMDQK-UHFFFAOYSA-N Hidralazin Chemical compound C1=CC=C2C(NN)=NN=CC2=C1 RPTUSVTUFVMDQK-UHFFFAOYSA-N 0.000 claims 2
- 102000014150 Interferons Human genes 0.000 claims 2
- 108010050904 Interferons Proteins 0.000 claims 2
- 102000009151 Luteinizing Hormone Human genes 0.000 claims 2
- 108010073521 Luteinizing Hormone Proteins 0.000 claims 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 claims 2
- 229930182555 Penicillin Natural products 0.000 claims 2
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 claims 2
- RJKFOVLPORLFTN-LEKSSAKUSA-N Progesterone Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](C(=O)C)[C@@]1(C)CC2 RJKFOVLPORLFTN-LEKSSAKUSA-N 0.000 claims 2
- MUMGGOZAMZWBJJ-DYKIIFRCSA-N Testostosterone Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 MUMGGOZAMZWBJJ-DYKIIFRCSA-N 0.000 claims 2
- JXLYSJRDGCGARV-WWYNWVTFSA-N Vinblastine Natural products O=C(O[C@H]1[C@](O)(C(=O)OC)[C@@H]2N(C)c3c(cc(c(OC)c3)[C@]3(C(=O)OC)c4[nH]c5c(c4CCN4C[C@](O)(CC)C[C@H](C3)C4)cccc5)[C@@]32[C@H]2[C@@]1(CC)C=CCN2CC3)C JXLYSJRDGCGARV-WWYNWVTFSA-N 0.000 claims 2
- ATBOMIWRCZXYSZ-XZBBILGWSA-N [1-[2,3-dihydroxypropoxy(hydroxy)phosphoryl]oxy-3-hexadecanoyloxypropan-2-yl] (9e,12e)-octadeca-9,12-dienoate Chemical compound CCCCCCCCCCCCCCCC(=O)OCC(COP(O)(=O)OCC(O)CO)OC(=O)CCCCCCC\C=C\C\C=C\CCCCC ATBOMIWRCZXYSZ-XZBBILGWSA-N 0.000 claims 2
- 239000002253 acid Substances 0.000 claims 2
- 238000013019 agitation Methods 0.000 claims 2
- AWUCVROLDVIAJX-UHFFFAOYSA-N alpha-glycerophosphate Natural products OCC(O)COP(O)(O)=O AWUCVROLDVIAJX-UHFFFAOYSA-N 0.000 claims 2
- 229940030600 antihypertensive agent Drugs 0.000 claims 2
- 239000002220 antihypertensive agent Substances 0.000 claims 2
- 229960001561 bleomycin Drugs 0.000 claims 2
- OYVAGSVQBOHSSS-UAPAGMARSA-O bleomycin A2 Chemical compound N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC=C(N=1)C=1SC=C(N=1)C(=O)NCCC[S+](C)C)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1N=CNC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C OYVAGSVQBOHSSS-UAPAGMARSA-O 0.000 claims 2
- 229960004015 calcitonin Drugs 0.000 claims 2
- BBBFJLBPOGFECG-VJVYQDLKSA-N calcitonin Chemical compound N([C@H](C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H]([C@@H](C)O)C(=O)N1[C@@H](CCC1)C(N)=O)C(C)C)C(=O)[C@@H]1CSSC[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1 BBBFJLBPOGFECG-VJVYQDLKSA-N 0.000 claims 2
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 claims 2
- 229960004316 cisplatin Drugs 0.000 claims 2
- OROGSEYTTFOCAN-DNJOTXNNSA-N codeine Chemical compound C([C@H]1[C@H](N(CC[C@@]112)C)C3)=C[C@H](O)[C@@H]1OC1=C2C3=CC=C1OC OROGSEYTTFOCAN-DNJOTXNNSA-N 0.000 claims 2
- STQGQHZAVUOBTE-VGBVRHCVSA-N daunorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(C)=O)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 STQGQHZAVUOBTE-VGBVRHCVSA-N 0.000 claims 2
- 229960000975 daunorubicin Drugs 0.000 claims 2
- QONQRTHLHBTMGP-UHFFFAOYSA-N digitoxigenin Natural products CC12CCC(C3(CCC(O)CC3CC3)C)C3C11OC1CC2C1=CC(=O)OC1 QONQRTHLHBTMGP-UHFFFAOYSA-N 0.000 claims 2
- SHIBSTMRCDJXLN-KCZCNTNESA-N digoxigenin Chemical compound C1([C@@H]2[C@@]3([C@@](CC2)(O)[C@H]2[C@@H]([C@@]4(C)CC[C@H](O)C[C@H]4CC2)C[C@H]3O)C)=CC(=O)OC1 SHIBSTMRCDJXLN-KCZCNTNESA-N 0.000 claims 2
- ZGSPNIOCEDOHGS-UHFFFAOYSA-L disodium [3-[2,3-di(octadeca-9,12-dienoyloxy)propoxy-oxidophosphoryl]oxy-2-hydroxypropyl] 2,3-di(octadeca-9,12-dienoyloxy)propyl phosphate Chemical compound [Na+].[Na+].CCCCCC=CCC=CCCCCCCCC(=O)OCC(OC(=O)CCCCCCCC=CCC=CCCCCC)COP([O-])(=O)OCC(O)COP([O-])(=O)OCC(OC(=O)CCCCCCCC=CCC=CCCCCC)COC(=O)CCCCCCCC=CCC=CCCCCC ZGSPNIOCEDOHGS-UHFFFAOYSA-L 0.000 claims 2
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 claims 2
- 229960004679 doxorubicin Drugs 0.000 claims 2
- 230000008020 evaporation Effects 0.000 claims 2
- 238000001704 evaporation Methods 0.000 claims 2
- 229960002949 fluorouracil Drugs 0.000 claims 2
- JYGXADMDTFJGBT-VWUMJDOOSA-N hydrocortisone Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 JYGXADMDTFJGBT-VWUMJDOOSA-N 0.000 claims 2
- 229960003971 influenza vaccine Drugs 0.000 claims 2
- 229940079322 interferon Drugs 0.000 claims 2
- 125000003473 lipid group Chemical group 0.000 claims 2
- 229940040129 luteinizing hormone Drugs 0.000 claims 2
- 229960001428 mercaptopurine Drugs 0.000 claims 2
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims 2
- BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical compound O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 claims 2
- 239000008188 pellet Substances 0.000 claims 2
- 229940049954 penicillin Drugs 0.000 claims 2
- 229960003712 propranolol Drugs 0.000 claims 2
- 229960003087 tioguanine Drugs 0.000 claims 2
- MNRILEROXIRVNJ-UHFFFAOYSA-N tioguanine Chemical compound N1C(N)=NC(=S)C2=NC=N[C]21 MNRILEROXIRVNJ-UHFFFAOYSA-N 0.000 claims 2
- 229960003048 vinblastine Drugs 0.000 claims 2
- JXLYSJRDGCGARV-XQKSVPLYSA-N vincaleukoblastine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-XQKSVPLYSA-N 0.000 claims 2
- 229960004528 vincristine Drugs 0.000 claims 2
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 claims 2
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 claims 2
- XWTYSIMOBUGWOL-UHFFFAOYSA-N (+-)-Terbutaline Chemical compound CC(C)(C)NCC(O)C1=CC(O)=CC(O)=C1 XWTYSIMOBUGWOL-UHFFFAOYSA-N 0.000 claims 1
- SFLSHLFXELFNJZ-QMMMGPOBSA-N (-)-norepinephrine Chemical compound NC[C@H](O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-QMMMGPOBSA-N 0.000 claims 1
- DNXIKVLOVZVMQF-UHFFFAOYSA-N (3beta,16beta,17alpha,18beta,20alpha)-17-hydroxy-11-methoxy-18-[(3,4,5-trimethoxybenzoyl)oxy]-yohimban-16-carboxylic acid, methyl ester Natural products C1C2CN3CCC(C4=CC=C(OC)C=C4N4)=C4C3CC2C(C(=O)OC)C(O)C1OC(=O)C1=CC(OC)=C(OC)C(OC)=C1 DNXIKVLOVZVMQF-UHFFFAOYSA-N 0.000 claims 1
- UCTWMZQNUQWSLP-VIFPVBQESA-N (R)-adrenaline Chemical compound CNC[C@H](O)C1=CC=C(O)C(O)=C1 UCTWMZQNUQWSLP-VIFPVBQESA-N 0.000 claims 1
- 229930182837 (R)-adrenaline Natural products 0.000 claims 1
- KWTSXDURSIMDCE-QMMMGPOBSA-N (S)-amphetamine Chemical compound C[C@H](N)CC1=CC=CC=C1 KWTSXDURSIMDCE-QMMMGPOBSA-N 0.000 claims 1
- BIABMEZBCHDPBV-MPQUPPDSSA-N 1,2-palmitoyl-sn-glycero-3-phospho-(1'-sn-glycerol) Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(=O)OC[C@@H](O)CO)OC(=O)CCCCCCCCCCCCCCC BIABMEZBCHDPBV-MPQUPPDSSA-N 0.000 claims 1
- WJFKNYWRSNBZNX-UHFFFAOYSA-N 10H-phenothiazine Chemical compound C1=CC=C2NC3=CC=CC=C3SC2=C1 WJFKNYWRSNBZNX-UHFFFAOYSA-N 0.000 claims 1
- SVUOLADPCWQTTE-UHFFFAOYSA-N 1h-1,2-benzodiazepine Chemical compound N1N=CC=CC2=CC=CC=C12 SVUOLADPCWQTTE-UHFFFAOYSA-N 0.000 claims 1
- CIVCELMLGDGMKZ-UHFFFAOYSA-N 2,4-dichloro-6-methylpyridine-3-carboxylic acid Chemical compound CC1=CC(Cl)=C(C(O)=O)C(Cl)=N1 CIVCELMLGDGMKZ-UHFFFAOYSA-N 0.000 claims 1
- SGTNSNPWRIOYBX-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-{[2-(3,4-dimethoxyphenyl)ethyl](methyl)amino}-2-(propan-2-yl)pentanenitrile Chemical compound C1=C(OC)C(OC)=CC=C1CCN(C)CCCC(C#N)(C(C)C)C1=CC=C(OC)C(OC)=C1 SGTNSNPWRIOYBX-UHFFFAOYSA-N 0.000 claims 1
- FSVJFNAIGNNGKK-UHFFFAOYSA-N 2-[cyclohexyl(oxo)methyl]-3,6,7,11b-tetrahydro-1H-pyrazino[2,1-a]isoquinolin-4-one Chemical compound C1C(C2=CC=CC=C2CC2)N2C(=O)CN1C(=O)C1CCCCC1 FSVJFNAIGNNGKK-UHFFFAOYSA-N 0.000 claims 1
- PCFUWBOSXMKGIP-UHFFFAOYSA-N 2-benzylpyridine Chemical compound C=1C=CC=NC=1CC1=CC=CC=C1 PCFUWBOSXMKGIP-UHFFFAOYSA-N 0.000 claims 1
- JIBOLVDYWMCJJZ-UHFFFAOYSA-N 2-phenyl-2-(propan-2-ylamino)ethane-1,1,2-triol Chemical compound CC(C)NC(O)(C(O)O)C1=CC=CC=C1 JIBOLVDYWMCJJZ-UHFFFAOYSA-N 0.000 claims 1
- DYUTXEVRMPFGTH-UHFFFAOYSA-N 4-(2,5-dimethylphenyl)-5-methyl-1,3-thiazol-2-amine Chemical compound S1C(N)=NC(C=2C(=CC=C(C)C=2)C)=C1C DYUTXEVRMPFGTH-UHFFFAOYSA-N 0.000 claims 1
- VUTBELPREDJDDH-UHFFFAOYSA-N 4-amino-5-hydroxymethyl-2-methylpyrimidine Chemical compound CC1=NC=C(CO)C(N)=N1 VUTBELPREDJDDH-UHFFFAOYSA-N 0.000 claims 1
- 108010042708 Acetylmuramyl-Alanyl-Isoglutamine Proteins 0.000 claims 1
- APKFDSVGJQXUKY-KKGHZKTASA-N Amphotericin-B Natural products O[C@H]1[C@@H](N)[C@H](O)[C@@H](C)O[C@H]1O[C@H]1C=CC=CC=CC=CC=CC=CC=C[C@H](C)[C@@H](O)[C@@H](C)[C@H](C)OC(=O)C[C@H](O)C[C@H](O)CC[C@@H](O)[C@H](O)C[C@H](O)C[C@](O)(C[C@H](O)[C@H]2C(O)=O)O[C@H]2C1 APKFDSVGJQXUKY-KKGHZKTASA-N 0.000 claims 1
- 229930186147 Cephalosporin Natural products 0.000 claims 1
- 102400000739 Corticotropin Human genes 0.000 claims 1
- 101800000414 Corticotropin Proteins 0.000 claims 1
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 claims 1
- 102000004127 Cytokines Human genes 0.000 claims 1
- 108090000695 Cytokines Proteins 0.000 claims 1
- 108010092160 Dactinomycin Proteins 0.000 claims 1
- 241000208011 Digitalis Species 0.000 claims 1
- 102000012673 Follicle Stimulating Hormone Human genes 0.000 claims 1
- 108010079345 Follicle Stimulating Hormone Proteins 0.000 claims 1
- 229930182566 Gentamicin Natural products 0.000 claims 1
- CEAZRRDELHUEMR-URQXQFDESA-N Gentamicin Chemical compound O1[C@H](C(C)NC)CC[C@@H](N)[C@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](NC)[C@@](C)(O)CO2)O)[C@H](N)C[C@@H]1N CEAZRRDELHUEMR-URQXQFDESA-N 0.000 claims 1
- 108090000288 Glycoproteins Proteins 0.000 claims 1
- 102000003886 Glycoproteins Human genes 0.000 claims 1
- 102000006771 Gonadotropins Human genes 0.000 claims 1
- 108010086677 Gonadotropins Proteins 0.000 claims 1
- 108010017080 Granulocyte Colony-Stimulating Factor Proteins 0.000 claims 1
- 102000004269 Granulocyte Colony-Stimulating Factor Human genes 0.000 claims 1
- 102000004457 Granulocyte-Macrophage Colony-Stimulating Factor Human genes 0.000 claims 1
- 102000018997 Growth Hormone Human genes 0.000 claims 1
- 108010051696 Growth Hormone Proteins 0.000 claims 1
- 241000606768 Haemophilus influenzae Species 0.000 claims 1
- 208000001953 Hypotension Diseases 0.000 claims 1
- 102000002746 Inhibins Human genes 0.000 claims 1
- 108010004250 Inhibins Proteins 0.000 claims 1
- 102000000589 Interleukin-1 Human genes 0.000 claims 1
- 108010002352 Interleukin-1 Proteins 0.000 claims 1
- KLDXJTOLSGUMSJ-JGWLITMVSA-N Isosorbide Chemical compound O[C@@H]1CO[C@@H]2[C@@H](O)CO[C@@H]21 KLDXJTOLSGUMSJ-JGWLITMVSA-N 0.000 claims 1
- 102000007547 Laminin Human genes 0.000 claims 1
- 108010085895 Laminin Proteins 0.000 claims 1
- 108010046938 Macrophage Colony-Stimulating Factor Proteins 0.000 claims 1
- 102000007651 Macrophage Colony-Stimulating Factor Human genes 0.000 claims 1
- XADCESSVHJOZHK-UHFFFAOYSA-N Meperidine Chemical compound C=1C=CC=CC=1C1(C(=O)OCC)CCN(C)CC1 XADCESSVHJOZHK-UHFFFAOYSA-N 0.000 claims 1
- NPPQSCRMBWNHMW-UHFFFAOYSA-N Meprobamate Chemical compound NC(=O)OCC(C)(CCC)COC(N)=O NPPQSCRMBWNHMW-UHFFFAOYSA-N 0.000 claims 1
- 108700020796 Oncogene Proteins 0.000 claims 1
- 102000043276 Oncogene Human genes 0.000 claims 1
- 102000001938 Plasminogen Activators Human genes 0.000 claims 1
- 108010001014 Plasminogen Activators Proteins 0.000 claims 1
- LCQMZZCPPSWADO-UHFFFAOYSA-N Reserpilin Natural products COC(=O)C1COCC2CN3CCc4c([nH]c5cc(OC)c(OC)cc45)C3CC12 LCQMZZCPPSWADO-UHFFFAOYSA-N 0.000 claims 1
- QEVHRUUCFGRFIF-SFWBKIHZSA-N Reserpine Natural products O=C(OC)[C@@H]1[C@H](OC)[C@H](OC(=O)c2cc(OC)c(OC)c(OC)c2)C[C@H]2[C@@H]1C[C@H]1N(C2)CCc2c3c([nH]c12)cc(OC)cc3 QEVHRUUCFGRFIF-SFWBKIHZSA-N 0.000 claims 1
- IWUCXVSUMQZMFG-AFCXAGJDSA-N Ribavirin Chemical compound N1=C(C(=O)N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 IWUCXVSUMQZMFG-AFCXAGJDSA-N 0.000 claims 1
- ZSJLQEPLLKMAKR-UHFFFAOYSA-N Streptozotocin Natural products O=NN(C)C(=O)NC1C(O)OC(CO)C(O)C1O ZSJLQEPLLKMAKR-UHFFFAOYSA-N 0.000 claims 1
- 239000004098 Tetracycline Substances 0.000 claims 1
- WKDDRNSBRWANNC-UHFFFAOYSA-N Thienamycin Natural products C1C(SCCN)=C(C(O)=O)N2C(=O)C(C(O)C)C21 WKDDRNSBRWANNC-UHFFFAOYSA-N 0.000 claims 1
- 239000007983 Tris buffer Substances 0.000 claims 1
- 108060008682 Tumor Necrosis Factor Proteins 0.000 claims 1
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 claims 1
- 108010059993 Vancomycin Proteins 0.000 claims 1
- OIRDTQYFTABQOQ-UHTZMRCNSA-N Vidarabine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@@H]1O OIRDTQYFTABQOQ-UHTZMRCNSA-N 0.000 claims 1
- 241000700605 Viruses Species 0.000 claims 1
- ZAKOWWREFLAJOT-ADUHFSDSSA-N [2,5,7,8-tetramethyl-2-[(4R,8R)-4,8,12-trimethyltridecyl]-3,4-dihydrochromen-6-yl] acetate Chemical group CC(=O)OC1=C(C)C(C)=C2OC(CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C ZAKOWWREFLAJOT-ADUHFSDSSA-N 0.000 claims 1
- 229960004150 aciclovir Drugs 0.000 claims 1
- MKUXAQIIEYXACX-UHFFFAOYSA-N aciclovir Chemical compound N1C(N)=NC(=O)C2=C1N(COCCO)C=N2 MKUXAQIIEYXACX-UHFFFAOYSA-N 0.000 claims 1
- 229930183665 actinomycin Natural products 0.000 claims 1
- DKNWSYNQZKUICI-UHFFFAOYSA-N amantadine Chemical compound C1C(C2)CC3CC2CC1(N)C3 DKNWSYNQZKUICI-UHFFFAOYSA-N 0.000 claims 1
- 229960003805 amantadine Drugs 0.000 claims 1
- 150000001409 amidines Chemical class 0.000 claims 1
- 229960004821 amikacin Drugs 0.000 claims 1
- PECIYKGSSMCNHN-UHFFFAOYSA-N aminophylline Chemical compound NCCN.O=C1N(C)C(=O)N(C)C2=NC=N[C]21.O=C1N(C)C(=O)N(C)C2=NC=N[C]21 PECIYKGSSMCNHN-UHFFFAOYSA-N 0.000 claims 1
- 229960003022 amoxicillin Drugs 0.000 claims 1
- LSQZJLSUYDQPKJ-NJBDSQKTSA-N amoxicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=C(O)C=C1 LSQZJLSUYDQPKJ-NJBDSQKTSA-N 0.000 claims 1
- APKFDSVGJQXUKY-INPOYWNPSA-N amphotericin B Chemical compound O[C@H]1[C@@H](N)[C@H](O)[C@@H](C)O[C@H]1O[C@H]1/C=C/C=C/C=C/C=C/C=C/C=C/C=C/[C@H](C)[C@@H](O)[C@@H](C)[C@H](C)OC(=O)C[C@H](O)C[C@H](O)CC[C@@H](O)[C@H](O)C[C@H](O)C[C@](O)(C[C@H](O)[C@H]2C(O)=O)O[C@H]2C1 APKFDSVGJQXUKY-INPOYWNPSA-N 0.000 claims 1
- 229960003942 amphotericin b Drugs 0.000 claims 1
- 229960000723 ampicillin Drugs 0.000 claims 1
- AVKUERGKIZMTKX-NJBDSQKTSA-N ampicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=CC=C1 AVKUERGKIZMTKX-NJBDSQKTSA-N 0.000 claims 1
- 229940035676 analgesics Drugs 0.000 claims 1
- 239000000730 antalgic agent Substances 0.000 claims 1
- 230000003288 anthiarrhythmic effect Effects 0.000 claims 1
- 239000003242 anti bacterial agent Substances 0.000 claims 1
- 230000003178 anti-diabetic effect Effects 0.000 claims 1
- 230000002141 anti-parasite Effects 0.000 claims 1
- 239000003416 antiarrhythmic agent Substances 0.000 claims 1
- 229940088710 antibiotic agent Drugs 0.000 claims 1
- 229940125715 antihistaminic agent Drugs 0.000 claims 1
- 239000000739 antihistaminic agent Substances 0.000 claims 1
- 239000002246 antineoplastic agent Substances 0.000 claims 1
- 229940041181 antineoplastic drug Drugs 0.000 claims 1
- 229940125687 antiparasitic agent Drugs 0.000 claims 1
- 239000003096 antiparasitic agent Substances 0.000 claims 1
- 239000003443 antiviral agent Substances 0.000 claims 1
- 229940121357 antivirals Drugs 0.000 claims 1
- LMEKQMALGUDUQG-UHFFFAOYSA-N azathioprine Chemical compound CN1C=NC([N+]([O-])=O)=C1SC1=NC=NC2=C1NC=N2 LMEKQMALGUDUQG-UHFFFAOYSA-N 0.000 claims 1
- 229960002170 azathioprine Drugs 0.000 claims 1
- 229940125717 barbiturate Drugs 0.000 claims 1
- 229940049706 benzodiazepine Drugs 0.000 claims 1
- 229960002537 betamethasone Drugs 0.000 claims 1
- UREBDLICKHMUKA-DVTGEIKXSA-N betamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-DVTGEIKXSA-N 0.000 claims 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims 1
- FAKRSMQSSFJEIM-RQJHMYQMSA-N captopril Chemical compound SC[C@@H](C)C(=O)N1CCC[C@H]1C(O)=O FAKRSMQSSFJEIM-RQJHMYQMSA-N 0.000 claims 1
- 229960000830 captopril Drugs 0.000 claims 1
- 229960003669 carbenicillin Drugs 0.000 claims 1
- FPPNZSSZRUTDAP-UWFZAAFLSA-N carbenicillin Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)C(C(O)=O)C1=CC=CC=C1 FPPNZSSZRUTDAP-UWFZAAFLSA-N 0.000 claims 1
- 229940097217 cardiac glycoside Drugs 0.000 claims 1
- 239000002368 cardiac glycoside Substances 0.000 claims 1
- 229960004841 cefadroxil Drugs 0.000 claims 1
- NBFNMSULHIODTC-CYJZLJNKSA-N cefadroxil monohydrate Chemical compound O.C1([C@@H](N)C(=O)N[C@H]2[C@@H]3N(C2=O)C(=C(CS3)C)C(O)=O)=CC=C(O)C=C1 NBFNMSULHIODTC-CYJZLJNKSA-N 0.000 claims 1
- 229960001139 cefazolin Drugs 0.000 claims 1
- MLYYVTUWGNIJIB-BXKDBHETSA-N cefazolin Chemical compound S1C(C)=NN=C1SCC1=C(C(O)=O)N2C(=O)[C@@H](NC(=O)CN3N=NN=C3)[C@H]2SC1 MLYYVTUWGNIJIB-BXKDBHETSA-N 0.000 claims 1
- 229960004261 cefotaxime Drugs 0.000 claims 1
- AZZMGZXNTDTSME-JUZDKLSSSA-M cefotaxime sodium Chemical compound [Na+].N([C@@H]1C(N2C(=C(COC(C)=O)CS[C@@H]21)C([O-])=O)=O)C(=O)\C(=N/OC)C1=CSC(N)=N1 AZZMGZXNTDTSME-JUZDKLSSSA-M 0.000 claims 1
- 108010015046 cell aggregation factors Proteins 0.000 claims 1
- 229940124587 cephalosporin Drugs 0.000 claims 1
- 150000001780 cephalosporins Chemical class 0.000 claims 1
- ZPEIMTDSQAKGNT-UHFFFAOYSA-N chlorpromazine Chemical compound C1=C(Cl)C=C2N(CCCN(C)C)C3=CC=CC=C3SC2=C1 ZPEIMTDSQAKGNT-UHFFFAOYSA-N 0.000 claims 1
- 229960001076 chlorpromazine Drugs 0.000 claims 1
- 229960001761 chlorpropamide Drugs 0.000 claims 1
- 229960004022 clotrimazole Drugs 0.000 claims 1
- VNFPBHJOKIVQEB-UHFFFAOYSA-N clotrimazole Chemical compound ClC1=CC=CC=C1C(N1C=NC=C1)(C=1C=CC=CC=1)C1=CC=CC=C1 VNFPBHJOKIVQEB-UHFFFAOYSA-N 0.000 claims 1
- 229960004126 codeine Drugs 0.000 claims 1
- 239000003246 corticosteroid Substances 0.000 claims 1
- 229960001334 corticosteroids Drugs 0.000 claims 1
- 229960004397 cyclophosphamide Drugs 0.000 claims 1
- 229960000684 cytarabine Drugs 0.000 claims 1
- KWGRBVOPPLSCSI-UHFFFAOYSA-N d-ephedrine Natural products CNC(C)C(O)C1=CC=CC=C1 KWGRBVOPPLSCSI-UHFFFAOYSA-N 0.000 claims 1
- 229960003957 dexamethasone Drugs 0.000 claims 1
- UREBDLICKHMUKA-CXSFZGCWSA-N dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 claims 1
- 229960000632 dexamfetamine Drugs 0.000 claims 1
- 229960000525 diphenhydramine hydrochloride Drugs 0.000 claims 1
- 229940042399 direct acting antivirals protease inhibitors Drugs 0.000 claims 1
- 239000006185 dispersion Substances 0.000 claims 1
- 229960003638 dopamine Drugs 0.000 claims 1
- 229960002179 ephedrine Drugs 0.000 claims 1
- 229960005139 epinephrine Drugs 0.000 claims 1
- 229960003276 erythromycin Drugs 0.000 claims 1
- 229940011871 estrogen Drugs 0.000 claims 1
- 239000000262 estrogen Substances 0.000 claims 1
- 239000003925 fat Substances 0.000 claims 1
- ODKNJVUHOIMIIZ-RRKCRQDMSA-N floxuridine Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(F)=C1 ODKNJVUHOIMIIZ-RRKCRQDMSA-N 0.000 claims 1
- 229960000961 floxuridine Drugs 0.000 claims 1
- 229940028334 follicle stimulating hormone Drugs 0.000 claims 1
- 239000000417 fungicide Substances 0.000 claims 1
- 108010074605 gamma-Globulins Proteins 0.000 claims 1
- 229960002518 gentamicin Drugs 0.000 claims 1
- XLXSAKCOAKORKW-AQJXLSMYSA-N gonadorelin Chemical compound C([C@@H](C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N1[C@@H](CCC1)C(=O)NCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)C1=CC=C(O)C=C1 XLXSAKCOAKORKW-AQJXLSMYSA-N 0.000 claims 1
- 239000002622 gonadotropin Substances 0.000 claims 1
- 239000000122 growth hormone Substances 0.000 claims 1
- 229960002474 hydralazine Drugs 0.000 claims 1
- OROGSEYTTFOCAN-UHFFFAOYSA-N hydrocodone Natural products C1C(N(CCC234)C)C2C=CC(O)C3OC2=C4C1=CC=C2OC OROGSEYTTFOCAN-UHFFFAOYSA-N 0.000 claims 1
- 229960000890 hydrocortisone Drugs 0.000 claims 1
- WVLOADHCBXTIJK-YNHQPCIGSA-N hydromorphone Chemical compound O([C@H]1C(CC[C@H]23)=O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O WVLOADHCBXTIJK-YNHQPCIGSA-N 0.000 claims 1
- 229960001410 hydromorphone Drugs 0.000 claims 1
- 229960002738 hydromorphone hydrochloride Drugs 0.000 claims 1
- ZQDWXGKKHFNSQK-UHFFFAOYSA-N hydroxyzine Chemical compound C1CN(CCOCCO)CCN1C(C=1C=CC(Cl)=CC=1)C1=CC=CC=C1 ZQDWXGKKHFNSQK-UHFFFAOYSA-N 0.000 claims 1
- 229960000930 hydroxyzine Drugs 0.000 claims 1
- 208000021822 hypotensive Diseases 0.000 claims 1
- 230000001077 hypotensive effect Effects 0.000 claims 1
- 229960002182 imipenem Drugs 0.000 claims 1
- ZSKVGTPCRGIANV-ZXFLCMHBSA-N imipenem Chemical compound C1C(SCC\N=C\N)=C(C(O)=O)N2C(=O)[C@H]([C@H](O)C)[C@H]21 ZSKVGTPCRGIANV-ZXFLCMHBSA-N 0.000 claims 1
- 230000001024 immunotherapeutic effect Effects 0.000 claims 1
- 229960002479 isosorbide Drugs 0.000 claims 1
- 229960001924 melphalan Drugs 0.000 claims 1
- SGDBTWWWUNNDEQ-LBPRGKRZSA-N melphalan Chemical compound OC(=O)[C@@H](N)CC1=CC=C(N(CCCl)CCCl)C=C1 SGDBTWWWUNNDEQ-LBPRGKRZSA-N 0.000 claims 1
- YACKEPLHDIMKIO-UHFFFAOYSA-L methylphosphonate(2-) Chemical compound CP([O-])([O-])=O YACKEPLHDIMKIO-UHFFFAOYSA-L 0.000 claims 1
- 229960000282 metronidazole Drugs 0.000 claims 1
- VAOCPAMSLUNLGC-UHFFFAOYSA-N metronidazole Chemical compound CC1=NC=C([N+]([O-])=O)N1CCO VAOCPAMSLUNLGC-UHFFFAOYSA-N 0.000 claims 1
- KKZJGLLVHKMTCM-UHFFFAOYSA-N mitoxantrone Chemical compound O=C1C2=C(O)C=CC(O)=C2C(=O)C2=C1C(NCCNCCO)=CC=C2NCCNCCO KKZJGLLVHKMTCM-UHFFFAOYSA-N 0.000 claims 1
- 229960001156 mitoxantrone Drugs 0.000 claims 1
- 229960005181 morphine Drugs 0.000 claims 1
- BSOQXXWZTUDTEL-ZUYCGGNHSA-N muramyl dipeptide Chemical compound OC(=O)CC[C@H](C(N)=O)NC(=O)[C@H](C)NC(=O)[C@@H](C)O[C@H]1[C@H](O)[C@@H](CO)O[C@@H](O)[C@@H]1NC(C)=O BSOQXXWZTUDTEL-ZUYCGGNHSA-N 0.000 claims 1
- 229960002748 norepinephrine Drugs 0.000 claims 1
- SFLSHLFXELFNJZ-UHFFFAOYSA-N norepinephrine Natural products NCC(O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-UHFFFAOYSA-N 0.000 claims 1
- 229940041024 other aminoglycosides in atc Drugs 0.000 claims 1
- LSQZJLSUYDQPKJ-UHFFFAOYSA-N p-Hydroxyampicillin Natural products O=C1N2C(C(O)=O)C(C)(C)SC2C1NC(=O)C(N)C1=CC=C(O)C=C1 LSQZJLSUYDQPKJ-UHFFFAOYSA-N 0.000 claims 1
- XDRYMKDFEDOLFX-UHFFFAOYSA-N pentamidine Chemical compound C1=CC(C(=N)N)=CC=C1OCCCCCOC1=CC=C(C(N)=N)C=C1 XDRYMKDFEDOLFX-UHFFFAOYSA-N 0.000 claims 1
- 229960004448 pentamidine Drugs 0.000 claims 1
- 239000000137 peptide hydrolase inhibitor Substances 0.000 claims 1
- 229960000482 pethidine Drugs 0.000 claims 1
- DDBREPKUVSBGFI-UHFFFAOYSA-N phenobarbital Chemical compound C=1C=CC=CC=1C1(CC)C(=O)NC(=O)NC1=O DDBREPKUVSBGFI-UHFFFAOYSA-N 0.000 claims 1
- 229960002695 phenobarbital Drugs 0.000 claims 1
- 229950000688 phenothiazine Drugs 0.000 claims 1
- 229940127126 plasminogen activator Drugs 0.000 claims 1
- 229960002957 praziquantel Drugs 0.000 claims 1
- 229960005205 prednisolone Drugs 0.000 claims 1
- OIGNJSKKLXVSLS-VWUMJDOOSA-N prednisolone Chemical compound O=C1C=C[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 OIGNJSKKLXVSLS-VWUMJDOOSA-N 0.000 claims 1
- 229960004618 prednisone Drugs 0.000 claims 1
- XOFYZVNMUHMLCC-ZPOLXVRWSA-N prednisone Chemical compound O=C1C=C[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 XOFYZVNMUHMLCC-ZPOLXVRWSA-N 0.000 claims 1
- 229960003387 progesterone Drugs 0.000 claims 1
- 239000000186 progesterone Substances 0.000 claims 1
- BJOIZNZVOZKDIG-MDEJGZGSSA-N reserpine Chemical compound O([C@H]1[C@@H]([C@H]([C@H]2C[C@@H]3C4=C([C]5C=CC(OC)=CC5=N4)CCN3C[C@H]2C1)C(=O)OC)OC)C(=O)C1=CC(OC)=C(OC)C(OC)=C1 BJOIZNZVOZKDIG-MDEJGZGSSA-N 0.000 claims 1
- 229960003147 reserpine Drugs 0.000 claims 1
- 230000000241 respiratory effect Effects 0.000 claims 1
- 229960000329 ribavirin Drugs 0.000 claims 1
- HZCAHMRRMINHDJ-DBRKOABJSA-N ribavirin Natural products O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1N=CN=C1 HZCAHMRRMINHDJ-DBRKOABJSA-N 0.000 claims 1
- MDMGHDFNKNZPAU-UHFFFAOYSA-N roserpine Natural products C1C2CN3CCC(C4=CC=C(OC)C=C4N4)=C4C3CC2C(OC(C)=O)C(OC)C1OC(=O)C1=CC(OC)=C(OC)C(OC)=C1 MDMGHDFNKNZPAU-UHFFFAOYSA-N 0.000 claims 1
- 150000003839 salts Chemical class 0.000 claims 1
- 229940125723 sedative agent Drugs 0.000 claims 1
- 239000000932 sedative agent Substances 0.000 claims 1
- 229930002534 steroid glycoside Natural products 0.000 claims 1
- 150000008143 steroidal glycosides Chemical class 0.000 claims 1
- 150000003431 steroids Chemical class 0.000 claims 1
- 229960001052 streptozocin Drugs 0.000 claims 1
- ZSJLQEPLLKMAKR-GKHCUFPYSA-N streptozocin Chemical compound O=NN(C)C(=O)N[C@H]1[C@@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O ZSJLQEPLLKMAKR-GKHCUFPYSA-N 0.000 claims 1
- OKQKDCXVLPGWPO-UHFFFAOYSA-N sulfanylidenephosphane Chemical compound S=P OKQKDCXVLPGWPO-UHFFFAOYSA-N 0.000 claims 1
- 229960000195 terbutaline Drugs 0.000 claims 1
- 229960003604 testosterone Drugs 0.000 claims 1
- 229960002180 tetracycline Drugs 0.000 claims 1
- 229930101283 tetracycline Natural products 0.000 claims 1
- 235000019364 tetracycline Nutrition 0.000 claims 1
- 150000003522 tetracyclines Chemical class 0.000 claims 1
- 229940043672 thyroid preparations Drugs 0.000 claims 1
- 229960000707 tobramycin Drugs 0.000 claims 1
- NLVFBUXFDBBNBW-PBSUHMDJSA-N tobramycin Chemical compound N[C@@H]1C[C@H](O)[C@@H](CN)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](N)[C@H](O)[C@@H](CO)O2)O)[C@H](N)C[C@@H]1N NLVFBUXFDBBNBW-PBSUHMDJSA-N 0.000 claims 1
- 125000002640 tocopherol group Chemical class 0.000 claims 1
- 235000019149 tocopherols Nutrition 0.000 claims 1
- 239000003204 tranquilizing agent Substances 0.000 claims 1
- 230000002936 tranquilizing effect Effects 0.000 claims 1
- 229960005294 triamcinolone Drugs 0.000 claims 1
- GFNANZIMVAIWHM-OBYCQNJPSA-N triamcinolone Chemical compound O=C1C=C[C@]2(C)[C@@]3(F)[C@@H](O)C[C@](C)([C@@]([C@H](O)C4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 GFNANZIMVAIWHM-OBYCQNJPSA-N 0.000 claims 1
- 229960005486 vaccine Drugs 0.000 claims 1
- 229960003165 vancomycin Drugs 0.000 claims 1
- MYPYJXKWCTUITO-UHFFFAOYSA-N vancomycin Natural products O1C(C(=C2)Cl)=CC=C2C(O)C(C(NC(C2=CC(O)=CC(O)=C2C=2C(O)=CC=C3C=2)C(O)=O)=O)NC(=O)C3NC(=O)C2NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(CC(C)C)NC)C(O)C(C=C3Cl)=CC=C3OC3=CC2=CC1=C3OC1OC(CO)C(O)C(O)C1OC1CC(C)(N)C(O)C(C)O1 MYPYJXKWCTUITO-UHFFFAOYSA-N 0.000 claims 1
- MYPYJXKWCTUITO-LYRMYLQWSA-O vancomycin(1+) Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=C2C=C3C=C1OC1=CC=C(C=C1Cl)[C@@H](O)[C@H](C(N[C@@H](CC(N)=O)C(=O)N[C@H]3C(=O)N[C@H]1C(=O)N[C@H](C(N[C@@H](C3=CC(O)=CC(O)=C3C=3C(O)=CC=C1C=3)C([O-])=O)=O)[C@H](O)C1=CC=C(C(=C1)Cl)O2)=O)NC(=O)[C@@H](CC(C)C)[NH2+]C)[C@H]1C[C@](C)([NH3+])[C@H](O)[C@H](C)O1 MYPYJXKWCTUITO-LYRMYLQWSA-O 0.000 claims 1
- 229960001722 verapamil Drugs 0.000 claims 1
- 229960003636 vidarabine Drugs 0.000 claims 1
- 229960002555 zidovudine Drugs 0.000 claims 1
- HBOMLICNUCNMMY-XLPZGREQSA-N zidovudine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](N=[N+]=[N-])C1 HBOMLICNUCNMMY-XLPZGREQSA-N 0.000 claims 1
- 239000011324 bead Substances 0.000 description 17
- 239000002775 capsule Substances 0.000 description 17
- BAECOWNUKCLBPZ-HIUWNOOHSA-N Triolein Natural products O([C@H](OCC(=O)CCCCCCC/C=C\CCCCCCCC)COC(=O)CCCCCCC/C=C\CCCCCCCC)C(=O)CCCCCCC/C=C\CCCCCCCC BAECOWNUKCLBPZ-HIUWNOOHSA-N 0.000 description 11
- PHYFQTYBJUILEZ-UHFFFAOYSA-N Trioleoylglycerol Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC(OC(=O)CCCCCCCC=CCCCCCCCC)COC(=O)CCCCCCCC=CCCCCCCCC PHYFQTYBJUILEZ-UHFFFAOYSA-N 0.000 description 11
- PHYFQTYBJUILEZ-IUPFWZBJSA-N triolein Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC(OC(=O)CCCCCCC\C=C/CCCCCCCC)COC(=O)CCCCCCC\C=C/CCCCCCCC PHYFQTYBJUILEZ-IUPFWZBJSA-N 0.000 description 11
- 229940117972 triolein Drugs 0.000 description 11
- OPTASPLRGRRNAP-UHFFFAOYSA-N cytosine Chemical compound NC=1C=CNC(=O)N=1 OPTASPLRGRRNAP-UHFFFAOYSA-N 0.000 description 8
- 238000002360 preparation method Methods 0.000 description 7
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
- 239000003513 alkali Substances 0.000 description 6
- 235000011187 glycerol Nutrition 0.000 description 6
- 239000000725 suspension Substances 0.000 description 5
- 229940104302 cytosine Drugs 0.000 description 4
- 238000007789 sealing Methods 0.000 description 4
- 108020004414 DNA Proteins 0.000 description 3
- 238000007920 subcutaneous administration Methods 0.000 description 3
- 102100039620 Granulocyte-macrophage colony-stimulating factor Human genes 0.000 description 2
- 239000000232 Lipid Bilayer Substances 0.000 description 2
- 108020004511 Recombinant DNA Proteins 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000012153 distilled water Substances 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 210000000981 epithelium Anatomy 0.000 description 2
- 239000003102 growth factor Substances 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- PSGAAPLEWMOORI-PEINSRQWSA-N medroxyprogesterone acetate Chemical compound C([C@@]12C)CC(=O)C=C1[C@@H](C)C[C@@H]1[C@@H]2CC[C@]2(C)[C@@](OC(C)=O)(C(C)=O)CC[C@H]21 PSGAAPLEWMOORI-PEINSRQWSA-N 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- 230000002085 persistent effect Effects 0.000 description 2
- 239000002356 single layer Substances 0.000 description 2
- CITHEXJVPOWHKC-UUWRZZSWSA-N 1,2-di-O-myristoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCCCCCCC CITHEXJVPOWHKC-UUWRZZSWSA-N 0.000 description 1
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
- 235000019737 Animal fat Nutrition 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- 108010071942 Colony-Stimulating Factors Proteins 0.000 description 1
- 102000007644 Colony-Stimulating Factors Human genes 0.000 description 1
- 239000000055 Corticotropin-Releasing Hormone Substances 0.000 description 1
- 101000904173 Homo sapiens Progonadoliberin-1 Proteins 0.000 description 1
- 108091028043 Nucleic acid sequence Proteins 0.000 description 1
- 102100024028 Progonadoliberin-1 Human genes 0.000 description 1
- 101000996723 Sus scrofa Gonadotropin-releasing hormone receptor Proteins 0.000 description 1
- MSCCTZZBYHQMQJ-AZAGJHQNSA-N Tocopheryl nicotinate Chemical compound C([C@@](OC1=C(C)C=2C)(C)CCC[C@H](C)CCC[C@H](C)CCCC(C)C)CC1=C(C)C=2OC(=O)C1=CC=CN=C1 MSCCTZZBYHQMQJ-AZAGJHQNSA-N 0.000 description 1
- KPBYZDRYGZZKIG-UHFFFAOYSA-N [hexadecanoyloxy(hydroxy)phosphoryl] hexadecanoate Chemical compound CCCCCCCCCCCCCCCC(=O)OP(O)(=O)OC(=O)CCCCCCCCCCCCCCC KPBYZDRYGZZKIG-UHFFFAOYSA-N 0.000 description 1
- 239000000159 acid neutralizing agent Substances 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 239000000853 adhesive Substances 0.000 description 1
- FQPFAHBPWDRTLU-UHFFFAOYSA-N aminophylline Chemical compound NCCN.O=C1N(C)C(=O)N(C)C2=C1NC=N2.O=C1N(C)C(=O)N(C)C2=C1NC=N2 FQPFAHBPWDRTLU-UHFFFAOYSA-N 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 230000005907 cancer growth Effects 0.000 description 1
- 229960003291 chlorphenamine Drugs 0.000 description 1
- SOYKEARSMXGVTM-UHFFFAOYSA-N chlorphenamine Chemical compound C=1C=CC=NC=1C(CCN(C)C)C1=CC=C(Cl)C=C1 SOYKEARSMXGVTM-UHFFFAOYSA-N 0.000 description 1
- 150000001840 cholesterol esters Chemical class 0.000 description 1
- GVJHHUAWPYXKBD-UHFFFAOYSA-N d-alpha-tocopherol Natural products OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 description 1
- BPHQZTVXXXJVHI-UHFFFAOYSA-N dimyristoyl phosphatidylglycerol Chemical compound CCCCCCCCCCCCCC(=O)OCC(COP(O)(=O)OCC(O)CO)OC(=O)CCCCCCCCCCCCC BPHQZTVXXXJVHI-UHFFFAOYSA-N 0.000 description 1
- BIABMEZBCHDPBV-UHFFFAOYSA-N dipalmitoyl phosphatidylglycerol Chemical compound CCCCCCCCCCCCCCCC(=O)OCC(COP(O)(=O)OCC(O)CO)OC(=O)CCCCCCCCCCCCCCC BIABMEZBCHDPBV-UHFFFAOYSA-N 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 235000019197 fats Nutrition 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 238000011010 flushing procedure Methods 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- XLXSAKCOAKORKW-UHFFFAOYSA-N gonadorelin Chemical compound C1CCC(C(=O)NCC(N)=O)N1C(=O)C(CCCN=C(N)N)NC(=O)C(CC(C)C)NC(=O)CNC(=O)C(NC(=O)C(CO)NC(=O)C(CC=1C2=CC=CC=C2NC=1)NC(=O)C(CC=1NC=NC=1)NC(=O)C1NC(=O)CC1)CC1=CC=C(O)C=C1 XLXSAKCOAKORKW-UHFFFAOYSA-N 0.000 description 1
- 230000002607 hemopoietic effect Effects 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 239000000960 hypophysis hormone Substances 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000011081 inoculation Methods 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- LMOINURANNBYCM-UHFFFAOYSA-N metaproterenol Chemical compound CC(C)NCC(O)C1=CC(O)=CC(O)=C1 LMOINURANNBYCM-UHFFFAOYSA-N 0.000 description 1
- YACKEPLHDIMKIO-UHFFFAOYSA-N methylphosphonic acid Chemical compound CP(O)(O)=O YACKEPLHDIMKIO-UHFFFAOYSA-N 0.000 description 1
- 210000004877 mucosa Anatomy 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 125000002811 oleoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])/C([H])=C([H])\C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 102000027450 oncoproteins Human genes 0.000 description 1
- 108091008819 oncoproteins Proteins 0.000 description 1
- 229960002657 orciprenaline Drugs 0.000 description 1
- 239000003087 receptor blocking agent Substances 0.000 description 1
- 239000003488 releasing hormone Substances 0.000 description 1
- 239000002195 soluble material Substances 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 229960001295 tocopherol Drugs 0.000 description 1
- 235000010384 tocopherol Nutrition 0.000 description 1
- 229940093609 tricaprylin Drugs 0.000 description 1
- VLPFTAMPNXLGLX-UHFFFAOYSA-N trioctanoin Chemical compound CCCCCCCC(=O)OCC(OC(=O)CCCCCCC)COC(=O)CCCCCCC VLPFTAMPNXLGLX-UHFFFAOYSA-N 0.000 description 1
- 238000009423 ventilation Methods 0.000 description 1
- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/127—Synthetic bilayered vehicles, e.g. liposomes or liposomes with cholesterol as the only non-phosphatidyl surfactant
- A61K9/1277—Preparation processes; Proliposomes
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Dispersion Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Manufacturing Of Micro-Capsules (AREA)
- Saccharide Compounds (AREA)
Abstract
本发明涉及制备含有至少两种不同物质的杂泡脂质体的方法，所述的不同物质被分别包封在水腔中，其中至少一种物质是生物活性物质。所述的杂泡脂质体可用来对患者进行治疗。
Description
本发明步及合成的杂泡脂质囊(hetero vesicular Cipidvesicles)或脂质体(liposomes)，其制备方法，各种材料在其内的包封，以及使用它们对患者进行治疗。
多泡(multivesicular)脂质体是三种主要类型的脂质体之一，它首先由Kim.等人制得(1983，Biochim，Biophys，Acta 782，339～348)。该脂质体不同于单层(unilamellar)(Huang，1969，Biochemistry 8，344～352；Kim，等1981.Biochim.Biophys.Acta 646，1～10)和多层(multilamellar)(Bangham，等1965，J.Mol.Bio.13,238～252)脂质体，在其内，有多个非同心的水腔。用于生产脂质体的现有技术涉及生产非多泡脂质体，如美国专利4，522，803-Lenk；4,310,506-Baldeschwieler 4,235,871-Papahadjopoulos；4,224,179-4,078,052-Papahadjopoulos，4,394,372-Taylor94,308,166-Marchetti；4,485,054-Mezei；4,508,703-Redziniak。各种脂质体制备方法的综合评述参见Szoka，等1980，Ann.Rev.Biophys.Bioeng.9：467～508。
杂泡脂质体是具有多个内部水腔的脂质囊或脂质体，在一个脂质体内的每单个水腔中，至少包封两种不同组成的物质。具有多个内部水腔的脂质囊或脂质体包括，但不限于，多层脂质体，稳定的少层(paucl lamellar)脂质体，和多泡脂质体。本发明提供的脂质体供给系统的优点在于：在单个脂质体中是在不同的腔室包封两种或多种不同的物质，而不是将它们一起包封在一个腔室内。
本发明的组分包含杂泡脂质体，即具有多个内部水腔的脂质囊或脂质体，其中两种或多种不同组成的物质被分别包封在一个脂质体的不同腔室内。
简而言之，本发明的方法包括制备“脂质包水”的乳化液，首先溶解两亲的脂质在一种或多种有机溶剂中作为第一种脂质组分；再向其中加入不混溶的第一种含水组分，该含水组分包含有欲被包封的物质，在其内最好还含有盐酸；然后机械乳化该混合物。在乳化液中，悬浮在有机溶剂中的水滴将形成内部水腔，连接水腔的两亲脂质的单层将成为最后产品中双层膜的一边。在一种可挥发的有机溶剂中溶解两亲脂质形成第二种脂质组分，向其中加入包含有第二种欲被包封物质的不混溶的第二种含水组分，最好含水组分中还含有盐酸。然后制得第二种乳化液。将第一和第二种乳化液结合而形成嵌合乳化液。嵌合乳化液由多个悬浮在有机溶剂中的水滴组成其中，两种不同组成的物质被分别溶解在不同的水滴中。嵌合乳化液再浸入第三种不混溶的含水组分中，该含水组分最好包含一种或多种非离子渗透剂和低离子强度的酸中和剂，然后机械地将其分散形成悬浮在第三种含水组份中的溶剂小球。溶剂小球含有多个水滴，在其内，两种不同组成的物质在一个溶剂小球内被分别溶解在不同的水滴中。最好通过向悬浮液中通气体流的方法将可挥发性有机溶剂从小球中蒸出。当溶剂被完全蒸出后，小球转化成具有多个内部水腔的杂泡脂质体，其中在一个脂质体内，两种不同组成的物质被分别包封在不同的腔内。
使用能减缓释放速度的含中和剂的盐酸或其它氢氯化物可以有效地进行包封并在生物流体中和体内减缓被包封的分子的释放速度。最好使用低离子强度的中和剂以防止溶剂小球的相互粘连。
相应地，本发明的目的之一是指供一种杂泡脂质囊或脂质体，它具有至少两种组成不同的分别被包封在脂质囊或脂质体的不同腔室内的物质。
本发明的另一个目的是提供一种杂泡脂质体，它包含至少两种不同组成的生物活性物质，它们分别在盐酸或其它可减缓它的释放的氢氯化物存在下被分别包封在脂质体的不同的腔室内。
本发明的另一个目的是提供一种杂泡脂质体，它包含至少两种不同组成的生物活性物质，它们分别在盐酸或其它氢氯化物和一种中和剂存在下被分别包封在脂质体的不同的腔室内。
本发明的另一个目的是提供生产上述杂泡脂质囊或脂质体的方法。
本发明的另一个目的是提供生产上述杂泡脂质囊或脂质体的工艺方法，该方法包括：首先制得溶解于一种或多种有机溶剂中的第一种脂质组分，向其内加入含有欲包封的第一种物质的不混溶的第一种含水组分，从而由两种不混溶的组分形成第一种油包水乳化液：再制得溶解于一种或多种有机溶剂的第二种脂质组分，向其内加入含有欲包封的第二种物质的不混溶的第二种含水组分，从而由第二种两不混溶的组分形成第二种油包水乳化液；将第一种和第二种油包水乳化液合在一起形成嵌合乳化液。转移并将嵌合乳化液浸入第三种不混溶的含水组分，分散嵌合乳化液形成溶剂小球：该溶剂小球包含多个含有第一种物质的第一种含水组分的液滴和含有第二种物质的第二种含水组分的液滴；使有机溶剂从溶剂小球中蒸出，形成了杂泡脂质囊或脂质体。
本发明的另一个目的是提供一种方法，其中，各种亲水的生物活性物质可被分别包封在杂泡脂质囊或脂质体的单个腔室内。
本发明的另一个目的是提供一种用至少两种不同组成的不同生物活性的物质给药于患者而对患者进行治疗的方法，活性物质被分别包封在杂泡囊或脂质体的不同的腔室内。
本发明的其它内容，进一步的目的，特征和优点在整个说明书和权利要求书中可显示出来。
图1-8为制备杂泡囊或脂质体的示意图。
在说明书和权利要求中使用的术语“多泡脂质体”(multivesicular Liposomes)是指由双分子脂膜组成的人造微观脂质囊，脂膜包封了含有同一组分的多个非同心的水腔。相反，说明书和权利要求中使用的术语“杂泡脂质体”(heterovesicular Liposomes)是指由双分子脂膜组成的人造微观脂质囊，其脂膜包封了多个水腔，其中至少有两个水腔分别包含不同组成的物质。微观脂质囊包括但不限于：多层(multi-lamellar)脂质体，稳定的少层(Paucilamellar)脂质体和多泡脂质体。
在说明书和权利要求中使用的术语“嵌合(Chimeric)乳化液”是指由悬浮在有机溶剂中的多个水滴组成的乳化液，其中，两种不同组成的物质分别溶解于不同的水滴。
在说明书和权利要求中使用的术语“溶剂小球”是指有机溶剂的微观球形体液滴，在其内部有多个更小的水溶液液滴。溶剂小球悬浮在第二种水溶液中，但总体上与之不互溶。
术语“中性脂质”(neutral Lipid)是指不具有通过自身成膜能力和缺乏亲水端基的油或脂肪。
术语“两亲脂质”(amphipathic Lipids)是指那些具有亲水端基和疏水尾基，并具有成膜能力的分子。
本发明的组分是至少具有两种不同组成的物质，同时每一种又分别被包封在囊或脂质体的不同腔内的杂泡囊或脂质体。
各种各样的生物物质可通过包封而掺入多泡脂质体。它们包括药物和其它种类的材料如DNA，RNA，各种类型的蛋白质，通过重组DNA技术而生产的对人体有作用的蛋白激素，造血生长因子，单核因子，淋巴因子，肿瘤坏死因子，抑制素，肿癌生长因子α和β，mullerian抑制物质，神经生长因子，成纤维细胞生长因子，血小板衍生生长因子，脑垂体激素(包括LH和共它释放激素)，降钙素，用于接种以免疫的蛋白质，和DNA与RNA序列。
下列表1包括了一系列代表性的生物活性物质，它们可在氢氯化物存在下包封入杂泡脂质体中并对人体有效。
表1止喘药二羟苯基异丙氨基乙醇氨茶碱茶碱特普它林〔1-(3，5-二羟基苯基)-2-特丁氨基乙醇〕氨甲酰苯麻黄素喘息定(异丙肾上腺素肾上腺素去甲肾上腺素抗心律失常药萘心安氨酰心安戊脉安巯甲丙脯酸异山梨糖醇安定药氯丙嗪苯〔并〕二氮丁酰苯羟嗪氨甲丙二酯吩噻嗪利血平硫蒽强心苷洋地黄洋地黄毒甙毛花甙C异羟洋地黄毒甙激素制尿药皮质类甾醇睾酮雌激素甲状腺(制剂)生长(激素)ACTH(促皮质素)孕酮促性腺激素盐[肾上腺]皮质激素LH(促黄体激素)LHRH(促黄体激素释放因子)FSH(促卵泡激素)降钙素类固醇(甾类化合物)强的松去炎松半琥酯氢化可的松地塞米松倍他米松强的松龙抗高血压药肼苯哒嗪氨酰心胺抗糖尿病药氨磺丙脲(Diabenese)胰岛素抗组胺药苄吡二胺(吡苄明)右旋氯苯吡胺(Chlor Pheniramine)盐酸苯海拉明抗寄生物药吡喹酮甲硝哒唑戊烷脒抗癌药硫唑嘌呤博来霉素环磷酰胺阿霉素柔红霉素长春新碱甲氨蝶呤6-TG(硫鸟嘌呤)6-MP(巯嘌呤)长春碱VP-16VM-26(鬼臼噻吩甙)顺氯氨铂Fu(氟尿嘧啶)镇静药和止痛药吗啡盐酸二氢吗啡酮可待因类可待因合成物度冷丁羟氢吗啡酮苯巴比妥巴比妥类抗生素青霉素四环素红霉素头孢菌素I亚胺培南头孢氨噻羧苄青霉素万古霉素庆大霉素妥布霉素氧哌嗪青霉素羟羧氧酰胺菌素羟氨苄青霉素氨苄青霉素头孢唑啉天孢羟氨苄头霉噻吩其它氨基糖甙类免疫治疗剂干扰素白细胞介素-2单克隆抗体丙种球蛋白菌苗流感(疫苗)呼吸多核的病毒嗜血杆菌属流感疫苗杀真菌药两性霉素B双氯苯咪唑胞壁酰二肽克霉唑抗低血坟药多巴胺右旋苯丙胺抗病毒药无环鸟苷和其衍生物二噁沙利(Winthrop-51711)三唑核苷金刚胺叠氮胸苷腺嘌呤阿拉伯糖苷脒类蛋白酶抑制剂蛋白质和糖蛋白淋巴因子白细胞介素-1，2，3，4，5，6细胞活素GM-CSFM-CSFG-CSF肿瘤坏死因子抑制素肿瘤生长因子穆勒氏抑制物质神经生长因子成纤维细胞生长因子血小板衍生生长因子凝聚因子(如VIII，IX，VII)胰岛素纤维蛋白溶酶原激活剂
组织相容性抗原
癌基因产物
髓磷脂碱蛋白
胶原
纤维结合素
层粘连蛋白
由重组DNA技术制得的其它蛋白
其它
细胞表面受体阻滞剂
核酸和类似物
DNA
RNA
膦酸甲酯和类似物
制备杂泡囊或脂质体的较好的方法示于附图，参见如下步骤：第1步(图1)，组成为10的第一种欲包封的含水物质被加入在小玻璃瓶(vial)14中的第一种脂质组分12中，小瓶被密封.第2步(图2)是混合和振荡，如被装于涡旋混合器，从而形成包含第一种欲包封的组成为10的物质的油包水乳化液16.第3步，(图3)，在第二个小瓶14a中，将第二种欲包封的组成为10a的含水物质加入到第二种脂质组分12a中，密封小瓶14a.第4步(图4)是混合，同样装入涡旋混合器中，从而形成包含第二种欲包封的组成为10a的物质的油包水乳化液16a。
第5步(图5)，第一种和第二种油包水乳化液16和16a加到一块并进行混合，如用人工混合，从而形成一种“嵌合乳化液”。
第6步(图6)，第5步的部分嵌合乳化液被单个地加到装有第3种不混溶的含水组分18a的多个小瓶中，如，该添加过程是通过迅速地喷射乳化液通过一个窄喷嘴的Pasteur漏斗型装置(narrowtip pasteur Pipette)进入两个1德拉姆(dram)瓶，这里显示了一个。
第7步(图7)，振荡第6步的瓶子，如通过涡旋混合器，第8步(图8)，在每个小瓶中的氯仿球状悬浮液被取出，蒸出氯仿，如通过氮气流，从而得到了包含在一个或多个内部水腔的第一种物质10，在其余内部水腔中的第二种物质10a的杂泡脂质体，上水腔均在一个脂质体内。
较好地，每一种欲包封的物质均在氢氯化物存在下进行包封，从而减小它们从脂质体或囊中的释放速率，氢氯化物的实例如盐酸。
如前面提到的，任何一种生物活性物质，如表1中所示的，均可分别地包封入囊或脂质体的腔中。
下列实例给出了两种不同组成的物质被包封入囊或脂质体的不同腔内的较好的方法。
例1.双去氧胞苷/葡萄糖杂泡脂质体的制备
第1步：第一种含水物质(1ml的20mg/ml的双去氧胞苷的水溶液，盐酸的浓度0.1N)被加入到盛有第一种脂质组分(9.3umoles的二油酰(diolocyl)卵磷脂，2.1umoles的二棕榈酰磷酯酰甘油，15umoles的胆甾醇，1.8umoles的三油精和1ml的氯仿)的1德拉姆瓶中。
第2步：密封第一个小瓶并装于涡旋混合器中以最大速度振荡6分钟，形成第一种油包水乳化液。
第3步：第二个小瓶中，第二种含水物质(1ml的30mg/ml葡萄糖水溶液，盐酸浓度0.1N)被加入到第二种脂质组分中(与第一种脂质组分相同)。
第4步：密封第二个小瓶并装于涡旋混合器中以最大速度振荡6分钟，形成第二种油包水乳化液。
第5步：将0.5ml第一种乳化液加到第二个瓶中，手动混合制得“嵌合”乳化液。
第6步：将一半的嵌合乳化液通过窄喷嘴的Pasteur漏斗迅速喷射入几个1德拉姆的小瓶，这些瓶内均包含有第三种不互混溶的含水组分(2.5ml水，32mg/ml葡萄糖，40mM游离碱(free-base)赖氨酸。
第7步：在涡旋混合器上振荡第6步的小瓶3秒钟(以第5挡)，形成包含多个第一和第二种含水物质在内的溶剂小球。
第8步：在每个小瓶中的氯仿小球悬浮液被转移到包含4.5ml水，35mg/ml葡萄糖，22mM游离碱赖氨酸的2L烧杯的底部。氮气流以7L/min的速度冲洗烧杯以在5分钟内15℃下蒸出氯仿。
上述的实例描述了一种在单个脂质体内包含约5/6的内部水腔的葡萄糖和约其余的1/6的内部水腔的双去氧胞苷的杂泡脂质体的制备方法。包含双去氧胞苷作为第一种含水物质和葡萄糖作为第二种含水物质的杂泡脂质体较之非杂泡脂质体具有显著的稳定性。
例2
这个例子是合成包含IL-2(白细胞介素-2)和盐酸赖氨酸的杂泡脂质体：每一次制备脂质体，1ml的含10mg/mlHSA(小造血清白蛋白)，1μg的IL-2，200mM盐酸赖氨酸，PH为7.13的水加入到一个1德拉姆瓶中，瓶内盛有9.3umoles的二油酰卵磷脂，2.1umoles的二棕榈酰磷脂酰甘油，15umoles的胆甾醇，1.8umoles的三油精和1ml的氯仿。(这是第一种油包水乳化液)。对第二种油包水乳化液，将1ml的盐酸赖氨酸(无IL-2)加入到含有9.3umoles的二油酰卵磷脂，2.1umoles的二棕榈酰磷脂酰甘油，15umoles的胆甾醇，1.8 umoles的三油精和1ml氯仿的1德拉姆的小瓶中。两个小瓶均被装到涡旋混合器上并在最大速度下振荡6分钟。
将0.5ml的第一种油包水乳化液加到2ml的第二种乳化液中，混合形成“嵌合”油包水乳化液。将一半的嵌合乳化液单个地通过窄喷嘴Pasteur漏斗型装置迅速地喷射入多个1德拉姆小瓶，每个小瓶内盛有2.5ml的4％葡萄糖水溶液，0.1ml200mM的赖氨酸游离碱，在最大速度下振荡小瓶3秒，以形成氯仿小球。将氯仿小球悬浮液转移至250ml的Erlenmeyer烧瓶中，烧瓶内盛有5ml 4％的葡萄糖水溶液和0.2ml，200mM的赖氨酸游离碱。氮气流以7L/min的速度冲洗烧瓶以在5分钟内在37℃下蒸出氯仿。
例3
这个例子为合成包含阿糖胞苷(ara-C)溶液作为第一种含水物质和蒸馏水作为第二种含水物质的杂泡脂质体。对每一次制备的脂质体，将含100mg/ml ara-C，PH1.1的1ml水加入到含有9.3umoles的二油酰卵磷脂，2.1umoles的二棕榈酰磷脂酰甘油，15umoles的胆甾醇，1.8umoles的三油精和1ml的氯仿的1德拉姆小瓶内，然后装小瓶到涡旋混合器上并在最大速度下振荡6分钟(这是第一种油包水乳化液)。对制备第二种油包水乳化液，将第一种油包水乳化液的一半取出，然后将1ml的蒸馏水加入到余下的第一种油包水乳化液中，在最大速度下振荡1德拉姆小瓶10秒。从而制得了“嵌合”油包水乳化液。将一半的“嵌合”乳化液被单个地通过窄喷嘴Pasteur漏斗型装置迅速喷射入多个1德拉姆小瓶，每个小瓶内盛有2.0ml的4％葡萄糖水溶液，0.5ml的200mM的赖氨酸游离碱；在最大速度下振荡小瓶3秒形成氯仿小球。将氯仿小球悬浮液转移至250ml的Erlermeyer烧瓶中，烧瓶内装有4ml的4％葡萄糖水溶液和0.5ml的200mM的赖氨酸游离碱。氮气流以7L/min的速度冲洗烧瓶以在5分钟内在37℃下蒸出氯仿。
例4.含粒细胞-Macrophase 菌落刺激因子(GM-CSF)的杂泡脂质体的合成
除了IL-2由1ug GM-CSF代替，其它例2中的步骤不变。
例5.各种脂质组成的杂泡脂质体的合成，各种材料对脂质体的掺入
代替使用二油酰卵磷脂，二棕榈酰磷脂酰甘油，胆甾醇和三油精(TO)，其它的两亲的脂质和中性的脂质可以各种组合使用得到类似的结果。两亲脂质如：磷脂酰胆碱(PC)，心脂(CL)，二肉豆蔻酰磷脂酰甘油(DMPG)，磷脂酰乙醇胺(PE)，磷脂酰丝氨酸(PS)，二肉豆蔻酰磷脂酸(DMPA)；中性脂质如：三辛酸甘油酯。例如，PC/C/CL/TO以4.5/4.5/1/1的摩尔比；DOPC/C/PS/TO以4.5/4.5/1/1的摩尔比；PC/C/DPPG/TC以5/4/1/1的摩尔比；PC/C/PG/TC以5/4/1/1的摩尔比；PE/C/CL/TO以4.5/4.5/1/1的摩尔比；PC/C/DMPA/TO以4.5/4.5/1/1的摩尔比被使用。掺入其它的水溶性材料，如葡萄糖，蔗糖，甲氨蝶呤，PonceauS可简单地替换所希望的材料，如在例2为IL-2。同时，其它的生物活性物质，如表1中给出的，均可以适当的剂量被类似地替换如在例2中的IL-2。
例6
在这个例子中，上述例子中的脂质组分中的三油精被替换而获得良好结果，其中替换的物质可以单个或组合起来使用，它们是甘油三酸酯，植物油，动物脂肪，生育酚，生育酚酯，胆甾醇酯，或烃。
例7
为了制得较小的脂质体(较之前述的例子，参考例1或2)，振荡或均化(例1或2的第4步)的机械强度或持续时间应增加，为了制得较大的脂质体，例1或2的第4步的振荡或均化的机械强度或持续时间应减小。
当希望给患者特定目的处理以提供两种单独的生物活性化合物时，杂泡脂质体可以通常的方式对患者给药。
对人体使用来说，剂量范围约包括1～6000mg/m于人体表面积。这个范围是如此大的原因是，对某些应用，如皮下给药，剂量可以相当小，但对其它的给药，如腹膜内给药，使用的剂量就绝对大。同时上述以外的剂量也可以给出，该范围覆盖所有的生物活性物质实际使用的广阔范围。
多泡脂质体可以通过任一希望的途径给药，例如，椎管内的，腹膜内的，皮下的，静脉内的，淋巴管内的，口服的，粘膜下的，在各种不同形式的上皮下，包括支气管上皮，胃肠上皮，泌尿生殖的上皮，和身体的各种粘膜，以及肌肉内的。
当在脂质体的腔内包封超过两种物质时，首先形成第三(或第四)种含第三或第四种生物活性物质的含水组分，进行混合形成第三或第四种油包水乳化液，然后，与第一和第二种乳化液一起进行混合，从而形成含有3种或多种生物活性物质的“嵌合”乳化液。其余的过程与包封两种生物活性物质或化合物时相同。
因而，本发明达到了其目的和要求，具有已经提到的与其相应的优点。
本发明的实例的给出用以解释其目的，其它在本发明的精神下做出的变化均在本发明的权利要求保护之内。
Claims (21)
1.一种制备含有至少两种不同物质的杂泡脂质体的方法，所述的不同物质被分别包封在水腔中，其中至少一种物质是生物活性物质，该方法包括下列步骤：
(a)从两个不混溶的组分中形成第一种油包水乳剂，所述的两个不混溶组分包括溶于一种或多种有机溶剂里的第一种脂质组分，和含有第一种欲被包封物质的含水组分；
(b)从两个不混溶的组分中形成第二种油包水乳剂，所述的两个不混溶组分包括溶于一种或多种有机溶剂里的第二种脂质组分，和含有第二种欲被包封物质的含水组分；
(c)通过使第一种油包水乳剂和第二种油包水乳剂在第三种不混溶的含水组分里混合来形成嵌合乳剂，从而形成溶剂小球；和
(d)从溶剂小球里蒸去有机溶剂以形成杂泡脂质体。
2.根据权利要求1所述的方法，其中步骤(a)和步骤(b)中所述的脂质组分是一种磷脂或几种磷脂的混合物。
3.根据权利要求2所述的方法，其中用另外的物质包封再重复形成油包水乳剂的步骤，即步骤(a)或(b)，结果所得的嵌合乳剂含至少三种油包水乳剂，每个在不混溶的含水组分里含不同的物质。
4.根据权利要求1所述的方法，其中步骤(a)和步骤(b)所述的脂质组分是相同的。
5.根据权利要求2所述的方法，其中所述的磷脂选自：磷脂酰胆碱，心脂，磷脂酰乙醇胺，磷脂酰丝氨酸，磷脂酰甘油，二肉豆蔻酰磷脂酸。
6.根据权利要求5所述的方法，其中所述的磷脂选自心脂，磷脂酰丝氨酸，磷脂酰甘油或二肉豆蔻酰磷脂酸。
7.根据权利要求2所述的方法，其中所述的磷脂是二油酰卵磷脂，二棕榈酰磷脂酰甘油，或两者兼有；所述的磷脂与胆甾醇形成混合物一起使用。
8.根据权利要求1所述的方法，其中所述的脂质组分之一是中性脂质，它或者单独使用，或者与选自下列的物质一起使用：甘油三酯类，植物油，动物脂肪，生育酚，生育酚酯，胆甾醇酯，烃类。
9.根据权利要求1所述的方法，其中有机溶剂是氯仿。
10.根据权利要求1所述的方法，其中所述的含水组分还包括氢氯化物，所述的氢氯化物选自：盐酸，盐酸赖氨酸，以及它们结合使用。
11.根据权利要求1所述的方法，其中生物活性物质是亲水的。
12.根据权利要求11所述的方法，其中亲水性生物活性物质选自：白细胞介素-2，阿糖胞苷，甲氨蝶呤，5-氟尿嘧啶，顺氯氨铂，5-氟脱氧尿苷，苯丙氨酸氮芥，6-巯基嘌呤，硫鸟嘌呤，硫化三(环氮丙基)磷，长春新碱，长春花碱，链尿佐菌素，6-D-亮氨酸-9-(N-乙烯基-L-脯氨酰胺)-10-脱甘氨酰胺促黄体生成激素，干扰素，降钙素，阿霉素，道诺红霉素，米托蒽醌，丁胺卡那霉素，放线霉素，博莱霉素。
13.根据权利要求1所述的方法，其中两种组分的乳化过程使用选自下述的方法进行：机械搅拌，喷嘴喷射。
14.根据权利要求1所述的方法，其中第三种含水组分至少包含一种酸中和剂。
15.根据权利要求14所述的方法，其中酸中和剂是游离碱赖氨酸，或者它们一起使用。
16.根据权利要求14所述的方法，其中第三种水溶液进一步包含选自葡萄糖和赖氨酸的溶质。
17.根据权利要求14所述的方法，其中第三种含水组分是一种水溶液，它包含选自下列或者单独使用或者一起使用的溶质：葡萄糖，蔗糖，和游离碱赖氨酸。
18.根据权利要求1所述的方法，其中形成溶剂小球的分散过程使用选自下述的方法：机械搅拌，喷嘴喷射。
19.根据权利要求1所述的方法，其中有机溶剂的蒸发是通过将氮气通入步骤(b)所述的含水组分而实现的。
20.根据权利要求1所述的方法，其中所述的欲被包封的生物活性物质选自：二羟苯基异丙氨基乙醇，氨茶碱，茶碱，特普它林，氨甲酰苯，麻黄素，喘息定，肾上腺素，去甲肾上腺素，萘心安，氨酰心安，戊脉安，巯甲丙脯酸，异山梨糖醇，氯丙嗪，苯并二氮，丁酰苯，羟嗪，氨甲丙二酯，吩噻嗪，利血平，硫蒽，洋地黄，洋地黄毒甙，毛花甙G，异羟洋地黄毒甙，制尿药，皮质类甾醇，睾酮，雌激素，甲状腺制剂，生长激素，促皮质素，孕酮，促性腺激素，盐肾上腺皮质激素，促黄体激素，促黄体激素释放因子，促卵泡激素，降钙素，强的松，去炎松半琥酯，氢化可的松，地塞米松，倍他米松，强的松龙，肼苯哒嗪，氨酰心安，氯磺丙脲，胰岛素，苄吡二胺，右旋氯苯吡胺，盐酸苯海拉明，吡喹酮，甲硝哒唑，戊烷脒，硫唑嘌呤，博来霉素，环磷酰胺，阿霉素，柔红霉素，长春新碱，甲氨蝶呤，硫鸟嘌呤，巯嘌呤，长春碱，VP-16，VM-26，顺氯氨铂，氟尿嘧啶，吗啡，盐酸二氢吗啡酮，可待因，类可待因合成物，度冷丁，羟氢吗啡酮，苯巴比妥，巴比妥类，青霉素，四环素，红霉素，头孢菌素I，亚胺培南，头孢氨噻，羧苄青霉素，万古霉素，庆大霉素，妥布霉素，氧哌嗪青霉素，羟羧氧酰胺菌素，羟氨苄青霉素，氨苄青霉素，头孢唑啉，天孢羟氨苄，头霉噻吩，其它氨基糖甙类，干扰素，白细胞介素-2，单克隆抗体，丙种球蛋白，流感疫苗，呼吸多核的病毒，嗜血杆菌属流感疫苗，两性霉素B，双氯苯咪唑，胞壁酰二肽，克霉唑，多巴胺，右旋苯丙胺，无环鸟苷和其衍生物，二噁沙利，三唑核苷，金刚胺，叠氮胸苷，腺嘌呤阿拉伯糖苷，脒类蛋白酶抑制剂，淋巴因子白细胞介素-1，2，3，4，5，6，细胞活素，GM-CSF，M-CSF，G-CSF，肿瘤坏死因子，抑制素，肿瘤生长因子，穆勒氏抑制物质，神经生长因子，成纤维细胞生长因子，血小板衍生生长因子，凝聚因子VIII，IX，VII，胰岛素，纤维蛋白溶酶原激活剂，组织相容性抗原，癌基因产物，髓磷脂碱蛋白，胶原，纤维结合素，层粘连蛋白，由重组DNA技术制得的其它蛋白，细胞表面受体阻滞剂，核酸和类似物，DNA，RNA，膦酸甲酯和类似物。
21.权利要求1的方法，其中，生物活性物质选自：抗心律失常药，止喘药，抗生素，抗癌药，抗糖尿病药，杀真菌药，抗组胺药，抗高血压药，抗低血压药，抗寄生物药，抗病毒药，细胞表面受体阻滞剂，葡萄糖，强心苷，激素，免疫治疗剂，核酸和类似物，蛋白质和糖蛋白，镇静药和止痛药，类固醇，安定药，菌苗。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US49684690A | 1990-03-21 | 1990-03-21 | |
| US496,846 | 1990-03-21 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1055663A CN1055663A (zh) | 1991-10-30 |
| CN1053101C true CN1053101C (zh) | 2000-06-07 |
Family
ID=23974416
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN91102478A Expired - Fee Related CN1053101C (zh) | 1990-03-21 | 1991-03-21 | 杂泡脂质体的制备方法 |
Country Status (20)
| Country | Link |
|---|---|
| EP (1) | EP0524968B1 (zh) |
| JP (1) | JP3461000B2 (zh) |
| KR (1) | KR100203223B1 (zh) |
| CN (1) | CN1053101C (zh) |
| AT (1) | ATE123412T1 (zh) |
| AU (1) | AU655177B2 (zh) |
| CA (1) | CA2078666C (zh) |
| DE (1) | DE69110281T2 (zh) |
| DK (1) | DK0524968T3 (zh) |
| ES (1) | ES2073164T3 (zh) |
| FI (1) | FI104464B (zh) |
| IE (1) | IE62772B1 (zh) |
| IL (1) | IL97615A (zh) |
| NO (1) | NO304576B1 (zh) |
| NZ (1) | NZ237464A (zh) |
| PT (1) | PT97101B (zh) |
| RU (1) | RU2120795C1 (zh) |
| SA (1) | SA93130496B1 (zh) |
| WO (1) | WO1991014445A1 (zh) |
| ZA (1) | ZA911974B (zh) |
Families Citing this family (190)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP3278273B2 (ja) * | 1993-12-17 | 2002-04-30 | キヤノン株式会社 | 薬剤徐放性カプセル |
| US6544523B1 (en) | 1996-11-13 | 2003-04-08 | Chiron Corporation | Mutant forms of Fas ligand and uses thereof |
| DE69725881T2 (de) | 1996-12-13 | 2004-09-09 | Chiron Corp. (N.D.Ges.D. Staates Delaware), Emeryville | Verfahren zur expression von heterologen proteinen in hefe |
| US5985214A (en) | 1997-05-16 | 1999-11-16 | Aurora Biosciences Corporation | Systems and methods for rapidly identifying useful chemicals in liquid samples |
| DE69841598D1 (de) | 1997-09-18 | 2010-05-20 | Pacira Pharmaceuticals Inc | Retardierte freisetzung liposmaler anesthetischer zusammensetzungen. |
| EP2278006A3 (en) | 1997-11-06 | 2011-03-02 | Novartis Vaccines and Diagnostics S.r.l. | Neisserial antigens |
| AU752802C (en) | 1997-11-14 | 2006-04-13 | Pacira Pharmaceuticals, Inc. | Production of multivesicular liposomes |
| DK1047784T4 (en) | 1998-01-14 | 2015-06-15 | Novartis Vaccines & Diagnostic | NEISSERA meningitidis ANTIGENS |
| MX343752B (es) | 1998-05-01 | 2016-11-22 | Novartis Vaccines & Diagnostics Inc | Antigenos de neisseria meningitidis y composiciones que los contienen. |
| EP1953229A3 (en) | 1998-10-15 | 2008-12-24 | Novartis Vaccines and Diagnostics, Inc. | Metastatic breast and colon cancer regulated genes |
| AU2367600A (en) | 1998-12-16 | 2000-07-03 | Chiron Corporation | Human cyclin-dependent kinase ((hpnqalre)) |
| US7393823B1 (en) | 1999-01-20 | 2008-07-01 | Oregon Health And Science University | HER-2 binding antagonists |
| US7625859B1 (en) | 2000-02-16 | 2009-12-01 | Oregon Health & Science University | HER-2 binding antagonists |
| JP2003518363A (ja) | 1999-04-30 | 2003-06-10 | カイロン エセ．ピー．アー． | 保存されたナイセリア抗原 |
| GB9911683D0 (en) | 1999-05-19 | 1999-07-21 | Chiron Spa | Antigenic peptides |
| GB9916529D0 (en) | 1999-07-14 | 1999-09-15 | Chiron Spa | Antigenic peptides |
| PT2275551E (pt) | 1999-10-29 | 2015-06-29 | Novartis Vaccines & Diagnostic | Péptidos antigénicos de neisseria |
| AU1922101A (en) | 1999-11-18 | 2001-05-30 | Chiron Corporation | Human fgf-21 gene and gene expression products |
| NZ520466A (en) | 2000-01-17 | 2003-09-26 | Chiron S | Outer membrane vesicle (OMV) vaccine comprising n. meningitidis serogroup B outer membrane proteins |
| EP1261638A2 (en) | 2000-03-08 | 2002-12-04 | Chiron Corporation | Human fgf-23 gene and gene expression products |
| EP1950297A2 (en) | 2000-05-31 | 2008-07-30 | Novartis Vaccines and Diagnostics, Inc. | Compositions and methods for treating neoplastic disease using chemotherapy and radiation sensitizers |
| US7700359B2 (en) | 2000-06-02 | 2010-04-20 | Novartis Vaccines And Diagnostics, Inc. | Gene products differentially expressed in cancerous cells |
| WO2001096523A2 (en) | 2000-06-15 | 2001-12-20 | Chiron Corporation | Polynucleotides related to colon cancer |
| EP1328543B1 (en) | 2000-10-27 | 2009-08-12 | Novartis Vaccines and Diagnostics S.r.l. | Nucleic acids and proteins from streptococcus groups a & b |
| AU2002227365A1 (en) | 2000-12-07 | 2002-06-18 | Chiron Corporation | Endogenous retroviruses up-regulated in prostate cancer |
| GB0107658D0 (en) | 2001-03-27 | 2001-05-16 | Chiron Spa | Streptococcus pneumoniae |
| GB0107661D0 (en) | 2001-03-27 | 2001-05-16 | Chiron Spa | Staphylococcus aureus |
| AU2002303261A1 (en) | 2001-04-06 | 2002-10-21 | Georgetown University | Gene brcc2 and diagnostic and therapeutic uses thereof |
| WO2002081641A2 (en) | 2001-04-06 | 2002-10-17 | Georgetown University | Gene scc-112 and diagnostic and therapeutic uses thereof |
| AU2002258728A1 (en) | 2001-04-06 | 2002-10-21 | Georgetown University | Gene brcc-3 and diagnostic and therapeutic uses thereof |
| US7309783B2 (en) | 2001-05-09 | 2007-12-18 | The University Of Connecticut | Mammalian early developmental regulator gene |
| KR20030022094A (ko) | 2001-05-24 | 2003-03-15 | (주)휴먼디엔에이테크놀로지 | 모낭에 존재하는 새로운 제 2 케라티노사이트 성장인자유사체 |
| ATE466020T1 (de) | 2001-11-09 | 2010-05-15 | Univ Georgetown | Neue isoform des gefässendothelzell wachstumshemmers (vegi) |
| KR100982204B1 (ko) | 2001-12-12 | 2010-09-14 | 노바티스 백신즈 앤드 다이아그노스틱스 에스.알.엘. | 클라미디아 트라코마티스에 대한 면역화 |
| ES2323456T3 (es) | 2002-01-08 | 2009-07-16 | Novartis Vaccines And Diagnostics, Inc. | Productos genicos diferencialmente expresados en celulas de pecho cancerosas y sus metodos de uso. |
| WO2003080808A2 (en) | 2002-03-21 | 2003-10-02 | Sagres Discovery, Inc. | Novel compositions and methods in cancer |
| US7138512B2 (en) | 2002-04-10 | 2006-11-21 | Georgetown University | Gene SHINC-2 and diagnostic and therapeutic uses thereof |
| US7244565B2 (en) | 2002-04-10 | 2007-07-17 | Georgetown University | Gene shinc-3 and diagnostic and therapeutic uses thereof |
| EP1532161B1 (en) | 2002-06-13 | 2012-02-15 | Novartis Vaccines and Diagnostics, Inc. | Vectors for expression of hml-2 polypeptides |
| US7135324B2 (en) | 2002-09-04 | 2006-11-14 | The University Of Connecticut | Viral recombinases, related articles, and methods of use thereof |
| ZA200502612B (en) | 2002-10-08 | 2007-07-25 | Rinat Neuroscience Corp | Methods for treating post-surgical pain by administering a nerve crowth factor antagonist and compositions containing the same |
| UA80447C2 (en) | 2002-10-08 | 2007-09-25 | Methods for treating pain by administering nerve growth factor antagonist and opioid analgesic | |
| AU2003304238A1 (en) | 2002-10-08 | 2005-01-13 | Rinat Neuroscience Corp. | Methods for treating post-surgical pain by administering an anti-nerve growth factor antagonist antibody and compositions containing the same |
| ATE466875T1 (de) | 2002-11-15 | 2010-05-15 | Novartis Vaccines & Diagnostic | Unerwartete oberflächenproteine in neisseria meningitidis |
| RU2239416C2 (ru) * | 2002-12-15 | 2004-11-10 | Ставропольский научно-исследовательский противочумный институт | Способ лечения бруцеллеза |
| RU2234311C1 (ru) * | 2002-12-15 | 2004-08-20 | Ставропольский научно-исследовательский противочумный институт | Способ лечения бруцеллеза |
| US9498530B2 (en) | 2002-12-24 | 2016-11-22 | Rinat Neuroscience Corp. | Methods for treating osteoarthritis pain by administering a nerve growth factor antagonist and compositions containing the same |
| SI2263692T1 (sl) | 2002-12-24 | 2020-10-30 | Rinat Neuroscience Corp. | Anti-NGF protitelesa in postopki, v katerih se le-ta uporabljajo |
| US7569364B2 (en) | 2002-12-24 | 2009-08-04 | Pfizer Inc. | Anti-NGF antibodies and methods using same |
| US20040170982A1 (en) | 2003-02-14 | 2004-09-02 | Morris David W. | Novel therapeutic targets in cancer |
| EP1592708A2 (en) | 2003-02-14 | 2005-11-09 | Sagres Discovery, Inc. | Therapeutic gpcr targets in cancer |
| US7767387B2 (en) | 2003-06-13 | 2010-08-03 | Sagres Discovery, Inc. | Therapeutic targets in cancer |
| KR20050111598A (ko) | 2003-02-19 | 2005-11-25 | 리나트 뉴로사이언스 코퍼레이션 | 신경 성장 인자 길항제 및 ｎｓａｉｄ를 투여함으로써통증을 치료하는 방법 및 그것을 함유하는 조성물 |
| GB0308198D0 (en) | 2003-04-09 | 2003-05-14 | Chiron Srl | ADP-ribosylating bacterial toxin |
| RU2395204C2 (ru) * | 2003-08-22 | 2010-07-27 | Даниско А/С | Микробицидная или микробиостатическая композиция, содержащая бактериоцин и экстракт растения семейства labiatae |
| JP4926707B2 (ja) | 2003-08-22 | 2012-05-09 | ダニスコ エイ／エス | 封入化抗菌材料 |
| GB2388581A (en) | 2003-08-22 | 2003-11-19 | Danisco | Coated aqueous beads |
| SG166768A1 (en) | 2003-12-23 | 2010-12-29 | Rinat Neuroscience Corp | Agonist anti-trkc antibodies and methods using same |
| JP4792390B2 (ja) | 2004-03-29 | 2011-10-12 | 株式会社ガルファーマ | 新規ガレクチン９改変体タンパク質及びその用途 |
| DK2206728T3 (en) | 2004-04-07 | 2018-04-23 | Rinat Neuroscience Corp | METHODS OF TREATING BONE CANCER PAIN BY SUBMITTING A NERVOUS FACTOR-ANTAGONISTIC ANTIBODY |
| PT1789593T (pt) | 2004-07-09 | 2017-04-24 | Henry M Jackson Found Advancement Military Medicine Inc | Formas solúveis de glicoproteína g de vírus hendra |
| US20060024677A1 (en) | 2004-07-20 | 2006-02-02 | Morris David W | Novel therapeutic targets in cancer |
| TWI355389B (en) | 2004-07-30 | 2012-01-01 | Rinat Neuroscience Corp | Antibodies directed against amyloid-beta peptide a |
| RU2404750C2 (ru) | 2004-11-23 | 2010-11-27 | Адамас Фармасьютикалс, Инк. | Композиция, содержащая основу или покрытие для замедленного высвобождения и антагонист nmda рецептора, способ введения такого nmda антагониста субъекту |
| US7619007B2 (en) | 2004-11-23 | 2009-11-17 | Adamas Pharmaceuticals, Inc. | Method and composition for administering an NMDA receptor antagonist to a subject |
| EP2623099A1 (en) | 2004-11-24 | 2013-08-07 | Neuromolecular Pharmaceuticals, Inc | Composition and method for treating neurological disease |
| US7939490B2 (en) | 2004-12-13 | 2011-05-10 | University Of Maryland, Baltimore | TWEAK as a therapeutic target for treating central nervous system diseases associated with cerebral edema and cell death |
| NZ560929A (en) | 2005-02-18 | 2009-12-24 | Novartis Vaccines & Diagnostic | Immunogens from uropathogenic escherichia coli |
| PL1874282T3 (pl) | 2005-04-06 | 2011-04-29 | Adamas Pharmaceuticals Inc | Sposoby i kompozycje do leczenia zaburzeń OUN |
| AU2006235276A1 (en) | 2005-04-07 | 2006-10-19 | Novartis Vaccines And Diagnostics Inc. | CACNA1E in cancer diagnosis, detection and treatment |
| EP1910557A2 (en) | 2005-04-07 | 2008-04-16 | Chiron Corporation | Cancer-related genes |
| UY29504A1 (es) | 2005-04-29 | 2006-10-31 | Rinat Neuroscience Corp | Anticuerpos dirigidos contra el péptido amiloide beta y métodos que utilizan los mismos. |
| JP4997239B2 (ja) | 2005-07-22 | 2012-08-08 | ワイズ・エー・シー株式会社 | 抗ｃｄ２６抗体およびその使用方法 |
| EP2380592B1 (en) | 2005-11-14 | 2018-03-07 | Teva Pharmaceuticals International GmbH | Antagonist antibody directed against calcitonin gene-related peptide |
| JP2009525319A (ja) | 2006-02-02 | 2009-07-09 | ライナット ニューロサイエンス コーポレイション | ｔｒｋＢアンタゴニストを投与することにより肥満を治療する方法 |
| RU2330664C2 (ru) * | 2006-04-26 | 2008-08-10 | Александр Иванович Арчаков | Лекарственный препарат и способ лечения ревматических заболеваний |
| NZ572561A (en) | 2006-06-07 | 2012-05-25 | Bioalliance Cv | Antibodies recognizing a carbohydrate containing epitope on cd-43 and cea expressed on cancer cells and methods using same |
| EP2035035A2 (en) | 2006-06-09 | 2009-03-18 | Novartis AG | Immunogenic compositions for streptococcus agalactiae |
| US20100166788A1 (en) | 2006-08-16 | 2010-07-01 | Novartis Vaccines And Diagnostics | Immunogens from uropathogenic escherichia coli |
| WO2008116032A1 (en) | 2007-03-21 | 2008-09-25 | Effat Emamian | Compositions and methods for inhibiting tumor cell growth |
| AP2009005028A0 (en) | 2007-04-10 | 2009-12-31 | Univ Tulane | Soluble and membrane-anchored forms of lassa virussubunit proteins |
| GB0714963D0 (en) | 2007-08-01 | 2007-09-12 | Novartis Ag | Compositions comprising antigens |
| AU2008337100B2 (en) | 2007-12-17 | 2013-02-28 | Pfizer Limited | Treatment of interstitial cystitis |
| JP5568478B2 (ja) | 2007-12-18 | 2014-08-06 | バイオアライアンス セー．フェー． | 癌細胞で発現するｃｄ−４３およびｃｅａの炭水化物含有エピトープを認識する抗体およびそれを使用する方法 |
| RU2367443C1 (ru) * | 2008-02-28 | 2009-09-20 | Общество с ограниченной ответственностью "Битеп" | Средство на основе природных фосфолипидов |
| EP3023502A1 (en) | 2008-04-10 | 2016-05-25 | Cell Signaling Technology, Inc. | Compositions and methods for detecting egfr mutations in cancer |
| WO2009150623A1 (en) | 2008-06-13 | 2009-12-17 | Pfizer Inc | Treatment of chronic prostatitis |
| TWI445716B (zh) | 2008-09-12 | 2014-07-21 | Rinat Neuroscience Corp | Ｐｃｓｋ９拮抗劑類 |
| WO2010086828A2 (en) | 2009-02-02 | 2010-08-05 | Rinat Neuroscience Corporation | Agonist anti-trkb monoclonal antibodies |
| AU2010220103A1 (en) | 2009-03-06 | 2011-09-22 | Novartis Ag | Chlamydia antigens |
| WO2010118243A2 (en) | 2009-04-08 | 2010-10-14 | Genentech, Inc. | Use of il-27 antagonists to treat lupus |
| DK2510947T3 (en) | 2009-04-14 | 2016-03-21 | Glaxosmithkline Biolog Sa | Compositions for Immunization against Staphylococcus aureus. |
| WO2010146511A1 (en) | 2009-06-17 | 2010-12-23 | Pfizer Limited | Treatment of overactive bladder |
| AU2010269961A1 (en) | 2009-07-07 | 2012-02-02 | Novartis Ag | Conserved Escherichia coli immunogens |
| CA2768343A1 (en) | 2009-07-16 | 2011-01-20 | Novartis Ag | Detoxified escherichia coli immunogens |
| GB0919690D0 (en) | 2009-11-10 | 2009-12-23 | Guy S And St Thomas S Nhs Foun | compositions for immunising against staphylococcus aureus |
| CN106389381A (zh) | 2009-12-02 | 2017-02-15 | 阿达玛斯医药公司 | 金刚烷胺组合物及其使用方法 |
| AR080291A1 (es) | 2010-02-24 | 2012-03-28 | Rinat Neuroscience Corp | Anticuerpos antagonistas anti receptor de il-7 y procedimientos |
| GB201003333D0 (en) | 2010-02-26 | 2010-04-14 | Novartis Ag | Immunogenic proteins and compositions |
| AU2011225716A1 (en) | 2010-03-11 | 2012-09-27 | Pfizer Inc. | Antibodies with pH dependent antigen binding |
| GB201005625D0 (en) | 2010-04-01 | 2010-05-19 | Novartis Ag | Immunogenic proteins and compositions |
| WO2011133931A1 (en) | 2010-04-22 | 2011-10-27 | Genentech, Inc. | Use of il-27 antagonists for treating inflammatory bowel disease |
| US9770414B2 (en) * | 2010-05-13 | 2017-09-26 | Pacira Pharmaceuticals, Inc. | Sustained release formulation of methotrexate as a disease-modifying antirheumatic drug (DMARD) and an anti-cancer agent |
| JP2013533286A (ja) | 2010-07-30 | 2013-08-22 | セントルイス ユニバーシティ | 疼痛を治療する方法 |
| WO2012072769A1 (en) | 2010-12-01 | 2012-06-07 | Novartis Ag | Pneumococcal rrgb epitopes and clade combinations |
| US20130071375A1 (en) | 2011-08-22 | 2013-03-21 | Saint Louis University | Compositions and methods for treating inflammation |
| WO2013028527A1 (en) | 2011-08-23 | 2013-02-28 | Indiana University Research And Technology Corporation | Compositions and methods for treating cancer |
| KR20140091040A (ko) | 2011-11-11 | 2014-07-18 | 리나트 뉴로사이언스 코프. | Trop-2에 특이적인 항체 및 그의 용도 |
| WO2013093707A1 (en) | 2011-12-22 | 2013-06-27 | Rinat Neuroscience Corp. | Human growth hormone receptor antagonist antibodies and methods of use thereof |
| WO2013093693A1 (en) | 2011-12-22 | 2013-06-27 | Rinat Neuroscience Corp. | Staphylococcus aureus specific antibodies and uses thereof |
| CA2877948C (en) | 2012-07-02 | 2019-07-30 | The Henry M. Jackson Foundation For The Advancement Of Military Medicine, Inc. | Paramyxovirus and methods of use |
| US8603470B1 (en) | 2012-08-07 | 2013-12-10 | National Cheng Kung University | Use of IL-20 antagonists for treating liver diseases |
| EP2917237A1 (en) | 2012-11-09 | 2015-09-16 | Pfizer Inc. | Platelet-derived growth factor b specific antibodies and compositions and uses thereof |
| CN111704672B (zh) | 2013-03-15 | 2024-06-04 | 武田药品工业株式会社 | 抗血浆激肽释放酶抗体 |
| RU2015147721A (ru) | 2013-05-07 | 2017-06-15 | Ринат Нейросаенз Корпорэйшн | Антитела против рецептора глюкагона и способы их использования |
| US10154971B2 (en) | 2013-06-17 | 2018-12-18 | Adamas Pharma, Llc | Methods of administering amantadine |
| US10208125B2 (en) | 2013-07-15 | 2019-02-19 | University of Pittsburgh—of the Commonwealth System of Higher Education | Anti-mucin 1 binding agents and uses thereof |
| JP6506280B2 (ja) | 2013-08-02 | 2019-05-08 | ファイザー・インク | 抗ｃｘｃｒ４抗体および抗体−薬剤コンジュゲート |
| SG11201602671WA (en) | 2013-11-13 | 2016-05-30 | Pfizer | Tumor necrosis factor-like ligand 1a specific antibodies and compositions and uses thereof |
| WO2015087187A1 (en) | 2013-12-10 | 2015-06-18 | Rinat Neuroscience Corp. | Anti-sclerostin antibodies |
| WO2015109212A1 (en) | 2014-01-17 | 2015-07-23 | Pfizer Inc. | Anti-il-2 antibodies and compositions and uses thereof |
| HRP20240159T1 (hr) | 2014-03-21 | 2024-04-12 | Teva Pharmaceuticals International Gmbh | Antagonistička protutijela usmjerena protiv peptida povezanog s genom kalcitonina i postupci koji ih koriste |
| IL295414B1 (en) | 2014-03-27 | 2025-10-01 | Takeda Pharmaceuticals Co | Compositions and methods for treating macular edema due to diabetes |
| WO2015168474A1 (en) | 2014-04-30 | 2015-11-05 | President And Fellows Of Harvard College | Fusion proteins for treating cancer and related methods |
| US9840553B2 (en) | 2014-06-28 | 2017-12-12 | Kodiak Sciences Inc. | Dual PDGF/VEGF antagonists |
| TWI595006B (zh) | 2014-12-09 | 2017-08-11 | 禮納特神經系統科學公司 | 抗ｐｄ－１抗體類和使用彼等之方法 |
| IL298086B2 (en) | 2015-01-02 | 2024-11-01 | Takeda Pharmaceuticals Co | Bispecific antibodies against plasma kallikrein and factor xii |
| US9758575B2 (en) | 2015-04-06 | 2017-09-12 | Yung Shin Pharmaceutical Industrial Co. Ltd. | Antibodies which specifically bind to canine vascular endothelial growth factor and uses thereof |
| SG10201912819XA (en) | 2015-04-13 | 2020-02-27 | Pfizer | Therapeutic antibodies and their uses |
| US10877045B2 (en) | 2015-07-21 | 2020-12-29 | Saint Louis University | Compositions and methods for diagnosing and treating endometriosis-related infertility |
| EP3325516B1 (en) | 2015-07-21 | 2021-12-15 | Takeda Pharmaceutical Company Limited | A monoclonal antibody inhibitor of factor xiia |
| CA3025896A1 (en) | 2015-07-23 | 2017-01-26 | The Regents Of The University Of California | Antibodies to coagulation factor xia and uses thereof |
| SG10201912817YA (en) | 2015-08-19 | 2020-02-27 | Pfizer | Tissue factor pathway inhibitor antibodies and uses thereof |
| ES3030258T3 (en) | 2015-09-15 | 2025-06-27 | Scholar Rock Inc | Anti-pro/latent-myostatin antibodies and uses thereof |
| JP6661319B2 (ja) * | 2015-09-28 | 2020-03-11 | 小林製薬株式会社 | リポソーム |
| AU2016340989B2 (en) | 2015-10-23 | 2023-09-14 | Pfizer Inc. | Anti-IL-2 antibodies and compositions and uses thereof |
| WO2017075037A1 (en) | 2015-10-27 | 2017-05-04 | Scholar Rock, Inc. | Primed growth factors and uses thereof |
| CN106699889A (zh) | 2015-11-18 | 2017-05-24 | 礼进生物医药科技（上海）有限公司 | 抗pd-1抗体及其治疗用途 |
| JP6902033B2 (ja) | 2015-12-30 | 2021-07-14 | アダマス ファーマシューティカルズ， インコーポレイテッド | 発作−関連障害の処置のための方法および組成物 |
| JP7088454B2 (ja) | 2015-12-30 | 2022-06-21 | コディアック サイエンシーズ インコーポレイテッド | 抗体および抗体複合体 |
| JP2019506398A (ja) | 2016-01-21 | 2019-03-07 | ファイザー・インク | 上皮増殖因子受容体変異体ｉｉｉおよびｃｄ３の単一および二重特異性抗体およびそれらの使用 |
| KR102069680B1 (ko) * | 2017-03-02 | 2020-01-23 | 단디바이오사이언스 주식회사 | 면역억제인자 제어물질을 포함하는 다중도메인캡슐, 이의 제조방법, 및 이를 포함하는 면역조절 조성물 |
| CA3054885A1 (en) | 2017-03-03 | 2018-09-07 | Rinat Neuroscience Corp. | Anti-gitr antibodies and methods of use thereof |
| CA3056182A1 (en) | 2017-03-16 | 2018-09-20 | Pfizer Inc. | Tyrosine prototrophy |
| CA3059938A1 (en) | 2017-04-14 | 2018-10-18 | Kodiak Sciences Inc. | Complement factor d antagonist antibodies and conjugates thereof |
| WO2018200885A1 (en) | 2017-04-26 | 2018-11-01 | Neurocentria, Inc. | Magnesium compositions and methods of use |
| AU2018275359C1 (en) | 2017-06-02 | 2022-02-03 | Pfizer Inc. | Antibodies specific for FLT3 and their uses |
| KR102396784B1 (ko) | 2017-06-13 | 2022-05-13 | 보스턴진 코포레이션 | 분자 기능적 프로파일을 생성하고, 시각화하고, 분류하는 시스템 및 방법 |
| CN110997002A (zh) | 2017-07-13 | 2020-04-10 | 麻省理工学院 | 靶向hdac2-sp3复合体以增强突触功能 |
| WO2019016784A1 (en) | 2017-07-21 | 2019-01-24 | Universidade De Coimbra | ANTI-NUCLEOLIN ANTIBODIES |
| US20200271657A1 (en) | 2017-10-04 | 2020-08-27 | Opko Pharmaceuticals, Llc | Articles and methods directed to personalized therapy of cancer |
| EP3625263B8 (en) | 2017-10-27 | 2025-05-28 | New York University | Anti-galectin-9 antibodies and uses thereof |
| WO2019152705A1 (en) | 2018-02-01 | 2019-08-08 | Pfizer Inc. | Antibodies specific for cd70 and their uses |
| TW201936633A (zh) | 2018-02-01 | 2019-09-16 | 美商輝瑞大藥廠 | 標靶至cd70的嵌合抗原受體 |
| EP3759129A1 (en) | 2018-02-28 | 2021-01-06 | Pfizer Inc | Il-15 variants and uses thereof |
| CN112203679A (zh) | 2018-03-02 | 2021-01-08 | 科达制药股份有限公司 | Il-6抗体及其融合构建体和缀合物 |
| TWI793325B (zh) | 2018-05-23 | 2023-02-21 | 美商輝瑞大藥廠 | 對cd3具特異性之抗體及其用途 |
| CN113286634A (zh) | 2018-05-23 | 2021-08-20 | 辉瑞公司 | 对gucy2c特异性的抗体及其用途 |
| WO2020078270A1 (en) | 2018-10-15 | 2020-04-23 | Elixiron Immunotherapeutics (hong Kong) Limited | Antibodies to granulocyte-macrophage colony stimulating factor and uses thereof |
| JP7575102B2 (ja) | 2018-12-21 | 2024-10-29 | マルチチュード インコーポレーテッド | Ｍｕｃ１８に特異的な抗体 |
| EP4434541A3 (en) | 2019-01-23 | 2025-02-26 | New York University | Antibodies specific to delta 1 chain of t cell receptor |
| WO2021028726A2 (en) | 2019-07-03 | 2021-02-18 | Bostongene Corporation | Systems and methods for sample preparation, sample sequencing, and sequencing data bias correction and quality control |
| EP4041308A1 (en) | 2019-10-07 | 2022-08-17 | University of Virginia Patent Foundation | Modulating lymphatic vessels in neurological disease |
| WO2021072265A1 (en) | 2019-10-10 | 2021-04-15 | Kodiak Sciences Inc. | Methods of treating an eye disorder |
| EP4041773A1 (en) | 2019-10-11 | 2022-08-17 | Beth Israel Deaconess Medical Center, Inc. | Anti-tn antibodies and uses thereof |
| WO2021151079A1 (en) | 2020-01-24 | 2021-07-29 | University Of Virginia Patent Foundation | Modulating lymphatic vessels in neurological disease |
| WO2021205325A1 (en) | 2020-04-08 | 2021-10-14 | Pfizer Inc. | Anti-gucy2c antibodies and uses thereof |
| US20230181750A1 (en) | 2020-05-06 | 2023-06-15 | Crispr Therapeutics Ag | Mask peptides and masked anti-ptk7 antibodies comprising such |
| WO2021257512A1 (en) | 2020-06-15 | 2021-12-23 | Academia Sinica | Humanized ace2-fc fusion protein for treatment and prevention of sars-cov-2 infection |
| PH12023550139A1 (en) | 2020-07-17 | 2024-06-24 | Pfizer | Therapeutic antibodies and their uses |
| EP4189093A1 (en) | 2020-07-30 | 2023-06-07 | Pfizer Inc. | Cells having gene duplications and uses thereof |
| CA3190513A1 (en) | 2020-09-03 | 2022-03-10 | Jeffrey S. Bartlett | Soluble alkaline phosphatase constructs and expression vectors including a polynucleotide encoding for soluble alkaline phosphatase constructs |
| US20240029829A1 (en) | 2020-12-04 | 2024-01-25 | Bostongene Corporation | Hierarchical machine learning techniques for identifying molecular categories from expression data |
| US11278494B1 (en) | 2021-01-22 | 2022-03-22 | Pacira Pharmaceuticals, Inc. | Manufacturing of bupivacaine multivesicular liposomes |
| US11033495B1 (en) | 2021-01-22 | 2021-06-15 | Pacira Pharmaceuticals, Inc. | Manufacturing of bupivacaine multivesicular liposomes |
| US12151024B2 (en) | 2021-01-22 | 2024-11-26 | Pacira Pharmaceuticals, Inc. | Manufacturing of bupivacaine multivesicular liposomes |
| US11357727B1 (en) | 2021-01-22 | 2022-06-14 | Pacira Pharmaceuticals, Inc. | Manufacturing of bupivacaine multivesicular liposomes |
| US20220372580A1 (en) | 2021-04-29 | 2022-11-24 | Bostongene Corporation | Machine learning techniques for estimating tumor cell expression in complex tumor tissue |
| US20240327496A1 (en) | 2021-08-02 | 2024-10-03 | Pfizer Inc. | Improved Expression Vectors and Uses Thereof |
| WO2023064464A1 (en) | 2021-10-14 | 2023-04-20 | Pacira Pharmaceuticals, Inc. | Bupivacaine multivesicular liposome formulations and uses thereof |
| JP2025505410A (ja) | 2022-01-31 | 2025-02-26 | ボストンジーン コーポレイション | サイトメトリーのための機械学習法 |
| KR20240139082A (ko) | 2022-02-02 | 2024-09-20 | 화이자 인코포레이티드 | 시스테인 프로토트로피 |
| WO2024015561A1 (en) | 2022-07-15 | 2024-01-18 | Bostongene Corporation | Techniques for detecting homologous recombination deficiency (hrd) |
| CN115957213A (zh) * | 2022-12-30 | 2023-04-14 | 青岛市胶州中心医院 | 一种抗感染甲硝唑制剂及其制备方法 |
| WO2025096811A1 (en) | 2023-10-31 | 2025-05-08 | Bostongene Corporation | Machine learning technique for identifying ici responders and non-responders |
| WO2025157994A1 (en) | 2024-01-25 | 2025-07-31 | Intervet International B.V. | Vaccine against ruminant respiratory disease |
| WO2025165590A1 (en) | 2024-02-02 | 2025-08-07 | Seven Bridges Genomics Inc. | Techniques for improved tumor mutational burden (tmb) determination using a population-specific genomic reference |
| US12246092B1 (en) | 2024-05-20 | 2025-03-11 | Pacira Pharmaceuticals, Inc. | Manufacturing of bupivacaine multivesicular liposomes |
| US12251468B1 (en) | 2024-05-20 | 2025-03-18 | Pacira Pharmaceuticals, Inc. | Manufacturing of bupivacaine multivesicular liposomes |
| US12251472B1 (en) | 2024-05-20 | 2025-03-18 | Pacira Pharmaceuticals, Inc. | Manufacturing of bupivacaine multivesicular liposomes |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1985000515A1 (en) * | 1983-08-01 | 1985-02-14 | The Liposome Company, Inc. | Enhancement of antimicrobial activity by incorporating mixture of antimicrobial agents into lipid vesicles |
| EP0199362A2 (en) * | 1985-04-26 | 1986-10-29 | Massachusetts Institute Of Technology | System and apparatus for delayed and pulsed release of biologically active substances |
| EP0280503A2 (en) * | 1987-02-23 | 1988-08-31 | Research Development Foundation | Multivesicular liposomes having a biologically active substance encapsulated therein in the presence of a hydrochloride |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4235871A (en) * | 1978-02-24 | 1980-11-25 | Papahadjopoulos Demetrios P | Method of encapsulating biologically active materials in lipid vesicles |
| FR2591105B1 (fr) * | 1985-12-11 | 1989-03-24 | Moet Hennessy Rech | Composition pharmaceutique, notamment dermatologique, ou cosmetique, a base de phases lamellaires lipidiques hydratees ou de liposomes contenant un retinoide ou un analogue structural dudit retinoide tel qu'un carotenoide. |
-
1991
- 1991-03-18 NZ NZ237464A patent/NZ237464A/en unknown
- 1991-03-18 ZA ZA911974A patent/ZA911974B/xx unknown
- 1991-03-19 IE IE91191A patent/IE62772B1/en not_active IP Right Cessation
- 1991-03-20 EP EP91906733A patent/EP0524968B1/en not_active Expired - Lifetime
- 1991-03-20 AU AU75806/91A patent/AU655177B2/en not_active Ceased
- 1991-03-20 IL IL9761591A patent/IL97615A/en not_active IP Right Cessation
- 1991-03-20 AT AT91906733T patent/ATE123412T1/de not_active IP Right Cessation
- 1991-03-20 DE DE69110281T patent/DE69110281T2/de not_active Expired - Lifetime
- 1991-03-20 DK DK91906733.0T patent/DK0524968T3/da active
- 1991-03-20 ES ES91906733T patent/ES2073164T3/es not_active Expired - Lifetime
- 1991-03-20 CA CA002078666A patent/CA2078666C/en not_active Expired - Lifetime
- 1991-03-20 JP JP50728091A patent/JP3461000B2/ja not_active Expired - Lifetime
- 1991-03-20 WO PCT/US1991/001849 patent/WO1991014445A1/en not_active Ceased
- 1991-03-21 CN CN91102478A patent/CN1053101C/zh not_active Expired - Fee Related
- 1991-03-21 PT PT97101A patent/PT97101B/pt not_active IP Right Cessation
- 1991-03-21 RU SU5053129A patent/RU2120795C1/ru not_active IP Right Cessation
-
1992
- 1992-09-17 NO NO923624A patent/NO304576B1/no unknown
- 1992-09-18 FI FI924193A patent/FI104464B/fi active
- 1992-09-21 KR KR1019920702302A patent/KR100203223B1/ko not_active Expired - Fee Related
-
1993
- 1993-04-27 SA SA93130496A patent/SA93130496B1/ar unknown
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1985000515A1 (en) * | 1983-08-01 | 1985-02-14 | The Liposome Company, Inc. | Enhancement of antimicrobial activity by incorporating mixture of antimicrobial agents into lipid vesicles |
| EP0199362A2 (en) * | 1985-04-26 | 1986-10-29 | Massachusetts Institute Of Technology | System and apparatus for delayed and pulsed release of biologically active substances |
| EP0280503A2 (en) * | 1987-02-23 | 1988-08-31 | Research Development Foundation | Multivesicular liposomes having a biologically active substance encapsulated therein in the presence of a hydrochloride |
Also Published As
| Publication number | Publication date |
|---|---|
| PT97101B (pt) | 1998-08-31 |
| EP0524968A4 (en) | 1993-03-24 |
| AU7580691A (en) | 1991-10-21 |
| RU2120795C1 (ru) | 1998-10-27 |
| KR100203223B1 (ko) | 1999-06-15 |
| WO1991014445A1 (en) | 1991-10-03 |
| FI924193L (fi) | 1992-09-18 |
| CN1055663A (zh) | 1991-10-30 |
| JP3461000B2 (ja) | 2003-10-27 |
| EP0524968B1 (en) | 1995-06-07 |
| AU655177B2 (en) | 1994-12-08 |
| EP0524968A1 (en) | 1993-02-03 |
| NO304576B1 (no) | 1999-01-18 |
| SA93130496B1 (ar) | 2004-08-14 |
| NZ237464A (en) | 1995-02-24 |
| NO923624D0 (no) | 1992-09-17 |
| ATE123412T1 (de) | 1995-06-15 |
| DK0524968T3 (da) | 1995-07-31 |
| CA2078666A1 (en) | 1991-09-22 |
| JPH05507680A (ja) | 1993-11-04 |
| DE69110281T2 (de) | 1995-11-09 |
| ZA911974B (en) | 1994-08-22 |
| IE910911A1 (en) | 1991-09-25 |
| CA2078666C (en) | 2001-10-02 |
| IL97615A0 (en) | 1992-06-21 |
| FI924193A0 (fi) | 1992-09-18 |
| IE62772B1 (en) | 1995-02-22 |
| NO923624L (no) | 1992-09-17 |
| IL97615A (en) | 1995-06-29 |
| ES2073164T3 (es) | 1995-08-01 |
| DE69110281D1 (de) | 1995-07-13 |
| PT97101A (pt) | 1991-11-29 |
| FI104464B (fi) | 2000-02-15 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN1053101C (zh) | 杂泡脂质体的制备方法 | |
| Uhumwangho et al. | Current trends in the production and biomedical applications of liposomes: a review | |
| KR970004907B1 (ko) | 하이드로클로라이드의 존재하에서 캅셀화된 생물학적 활성물질을 함유하는 다소포성 리포좀 | |
| US5723147A (en) | Multivesicular liposomes having a biologically active substance encapsulated therein in the presence of a hydrochloride | |
| US5807572A (en) | Multivesicular liposomes having a biologically active substance encapsulated therein in the presence of a hydrochloride | |
| DE69837339T2 (de) | Veränderung der Wirkstoffladung in multivesikulären Liposomen | |
| EP0729351B1 (en) | Vesicles with controlled release of actives | |
| FI119621B (fi) | Multivesikulääristen liposomien valmistus aktiivisten aineiden vapauttamiseksi kontrolloidusti | |
| KR930700134A (ko) | 이종 소포 리포좀 | |
| JP2008163040A (ja) | 封入された化合物のパーセントが増加したリポソーム | |
| CN1280490A (zh) | 共冷冻干燥法制备肽/脂类络合物 | |
| US5576017A (en) | Heterovesicular liposomes | |
| AU745000B2 (en) | Multilamellar coalescence vesicles (MLCV) containing biologically active compounds | |
| NZ247547A (en) | Process for preparing heterovesicular lipid vesicles or liposomes; vesicles containing a chloride and an active agent | |
| HK1013259A1 (zh) | 可控制活性物的释放的小囊 | |
| HK1013259B (zh) | 可控制活性物的释放的小囊 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C53 | Correction of patent of invention or patent application | ||
| COR | Change of bibliographic data |
Free format text: CORRECT: APPLICANT; FROM: FOUNDATION OF RESEARCH AND DEVELOPMENT TO: BODIPO TECHNOLOGY CO., LTD. |
|
| CP03 | Change of name, title or address |
Address after: American California Applicant after: Lap Wave Technology Co Ltd Address before: Nevada Applicant before: Research Development Foudation |
|
| C53 | Correction of patent of invention or patent application | ||
| COR | Change of bibliographic data |
Free format text: CORRECT: PATENTEE; FROM: BODIPO TECHNOLOGY CO., LTD. TO: SKYE DRUG CO., LTD. |
|
| CP01 | Change in the name or title of a patent holder |
Patentee after: Sky Medicaments Co., Ltd. Patentee before: Lap Wave Technology Co Ltd |
|
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| C15 | Extension of patent right duration from 15 to 20 years for appl. with date before 31.12.1992 and still valid on 11.12.2001 (patent law change 1993) | ||
| OR01 | Other related matters | ||
| C17 | Cessation of patent right | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20000607 |