WO2009087081A2 - Neue insulinderivate mit extrem verzögertem zeit-/wirkungsprofil - Google Patents
Neue insulinderivate mit extrem verzögertem zeit-/wirkungsprofil Download PDFInfo
- Publication number
- WO2009087081A2 WO2009087081A2 PCT/EP2009/000017 EP2009000017W WO2009087081A2 WO 2009087081 A2 WO2009087081 A2 WO 2009087081A2 EP 2009000017 W EP2009000017 W EP 2009000017W WO 2009087081 A2 WO2009087081 A2 WO 2009087081A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- arg
- asp
- pro
- glu
- lys
- Prior art date
Links
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical class 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 title claims abstract description 175
- 230000003111 delayed effect Effects 0.000 title description 11
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 claims abstract description 126
- 102000004877 Insulin Human genes 0.000 claims abstract description 69
- 108090001061 Insulin Proteins 0.000 claims abstract description 69
- ULEBESPCVWBNIF-BYPYZUCNSA-N L-arginine amide Chemical compound NC(=O)[C@@H](N)CCCNC(N)=N ULEBESPCVWBNIF-BYPYZUCNSA-N 0.000 claims abstract description 24
- 125000000539 amino acid group Chemical group 0.000 claims abstract description 15
- 239000004475 Arginine Substances 0.000 claims abstract description 11
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 claims abstract description 11
- -1 arginine radical Chemical class 0.000 claims abstract description 11
- JUFFVKRROAPVBI-PVOYSMBESA-N chembl1210015 Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(=O)N[C@H]1[C@@H]([C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O)[C@@H](O)[C@@H](CO[C@]3(O[C@@H](C[C@H](O)[C@H](O)CO)[C@H](NC(C)=O)[C@@H](O)C3)C(O)=O)O2)O)[C@@H](CO)O1)NC(C)=O)C(=O)NCC(=O)NCC(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CO)C(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCSC)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)CNC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 JUFFVKRROAPVBI-PVOYSMBESA-N 0.000 claims description 133
- 101000976075 Homo sapiens Insulin Proteins 0.000 claims description 120
- ODKSFYDXXFIFQN-BYPYZUCNSA-N L-arginine Chemical compound OC(=O)[C@@H](N)CCCN=C(N)N ODKSFYDXXFIFQN-BYPYZUCNSA-N 0.000 claims description 118
- 239000004026 insulin derivative Substances 0.000 claims description 92
- PBGKTOXHQIOBKM-FHFVDXKLSA-N insulin (human) Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@H]1CSSC[C@H]2C(=O)N[C@H](C(=O)N[C@@H](CO)C(=O)N[C@H](C(=O)N[C@H](C(N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=3C=CC(O)=CC=3)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=3C=CC(O)=CC=3)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=3C=CC(O)=CC=3)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=3NC=NC=3)NC(=O)[C@H](CO)NC(=O)CNC1=O)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(O)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O)=O)CSSC[C@@H](C(N2)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](NC(=O)CN)[C@@H](C)CC)[C@@H](C)CC)[C@@H](C)O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)CC=1C=CC=CC=1)C(C)C)C1=CN=CN1 PBGKTOXHQIOBKM-FHFVDXKLSA-N 0.000 claims description 82
- 108010011459 Exenatide Proteins 0.000 claims description 77
- 229960001519 exenatide Drugs 0.000 claims description 74
- 239000000203 mixture Substances 0.000 claims description 50
- 239000002243 precursor Substances 0.000 claims description 50
- 238000009472 formulation Methods 0.000 claims description 44
- 229940125396 insulin Drugs 0.000 claims description 40
- 230000000694 effects Effects 0.000 claims description 24
- 239000011701 zinc Substances 0.000 claims description 17
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 16
- 229910052725 zinc Inorganic materials 0.000 claims description 16
- 238000002360 preparation method Methods 0.000 claims description 15
- 239000000126 substance Chemical group 0.000 claims description 14
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 12
- 150000003839 salts Chemical class 0.000 claims description 12
- 206010012601 diabetes mellitus Diseases 0.000 claims description 11
- 239000003814 drug Substances 0.000 claims description 11
- 238000004519 manufacturing process Methods 0.000 claims description 8
- 125000003277 amino group Chemical group 0.000 claims description 6
- 125000000637 arginyl group Chemical group N[C@@H](CCCNC(N)=N)C(=O)* 0.000 claims description 6
- VOUAQYXWVJDEQY-QENPJCQMSA-N 33017-11-7 Chemical compound OC(=O)CC[C@H](N)C(=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](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](C(C)C)C(=O)NCC(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)NCC(=O)NCC(=O)N1CCC[C@H]1C(=O)NCC(=O)N[C@@H](C)C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N1[C@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O)CCC1 VOUAQYXWVJDEQY-QENPJCQMSA-N 0.000 claims description 5
- 102000004142 Trypsin Human genes 0.000 claims description 5
- 108090000631 Trypsin Proteins 0.000 claims description 5
- 238000000034 method Methods 0.000 claims description 5
- GCYXWQUSHADNBF-AAEALURTSA-N preproglucagon 78-108 Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1N=CNC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 GCYXWQUSHADNBF-AAEALURTSA-N 0.000 claims description 5
- 239000012588 trypsin Substances 0.000 claims description 5
- 108010075254 C-Peptide Proteins 0.000 claims description 4
- 241000243127 Geodia Species 0.000 claims description 4
- 235000010650 Hyssopus officinalis Nutrition 0.000 claims description 4
- SSAAJZQUEUTACT-MDBKHZGBSA-N exendin 2 Chemical compound C([C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(N)=O)C1=CN=CN1 SSAAJZQUEUTACT-MDBKHZGBSA-N 0.000 claims description 4
- 108010028997 heliodermin Proteins 0.000 claims description 4
- 125000003588 lysine group Chemical group [H]N([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 claims description 4
- 108090000790 Enzymes Proteins 0.000 claims description 3
- 102000004190 Enzymes Human genes 0.000 claims description 3
- 101800004266 Glucagon-like peptide 1(7-37) Proteins 0.000 claims description 3
- 108010006519 Molecular Chaperones Proteins 0.000 claims description 3
- 239000013011 aqueous formulation Substances 0.000 claims description 3
- 108010015174 exendin 3 Proteins 0.000 claims description 3
- LMHMJYMCGJNXRS-IOPUOMRJSA-N exendin-3 Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)NCC(=O)NCC(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CO)C(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCSC)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC=1N=CNC=1)[C@H](C)O)[C@H](C)O)C(C)C)C1=CC=CC=C1 LMHMJYMCGJNXRS-IOPUOMRJSA-N 0.000 claims description 3
- 239000000843 powder Substances 0.000 claims description 3
- 230000008929 regeneration Effects 0.000 claims description 3
- 238000011069 regeneration method Methods 0.000 claims description 3
- 239000000725 suspension Substances 0.000 claims description 3
- 108010019598 Liraglutide Proteins 0.000 claims description 2
- YSDQQAXHVYUZIW-QCIJIYAXSA-N Liraglutide Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)NCC(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCNC(=O)CC[C@H](NC(=O)CCCCCCCCCCCCCCC)C(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=C(O)C=C1 YSDQQAXHVYUZIW-QCIJIYAXSA-N 0.000 claims description 2
- 210000000227 basophil cell of anterior lobe of hypophysis Anatomy 0.000 claims description 2
- 230000008878 coupling Effects 0.000 claims description 2
- 238000010168 coupling process Methods 0.000 claims description 2
- 238000005859 coupling reaction Methods 0.000 claims description 2
- 125000002642 gamma-glutamyl group Chemical group 0.000 claims description 2
- 229960002701 liraglutide Drugs 0.000 claims description 2
- 230000008569 process Effects 0.000 claims description 2
- 230000001225 therapeutic effect Effects 0.000 claims description 2
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 abstract description 80
- 238000007792 addition Methods 0.000 abstract description 19
- 239000004472 Lysine Substances 0.000 abstract description 11
- 238000006467 substitution reaction Methods 0.000 abstract description 9
- 125000003275 alpha amino acid group Chemical group 0.000 abstract description 7
- 125000000729 N-terminal amino-acid group Chemical group 0.000 abstract description 2
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 abstract description 2
- DXMZNKNJOBUNRO-UHFFFAOYSA-N glycyl radical Chemical compound N[CH]C(O)=O DXMZNKNJOBUNRO-UHFFFAOYSA-N 0.000 abstract 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 142
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 134
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 131
- 239000013612 plasmid Substances 0.000 description 118
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 112
- 108010066381 preproinsulin Proteins 0.000 description 67
- 108020004414 DNA Proteins 0.000 description 48
- 238000010276 construction Methods 0.000 description 46
- 150000001875 compounds Chemical class 0.000 description 40
- 230000009435 amidation Effects 0.000 description 36
- 238000007112 amidation reaction Methods 0.000 description 36
- 238000006243 chemical reaction Methods 0.000 description 33
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 31
- 101150102573 PCR1 gene Proteins 0.000 description 27
- 239000000047 product Substances 0.000 description 25
- HKXLAGBDJVHRQG-YFKPBYRVSA-N L-lysinamide Chemical compound NCCCC[C@H](N)C(N)=O HKXLAGBDJVHRQG-YFKPBYRVSA-N 0.000 description 21
- 230000009471 action Effects 0.000 description 21
- 101100519158 Arabidopsis thaliana PCR2 gene Proteins 0.000 description 20
- 230000002218 hypoglycaemic effect Effects 0.000 description 17
- 238000003752 polymerase chain reaction Methods 0.000 description 17
- 235000001014 amino acid Nutrition 0.000 description 15
- 108020004705 Codon Proteins 0.000 description 14
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 14
- 229940024606 amino acid Drugs 0.000 description 13
- 150000001413 amino acids Chemical class 0.000 description 12
- 241000282472 Canis lupus familiaris Species 0.000 description 9
- 235000013922 glutamic acid Nutrition 0.000 description 9
- 239000004220 glutamic acid Substances 0.000 description 9
- 108090000623 proteins and genes Proteins 0.000 description 9
- 241001465754 Metazoa Species 0.000 description 8
- 108010076181 Proinsulin Proteins 0.000 description 8
- 235000003704 aspartic acid Nutrition 0.000 description 8
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 8
- 230000029087 digestion Effects 0.000 description 8
- 102000004196 processed proteins & peptides Human genes 0.000 description 8
- 235000018102 proteins Nutrition 0.000 description 8
- 102000004169 proteins and genes Human genes 0.000 description 8
- 239000008280 blood Substances 0.000 description 7
- 210000004369 blood Anatomy 0.000 description 7
- 125000000291 glutamic acid group Chemical group N[C@@H](CCC(O)=O)C(=O)* 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- 239000011592 zinc chloride Substances 0.000 description 7
- 235000005074 zinc chloride Nutrition 0.000 description 7
- 241000196324 Embryophyta Species 0.000 description 5
- 101800000224 Glucagon-like peptide 1 Proteins 0.000 description 5
- 102400000322 Glucagon-like peptide 1 Human genes 0.000 description 5
- DTHNMHAUYICORS-KTKZVXAJSA-N Glucagon-like peptide 1 Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1N=CNC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 DTHNMHAUYICORS-KTKZVXAJSA-N 0.000 description 5
- 108010057186 Insulin Glargine Proteins 0.000 description 5
- COCFEDIXXNGUNL-RFKWWTKHSA-N Insulin glargine Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@H]1CSSC[C@H]2C(=O)N[C@H](C(=O)N[C@@H](CO)C(=O)N[C@H](C(=O)N[C@H](C(N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=3C=CC(O)=CC=3)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=3C=CC(O)=CC=3)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=3C=CC(O)=CC=3)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=3NC=NC=3)NC(=O)[C@H](CO)NC(=O)CNC1=O)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)C(=O)NCC(O)=O)=O)CSSC[C@@H](C(N2)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](NC(=O)CN)[C@@H](C)CC)[C@@H](C)CC)[C@@H](C)O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)CC=1C=CC=CC=1)C(C)C)C1=CN=CN1 COCFEDIXXNGUNL-RFKWWTKHSA-N 0.000 description 5
- 241000700159 Rattus Species 0.000 description 5
- 230000002378 acidificating effect Effects 0.000 description 5
- 238000003776 cleavage reaction Methods 0.000 description 5
- 238000002474 experimental method Methods 0.000 description 5
- 239000003755 preservative agent Substances 0.000 description 5
- 230000007017 scission Effects 0.000 description 5
- 238000002560 therapeutic procedure Methods 0.000 description 5
- 230000008901 benefit Effects 0.000 description 4
- 210000004027 cell Anatomy 0.000 description 4
- 238000011161 development Methods 0.000 description 4
- 230000018109 developmental process Effects 0.000 description 4
- 238000011156 evaluation Methods 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- 229960002869 insulin glargine Drugs 0.000 description 4
- 101100519159 Arabidopsis thaliana PCR3 gene Proteins 0.000 description 3
- 241000894006 Bacteria Species 0.000 description 3
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000004480 active ingredient Substances 0.000 description 3
- 239000000872 buffer Substances 0.000 description 3
- 210000004899 c-terminal region Anatomy 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 230000005923 long-lasting effect Effects 0.000 description 3
- 230000007935 neutral effect Effects 0.000 description 3
- 230000001019 normoglycemic effect Effects 0.000 description 3
- 230000000144 pharmacologic effect Effects 0.000 description 3
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 3
- 238000012545 processing Methods 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 241000195940 Bryophyta Species 0.000 description 2
- HTQBXNHDCUEHJF-XWLPCZSASA-N Exenatide Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)NCC(=O)NCC(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CO)C(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCSC)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)CNC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 HTQBXNHDCUEHJF-XWLPCZSASA-N 0.000 description 2
- 101000829958 Homo sapiens N-acetyllactosaminide beta-1,6-N-acetylglucosaminyl-transferase Proteins 0.000 description 2
- 102100023315 N-acetyllactosaminide beta-1,6-N-acetylglucosaminyl-transferase Human genes 0.000 description 2
- 108091028043 Nucleic acid sequence Proteins 0.000 description 2
- 102000007327 Protamines Human genes 0.000 description 2
- 108010007568 Protamines Proteins 0.000 description 2
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- PTFCDOFLOPIGGS-UHFFFAOYSA-N Zinc dication Chemical compound [Zn+2] PTFCDOFLOPIGGS-UHFFFAOYSA-N 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 230000001580 bacterial effect Effects 0.000 description 2
- 238000011109 contamination Methods 0.000 description 2
- 238000012217 deletion Methods 0.000 description 2
- 230000037430 deletion Effects 0.000 description 2
- 230000001419 dependent effect Effects 0.000 description 2
- 238000013461 design Methods 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 230000002255 enzymatic effect Effects 0.000 description 2
- 239000012634 fragment Substances 0.000 description 2
- 102000037865 fusion proteins Human genes 0.000 description 2
- 108020001507 fusion proteins Proteins 0.000 description 2
- 125000003630 glycyl group Chemical group [H]N([H])C([H])([H])C(*)=O 0.000 description 2
- HTMVMVKJOPFRMK-OYZAELBCSA-N helospectin i Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)O)C1=CC=C(O)C=C1 HTMVMVKJOPFRMK-OYZAELBCSA-N 0.000 description 2
- 125000000487 histidyl group Chemical group [H]N([H])C(C(=O)O*)C([H])([H])C1=C([H])N([H])C([H])=N1 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 239000007951 isotonicity adjuster Substances 0.000 description 2
- RLSSMJSEOOYNOY-UHFFFAOYSA-N m-cresol Chemical compound CC1=CC=CC(O)=C1 RLSSMJSEOOYNOY-UHFFFAOYSA-N 0.000 description 2
- 238000005457 optimization Methods 0.000 description 2
- 239000008194 pharmaceutical composition Substances 0.000 description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- 230000002335 preservative effect Effects 0.000 description 2
- 229940048914 protamine Drugs 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 2
- FWMNVWWHGCHHJJ-SKKKGAJSSA-N 4-amino-1-[(2r)-6-amino-2-[[(2r)-2-[[(2r)-2-[[(2r)-2-amino-3-phenylpropanoyl]amino]-3-phenylpropanoyl]amino]-4-methylpentanoyl]amino]hexanoyl]piperidine-4-carboxylic acid Chemical compound C([C@H](C(=O)N[C@H](CC(C)C)C(=O)N[C@H](CCCCN)C(=O)N1CCC(N)(CC1)C(O)=O)NC(=O)[C@H](N)CC=1C=CC=CC=1)C1=CC=CC=C1 FWMNVWWHGCHHJJ-SKKKGAJSSA-N 0.000 description 1
- 229940090248 4-hydroxybenzoic acid Drugs 0.000 description 1
- VWEWCZSUWOEEFM-WDSKDSINSA-N Ala-Gly-Ala-Gly Chemical compound C[C@H](N)C(=O)NCC(=O)N[C@@H](C)C(=O)NCC(O)=O VWEWCZSUWOEEFM-WDSKDSINSA-N 0.000 description 1
- 108700007397 Arg(B31)- insulin Proteins 0.000 description 1
- OMLWNBVRVJYMBQ-YUMQZZPRSA-N Arg-Arg Chemical compound NC(N)=NCCC[C@H](N)C(=O)N[C@@H](CCCN=C(N)N)C(O)=O OMLWNBVRVJYMBQ-YUMQZZPRSA-N 0.000 description 1
- DCXYFEDJOCDNAF-UHFFFAOYSA-N Asparagine Natural products OC(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-N 0.000 description 1
- 210000002237 B-cell of pancreatic islet Anatomy 0.000 description 1
- 108010065691 Biphasic Insulins Proteins 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 101001011741 Bos taurus Insulin Proteins 0.000 description 1
- 240000002791 Brassica napus Species 0.000 description 1
- 235000006008 Brassica napus var napus Nutrition 0.000 description 1
- WEDIKSVWBUKTRA-WTKGVUNUSA-N CC[C@H](C)[C@H](NC(=O)CN)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@H]1CSSC[C@@H]2NC(=O)[C@@H](NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CSSC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](Cc3c[nH]cn3)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)Cc3ccccc3)C(C)C)C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](Cc3c[nH]cn3)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](Cc3ccc(O)cc3)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](Cc3ccc(O)cc3)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](Cc3ccc(O)cc3)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC2=O)C(=O)N[C@@H](CC(N)=O)C(O)=O)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](Cc2ccccc2)C(=O)N[C@@H](Cc2ccccc2)C(=O)N[C@@H](Cc2ccc(O)cc2)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(O)=O)NC1=O)[C@@H](C)O)[C@@H](C)CC Chemical compound CC[C@H](C)[C@H](NC(=O)CN)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@H]1CSSC[C@@H]2NC(=O)[C@@H](NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CSSC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](Cc3c[nH]cn3)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)Cc3ccccc3)C(C)C)C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](Cc3c[nH]cn3)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](Cc3ccc(O)cc3)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](Cc3ccc(O)cc3)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](Cc3ccc(O)cc3)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC2=O)C(=O)N[C@@H](CC(N)=O)C(O)=O)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](Cc2ccccc2)C(=O)N[C@@H](Cc2ccccc2)C(=O)N[C@@H](Cc2ccc(O)cc2)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(O)=O)NC1=O)[C@@H](C)O)[C@@H](C)CC WEDIKSVWBUKTRA-WTKGVUNUSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 241000196319 Chlorophyceae Species 0.000 description 1
- 241000132536 Cirsium Species 0.000 description 1
- 241000195493 Cryptophyta Species 0.000 description 1
- 241000192700 Cyanobacteria Species 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- 102000012410 DNA Ligases Human genes 0.000 description 1
- 108010061982 DNA Ligases Proteins 0.000 description 1
- 229940124213 Dipeptidyl peptidase 4 (DPP IV) inhibitor Drugs 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 240000005979 Hordeum vulgare Species 0.000 description 1
- 235000007340 Hordeum vulgare Nutrition 0.000 description 1
- 208000013016 Hypoglycemia Diseases 0.000 description 1
- 108010073961 Insulin Aspart Proteins 0.000 description 1
- 108010065920 Insulin Lispro Proteins 0.000 description 1
- 101500021084 Locusta migratoria 5 kDa peptide Proteins 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 102000005431 Molecular Chaperones Human genes 0.000 description 1
- 244000061176 Nicotiana tabacum Species 0.000 description 1
- 235000002637 Nicotiana tabacum Nutrition 0.000 description 1
- 206010034912 Phobia Diseases 0.000 description 1
- 240000004713 Pisum sativum Species 0.000 description 1
- 108010005991 Pork Regular Insulin Proteins 0.000 description 1
- 241000700157 Rattus norvegicus Species 0.000 description 1
- 241000206572 Rhodophyta Species 0.000 description 1
- 238000012300 Sequence Analysis Methods 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 241000592344 Spermatophyta Species 0.000 description 1
- 229940100389 Sulfonylurea Drugs 0.000 description 1
- 101710162629 Trypsin inhibitor Proteins 0.000 description 1
- 229940122618 Trypsin inhibitor Drugs 0.000 description 1
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 240000008042 Zea mays Species 0.000 description 1
- 235000016383 Zea mays subsp huehuetenangensis Nutrition 0.000 description 1
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 1
- LNUFLCYMSVYYNW-ZPJMAFJPSA-N [(2r,3r,4s,5r,6r)-2-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[[(3s,5s,8r,9s,10s,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-3-yl]oxy]-4,5-disulfo Chemical compound O([C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1C[C@@H]2CC[C@H]3[C@@H]4CC[C@@H]([C@]4(CC[C@@H]3[C@@]2(C)CC1)C)[C@H](C)CCCC(C)C)[C@H]1O[C@H](COS(O)(=O)=O)[C@@H](OS(O)(=O)=O)[C@H](OS(O)(=O)=O)[C@H]1OS(O)(=O)=O LNUFLCYMSVYYNW-ZPJMAFJPSA-N 0.000 description 1
- 239000008351 acetate buffer Substances 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 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 description 1
- 229960000723 ampicillin Drugs 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 210000004102 animal cell Anatomy 0.000 description 1
- RCHHVVGSTHAVPF-ZPHPLDECSA-N apidra Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@H]1CSSC[C@H]2C(=O)N[C@H](C(=O)N[C@@H](CO)C(=O)N[C@H](C(=O)N[C@H](C(N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=3C=CC(O)=CC=3)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=3C=CC(O)=CC=3)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=3C=CC(O)=CC=3)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=3N=CNC=3)NC(=O)[C@H](CO)NC(=O)CNC1=O)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O)=O)CSSC[C@@H](C(N2)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](NC(=O)CN)[C@@H](C)CC)[C@@H](C)CC)[C@@H](C)O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](NC(=O)[C@@H](N)CC=1C=CC=CC=1)C(C)C)C1=CNC=N1 RCHHVVGSTHAVPF-ZPHPLDECSA-N 0.000 description 1
- 229940112930 apidra Drugs 0.000 description 1
- 108010068380 arginylarginine Proteins 0.000 description 1
- 235000009582 asparagine Nutrition 0.000 description 1
- 229960001230 asparagine Drugs 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 238000002306 biochemical method Methods 0.000 description 1
- 238000011138 biotechnological process Methods 0.000 description 1
- IXIBAKNTJSCKJM-BUBXBXGNSA-N bovine insulin Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@H]1CSSC[C@H]2C(=O)N[C@@H](C)C(=O)N[C@@H](CO)C(=O)N[C@H](C(=O)N[C@H](C(N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=3C=CC(O)=CC=3)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=3C=CC(O)=CC=3)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=3C=CC(O)=CC=3)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=3NC=NC=3)NC(=O)[C@H](CO)NC(=O)CNC1=O)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(O)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O)=O)CSSC[C@@H](C(N2)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](NC(=O)CN)[C@@H](C)CC)C(C)C)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)CC=1C=CC=CC=1)C(C)C)C1=CN=CN1 IXIBAKNTJSCKJM-BUBXBXGNSA-N 0.000 description 1
- 229940084891 byetta Drugs 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 229940043430 calcium compound Drugs 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 125000003636 chemical group Chemical group 0.000 description 1
- 238000007385 chemical modification Methods 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 238000002648 combination therapy Methods 0.000 description 1
- 239000012228 culture supernatant Substances 0.000 description 1
- 238000004925 denaturation Methods 0.000 description 1
- 230000036425 denaturation Effects 0.000 description 1
- 108700025974 depot- insulin Proteins 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 239000003603 dipeptidyl peptidase IV inhibitor Substances 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 238000000855 fermentation Methods 0.000 description 1
- 230000004151 fermentation Effects 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 238000001502 gel electrophoresis Methods 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 230000002641 glycemic effect Effects 0.000 description 1
- PJJJBBJSCAKJQF-UHFFFAOYSA-N guanidinium chloride Chemical compound [Cl-].NC(N)=[NH2+] PJJJBBJSCAKJQF-UHFFFAOYSA-N 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 108010069764 helospectin I Proteins 0.000 description 1
- WNRQPCUGRUFHED-DETKDSODSA-N humalog Chemical compound C([C@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)[C@H](CS)NC(=O)[C@H]([C@@H](C)CC)NC(=O)[C@H](CO)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CS)NC(=O)[C@H](CS)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](NC(=O)CN)[C@@H](C)CC)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(N)=O)C(O)=O)C1=CC=C(O)C=C1.C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CS)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCCN)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H]([C@@H](C)O)C(O)=O)C(C)C)NC(=O)[C@H](CO)NC(=O)CNC(=O)[C@H](CS)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)CC=1C=CC=CC=1)C(C)C)C1=CN=CN1 WNRQPCUGRUFHED-DETKDSODSA-N 0.000 description 1
- 229940038661 humalog Drugs 0.000 description 1
- 210000003000 inclusion body Anatomy 0.000 description 1
- 239000000859 incretin Substances 0.000 description 1
- 108700039926 insulin glulisine Proteins 0.000 description 1
- 230000003914 insulin secretion Effects 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 229940060975 lantus Drugs 0.000 description 1
- 230000007775 late Effects 0.000 description 1
- 238000007169 ligase reaction Methods 0.000 description 1
- 150000002681 magnesium compounds Chemical class 0.000 description 1
- 235000009973 maize Nutrition 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- XZWYZXLIPXDOLR-UHFFFAOYSA-N metformin Chemical compound CN(C)C(=N)NC(N)=N XZWYZXLIPXDOLR-UHFFFAOYSA-N 0.000 description 1
- 229960003105 metformin Drugs 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000002105 nanoparticle Substances 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 210000001322 periplasm Anatomy 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 208000019899 phobic disease Diseases 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 108091008146 restriction endonucleases Proteins 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 238000005507 spraying Methods 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 210000000130 stem cell Anatomy 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 230000001550 time effect Effects 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 239000002753 trypsin inhibitor Substances 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/575—Hormones
- C07K14/62—Insulins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/22—Hormones
- A61K38/28—Insulins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
- C12N15/09—Recombinant DNA-technology
- C12N15/10—Processes for the isolation, preparation or purification of DNA or RNA
- C12N15/102—Mutagenizing nucleic acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Definitions
- the invention relates to novel insulin analogues with a basal time / activity profile, their preparation and use.
- insulin analogues and "insulins” are used interchangeably herein.
- the concept of intensified insulin therapy seeks to reduce the health risk by aiming for a stable control of blood sugar levels by early administration of basal insulin.
- An ideal basal insulin will certainly work in every patient for at least 24 hours.
- the effect of insulin is delayed and with the shortest possible time / effect profile, so that the risk of short-term hypoglycaemia is clearly minimized and the application can even take place without prior intake of food.
- basal insulin A good supply of basal insulin is given when the insulin effect as long as possible persists as long as possible, ie the Body is supplied with a constant amount of insulin. This minimizes the risk of hypoglycemic events and minimizes patient and tag-specific variability.
- the pharmacokinetic profile of an ideal basal insulin should therefore be characterized by a delayed onset of action and by a delayed, ie long-lasting and uniform effect.
- pI isoelectric point
- the B chain end consists of an amidated basic amino acid residue such as lysine or argininamide, i. in the amidated basic amino acid residue at the B chain end, the carboxyl group of the terminal amino acid is in its amidated form, and
- the N-terminal amino acid residue of the insulin A chain is a lysine or arginine residue
- FIG. 1 shows the hypoglycemic effect of the compound YKL205 according to the invention compared with that of insulin glargine.
- the invention thus relates to an insulin analog of the formula I.
- articles of the invention are insulin analogs as set forth above in which independently of one another AO Arg corresponds, or wherein A5 corresponds to GIu, or where A15 corresponds to GIu, or where A18 corresponds to Asp, or where B-1 corresponds to an amino group, or where BO corresponds to GIu , or wherein B1 corresponds to Asp, or wherein B2 corresponds to VaI, or wherein B3 corresponds to Asp, or wherein B4 corresponds to GIu, or wherein B29 corresponds to Lys, or wherein B30 corresponds to Thr, or where B31 corresponds to Arg or Lys.
- a particularly preferred subject of the invention is an insulin analog selected from a group comprising:
- human insulin in the names of said insulin analogs, reference is made to the amino acid sequences of the A and B chains of human insulin, and all deviations (additions, substitutions, deletions) thereof are given in a given name of an insulin analog.
- Another object of the invention is a method for producing an insulin analogue as mentioned above, in particular wherein a precursor of the
- Insulin analogue is recombinantly produced, the precursor is enzymatically processed into two - chain insulin and a coupling with arginine amide in the presence of an enzyme with trypsin activity is performed and the insulin analog is isolated.
- Another object of the invention is a use of an insulin analogue as described above for the manufacture of a medicament for the treatment of diabetes, in particular of diabetes type I or type II.
- the invention likewise provides a use of an insulin analogue as described above for the manufacture of a medicament to support the beta cell regeneration
- Another object of the invention is a medicament containing an insulin analog as described above and / or physiologically acceptable salts thereof.
- Another object of the invention is a formulation of the insulin analog as described above, wherein the formulation is in aqueous form containing the dissolved insulin analog.
- Another object of the invention is a formulation of the insulin analogue as described above, wherein the formulation is in the form of powder.
- Another object of the invention is a formulation as described above, wherein the insulin analogue as described above in crystalline and / or amorphous form is present.
- Another object of the invention is a formulation of the insulin analogue as described above, wherein the formulation is in the form of a suspension.
- Another object of the invention is a formulation of the insulin analogue as described above, wherein the formulation additionally contains a chemical chaperone.
- Another object of the invention is a DNA coding for a precursor of an insulin analogue as described above, or for the A-chain or B-chain of an insulin analogue as described above.
- Another object of the invention is a vector containing a DNA as described above.
- Another object of the invention is a host organism containing a DNA as described above or a vector as described above.
- Another object of the invention is a recuperatorinanalogon, characterized in that the C-peptide carries at its N-terminus the amino acid residue arginine and at its C-terminus two arginine residues or an arginine residue and a lysine residue, in which latter case the lysine residue is the actual C - Term forms.
- Another object of the invention is a formulation as described above, in addition to a glucagon-like peptide-1 (GLP1) or an analog or derivative thereof, or exendin-3 or -4 or an analog or derivative thereof, preferably exendin -4 is included.
- GLP1 glucagon-like peptide-1
- exendin-4 is included.
- a further subject of the invention is a formulation as described above in which an analogue of exendin-4 is selected from a group comprising H-desPro 36 -exendin-4-Lys 6 -NH 2 , H-des (Pro 36 37 ) - exendin-4-Lys 4 -NH 2, and H-des (Pro 36 - 37) -Exendin-4-Lys 5 -NH 2, or a pharmacologically tolerable salt thereof.
- Another object of the invention is a formulation as described above, wherein an analog of exendin-4 is selected from a group containing the Pro 36 [Asp 28 ] exendin-4 (1-39), the Pro 36 [isoSp 28 ] exendin-4 (1-39), Pro 36 [Met (O) 14 , Asp 28 ] Exendin-4 (1-39), Pro 36 [Met (O) 14 , IsoPs 28 ] Exendin-4 (1-39), Pro 36 [TrP (O 2 ) 25 , Asp 28 ] Exendin-2 (1-39), Pro 36 [Trp (O 2 ) 25 , IsoPs 28 ] Exendin-2 (1-39), Pro 36 [Met (O) 14 Trp (O 2 ) 25 , Asp 28 ] Exendin-4 (1-39) and desPro 36 [Met (O) 14 Trp (O 2 ) 25 , IsoSp 28 ] Exendin-4 (1-39), or a pharmacologically tolerable Salt of it.
- Another object of the invention is a formulation as described in the previous paragraph, in which the C-termini of the analogs of exendin-4, the peptide -
- Another object of the invention is a formulation as described above, in which an analog of exendin-4 is selected from a group containing H- (LyS) 6 - of the Pro 36 [Asp 28 ] exendin-4 (1-39) -Lys 6 -NH 2 of the Asp 28 Pro 36 , Pro 37 , Pro 38, Exendin-4 (1-39) -NH 2 , H- (LyS) 6 - of the Pro 36 , Pro 37 , Pro 38 [Asp 28 ] Exendin-4 (1-39) -NH 2 , H-Asn- (Glu) 5 of Pro 36 , Pro 37 , Pro 38 [Asp 28 ] Exendin-4 (1-39) -NH 2 , Pro 36 , Pro 37 , Pro 38 [Asp 28 ] Exendin-4 (1-39) -NH 2 , Pro 36 , Pro 37 , Pro 38 [Asp 28 ] Exendin-4 (1-39) - (Lys) 6 -NH 2 , H- (LyS
- Another object of the invention is a formulation as described above, in which in addition Arg 34 , Lys 26 (N ⁇ ( ⁇ -glutamyl (N ⁇ -hexadecanoyl))) GLP-1 (7-37) [liraglutide] or a pharmacologically tolerable Salt thereof is included.
- the insulins according to the invention can be the subject of a pharmaceutical formulation which has an advantageous effect after administration. It is based on aqueous solutions. Accordingly, further components must be miscible. The danger of viral animal contamination is minimized by the fact that the preparation should not contain components derived from animal sources. It is also advantageous to prevent microbial contamination by adding preservatives. By adding isotonic agents, a possible negative effect of the formulation on the physiology of the tissue cells at the site of application can be compensated. The addition of protamine can have a stabilizing effect, so that largely salt-free insulin preparation can be obtained if protamine is added to the formulation.
- a phenolic component can lead to a stabilization of the structure of the insulin analog used and thus additionally effect, inter alia, the delay effect on onset of action.
- Added to the formulation may also be substances which stabilize the spatial structure of the delay insulins according to the invention and lead to better thermal stability.
- Such chemical chaperones may include, for example, short synthetic peptides, which may also contain amino acid analogs, or include, for example, peptide sequences derived from the insulin-derived C peptide.
- the insulins according to the invention can be incorporated into nanoparticles. Also conceivable are so-called “slow-release” formulations in which the delaying insulin according to the invention is reversibly bound to polymeric carriers.
- the insulins of the invention may parallel with rapid-acting insulins such as Apidra ®, NovoRapid ®, Humalog ® or under development insulin derivatives or formulations with appropriate time - / action profile or inhalable insulin or nasally or orally administered insulin, resulting in
- the insulin analogs according to the invention can be used in pharmaceutical preparations which contain peptides which are described by activity comparable to GLP-1 (glucagon-like peptide-1) or exendin-4 or exendin-3.
- GLP-1 glycol-like peptide-1
- exendin-4 or exendin-3 examples of such peptides are GLP-1 (7-37), Exenatide (Byetta ®) or peptides, their production in the patent applications WO 2006/058620, WO 2001/04156, WO 2004/005342 and WO 98/08871 described, represents .
- formulations which contain a depot formulation of these peptides are especially advantageous.
- compositions according to the invention which, in parallel with the administration of the pharmaceuticals according to the invention, provide for increasing the insulin action, for example metformin.
- Combination therapies with dipeptidyl peptidase-4 inhibitors, which increase the level of incretins, are also possible, as are combinations with sulfonylureas, which increase insulin secretion in the pancreas.
- the delay insulins according to the invention can be used particularly advantageously if the regeneration of pancreatic beta cells from corresponding stem cells is initiated by application of differentiation factors. All of these applications are exemplary for the therapy of diabetes called and also subject of the invention.
- Another object of the invention is thus the use of the insulins according to the invention in combination with other active ingredients for the treatment of diabetes, in particular diabetes type I or type II diabetes.
- Another object of the invention is a pharmaceutical composition containing an insulin analog according to the invention, which is in particular an aqueous formulation or a powder.
- the drug is a pharmaceutical preparation, which is preferably a solution or suspension for injection purposes; it is characterized by a content of at least one insulin analog according to the invention, and / or at least one of the physiologically acceptable salts thereof in dissolved, amorphous and / or crystalline - preferably in dissolved form.
- the preparation preferably has a pH between about 2.5 and 8.5, more preferably between about 4.0 and 8.5, preferably contains a suitable isotonizing agent, a suitable preservative and optionally a suitable buffer, and preferably also a particular one Zinc ion concentration, in sterile aqueous solution.
- Suitable isotonizing agents are, for example, glycerol, glucose, mannitol, NaCl, calcium or magnesium compounds such as CaCk, etc.
- Suitable preservatives are e.g. Phenol, m-cresol, benzyl alcohol and / or p-hydroxybenzoic acid ester.
- buffer substances in particular for the adjustment of a pH value between approximately 4.0 and 8.5, e.g. Sodium acetate, sodium citrate, sodium phosphate, etc. can be used. Otherwise, physiologically acceptable dilute acids (typically HCl) or alkalis (typically NaOH) are also suitable for adjusting the pH.
- physiologically acceptable dilute acids typically HCl
- alkalis typically NaOH
- the preparation has a zinc content, it is preferred to be from 1 to 2 mg / ml, in particular from 1 ⁇ g / ml to 200 ⁇ g zinc / ml.
- the addition of Zn allows the action profile of the invention
- Insulin analogues affect surprisingly well. This allows preparations that differ in terms of total duration of action, the rate of onset of action and the profile of the effect curve and thus allow an individual adjustment of the patient. Another possibility results from the use of a "two-chamber insulin device", which allows the application of a formulation with rapid onset of action and / or slow shallow onset of action depending on the life situation.
- Unmodified insulin preferably bovine, porcine or human insulin, in particular human insulin, or insulin analogs and derivatives thereof can also be admixed for the purpose of varying the active substance profile of the preparation according to the invention.
- one or more exendin-4 derivatives or peptides characterized by GLP-1 (glucagon like peptide-1) -like activity, or directly corresponding to GLP-1, can be mixed.
- Such drugs (preparations) are also the subject of the invention.
- Preferred drug concentrations are those corresponding to about 1-1500, more preferably about 5-1000 and especially about 40-400 international units / ml.
- the insulin analogs according to the invention are first prepared biotechnologically as a precursor which does not yet comprise the amide. It is well known to those skilled in the art that there are a variety of ways to make insulins.
- the host cell systems used are bacteria, yeasts and plants or plant cells to be cultivated by fermentation. If cost considerations allow it, expression systems using animal cells as a host system are also conceivable. However, this requires a safe freedom from animal viruses. Thus, it is clear that the expression systems described by way of example represent only a small portion of the host / vector systems developed for the recombinant production of proteins.
- host organisms can be selected from the plant kingdom of organisms of the first division Schizophyta containing Schizomycetes, bacteria or blue-green algae, organisms of the second division Phycophyta V. class Chlorophyceae, organisms of the second division Phycophyta VII. Class Rhodophyceae, organisms of the 3rd division Mycophyta , Organisms of the 5th division Bryophyta and organisms of the 7th division Spermatophyta.
- European Patent Application EP-A 1 222 207 describes a plasmid pINT358d which codes for a pre-proinsulin comprising an altered C-peptide.
- PCR polymerase chain reaction
- Corresponding fusion proteins do not necessarily have to be produced intracellularly. It is clear to the person skilled in the art that such proteins can also be produced by bacterial expression with subsequent secretion into the periplasm and / or into the culture supernatant.
- European Patent Application EP-A 1 364 029 describes this by way of example.
- the proinsulin Precursors which lead to the analogs according to the invention are likewise provided by the invention.
- the proinsulins produced in this way can in principle be converted into an insulin analogue precursor which comprises lysine or arginine in position AO and carries lysine or arginine at the C-terminal end of the B chain.
- proinsulins according to the invention are present as inclusion bodies or soluble after intracellular expression in bacteria, these precursors must be folded into the correct conformation by in vitro folding before the processing and biochemical modification can be carried out.
- the described fusion protein allows direct folding after denaturation by means of urea or guanidinium hydrochloride, folding intermediates are also the subject of the invention.
- Another object of the invention is a method for producing the insulin analogs according to the invention, wherein a precursor of the insulin analog recombinant produced and enzymatically converted to a 2 - chain insulin precursor N-terminal to amino acid 1 of the A chain arginine or lysine carries and am C-terminal end of the B chain has a lysine or arginine, which is converted with arginine amide or lysine amide in the presence of an enzyme having trypsin activity in the amide and thus in the delay insulin according to the invention and highly purified by a biochemical purification process.
- Proteins which are obtained by substitution of at least one naturally occurring amino acid residue with other amino acid residues and / or addition and / or Removing at least one amino acid residue from the corresponding otherwise identical naturally occurring protein are referred to as "analogs" of proteins, and the added and / or replaced amino acid residues may also be those that are not naturally occurring.
- Proteins obtained by chemically modifying certain amino acid residues of parent proteins are referred to as "derivatives" of proteins
- the chemical modification may be, for example, the addition of one or more particular chemical groups to one or more amino acids.
- Fig. 1 Hypoglycaemic effect of new insulin analogues in rats
- Fig. 2 Hypoglycemic effect of new insulin analogues in the dog
- Fig. 3 Hypoglycemic effect of YKL205 in the dog
- Fig. 4 Zinc-dependence of the hypoglycemic effect of YKL205 in the dog
- Example 1 Preparation of vector derivative plNT3580 encoding GIy (A21) -insulin and a modified C-peptide carrying Arg Arg / C chain boundary.
- European Patent Application EP-A 1 222 207 describes the plasmids pINT358d, pINT91d and the primer sequence Tir. DNA of these products is used in the construction of plasmid pINT3580.
- the plasmid plNT358d is characterized by a gene sequence which codes for a modified C-peptide with special properties. Three primer sequences are synthesized:
- This primer serves to introduce arginine instead of lysine at the insulin A / B chain boundary.
- the codon for the arginine to be introduced is bold in both primers.
- a PCR is carried out with the primer pairs Tir / arg_cjunc_rev and arg cjuncf / pint3580_glya21rev in accordance with European Patent Application EP-A 1 222 207. Aliquots of the products of both reactions are combined and used together with the primer pair Tir / pint3580_glya21rev in a third PCR.
- the product of this reaction is purified by gel electrophoretic separation of the reaction mixture and digested with the restriction enzymes Sali / Nco1 according to the manufacturer in one and the same reaction, the reaction mixture gelelektrophoretisch separated and isolated the proinsulin sequence encoding DNA fragment. The fragment is then inserted via a DNA ligase reaction into the Nco1 / Sali opened plNT91d vector DNA.
- Competent E. coli bacterial cells are transformed with the ligation mixture.
- the transformation mixture is plated on selection plates containing 25 mg / l ampicillin. Plasmid DNA is isolated from colonies and characterized by DNA sequence analysis. Proper plasmids are named plNT3580.
- Example 2 Construction of the plasmid pINT3581 encoding His (A8), Gly (A21) preproinsulin
- the construction is carried out as described in Example 1 via 3 polymerase chain reactions.
- the product of the third reaction is inserted after Nco1 / Sali digestion into the Nco1 / Sali opened plNT91d vector DNA.
- the primers Tir and pint3580_glya21rev are used. Two more primers are synthesized:
- PCR1 and 2 are DNA of plasmid pINT3580.
- PCR1 is performed with the primer pair Tir / pint3580_Ha8rev and PCR2 with the primer pair pint3580_Ha8f / pint3580_glya21 rev.
- primer pair Tir / pint3580_glya21 rev is used.
- Template is a mixture of the reaction products of PCR1 and PCR2.
- Proper plasmids are named plNT3581.
- Example 3 Construction of the plasmid pINT3582 encoding His (A8), Glu (A5), Gly (A21) preproinsulin
- the construction is carried out as described in Example 1 and 2 via 3 polymerase chain reactions.
- the product of the third reaction is inserted after Nco1 / Sali digestion into the Nco1 / SaM opened plNT91d vector DNA.
- the primers Tir and pint3580_glya21rev are used. Two more primers are synthesized: pint3581_Ea5f
- Example 2 The construction is carried out deviating from Example 1 via only one polymerase chain reaction.
- the product of this reaction is inserted after Nco1 / Sali digestion into the Nco1 / Sali opened plNT91d vector DNA.
- the primer Tir is used.
- Another primer is synthesized:
- Template is DNA of plasmid pINT3581. Proper plasmids are named plNT3583.
- Example 5 Construction of the plasmid pINT3584 encoding His (A8), Glu (A5) Asp (A18), Gly (A21) preproinsulin
- the construction is carried out deviating from Example 1 via only one polymerase chain reaction.
- the product of this reaction is inserted into the Nco1 / Sah opened plNT91d vector DNA after Nco1 / Saw digestion.
- the primer Tir pint3580_Da18rev (example 4) is used.
- Template is DNA of plasmid pINT3582.
- Proper plasmids are named plNT3584.
- the pre-proinsulin coded by the plasmid is precursor for the compound YKL205-1, which is formed after amidation with argininamide and describes the following structure:
- the primer Tir is used.
- Example 2 The construction is carried out deviating from Example 1 via only one polymerase chain reaction.
- the product of this reaction is inserted into the Nco1 / Sah opened plNT91d vector DNA after Nco1 / Saw digestion.
- the primer Tir is used.
- Another primer is synthesized:
- Plasmids plNT3581 Proper plasmids are named plNT3586.
- the pre-proinsulin encoded by the plasmid is precursor for the compound YKL205, which is formed after amidation with arginine amide and describes the following structure:
- the pre-proinsulin encoded by the plasmid is precursor for the compound YKL205b, which, after amidation with lysineamide, forms the following structure:
- Example 8 Construction of the plasmid pINT3587 encoding GIu (A5), His (A8), Glu (A15), Gly (A21) preproinsulin
- the construction is carried out deviating from Example 1 via only one polymerase chain reaction.
- the product of this reaction is inserted into the Nco1 / Sah opened plNT91d vector DNA after Nco1 / Saw digestion.
- the primer T ⁇ r and pint3580_Ea15rev according to Example 6 are used.
- Template is DNA of the plasmid pINT3582.
- Proper plasmids are named plNT3587.
- the pre-proinsulin encoded by the plasmid is precursor for the compound YKL205-2, which is formed after amidation with argininamide and describes the following structure:
- the pre-proinsulin encoded by the plasmid is precursor for the compound YKL205-2b, which, after amidation with lysineamide, forms the following structure:
- the construction is carried out as described in Example 1 and 2 via 3 polymerase chain reactions.
- the product of the third reaction is inserted after Nco1 / SaM cleavage into the Nco1 / SaM opened plNT91d vector DNA.
- the primers Tir and pint3580_glya21rev are used. Two more primers are synthesized:
- the pre-proinsulin encoded by the plasmid is precursor to the compound
- the pre-proinsulin encoded by the plasmid is precursor for the compound YKL205-3b, which, after amidation with lysineamide, forms the following structure:
- Plasmid pINT3590 Plasmid pINT3590.
- the pre-proinsulin encoded by the plasmid is precursor for the compound YKL205-4, which is formed after amidation with arginine amide and describes the following structure:
- the pre-proinsulin encoded by the plasmid is precursor for the compound YKL205-4b, which, after amidation with lysineamide, forms the following structure:
- the pre-proinsulin coded by the plasmid is precursor for the compound YKL205-5, which is formed after amidation with argininamide and describes the following structure:
- the pre-proinsulin encoded by the plasmid is precursor for the compound YKL205-5b, which is formed after amidation with lysinamide and describes the following structure:
- the construction is carried out as described in Example 1 and 2 via 3 polymerase chain reactions.
- the product of the third reaction is inserted after Nco1 / SaM cleavage into the Nco1 / Sah opened plNT91d vector DNA.
- the primers Tir and pint3580_glya21rev are used. Two more primers are synthesized:
- the codon which codes for aspartic acid in position 3 and glutamic acid in position 4 of the insulin B chain is shown in bold.
- Template is DNA of plasmid pINT3581.
- Proper plasmids are named plNT3592.
- the pre-proinsulin encoded by the plasmid is precursor for the compound YKL205-6, which is formed after amidation with argininamide and describes the following structure:
- the pre-proinsulin coded by the plasmid is precursor for the compound YKL205-6b, which is formed after amidation with lysinamide and describes the following structure:
- the construction is carried out as described in Example 1 and 2 via 3 polymerase chain reactions.
- the product of the third reaction is inserted after Nco1 / Sali digestion into the Nco1 / Sali opened plNT91d vector DNA.
- the primers Tir and pint3580_glya21 rev are used. Two more primers are synthesized:
- Example 15 Construction of plasmid pINT3594 encoding Glu (A5), His (A8), Gly (A21), Glu (B4) - preproinsulin.
- the proinsulin is precursor for the compound YKL205-7, which arises after amidation with argininamide and describes the following structure:
- the proinsulin is a precursor for the compound YKL205-7b, which is formed after amidation with lysinamide and which describes the following structure: Arg (AO), Glu (A5), His (A8), Gly (A21), Glu (B4), Arg ( B31), Lys (B32) - NH 2 - human insulin
- the pre-proinsulin encoded by the plasmid is a precursor for the compound YKL205-8, which is formed after amidation with argininamide and describes the following structure:
- the pre-proinsulin encoded by the plasmid is precursor to the compound
- the pre-proinsulin encoded by the plasmid is precursor for the compound YKL205-9, which is formed after amidation with arginine amide and describes the following structure:
- the pre-proinsulin encoded by the plasmid is precursor for the compound YKL205-9b, which is formed after amidation with lysinamide and describes the following structure:
- the construction takes place via 2 polymerase chain reactions.
- the primer pint3580_glya21rev is used. Two more primers are synthesized:
- Pint3581_Eb0f2 contains an Ncol recognition sequence. This is underlined. The codon used for Glutamic acid coded in position 0 at the beginning B chain is highlighted in bold.
- Template for PCR1 is DNA of the plasmid plNT3581.
- PCR1 is performed with the primer pair pint3581_Eb-1f2 / pint3580_glya21rev.
- Template for PCR2 is the product of PCR1.
- PCR2 is performed with the primer pair pint3581_Eb-1f2 / pint3580_glya21 rev.
- the product from PCR2 outlines the complete preproinsulin sequence.
- the product of the second reaction is inserted after Nco1 / SaM cleavage into the Nco1 / SaM opened plNT91d vector DNA.
- Proper plasmids are named plNT3597. Replacing the codon for glutamic acid in position BO by the codon of aspartic acid and following the example, one arrives at plasmids carrying aspartic acid in position BO instead of glutamic acid.
- the pre-proinsulin encoded by the plasmid is a precursor for the compound YKL205-10, which is formed after amidation with argininamide and describes the following structure:
- the pre-proinsulin encoded by the plasmid is precursor for the compound YKL205-10b, which is formed after amidation with lysinamide and describes the following structure:
- the pre-proinsulin encoded by the plasmid is precursor for the compound YKL205-11, which is formed after amidation with argininamide and describes the following structure:
- the pre-proinsulin encoded by the plasmid is precursor for the compound YKL205-11b, which, after amidation with lysineamide, forms the following structure:
- plasmid pNT3600 is obtained.
- the pre-proinsulin coded by the plasmid is precursor for the compound YKL205-12, which is formed after amidation with argininamide and describes the following structure:
- the pre-proinsulin encoded by the plasmid is precursor for the compound YKL205-12b, which is formed after amidation with lysinamide and describes the following structure:
- Example 22 Construction of the plasmid pINT3601 coding for His (A8), Gly (A21), Asp (B1) - preproinsulin
- the construction takes place via 2 polymerase chain reactions.
- the primer pint3580_glya21rev is used. Two more primers are synthesized:
- Pint3581_Db-1f2 contains an Ncol recognition sequence. This is underlined. The codon coding for aspartic acid in position 1 of the B chain is highlighted in bold.
- Template for PCR1 is DNA of the plasmid plNT3581. PCR1 is performed with the primer pair pint3581_Db1f1 / pint3580_glya21rev. Template for PCR2 is the product of PCR1. PCR2 is performed with the primer pair pint3581_Db1f2 / pint3580_glya21 rev. The product from PCR2 covers the complete preproinsulin sequence.
- the product of the second reaction is inserted after Nco1 / SaM cleavage into the Nco1 / Sah opened plNT91d vector DNA.
- Proper plasmids are named plNT3601.
- Example 23 Construction of the plasmid pINT3602 coding for Glu (A5), His (A8), Gly (A21), Asp (B1) preproinsulin
- the pre-proinsulin encoded by the plasmid is precursor for the compound YKL205-13, which is formed after amidation with arginine amide and describes the following structure:
- the pre-proinsulin encoded by the plasmid is precursor for the compound YKL205-13b, which, after amidation with lysineamide, forms the following structure:
- the pre-proinsulin encoded by the plasmid is precursor for the compound YKL205-14, which is formed after amidation with argininamide and describes the following structure:
- the pre-proinsulin encoded by the plasmid is precursor for the compound YKL205-14b, which is formed after amidation with lysinamide and describes the following structure:
- Example 25 Construction of the plasmid pINT3604 encoding His (A8), Asp (A18), Gly (A21), Asp (B1) - preproinsulin
- the pre-proinsulin encoded by the plasmid is precursor for the compound YKL205-15, which is formed after amidation with argininamide and describes the following structure:
- the pre-proinsulin encoded by the plasmid is precursor for the compound YKL205-15b, which, after amidation with lysineamide, forms the following structure:
- Example 26 Construction of the plasmid pINT3605 coding for His (A8), Gly (A21), Glu (BO), Asp (B1) preproinsulin
- the construction takes place via 2 polymerase chain reactions.
- the primer pint3580_glya21rev and the primer pint3581_EbO1f2 described in Example 18 are used.
- the primer pint3597_Db1f is synthesized: 5 -CAACAGGAA ATTCGGCACG AGAGGACGTG AACCAGCACC TGTGC-3 1 (SEQ ID NO: 23)
- Template for PCR1 is DNA of plasmid pINT3597. PCR1 is performed with the primer pair pint3597_Db1f / pint3580_glya21 rev. Template for PCR2 is the product of PCR1. PCR2 is performed with the primer pair pint3581_Eb1f2 / pint3580_glya21rev. The product from PCR2 covers the complete preproinsulin sequence. The product of the second reaction is inserted into the Nco1 / Saw opened plNT91d vector DNA after Nco1 / Saw digestion. Proper plasmids are named plNT3605. The pre-proinsulin encoded by the plasmid is precursor for the compound YKL205-16, which is formed after amidation with arginine amide and describes the following structure:
- the pre-proinsulin encoded by the plasmid is precursor for the compound YKL205-16b, which is formed after amidation with lysinamide and describes the following structure:
- Example 27 Construction of the plasmid pINT3606 encoding His (A8), Glu (A15), Asp (A18), Gly (A21), of theThr (B30) preproinsulin
- the construction is carried out as described in Example 1 and 2 via 3 polymerase chain reactions.
- the primers Tir and pint3580_glya21rev are used. Two more primers are synthesized:
- Template for PCR1 and PCR2 is DNA of the plasmid plNT3586.
- PCR1 is performed with the primer pair of B30f / pint3580_glya21rev and PCR2 is performed with primer pair Tir / B30rev template.
- the reaction is carried out with the primer pair Tir / pint3580_glya21rev.
- the product from PCR3 covers the complete preproinsulin sequence.
- the product of the third reaction is inserted after Nco1 / SaM cleavage into the Nco1 / SaM opened plNT91d vector DNA.
- the pre-proinsulin encoded by the plasmid is precursor to the compound
- the pre-proinsulin encoded by the plasmid is precursor for the compound YKL205-17b, which, after amidation with lysineamide, forms the following structure:
- Example 30 Enzymatic processing of the folded preproinsulin to the 2-chain Arg (AO) insulin precursor whose C-terminal B chain end is characterized by lysine or arginine.
- the enzymatic processing of the folded preproinsulin precursor is as described e.g. in Example 4 of WO91 / 03550.
- the use of the trypsin variant described in WO 2007/031187 A1 proves to be particularly advantageous.
- Example 31 Preparation of an Arg (AO), His (A8), Gly (A21), Arg (B31), Arg (B32) - NH 2 - human insulin
- a standard reaction is performed as follows: 100 mg Arg (AO), Gly (A21), Arg (B31) insulin analog are dissolved in 0.95 ml arginine amide solution (446 g / L), 0.13 mL M Na acetate buffer (pH 5.8) and 2 ml of DMF were added. The reaction mixture is cooled to 12 ° C and by addition of 0.094 ml of trypsin (0.075 mg, Roche
- the corresponding lysinamide compound is prepared analogously. However, it is based on an aqueous lysinamide stock solution containing dissolved 366g / L lysinamide.
- Example 32 Formulation of the amidated induline derivatives
- the compounds A solution was prepared as follows: The insulin derivative according to the invention was dissolved at a target concentration of 240 ⁇ 5 ⁇ M in 1 mM hydrochloric acid with 80 ⁇ g / ml zinc (as zinc chloride).
- compositions were used as the solution medium: a) 1 mM hydrochloric acid b) 1 mM hydrochloric acid, 5 ⁇ g / ml zinc (added as zinc chloride or hydrochloric acid) c) 1 mM hydrochloric acid, 10 ⁇ g / ml zinc (added as zinc chloride or hydrochloric acid) d) 1 mM hydrochloric acid, 15 ⁇ g / ml zinc (added as zinc chloride or hydrochloric acid) e) 1 mM hydrochloric acid, 30 ⁇ g / ml zinc (added as zinc chloride or hydrochloric acid) f) 1 mM hydrochloric acid, 80 ⁇ g / ml zinc (as zinc chloride or hydrochloric acid g) 1 mM hydrochloric acid, 120 ⁇ g / ml zinc (added as zinc chloride or hydrochloric acid)
- freeze-dried material was first about a 30% higher amount than due to the molecular weight and the desired
- Target concentration of 240 ⁇ 5 ⁇ M the finished solution was transferred by means of a syringe with a 0.2 micron filter attachment in a sealed with a septum and a crimp cap sterile vial.
- no optimization of the formulations e.g. with regard to an addition of isotonic agents, preservatives or buffer substances.
- Example 33 Evaluation of the hypoglycemic effect of novel insulin analogues in the rat
- the hypoglycemic effect of selected new insulin analogues is tested in male, healthy, normoglycemic Wistar rats.
- Male rats A dose of 9 nmol / kg of an insulin analog is injected subcutaneously.
- blood samples are taken from the animals and the blood sugar content is determined therein.
- the experiment clearly shows (compare Fig. 1) that the insulin analog according to the invention used leads to a significantly delayed onset of action and a longer, uniform duration of action.
- Example 34 Evaluation of the hypoglycemic effect of new insulin analogues in the dog
- the hypoglycemic effect of selected new insulin analogues is tested in male, healthy, normoglycemic beagle dogs.
- Male animals are injected subcutaneously with a dose of 6 nmol / kg of an insulin analogue.
- blood samples are taken from the animals and the blood sugar content is determined therein.
- the experiment clearly shows (compare Fig. 2) that the insulin analog according to the invention used leads to a significantly delayed onset of action and a longer, uniform duration of action.
- Example 35 Evaluation of the hypoglycemic effect in dogs at twice the dose
- hypoglycemic effect of selected new insulin analogues is tested in male, healthy, normoglycemic beagle dogs.
- Male animals are injected subcutaneously with a dose of 6 nmol / kg and 12 nmol / kg of an insulin analogue.
- blood samples are taken from the animals and the blood sugar content is determined therein.
- Example 36 Evaluation of the hypoglycemic effect in dogs at different zinc concentrations in the formulation
- FIG. 4 shows the result. Thereafter, the time-effect curve of the insulin analog according to the invention by the content of zinc ions in the formulation at the same concentration of insulin influence in such a way that at zero or low zinc content observed a rapid onset and the effect persists over 24 hours, while at higher zinc content low onset of action is observed and the insulin action persists well longer than 24 hours.
Abstract
Description
Claims
Priority Applications (17)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DK09701358.5T DK2229407T3 (en) | 2008-01-09 | 2009-01-06 | NEW INSULIN DERIVATIVES WITH EXTREMELY DELAYED TIME / EFFECTS PROFILE |
NZ586590A NZ586590A (en) | 2008-01-09 | 2009-01-06 | Insulin analogues or derivatives having an extremely delayed time-action profile |
EP09701358.5A EP2229407B1 (de) | 2008-01-09 | 2009-01-06 | Neue insulinderivate mit extrem verzögertem zeit- / wirkungsprofil |
RU2010133231/10A RU2524423C2 (ru) | 2008-01-09 | 2009-01-06 | Новые производные инсулина с чрезвычайно замедленным профилем время/действие |
BRPI0907371A BRPI0907371A2 (pt) | 2008-01-09 | 2009-01-06 | derivados de insulina com um perfil de tempo-ação muito retardado |
AU2009203809A AU2009203809B2 (en) | 2008-01-09 | 2009-01-06 | Novel insulin derivatives having an extremely delayed time-action profile |
JP2010541743A JP5694779B2 (ja) | 2008-01-09 | 2009-01-06 | 極度に遅延した時間作用プロファイルを有する新規なインスリン誘導体 |
CA2711749A CA2711749A1 (en) | 2008-01-09 | 2009-01-06 | Novel insulin derivatives having an extremely delayed time-action profile |
CN200980101962.3A CN102007143B (zh) | 2008-01-09 | 2009-01-06 | 具有超延迟时效特征的新型胰岛素衍生物 |
ES09701358.5T ES2613152T3 (es) | 2008-01-09 | 2009-01-06 | Nuevos derivados de insulina con perfil tiempo/acción extremadamente retardado |
UAA201009821A UA103015C2 (ru) | 2008-01-09 | 2009-01-06 | Новые производные инсулина с чрезвычайно замедленным профилем время/действие |
ZA2010/03926A ZA201003926B (en) | 2008-01-09 | 2010-06-02 | Novel insulin derivatives having an extremely delayed time-action profile |
US12/820,722 US9644017B2 (en) | 2008-01-09 | 2010-06-22 | Insulin derivatives having an extremely delayed time-action profile |
TN2010000298A TN2010000298A1 (en) | 2008-01-09 | 2010-06-25 | Novel insulin derivatives having an extremely delayed time-action profile |
MA32985A MA31998B1 (fr) | 2008-01-09 | 2010-07-05 | Nouveaux derives d'insuline ayant un profil temps-action extremement retarde |
IL206844A IL206844A (en) | 2008-01-09 | 2010-07-06 | Insulin derivatives with a highly delayed action profile |
HK11104060.4A HK1149772A1 (zh) | 2008-01-09 | 2011-04-21 | 具有超延遲時效特徵的新型胰島素衍生物 |
Applications Claiming Priority (6)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE200810003568 DE102008003568A1 (de) | 2008-01-09 | 2008-01-09 | Neue Insulinderivate mit extrem verzögertem Zeit-/ Wirkungsprofil |
DE102008003568.8 | 2008-01-09 | ||
US4465908P | 2008-04-14 | 2008-04-14 | |
US61/044,659 | 2008-04-14 | ||
DE102008025008.2 | 2008-05-24 | ||
DE200810025008 DE102008025008A1 (de) | 2008-05-24 | 2008-05-24 | Neue Insulinderivate mit extrem verzögertem Zeit-/ Wirkungsprofil |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US12/820,722 Continuation US9644017B2 (en) | 2008-01-09 | 2010-06-22 | Insulin derivatives having an extremely delayed time-action profile |
Publications (2)
Publication Number | Publication Date |
---|---|
WO2009087081A2 true WO2009087081A2 (de) | 2009-07-16 |
WO2009087081A3 WO2009087081A3 (de) | 2009-09-17 |
Family
ID=40568276
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP2009/000017 WO2009087081A2 (de) | 2008-01-09 | 2009-01-06 | Neue insulinderivate mit extrem verzögertem zeit-/wirkungsprofil |
Country Status (32)
Country | Link |
---|---|
US (1) | US9644017B2 (de) |
EP (1) | EP2229407B1 (de) |
JP (1) | JP5694779B2 (de) |
KR (1) | KR20100111682A (de) |
CN (1) | CN102007143B (de) |
AR (1) | AR070118A1 (de) |
AU (1) | AU2009203809B2 (de) |
BR (1) | BRPI0907371A2 (de) |
CA (1) | CA2711749A1 (de) |
CL (1) | CL2009000017A1 (de) |
CO (1) | CO6311108A2 (de) |
DK (1) | DK2229407T3 (de) |
DO (1) | DOP2010000209A (de) |
EC (1) | ECSP10010333A (de) |
ES (1) | ES2613152T3 (de) |
GT (1) | GT201000199A (de) |
HK (1) | HK1149772A1 (de) |
HU (1) | HUE030537T2 (de) |
IL (1) | IL206844A (de) |
MA (1) | MA31998B1 (de) |
MY (1) | MY152979A (de) |
NI (1) | NI201000114A (de) |
NZ (1) | NZ586590A (de) |
PA (1) | PA8811601A1 (de) |
PE (1) | PE20091377A1 (de) |
PL (1) | PL2229407T3 (de) |
RU (1) | RU2524423C2 (de) |
TN (1) | TN2010000298A1 (de) |
TW (1) | TW200942256A (de) |
UY (1) | UY31596A1 (de) |
WO (1) | WO2009087081A2 (de) |
ZA (1) | ZA201003926B (de) |
Cited By (52)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2011003820A1 (de) * | 2009-07-06 | 2011-01-13 | Sanofi-Aventis Deutschland Gmbh | Hitze- und schüttelstabile insulinzubereitungen |
WO2011003823A1 (de) * | 2009-07-06 | 2011-01-13 | Sanofi-Aventis Deutschland Gmbh | Langsamwirkende insulinzubereitungen |
WO2011003822A3 (de) * | 2009-07-06 | 2011-08-25 | Sanofi-Aventis Deutschland Gmbh | Wässrige insulinzubereitungen enthaltend methionin |
WO2011161161A1 (en) | 2010-06-24 | 2011-12-29 | Boehringer Ingelheim International Gmbh | Diabetes therapy |
WO2012062698A1 (en) | 2010-11-08 | 2012-05-18 | Boehringer Ingelheim International Gmbh | Pharmaceutical composition, methods for treating and uses thereof |
WO2012098462A1 (en) | 2011-01-20 | 2012-07-26 | Zealand Pharma A/S | Combination of acylated glucagon analogues with insulin analogues |
US20120295846A1 (en) * | 2009-11-13 | 2012-11-22 | Sanofi-Aventis Deutschland Gmbh | Pharmaceutical composition comprising a glp-1 agonist, an insulin and methionine |
US8343914B2 (en) | 2006-01-06 | 2013-01-01 | Case Western Reserve University | Fibrillation resistant proteins |
CN102933599A (zh) * | 2010-06-23 | 2013-02-13 | 诺沃—诺迪斯克有限公司 | 包含额外的二硫键的人胰岛素 |
US8399407B2 (en) | 2009-09-17 | 2013-03-19 | Case Western Reserve University | Non-standard insulin analogues |
US20130096057A1 (en) * | 2011-10-18 | 2013-04-18 | AmideBio LLC | Chemically and Thermodynamically Stable Insulin Analogues and Improved Methods for their Production |
US8501440B2 (en) | 2006-10-04 | 2013-08-06 | Case Western Reserve University | Fibrillation-resistant insulin and insulin analogues |
US8633156B2 (en) | 2008-01-09 | 2014-01-21 | Sanofi-Aventis Deutschland Gmbh | Insulin derivatives having an extremely delayed time-action profile |
US8642541B2 (en) | 2008-12-15 | 2014-02-04 | Zealand Pharma A/S | Glucagon analogues |
US8642540B2 (en) | 2008-12-15 | 2014-02-04 | Zealand Pharma A/S | Glucagon analogues |
US8680049B2 (en) | 2008-12-15 | 2014-03-25 | Zealand Pharma A/S | Glucagon analogues |
US8685919B2 (en) | 2008-12-15 | 2014-04-01 | Zealand Pharma A/S | Glucagon analogues |
US8853155B2 (en) | 2010-06-23 | 2014-10-07 | Novo Nordisk A/S | Insulin derivatives containing additional disulfide bonds |
US8921313B2 (en) | 2008-07-31 | 2014-12-30 | Case Western Reserve University | Halogen-stabilized insulin |
US8993516B2 (en) | 2008-04-14 | 2015-03-31 | Case Western Reserve University | Meal-time insulin analogues of enhanced stability |
US9079975B2 (en) | 2009-12-11 | 2015-07-14 | Case Western Reserve University | Insulin analogues with chlorinated amino acids |
US9156901B2 (en) | 2009-07-13 | 2015-10-13 | Ditte Riber | Acylated glucagon analogues |
US9169310B2 (en) | 2010-06-24 | 2015-10-27 | Zealand Pharma A/S | Glucagon analogues |
US9180169B2 (en) | 2012-09-17 | 2015-11-10 | Zealand Pharma A/S | Glucagon analogues |
US9200053B2 (en) | 2008-07-31 | 2015-12-01 | Case Western Reserve University | Insulin analogues containing penta-fluoro-Phenylalanine at position B24 |
US9403894B2 (en) | 2010-06-23 | 2016-08-02 | Zealand Pharma A/S | Glucagon analogues |
US9408893B2 (en) | 2011-08-29 | 2016-08-09 | Sanofi-Aventis Deutschland Gmbh | Pharmaceutical combination for use in glycemic control in diabetes type 2 patients |
US9526764B2 (en) | 2008-10-17 | 2016-12-27 | Sanofi-Aventis Deutschland Gmbh | Combination of an insulin and a GLP-1-agonist |
US9644017B2 (en) | 2008-01-09 | 2017-05-09 | Sanofi-Aventis Deutschland Gmbh | Insulin derivatives having an extremely delayed time-action profile |
US9707176B2 (en) | 2009-11-13 | 2017-07-18 | Sanofi-Aventis Deutschland Gmbh | Pharmaceutical composition comprising a GLP-1 agonist and methionine |
US9821032B2 (en) | 2011-05-13 | 2017-11-21 | Sanofi-Aventis Deutschland Gmbh | Pharmaceutical combination for improving glycemic control as add-on therapy to basal insulin |
US9839675B2 (en) | 2013-02-04 | 2017-12-12 | Sanofi | Stabilized pharmaceutical formulations of insulin analogues and/or insulin derivatives |
US9839692B2 (en) | 2014-01-09 | 2017-12-12 | Sanofi | Stabilized pharmaceutical formulations of insulin analogues and/or insulin derivatives |
US9896495B2 (en) | 2013-10-17 | 2018-02-20 | Zealand Pharma A/S | Acylated glucagon analogues |
US9895424B2 (en) | 2014-01-09 | 2018-02-20 | Sanofi | Stabilized pharmaceutical formulations of insulin analogues and/or insulin derivatives |
US9895423B2 (en) | 2014-01-09 | 2018-02-20 | Sanofi | Stabilized pharmaceutical formulations of insulin aspart |
US9950039B2 (en) | 2014-12-12 | 2018-04-24 | Sanofi-Aventis Deutschland Gmbh | Insulin glargine/lixisenatide fixed ratio formulation |
US9981013B2 (en) | 2010-08-30 | 2018-05-29 | Sanofi-Aventis Deutschland Gmbh | Use of AVE0010 for the treatment of diabetes mellitus type 2 |
US9988429B2 (en) | 2013-10-17 | 2018-06-05 | Zealand Pharma A/S | Glucagon analogues |
US9987332B2 (en) | 2011-09-01 | 2018-06-05 | Sanofi-Aventis Deutschland Gmbh | Pharmaceutical composition for use in the treatment of a neurodegenerative disease |
US10093713B2 (en) | 2013-11-06 | 2018-10-09 | Zealand Pharma A/S | GIP-GLP-1 dual agonist compounds and methods |
US10100097B2 (en) | 2012-05-03 | 2018-10-16 | Zealand Pharma A/S | GIP-GLP-1 dual agonist compounds and methods |
US10131702B2 (en) | 2013-11-06 | 2018-11-20 | Zealand Pharma A/S | Glucagon-GLP-1-GIP triple agonist compounds |
US10159713B2 (en) | 2015-03-18 | 2018-12-25 | Sanofi-Aventis Deutschland Gmbh | Treatment of type 2 diabetes mellitus patients |
US10253078B2 (en) | 2014-10-29 | 2019-04-09 | Zealand Pharma A/S | GIP agonist compounds and methods |
US10253079B2 (en) | 2012-12-21 | 2019-04-09 | Sanofi | Functionalized Exendin-4 derivatives |
US10336802B2 (en) | 2015-04-16 | 2019-07-02 | Zealand Pharma A/S | Acylated glucagon analogue |
CN109999180A (zh) * | 2011-06-02 | 2019-07-12 | 韩美科学株式会社 | 用于治疗糖尿病的包括长效胰岛素缀合物和长效促胰岛素肽缀合物的组合物 |
US10392429B2 (en) | 2014-10-06 | 2019-08-27 | Case Western Reserve University | Biphasic single-chain insulin analogues |
US10434147B2 (en) | 2015-03-13 | 2019-10-08 | Sanofi-Aventis Deutschland Gmbh | Treatment type 2 diabetes mellitus patients |
US10442847B2 (en) | 2012-07-23 | 2019-10-15 | Zealand Pharma A/S | Glucagon analogues |
US10758592B2 (en) | 2012-10-09 | 2020-09-01 | Sanofi | Exendin-4 derivatives as dual GLP1/glucagon agonists |
Families Citing this family (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE102005046113A1 (de) * | 2005-09-27 | 2007-03-29 | Sanofi-Aventis Deutschland Gmbh | Verfahren zur Amidierung von Polypetiden mit C-terminalen basischen Aminosäuren unter Verwendung spezifischer Endoproteasen |
RU2010147076A (ru) * | 2008-04-22 | 2012-05-27 | Кейз Вестерн Ризев Юнивесити (Us) | Аналоги инсулина специфичные к изоформам |
US9163073B2 (en) | 2013-04-17 | 2015-10-20 | Amidebio, Llc | Chemically and thermodynamically stable insulin analogues and improved methods for their production |
EP3098235A4 (de) | 2014-01-20 | 2017-10-18 | Hanmi Pharm. Co., Ltd. | Langwirkendes insulin und verwendung davon |
AR100639A1 (es) | 2014-05-29 | 2016-10-19 | Hanmi Pharm Ind Co Ltd | Composición para tratar diabetes que comprende conjugados de análogos de insulina de acción prolongada y conjugados de péptidos insulinotrópicos de acción prolongada |
TWI684458B (zh) | 2014-05-30 | 2020-02-11 | 南韓商韓美藥品股份有限公司 | 包含胰島素及glp-1/昇糖素雙重促效劑之治療糖尿病之組成物 |
UY36870A (es) | 2015-08-28 | 2017-03-31 | Hanmi Pharm Ind Co Ltd | Análogos de insulina novedosos |
EP3517544A4 (de) | 2016-09-23 | 2020-06-03 | Hanmi Pharm. Co., Ltd. | Insulinanalogon mit reduzierter bindungskraft an den insulinrezeptor und verwendung davon |
JP2020511513A (ja) | 2017-03-23 | 2020-04-16 | ハンミ ファーマシューティカル カンパニー リミテッド | インスリン受容体との結合力が減少されたインスリンアナログの結合体及びその用途 |
Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1989010937A1 (en) * | 1988-05-11 | 1989-11-16 | Novo Nordisk A/S | Insulin analogues |
US6100376A (en) * | 1988-11-08 | 2000-08-08 | Hoechst Aktiengesellschaft | A21, B30, modified insulin derivatives having an altered action profile |
WO2001025278A1 (de) * | 1999-10-02 | 2001-04-12 | Aventis Pharma Deutschland Gmbh | C-peptid zur verbesserten herstellung von insulin und insulinanaloga |
WO2002079250A1 (en) * | 2001-04-02 | 2002-10-10 | Novo Nordisk A/S | Insulin precursors and a process for their preparation |
WO2003053339A2 (en) * | 2001-12-20 | 2003-07-03 | Eli Lilly And Company | Insulin molecule having protracted time action |
WO2007081824A2 (en) * | 2006-01-06 | 2007-07-19 | Case Western Reserve University | Fibrillation resistant proteins |
Family Cites Families (84)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3984696A (en) | 1974-12-11 | 1976-10-05 | Medi-Ray, Inc. | Radiation guard for X-ray table |
JPS6033474B2 (ja) | 1978-05-11 | 1985-08-02 | 藤沢薬品工業株式会社 | 新規なヒアルロニダ−ゼbmp−8231およびその製造法 |
DK113585D0 (da) | 1985-03-12 | 1985-03-12 | Novo Industri As | Nye peptider |
US5008241A (en) * | 1985-03-12 | 1991-04-16 | Novo Nordisk A/S | Novel insulin peptides |
DK347086D0 (da) * | 1986-07-21 | 1986-07-21 | Novo Industri As | Novel peptides |
PH25772A (en) | 1985-08-30 | 1991-10-18 | Novo Industri As | Insulin analogues, process for their preparation |
WO1988006599A1 (en) | 1987-02-25 | 1988-09-07 | Novo Industri A/S | Novel insulin derivatives |
US4923162A (en) | 1988-09-19 | 1990-05-08 | Fleming Matthew C | Radiation shield swivel mount |
US5225323A (en) * | 1988-11-21 | 1993-07-06 | Baylor College Of Medicine | Human high-affinity neurotransmitter uptake system |
AU641631B2 (en) | 1988-12-23 | 1993-09-30 | Novo Nordisk A/S | Human insulin analogues |
PT93057B (pt) | 1989-02-09 | 1995-12-29 | Lilly Co Eli | Processo para a preparacao de analogos da insulina |
DK134189D0 (da) | 1989-03-20 | 1989-03-20 | Nordisk Gentofte | Insulinforbindelser |
US5006718A (en) | 1989-07-21 | 1991-04-09 | Lenhart Mark J | X-ray shield for X-ray examination table |
GR1005153B (el) | 1989-08-29 | 2006-03-13 | The General Hospital Corporation | Πρωτεινες συντηξεως, παρασκευη τους και χρηση τους. |
DK155690D0 (da) | 1990-06-28 | 1990-06-28 | Novo Nordisk As | Nye peptider |
DK10191D0 (da) * | 1991-01-22 | 1991-01-22 | Novo Nordisk As | Hidtil ukendte peptider |
US5358708A (en) | 1993-01-29 | 1994-10-25 | Schering Corporation | Stabilization of protein formulations |
DE4405388A1 (de) | 1994-02-19 | 1995-08-24 | Hoechst Ag | Verfahren zur Herstellung von Polyalkyl-1-oxa-diazaspirodecan-Verbindungen |
YU18596A (sh) | 1995-03-31 | 1998-07-10 | Eli Lilly And Company | Analogne formulacije monomernog insulina |
CA2223272A1 (en) | 1995-05-05 | 1996-11-07 | Ronald Eugene Chance | Single chain insulin with high bioactivity |
JPH11292787A (ja) | 1995-08-15 | 1999-10-26 | Asahi Chem Ind Co Ltd | 生理活性ペプチドを含有する経粘膜投与製剤 |
DE19637230A1 (de) | 1996-09-13 | 1998-03-19 | Boehringer Mannheim Gmbh | Exendin-Analoga, Verfahren zu deren Herstellung und diese enthaltende Arzneimittel |
IL127365A0 (en) | 1996-06-20 | 1999-10-28 | Novo Nordisk As | Insulin preparations containing carbohydrates |
DE69737479T4 (de) | 1996-08-30 | 2010-05-06 | Novo Nordisk A/S | Glp-1 derivate |
US7312196B2 (en) | 1997-01-08 | 2007-12-25 | Amylin Pharmaceuticals, Inc. | Formulations for amylin agonist peptides |
DE19726167B4 (de) | 1997-06-20 | 2008-01-24 | Sanofi-Aventis Deutschland Gmbh | Insulin, Verfahren zu seiner Herstellung und es enthaltende pharmazeutische Zubereitung |
DE19735711C2 (de) | 1997-08-18 | 2001-04-26 | Aventis Pharma Gmbh | Verfahren zur Herstellung eines Vorläufers von Insulin oder Insulinderivaten mit korrekt verbundenen Cystinbrücken |
IL134901A0 (en) * | 1997-10-24 | 2001-05-20 | Lilly Co Eli | Insoluble insulin compositions |
US6444641B1 (en) * | 1997-10-24 | 2002-09-03 | Eli Lilly Company | Fatty acid-acylated insulin analogs |
US5981964A (en) | 1997-12-22 | 1999-11-09 | Bruce J. McAuley | Adjustable X-ray shield and on-line dosimetry system using same |
ATE290877T1 (de) | 1998-01-09 | 2005-04-15 | Novo Nordisk As | Stabilisierte insulin-zubereitungen |
AU741037B2 (en) | 1998-02-23 | 2001-11-22 | Neurocrine Biosciences, Inc. | Methods for treatment of diabetes using peptide analogues of insulin |
EP1083930B1 (de) | 1998-06-05 | 2008-11-12 | Nutrinia Limited | Insulin angereichertes säuglingsnährpräparat |
JP2007204498A (ja) | 1999-03-01 | 2007-08-16 | Chugai Pharmaceut Co Ltd | 長期安定化製剤 |
JP2000247903A (ja) | 1999-03-01 | 2000-09-12 | Chugai Pharmaceut Co Ltd | 長期安定化製剤 |
EP1076066A1 (de) | 1999-07-12 | 2001-02-14 | Zealand Pharmaceuticals A/S | Peptide zur Senkung des Blutglukosespiegels |
CN100389821C (zh) | 1999-10-04 | 2008-05-28 | 希龙公司 | 稳定化的含多肽的液体药物组合物 |
US7060675B2 (en) | 2001-02-15 | 2006-06-13 | Nobex Corporation | Methods of treating diabetes mellitus |
DE10108211A1 (de) | 2001-02-20 | 2002-08-22 | Aventis Pharma Gmbh | Verwendung von Fusionsproteinen, deren N-terminaler Anteil aus einem Hirudinderivat besteht, zur Herstellung rekombinanter Proteine über Sekretion durch Hefen |
DE10108212A1 (de) | 2001-02-20 | 2002-08-22 | Aventis Pharma Gmbh | Fusionsprotein zur Sekretion von Wertprotein in bakterielle Überstände |
US6852694B2 (en) | 2001-02-21 | 2005-02-08 | Medtronic Minimed, Inc. | Stabilized insulin formulations |
DE10114178A1 (de) | 2001-03-23 | 2002-10-10 | Aventis Pharma Gmbh | Zinkfreie und zinkarme Insulinzubereitungen mit verbesserter Stabilität |
EP1432430A4 (de) | 2001-08-28 | 2006-05-10 | Lilly Co Eli | Vormischungen von glp-1 und basalinsulin |
BR0215216A (pt) | 2001-12-21 | 2004-11-16 | Novo Nordisk Healthcare Ag | Composição aquosa lìquida, método para preparar uma composição aquosa lìquida de um polipeptìdeo de fator vii, uso de uma composição aquosa lìquida, e, método para o tratamento de uma sìndrome de resposta ao fator vii |
US8058233B2 (en) | 2002-01-10 | 2011-11-15 | Oregon Health And Science University | Modification of feeding behavior using PYY and GLP-1 |
DE10227232A1 (de) | 2002-06-18 | 2004-01-15 | Aventis Pharma Deutschland Gmbh | Saure Insulinzubereitungen mit verbesserter Stabilität |
AU2003243929B2 (en) | 2002-07-04 | 2009-06-04 | Zp Holding Spv K/S | GLP-1 and methods for treating diabetes |
KR20050083713A (ko) | 2002-10-02 | 2005-08-26 | 질랜드 파마 에이/에스 | 안정화된 엑센딘-4 화합물 |
CA2518776A1 (en) | 2003-04-29 | 2004-11-11 | Eli Lilly And Company | Insulin analogs having protracted time action |
DE10325567B4 (de) | 2003-06-05 | 2008-03-13 | Mavig Gmbh | Strahlenschutzanordnung mit separierbarer Umhüllung |
ATE525083T1 (de) | 2003-11-13 | 2011-10-15 | Novo Nordisk As | Pharmazeutische zusammensetzung umfassend eine insulinotrope glp-1(7-37) analoge, asp(b28)- insulin, und eine oberflächenaktive verbindung |
US20080090753A1 (en) | 2004-03-12 | 2008-04-17 | Biodel, Inc. | Rapid Acting Injectable Insulin Compositions |
US20080248999A1 (en) | 2007-04-04 | 2008-10-09 | Biodel Inc. | Amylin formulations |
BRPI0512396A (pt) | 2004-07-21 | 2008-03-11 | Ambrx Inc | polipeptìdeos biossintéticos utilizando aminoácidos codificados não naturalmente |
JP2008513384A (ja) | 2004-09-17 | 2008-05-01 | ノボ ノルディスク アクティーゼルスカブ | インスリンおよびインスリン分泌性ペプチドを含有する医薬組成物 |
DE102004058306A1 (de) | 2004-12-01 | 2006-07-27 | Sanofi-Aventis Deutschland Gmbh | Verfahren zur Herstellung von Carboxy-terminal amidierten Peptiden |
US20090142338A1 (en) | 2005-03-04 | 2009-06-04 | Curedm, Inc. | Methods and Compositions for Treating Type 1 and Type 2 Diabetes Mellitus and Related Conditions |
KR101304958B1 (ko) | 2005-09-14 | 2013-09-17 | 에프. 호프만-라 로슈 아게 | 트립신 변이체에 의한 인슐린 전구체의 절단 |
KR101105871B1 (ko) | 2005-09-27 | 2012-01-16 | 주식회사 엘지생명과학 | 인 난포자극호르몬의 안정한 용액 제형 |
EP1972149B1 (de) | 2006-01-10 | 2017-12-13 | Thomson Licensing DTV | Verfahren und anordnung zur parallel ausführung von 4:4:4 codierung |
US20070191271A1 (en) | 2006-02-10 | 2007-08-16 | Dow Pharmaceutical Sciences | Method for stabilizing polypeptides lacking methionine |
EP1986674A4 (de) | 2006-02-13 | 2009-11-11 | Nektar Therapeutics | Methioninhaltige protein- oder peptidzusammensetzungen sowie verfahren zu ihrer herstellung und verwendung |
US7763582B2 (en) | 2006-02-21 | 2010-07-27 | University Of Medicine And Dentistry Of New Jersey | Localized insulin delivery for bone healing |
TW200806317A (en) | 2006-03-20 | 2008-02-01 | Wyeth Corp | Methods for reducing protein aggregation |
DE102006031962A1 (de) | 2006-07-11 | 2008-01-17 | Sanofi-Aventis Deutschland Gmbh | Amidiertes Insulin Glargin |
RU2524150C2 (ru) | 2006-09-22 | 2014-07-27 | Ново Нордиск А/С | Аналоги инсулина, устойчивые к протеазам |
MX2009011123A (es) | 2007-04-23 | 2009-11-02 | Intarcia Therapeutics Inc | Formulaciones de suspensiones de peptidos insulinotropicos y sus usos. |
WO2008145323A1 (en) | 2007-05-31 | 2008-12-04 | F. Hoffmann-La Roche Ag | Pharmaceutical formulation for interferons |
EP2173407B1 (de) | 2007-07-02 | 2020-02-19 | Roche Diabetes Care GmbH | Vorrichtung zur abgabe von arzneimitteln |
SI2219607T1 (sl) | 2007-11-01 | 2012-09-28 | Merck Serono Sa | Tekoäśe formulacije lh |
US8710000B2 (en) | 2007-11-08 | 2014-04-29 | Novo Nordisk A/S | Insulin derivative |
BRPI0907119A2 (pt) | 2008-01-09 | 2015-07-14 | Sanofi Aventis Deutschland | Derivados de insulina tendo um perfil de ação de tempo extremamente retardado |
MY152979A (en) | 2008-01-09 | 2014-12-15 | Sanofi Aventis Deutschland | Novel insulin derivatives having an extremely delayed time-action profile |
TWI394580B (zh) | 2008-04-28 | 2013-05-01 | Halozyme Inc | 超快起作用胰島素組成物 |
KR101939557B1 (ko) | 2008-10-17 | 2019-01-17 | 사노피-아벤티스 도이칠란트 게엠베하 | 인슐린과 glp-1 효능제의 병용물 |
JP2009091363A (ja) | 2008-11-21 | 2009-04-30 | Asahi Kasei Pharma Kk | Pthの安定化水溶液注射剤 |
JP2012532177A (ja) | 2009-07-06 | 2012-12-13 | サノフィ−アベンティス・ドイチュラント・ゲゼルシャフト・ミット・ベシュレンクテル・ハフツング | 熱及び振動安定性インスリン製剤 |
JP5675799B2 (ja) | 2009-07-06 | 2015-02-25 | サノフィ−アベンティス・ドイチュラント・ゲゼルシャフト・ミット・ベシュレンクテル・ハフツング | 遅効性インスリン製剤 |
BR112012000177B1 (pt) | 2009-07-06 | 2021-06-01 | Sanofi-Aventis Deutschland Gmbh | Formulação farmacêutica aquosa contendo metionina, processo para sua preparação, uso da mesma e medicamento para tratar diabetes mellitus |
RU2537239C2 (ru) | 2009-11-13 | 2014-12-27 | Санофи-Авентис Дойчланд Гмбх | Фармацевтическая композиция, включающая агонист glp-1, инсулин и метионин |
AU2010317994B2 (en) | 2009-11-13 | 2014-03-06 | Sanofi-Aventis Deutschland Gmbh | Pharmaceutical composition comprising a GLP-1 agonist and methionine |
AU2011202239C1 (en) | 2010-05-19 | 2017-03-16 | Sanofi | Long-acting formulations of insulins |
GB201303771D0 (en) | 2013-03-04 | 2013-04-17 | Midatech Ltd | Nanoparticles peptide compositions |
AR098168A1 (es) | 2013-10-25 | 2016-05-04 | Sanofi Sa | Formulación estable de insulina glulisina |
-
2009
- 2009-01-06 MY MYPI20102683 patent/MY152979A/en unknown
- 2009-01-06 HU HUE09701358A patent/HUE030537T2/en unknown
- 2009-01-06 CA CA2711749A patent/CA2711749A1/en not_active Abandoned
- 2009-01-06 BR BRPI0907371A patent/BRPI0907371A2/pt not_active IP Right Cessation
- 2009-01-06 NZ NZ586590A patent/NZ586590A/en not_active IP Right Cessation
- 2009-01-06 AU AU2009203809A patent/AU2009203809B2/en not_active Ceased
- 2009-01-06 JP JP2010541743A patent/JP5694779B2/ja not_active Expired - Fee Related
- 2009-01-06 RU RU2010133231/10A patent/RU2524423C2/ru not_active IP Right Cessation
- 2009-01-06 KR KR1020107014961A patent/KR20100111682A/ko not_active Application Discontinuation
- 2009-01-06 ES ES09701358.5T patent/ES2613152T3/es active Active
- 2009-01-06 PL PL09701358T patent/PL2229407T3/pl unknown
- 2009-01-06 CN CN200980101962.3A patent/CN102007143B/zh not_active Expired - Fee Related
- 2009-01-06 WO PCT/EP2009/000017 patent/WO2009087081A2/de active Application Filing
- 2009-01-06 EP EP09701358.5A patent/EP2229407B1/de active Active
- 2009-01-06 DK DK09701358.5T patent/DK2229407T3/en active
- 2009-01-07 CL CL2009000017A patent/CL2009000017A1/es unknown
- 2009-01-07 UY UY031596A patent/UY31596A1/es not_active Application Discontinuation
- 2009-01-07 PA PA20098811601A patent/PA8811601A1/es unknown
- 2009-01-07 AR ARP090100035A patent/AR070118A1/es unknown
- 2009-01-07 PE PE2009000009A patent/PE20091377A1/es not_active Application Discontinuation
- 2009-01-07 TW TW098100281A patent/TW200942256A/zh unknown
-
2010
- 2010-06-02 ZA ZA2010/03926A patent/ZA201003926B/en unknown
- 2010-06-22 US US12/820,722 patent/US9644017B2/en not_active Expired - Fee Related
- 2010-06-25 TN TN2010000298A patent/TN2010000298A1/fr unknown
- 2010-06-28 NI NI201000114A patent/NI201000114A/es unknown
- 2010-06-30 CO CO10079133A patent/CO6311108A2/es not_active Application Discontinuation
- 2010-07-02 DO DO2010000209A patent/DOP2010000209A/es unknown
- 2010-07-05 MA MA32985A patent/MA31998B1/fr unknown
- 2010-07-06 IL IL206844A patent/IL206844A/en not_active IP Right Cessation
- 2010-07-08 GT GT201000199A patent/GT201000199A/es unknown
- 2010-07-08 EC EC2010010333A patent/ECSP10010333A/es unknown
-
2011
- 2011-04-21 HK HK11104060.4A patent/HK1149772A1/zh not_active IP Right Cessation
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1989010937A1 (en) * | 1988-05-11 | 1989-11-16 | Novo Nordisk A/S | Insulin analogues |
US6100376A (en) * | 1988-11-08 | 2000-08-08 | Hoechst Aktiengesellschaft | A21, B30, modified insulin derivatives having an altered action profile |
WO2001025278A1 (de) * | 1999-10-02 | 2001-04-12 | Aventis Pharma Deutschland Gmbh | C-peptid zur verbesserten herstellung von insulin und insulinanaloga |
WO2002079250A1 (en) * | 2001-04-02 | 2002-10-10 | Novo Nordisk A/S | Insulin precursors and a process for their preparation |
WO2003053339A2 (en) * | 2001-12-20 | 2003-07-03 | Eli Lilly And Company | Insulin molecule having protracted time action |
WO2007081824A2 (en) * | 2006-01-06 | 2007-07-19 | Case Western Reserve University | Fibrillation resistant proteins |
Non-Patent Citations (1)
Title |
---|
See also references of EP2229407A2 * |
Cited By (78)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8343914B2 (en) | 2006-01-06 | 2013-01-01 | Case Western Reserve University | Fibrillation resistant proteins |
US8501440B2 (en) | 2006-10-04 | 2013-08-06 | Case Western Reserve University | Fibrillation-resistant insulin and insulin analogues |
US9644017B2 (en) | 2008-01-09 | 2017-05-09 | Sanofi-Aventis Deutschland Gmbh | Insulin derivatives having an extremely delayed time-action profile |
US8633156B2 (en) | 2008-01-09 | 2014-01-21 | Sanofi-Aventis Deutschland Gmbh | Insulin derivatives having an extremely delayed time-action profile |
US8993516B2 (en) | 2008-04-14 | 2015-03-31 | Case Western Reserve University | Meal-time insulin analogues of enhanced stability |
US9388228B2 (en) | 2008-07-31 | 2016-07-12 | Case Western Reserve University | Halogen-stabilized insulin |
US9200053B2 (en) | 2008-07-31 | 2015-12-01 | Case Western Reserve University | Insulin analogues containing penta-fluoro-Phenylalanine at position B24 |
US8921313B2 (en) | 2008-07-31 | 2014-12-30 | Case Western Reserve University | Halogen-stabilized insulin |
US10117909B2 (en) | 2008-10-17 | 2018-11-06 | Sanofi-Aventis Deutschland Gmbh | Combination of an insulin and a GLP-1 agonist |
EP2349324B1 (de) * | 2008-10-17 | 2017-09-06 | Sanofi-Aventis Deutschland GmbH | Kombination von einem insulin und einem glp-1-agonisten |
US9526764B2 (en) | 2008-10-17 | 2016-12-27 | Sanofi-Aventis Deutschland Gmbh | Combination of an insulin and a GLP-1-agonist |
US8680049B2 (en) | 2008-12-15 | 2014-03-25 | Zealand Pharma A/S | Glucagon analogues |
US8642540B2 (en) | 2008-12-15 | 2014-02-04 | Zealand Pharma A/S | Glucagon analogues |
US8685919B2 (en) | 2008-12-15 | 2014-04-01 | Zealand Pharma A/S | Glucagon analogues |
US8642541B2 (en) | 2008-12-15 | 2014-02-04 | Zealand Pharma A/S | Glucagon analogues |
WO2011003820A1 (de) * | 2009-07-06 | 2011-01-13 | Sanofi-Aventis Deutschland Gmbh | Hitze- und schüttelstabile insulinzubereitungen |
WO2011003822A3 (de) * | 2009-07-06 | 2011-08-25 | Sanofi-Aventis Deutschland Gmbh | Wässrige insulinzubereitungen enthaltend methionin |
WO2011003823A1 (de) * | 2009-07-06 | 2011-01-13 | Sanofi-Aventis Deutschland Gmbh | Langsamwirkende insulinzubereitungen |
JP2012532179A (ja) * | 2009-07-06 | 2012-12-13 | サノフィ−アベンティス・ドイチュラント・ゲゼルシャフト・ミット・ベシュレンクテル・ハフツング | 遅効性インスリン製剤 |
US10004786B2 (en) | 2009-07-13 | 2018-06-26 | Zealand Pharma A/S | Acylated glucagon analogues |
US9156901B2 (en) | 2009-07-13 | 2015-10-13 | Ditte Riber | Acylated glucagon analogues |
US8399407B2 (en) | 2009-09-17 | 2013-03-19 | Case Western Reserve University | Non-standard insulin analogues |
US10028910B2 (en) | 2009-11-13 | 2018-07-24 | Sanofi-Aventis Deutschland Gmbh | Pharmaceutical composition comprising a GLP-1-agonist and methionine |
US20120295846A1 (en) * | 2009-11-13 | 2012-11-22 | Sanofi-Aventis Deutschland Gmbh | Pharmaceutical composition comprising a glp-1 agonist, an insulin and methionine |
US9707176B2 (en) | 2009-11-13 | 2017-07-18 | Sanofi-Aventis Deutschland Gmbh | Pharmaceutical composition comprising a GLP-1 agonist and methionine |
US10029011B2 (en) * | 2009-11-13 | 2018-07-24 | Sanofi-Aventis Deutschland Gmbh | Pharmaceutical composition comprising a GLP-1 agonist, an insulin and methionine |
US9079975B2 (en) | 2009-12-11 | 2015-07-14 | Case Western Reserve University | Insulin analogues with chlorinated amino acids |
US8883722B2 (en) | 2010-06-23 | 2014-11-11 | Novo Nordisk A/S | Human insulin containing additional disulfide bonds |
CN102933599A (zh) * | 2010-06-23 | 2013-02-13 | 诺沃—诺迪斯克有限公司 | 包含额外的二硫键的人胰岛素 |
US9403894B2 (en) | 2010-06-23 | 2016-08-02 | Zealand Pharma A/S | Glucagon analogues |
US8853155B2 (en) | 2010-06-23 | 2014-10-07 | Novo Nordisk A/S | Insulin derivatives containing additional disulfide bonds |
RU2598273C2 (ru) * | 2010-06-23 | 2016-09-20 | Ново Нордиск А/С | Производные инсулина, содержащие дополнительные дисульфидные связи |
US9512195B2 (en) | 2010-06-23 | 2016-12-06 | Novo Nordisk A/S | Insulin derivatives containing additional disulfide bonds |
US9169310B2 (en) | 2010-06-24 | 2015-10-27 | Zealand Pharma A/S | Glucagon analogues |
WO2011161161A1 (en) | 2010-06-24 | 2011-12-29 | Boehringer Ingelheim International Gmbh | Diabetes therapy |
US9981013B2 (en) | 2010-08-30 | 2018-05-29 | Sanofi-Aventis Deutschland Gmbh | Use of AVE0010 for the treatment of diabetes mellitus type 2 |
WO2012062698A1 (en) | 2010-11-08 | 2012-05-18 | Boehringer Ingelheim International Gmbh | Pharmaceutical composition, methods for treating and uses thereof |
EP3539540A1 (de) | 2010-11-08 | 2019-09-18 | Boehringer Ingelheim International GmbH | Pharmazeutische zusammensetzung, verfahren zur behandlung und verwendung |
WO2012098462A1 (en) | 2011-01-20 | 2012-07-26 | Zealand Pharma A/S | Combination of acylated glucagon analogues with insulin analogues |
US9821032B2 (en) | 2011-05-13 | 2017-11-21 | Sanofi-Aventis Deutschland Gmbh | Pharmaceutical combination for improving glycemic control as add-on therapy to basal insulin |
CN109999180A (zh) * | 2011-06-02 | 2019-07-12 | 韩美科学株式会社 | 用于治疗糖尿病的包括长效胰岛素缀合物和长效促胰岛素肽缀合物的组合物 |
US9408893B2 (en) | 2011-08-29 | 2016-08-09 | Sanofi-Aventis Deutschland Gmbh | Pharmaceutical combination for use in glycemic control in diabetes type 2 patients |
US9987332B2 (en) | 2011-09-01 | 2018-06-05 | Sanofi-Aventis Deutschland Gmbh | Pharmaceutical composition for use in the treatment of a neurodegenerative disease |
US9006176B2 (en) * | 2011-10-18 | 2015-04-14 | AmideBio LLC | Chemically and thermodynamically stable insulin analogues and improved methods for their production |
US20130096057A1 (en) * | 2011-10-18 | 2013-04-18 | AmideBio LLC | Chemically and Thermodynamically Stable Insulin Analogues and Improved Methods for their Production |
US10100097B2 (en) | 2012-05-03 | 2018-10-16 | Zealand Pharma A/S | GIP-GLP-1 dual agonist compounds and methods |
US11795204B2 (en) | 2012-07-23 | 2023-10-24 | Zealand Pharma A/S | Glucagon analogues |
US10442847B2 (en) | 2012-07-23 | 2019-10-15 | Zealand Pharma A/S | Glucagon analogues |
US10253081B2 (en) | 2012-09-17 | 2019-04-09 | Zealand Pharma A/S | Glucagon analogues |
US9975939B2 (en) | 2012-09-17 | 2018-05-22 | Zealand Pharma A/S | Glucagon analogues |
US9180169B2 (en) | 2012-09-17 | 2015-11-10 | Zealand Pharma A/S | Glucagon analogues |
US10758592B2 (en) | 2012-10-09 | 2020-09-01 | Sanofi | Exendin-4 derivatives as dual GLP1/glucagon agonists |
US10253079B2 (en) | 2012-12-21 | 2019-04-09 | Sanofi | Functionalized Exendin-4 derivatives |
US9839675B2 (en) | 2013-02-04 | 2017-12-12 | Sanofi | Stabilized pharmaceutical formulations of insulin analogues and/or insulin derivatives |
US11091528B2 (en) | 2013-10-17 | 2021-08-17 | Zealand Pharma A/S | Acylated glucagon analogues |
US11884713B2 (en) | 2013-10-17 | 2024-01-30 | Zealand Pharma A/S | Acylated glucagon analogues |
US9988429B2 (en) | 2013-10-17 | 2018-06-05 | Zealand Pharma A/S | Glucagon analogues |
US9896495B2 (en) | 2013-10-17 | 2018-02-20 | Zealand Pharma A/S | Acylated glucagon analogues |
US10457714B2 (en) | 2013-10-17 | 2019-10-29 | Zealand Pharma A/S | Acylated glucagon analogues |
US11034747B2 (en) | 2013-10-17 | 2021-06-15 | Zealand Pharma A/S | Glucagon analogues and methods of use |
US10131702B2 (en) | 2013-11-06 | 2018-11-20 | Zealand Pharma A/S | Glucagon-GLP-1-GIP triple agonist compounds |
US11111285B2 (en) | 2013-11-06 | 2021-09-07 | Zealand Pharma A/S | Glucagon-GLP-1-GIP triple agonist compounds |
US10093713B2 (en) | 2013-11-06 | 2018-10-09 | Zealand Pharma A/S | GIP-GLP-1 dual agonist compounds and methods |
US11008375B2 (en) | 2013-11-06 | 2021-05-18 | Zealand Pharma A/S | GIP-GLP-1 dual agonist compounds and methods |
US10610595B2 (en) | 2014-01-09 | 2020-04-07 | Sanofi | Stabilized pharmaceutical formulations of insulin analogues and/or insulin derivatives |
US9895424B2 (en) | 2014-01-09 | 2018-02-20 | Sanofi | Stabilized pharmaceutical formulations of insulin analogues and/or insulin derivatives |
US9895423B2 (en) | 2014-01-09 | 2018-02-20 | Sanofi | Stabilized pharmaceutical formulations of insulin aspart |
US9839692B2 (en) | 2014-01-09 | 2017-12-12 | Sanofi | Stabilized pharmaceutical formulations of insulin analogues and/or insulin derivatives |
US11142560B2 (en) | 2014-10-06 | 2021-10-12 | Case Western Reserve University | Biphasic single-chain insulin analogues |
US10392429B2 (en) | 2014-10-06 | 2019-08-27 | Case Western Reserve University | Biphasic single-chain insulin analogues |
US11001619B2 (en) | 2014-10-29 | 2021-05-11 | Zealand Pharma A/S | GIP agonist compounds and methods |
US11814417B2 (en) | 2014-10-29 | 2023-11-14 | Zealand Pharma A/S | GIP agonist compounds and methods |
US10253078B2 (en) | 2014-10-29 | 2019-04-09 | Zealand Pharma A/S | GIP agonist compounds and methods |
US9950039B2 (en) | 2014-12-12 | 2018-04-24 | Sanofi-Aventis Deutschland Gmbh | Insulin glargine/lixisenatide fixed ratio formulation |
US10434147B2 (en) | 2015-03-13 | 2019-10-08 | Sanofi-Aventis Deutschland Gmbh | Treatment type 2 diabetes mellitus patients |
US10159713B2 (en) | 2015-03-18 | 2018-12-25 | Sanofi-Aventis Deutschland Gmbh | Treatment of type 2 diabetes mellitus patients |
US10336802B2 (en) | 2015-04-16 | 2019-07-02 | Zealand Pharma A/S | Acylated glucagon analogue |
US11274136B2 (en) | 2015-04-16 | 2022-03-15 | Zealand Pharma A/S | Acylated glucagon analogue |
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
EP2229407B1 (de) | Neue insulinderivate mit extrem verzögertem zeit- / wirkungsprofil | |
EP2229406B1 (de) | Neue insulinderivate mit extrem verzögertem zeit- / wirkungsprofil | |
DE102008003568A1 (de) | Neue Insulinderivate mit extrem verzögertem Zeit-/ Wirkungsprofil | |
DE102008003566A1 (de) | Neue Insulinderivate mit extrem verzögertem Zeit-/ Wirkungsprofil | |
EP2041169B1 (de) | Amidiertes insulin glargin | |
EP0885961B1 (de) | Neue Insulinderivate mit schnellem Wirkungseintritt | |
EP2451437B1 (de) | Wässrige insulinzubereitungen enthaltend methionin | |
DE69629210T2 (de) | Insulinabkömmlinge | |
WO2011003823A1 (de) | Langsamwirkende insulinzubereitungen | |
DE102008025008A1 (de) | Neue Insulinderivate mit extrem verzögertem Zeit-/ Wirkungsprofil | |
EP1084248B1 (de) | Neue insulinanaloga mit erhöhter zinkbindung | |
DE102008025007A1 (de) | Neue Insulinderivate mit extrem verzögertem Zeit-/ Wirkungsprofil |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
WWE | Wipo information: entry into national phase |
Ref document number: 200980101962.3 Country of ref document: CN |
|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 09701358 Country of ref document: EP Kind code of ref document: A2 |
|
WWE | Wipo information: entry into national phase |
Ref document number: 12010501284 Country of ref document: PH |
|
REEP | Request for entry into the european phase |
Ref document number: 2009701358 Country of ref document: EP |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2009701358 Country of ref document: EP |
|
WWE | Wipo information: entry into national phase |
Ref document number: 201011511 Country of ref document: CR Ref document number: CR2010-011511 Country of ref document: CR |
|
WWE | Wipo information: entry into national phase |
Ref document number: 10079133 Country of ref document: CO |
|
WWE | Wipo information: entry into national phase |
Ref document number: 4072/CHENP/2010 Country of ref document: IN Ref document number: MX/A/2010/007320 Country of ref document: MX |
|
WWE | Wipo information: entry into national phase |
Ref document number: 586590 Country of ref document: NZ |
|
WWE | Wipo information: entry into national phase |
Ref document number: DZP2010000419 Country of ref document: DZ |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2009203809 Country of ref document: AU |
|
ENP | Entry into the national phase |
Ref document number: 20107014961 Country of ref document: KR Kind code of ref document: A |
|
WWE | Wipo information: entry into national phase |
Ref document number: 206844 Country of ref document: IL |
|
ENP | Entry into the national phase |
Ref document number: 1001104 Country of ref document: KE |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2711749 Country of ref document: CA Ref document number: 2010541743 Country of ref document: JP |
|
WWE | Wipo information: entry into national phase |
Ref document number: PI 2010002683 Country of ref document: MY |
|
ENP | Entry into the national phase |
Ref document number: 2009203809 Country of ref document: AU Date of ref document: 20090106 Kind code of ref document: A |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2010133231 Country of ref document: RU Ref document number: A201009821 Country of ref document: UA |
|
ENP | Entry into the national phase |
Ref document number: PI0907371 Country of ref document: BR Kind code of ref document: A2 Effective date: 20100709 |