SA516370893B1 - مشتق جديد من نظير إنسولين - Google Patents
مشتق جديد من نظير إنسولين Download PDFInfo
- Publication number
- SA516370893B1 SA516370893B1 SA516370893A SA516370893A SA516370893B1 SA 516370893 B1 SA516370893 B1 SA 516370893B1 SA 516370893 A SA516370893 A SA 516370893A SA 516370893 A SA516370893 A SA 516370893A SA 516370893 B1 SA516370893 B1 SA 516370893B1
- Authority
- SA
- Saudi Arabia
- Prior art keywords
- compound
- insulin
- hexamer
- frequently
- ethoxy
- 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 description 237
- 239000004026 insulin derivative Substances 0.000 title description 12
- PBGKTOXHQIOBKM-FHFVDXKLSA-N insulin (human) Chemical class 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 abstract description 51
- 101000976075 Homo sapiens Insulin Proteins 0.000 claims abstract description 41
- 238000011282 treatment Methods 0.000 claims abstract description 40
- 206010012601 diabetes mellitus Diseases 0.000 claims abstract description 36
- 102000004877 Insulin Human genes 0.000 claims description 101
- 108090001061 Insulin Proteins 0.000 claims description 101
- 229940125396 insulin Drugs 0.000 claims description 98
- 150000001875 compounds Chemical class 0.000 claims description 80
- 239000011701 zinc Substances 0.000 claims description 43
- PTFCDOFLOPIGGS-UHFFFAOYSA-N Zinc dication Chemical compound [Zn+2] PTFCDOFLOPIGGS-UHFFFAOYSA-N 0.000 claims description 36
- 239000008194 pharmaceutical composition Substances 0.000 claims description 31
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 26
- 239000000243 solution Substances 0.000 claims description 26
- 229910052725 zinc Inorganic materials 0.000 claims description 24
- 239000007864 aqueous solution Substances 0.000 claims description 15
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 9
- 230000004224 protection Effects 0.000 claims description 6
- 150000002500 ions Chemical class 0.000 claims description 3
- 238000005516 engineering process Methods 0.000 claims description 2
- JNNNAJIAXISWGB-UHFFFAOYSA-N icosane-1,1-diol Chemical compound CCCCCCCCCCCCCCCCCCCC(O)O JNNNAJIAXISWGB-UHFFFAOYSA-N 0.000 claims description 2
- 241000196324 Embryophyta Species 0.000 claims 1
- FEXCMMPRRBSCRG-UHFFFAOYSA-N hexasulfur Chemical compound S1SSSSS1 FEXCMMPRRBSCRG-UHFFFAOYSA-N 0.000 claims 1
- 239000007921 spray Substances 0.000 claims 1
- -1 A14E Chemical class 0.000 abstract description 38
- 239000003814 drug Substances 0.000 abstract description 5
- 229940079593 drug Drugs 0.000 abstract description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 168
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 99
- 239000011780 sodium chloride Substances 0.000 description 84
- 229940125904 compound 1 Drugs 0.000 description 79
- 238000000034 method Methods 0.000 description 69
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 51
- 239000000203 mixture Substances 0.000 description 39
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 34
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 30
- 239000002245 particle Substances 0.000 description 25
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 25
- 238000009472 formulation Methods 0.000 description 23
- 239000002253 acid Substances 0.000 description 22
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 20
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 18
- 238000002360 preparation method Methods 0.000 description 18
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 16
- 235000001014 amino acid Nutrition 0.000 description 16
- 230000015572 biosynthetic process Effects 0.000 description 16
- 238000012360 testing method Methods 0.000 description 16
- 125000002252 acyl group Chemical group 0.000 description 15
- 238000003556 assay Methods 0.000 description 15
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 14
- 239000000126 substance Substances 0.000 description 14
- 230000001225 therapeutic effect Effects 0.000 description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 14
- 150000001413 amino acids Chemical class 0.000 description 12
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 11
- 239000007853 buffer solution Substances 0.000 description 11
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 11
- 102000004190 Enzymes Human genes 0.000 description 10
- 108090000790 Enzymes Proteins 0.000 description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 10
- 229940088598 enzyme Drugs 0.000 description 10
- JFCQEDHGNNZCLN-UHFFFAOYSA-N glutaric acid Chemical compound OC(=O)CCCC(O)=O JFCQEDHGNNZCLN-UHFFFAOYSA-N 0.000 description 10
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 10
- 241001136792 Alle Species 0.000 description 9
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 9
- 239000008280 blood Substances 0.000 description 9
- 210000004369 blood Anatomy 0.000 description 9
- 238000004128 high performance liquid chromatography Methods 0.000 description 9
- 239000000047 product Substances 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 8
- 241001465754 Metazoa Species 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 8
- 230000000694 effects Effects 0.000 description 8
- 150000002148 esters Chemical class 0.000 description 8
- ISYWECDDZWTKFF-UHFFFAOYSA-N nonadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCCC(O)=O ISYWECDDZWTKFF-UHFFFAOYSA-N 0.000 description 8
- 108090000623 proteins and genes Proteins 0.000 description 8
- QTWJRLJHJPIABL-UHFFFAOYSA-N 2-methylphenol;3-methylphenol;4-methylphenol Chemical compound CC1=CC=C(O)C=C1.CC1=CC=CC(O)=C1.CC1=CC=CC=C1O QTWJRLJHJPIABL-UHFFFAOYSA-N 0.000 description 7
- 229940126062 Compound A Drugs 0.000 description 7
- 206010016654 Fibrosis Diseases 0.000 description 7
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 7
- 239000012736 aqueous medium Substances 0.000 description 7
- 239000003153 chemical reaction reagent Substances 0.000 description 7
- 229930003836 cresol Natural products 0.000 description 7
- 230000002354 daily effect Effects 0.000 description 7
- 230000004761 fibrosis Effects 0.000 description 7
- JJOJFIHJIRWASH-UHFFFAOYSA-N icosanedioic acid Chemical compound OC(=O)CCCCCCCCCCCCCCCCCCC(O)=O JJOJFIHJIRWASH-UHFFFAOYSA-N 0.000 description 7
- 235000018102 proteins Nutrition 0.000 description 7
- 102000004169 proteins and genes Human genes 0.000 description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 7
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 7
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 6
- 241000282472 Canis lupus familiaris Species 0.000 description 6
- 102000003746 Insulin Receptor Human genes 0.000 description 6
- 108010001127 Insulin Receptor Proteins 0.000 description 6
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 description 6
- 239000003795 chemical substances by application Substances 0.000 description 6
- 238000002347 injection Methods 0.000 description 6
- 239000007924 injection Substances 0.000 description 6
- 229960005232 insulin (human) Drugs 0.000 description 6
- 238000001990 intravenous administration Methods 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- 239000011347 resin Substances 0.000 description 6
- 229920005989 resin Polymers 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 6
- 239000005695 Ammonium acetate Substances 0.000 description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 5
- 229940043376 ammonium acetate Drugs 0.000 description 5
- 235000019257 ammonium acetate Nutrition 0.000 description 5
- 239000000872 buffer Substances 0.000 description 5
- 230000006870 function Effects 0.000 description 5
- 239000000178 monomer Substances 0.000 description 5
- RIVIDPPYRINTTH-UHFFFAOYSA-N n-ethylpropan-2-amine Chemical compound CCNC(C)C RIVIDPPYRINTTH-UHFFFAOYSA-N 0.000 description 5
- 150000003839 salts Chemical class 0.000 description 5
- 238000003860 storage Methods 0.000 description 5
- FQFILJKFZCVHNH-UHFFFAOYSA-N tert-butyl n-[3-[(5-bromo-2-chloropyrimidin-4-yl)amino]propyl]carbamate Chemical compound CC(C)(C)OC(=O)NCCCNC1=NC(Cl)=NC=C1Br FQFILJKFZCVHNH-UHFFFAOYSA-N 0.000 description 5
- 108700028369 Alleles Proteins 0.000 description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
- ATHHXGZTWNVVOU-UHFFFAOYSA-N N-methylformamide Chemical compound CNC=O ATHHXGZTWNVVOU-UHFFFAOYSA-N 0.000 description 4
- ZOIORXHNWRGPMV-UHFFFAOYSA-N acetic acid;zinc Chemical compound [Zn].CC(O)=O.CC(O)=O ZOIORXHNWRGPMV-UHFFFAOYSA-N 0.000 description 4
- 230000002378 acidificating effect Effects 0.000 description 4
- 125000003275 alpha amino acid group Chemical group 0.000 description 4
- 125000004063 butyryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 4
- 230000008859 change Effects 0.000 description 4
- 239000003085 diluting agent Substances 0.000 description 4
- 238000010790 dilution Methods 0.000 description 4
- 239000012895 dilution Substances 0.000 description 4
- 150000002009 diols Chemical class 0.000 description 4
- 238000002296 dynamic light scattering Methods 0.000 description 4
- 238000003384 imaging method Methods 0.000 description 4
- 239000012535 impurity Substances 0.000 description 4
- 239000010410 layer Substances 0.000 description 4
- 238000005259 measurement Methods 0.000 description 4
- 239000002609 medium Substances 0.000 description 4
- 239000012071 phase Substances 0.000 description 4
- NMHMNPHRMNGLLB-UHFFFAOYSA-N phloretic acid Chemical compound OC(=O)CCC1=CC=C(O)C=C1 NMHMNPHRMNGLLB-UHFFFAOYSA-N 0.000 description 4
- 230000036470 plasma concentration Effects 0.000 description 4
- 239000003755 preservative agent Substances 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- 108090000765 processed proteins & peptides Proteins 0.000 description 4
- 230000000306 recurrent effect Effects 0.000 description 4
- 238000004366 reverse phase liquid chromatography Methods 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 4
- 206010002091 Anaesthesia Diseases 0.000 description 3
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- 241000700159 Rattus Species 0.000 description 3
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 239000007983 Tris buffer Substances 0.000 description 3
- 230000004913 activation Effects 0.000 description 3
- 230000037005 anaesthesia Effects 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 239000003963 antioxidant agent Substances 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 3
- 230000015556 catabolic process Effects 0.000 description 3
- 210000004027 cell Anatomy 0.000 description 3
- 238000006731 degradation reaction Methods 0.000 description 3
- 238000004090 dissolution Methods 0.000 description 3
- 238000002523 gelfiltration Methods 0.000 description 3
- 239000004615 ingredient Substances 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 230000007935 neutral effect Effects 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 230000001105 regulatory effect Effects 0.000 description 3
- 229920002545 silicone oil Polymers 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 230000002123 temporal effect Effects 0.000 description 3
- 208000035408 type 1 diabetes mellitus 1 Diseases 0.000 description 3
- 238000004704 ultra performance liquid chromatography Methods 0.000 description 3
- 239000003643 water by type Substances 0.000 description 3
- 230000003442 weekly effect Effects 0.000 description 3
- 239000004246 zinc acetate Substances 0.000 description 3
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 2
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 235000017274 Diospyros sandwicensis Nutrition 0.000 description 2
- 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 2
- 101000852815 Homo sapiens Insulin receptor Proteins 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- 206010022489 Insulin Resistance Diseases 0.000 description 2
- 229920001202 Inulin Polymers 0.000 description 2
- 241000282838 Lama Species 0.000 description 2
- 108010092217 Long-Acting Insulin Proteins 0.000 description 2
- 102000016261 Long-Acting Insulin Human genes 0.000 description 2
- 229940100066 Long-acting insulin Drugs 0.000 description 2
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 2
- 239000004472 Lysine Substances 0.000 description 2
- 239000012606 POROS 50 HQ resin Substances 0.000 description 2
- 108091005804 Peptidases Proteins 0.000 description 2
- JIAARYAFYJHUJI-UHFFFAOYSA-L Zinc chloride Inorganic materials [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 230000010933 acylation Effects 0.000 description 2
- 238000005917 acylation reaction Methods 0.000 description 2
- 125000000539 amino acid group Chemical group 0.000 description 2
- 238000005571 anion exchange chromatography Methods 0.000 description 2
- 229940127003 anti-diabetic drug Drugs 0.000 description 2
- 239000003472 antidiabetic agent Substances 0.000 description 2
- 239000012298 atmosphere Substances 0.000 description 2
- 239000012267 brine Substances 0.000 description 2
- 239000004067 bulking agent Substances 0.000 description 2
- 238000004364 calculation method Methods 0.000 description 2
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 2
- 230000021615 conjugation Effects 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000000354 decomposition reaction Methods 0.000 description 2
- 230000007423 decrease Effects 0.000 description 2
- 229940042399 direct acting antivirals protease inhibitors Drugs 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 238000009826 distribution Methods 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 239000004220 glutamic acid Substances 0.000 description 2
- 235000013922 glutamic acid Nutrition 0.000 description 2
- 102000047882 human INSR Human genes 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 230000000968 intestinal effect Effects 0.000 description 2
- 229940029339 inulin Drugs 0.000 description 2
- JYJIGFIDKWBXDU-MNNPPOADSA-N inulin Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)OC[C@]1(OC[C@]2(OC[C@]3(OC[C@]4(OC[C@]5(OC[C@]6(OC[C@]7(OC[C@]8(OC[C@]9(OC[C@]%10(OC[C@]%11(OC[C@]%12(OC[C@]%13(OC[C@]%14(OC[C@]%15(OC[C@]%16(OC[C@]%17(OC[C@]%18(OC[C@]%19(OC[C@]%20(OC[C@]%21(OC[C@]%22(OC[C@]%23(OC[C@]%24(OC[C@]%25(OC[C@]%26(OC[C@]%27(OC[C@]%28(OC[C@]%29(OC[C@]%30(OC[C@]%31(OC[C@]%32(OC[C@]%33(OC[C@]%34(OC[C@]%35(OC[C@]%36(O[C@@H]%37[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O%37)O)[C@H]([C@H](O)[C@@H](CO)O%36)O)[C@H]([C@H](O)[C@@H](CO)O%35)O)[C@H]([C@H](O)[C@@H](CO)O%34)O)[C@H]([C@H](O)[C@@H](CO)O%33)O)[C@H]([C@H](O)[C@@H](CO)O%32)O)[C@H]([C@H](O)[C@@H](CO)O%31)O)[C@H]([C@H](O)[C@@H](CO)O%30)O)[C@H]([C@H](O)[C@@H](CO)O%29)O)[C@H]([C@H](O)[C@@H](CO)O%28)O)[C@H]([C@H](O)[C@@H](CO)O%27)O)[C@H]([C@H](O)[C@@H](CO)O%26)O)[C@H]([C@H](O)[C@@H](CO)O%25)O)[C@H]([C@H](O)[C@@H](CO)O%24)O)[C@H]([C@H](O)[C@@H](CO)O%23)O)[C@H]([C@H](O)[C@@H](CO)O%22)O)[C@H]([C@H](O)[C@@H](CO)O%21)O)[C@H]([C@H](O)[C@@H](CO)O%20)O)[C@H]([C@H](O)[C@@H](CO)O%19)O)[C@H]([C@H](O)[C@@H](CO)O%18)O)[C@H]([C@H](O)[C@@H](CO)O%17)O)[C@H]([C@H](O)[C@@H](CO)O%16)O)[C@H]([C@H](O)[C@@H](CO)O%15)O)[C@H]([C@H](O)[C@@H](CO)O%14)O)[C@H]([C@H](O)[C@@H](CO)O%13)O)[C@H]([C@H](O)[C@@H](CO)O%12)O)[C@H]([C@H](O)[C@@H](CO)O%11)O)[C@H]([C@H](O)[C@@H](CO)O%10)O)[C@H]([C@H](O)[C@@H](CO)O9)O)[C@H]([C@H](O)[C@@H](CO)O8)O)[C@H]([C@H](O)[C@@H](CO)O7)O)[C@H]([C@H](O)[C@@H](CO)O6)O)[C@H]([C@H](O)[C@@H](CO)O5)O)[C@H]([C@H](O)[C@@H](CO)O4)O)[C@H]([C@H](O)[C@@H](CO)O3)O)[C@H]([C@H](O)[C@@H](CO)O2)O)[C@@H](O)[C@H](O)[C@@H](CO)O1 JYJIGFIDKWBXDU-MNNPPOADSA-N 0.000 description 2
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 2
- 235000019341 magnesium sulphate Nutrition 0.000 description 2
- 238000012423 maintenance Methods 0.000 description 2
- 208000030159 metabolic disease Diseases 0.000 description 2
- 229910021645 metal ion Inorganic materials 0.000 description 2
- 210000000496 pancreas Anatomy 0.000 description 2
- 238000007911 parenteral administration Methods 0.000 description 2
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 230000035935 pregnancy Effects 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 102000004196 processed proteins & peptides Human genes 0.000 description 2
- 238000012545 processing Methods 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 2
- 238000004007 reversed phase HPLC Methods 0.000 description 2
- 238000002821 scintillation proximity assay Methods 0.000 description 2
- VWDWKYIASSYTQR-UHFFFAOYSA-N sodium nitrate Chemical compound [Na+].[O-][N+]([O-])=O VWDWKYIASSYTQR-UHFFFAOYSA-N 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- GGKLADJTQDGVBP-UHFFFAOYSA-M sodium;propane-1,2,3-triol;chloride Chemical compound [Na+].[Cl-].OCC(O)CO GGKLADJTQDGVBP-UHFFFAOYSA-M 0.000 description 2
- 239000007790 solid phase Substances 0.000 description 2
- 241000894007 species Species 0.000 description 2
- 239000003381 stabilizer Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 210000002784 stomach Anatomy 0.000 description 2
- 238000010254 subcutaneous injection Methods 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- 239000004094 surface-active agent Substances 0.000 description 2
- PBIMIGNDTBRRPI-UHFFFAOYSA-N trifluoro borate Chemical compound FOB(OF)OF PBIMIGNDTBRRPI-UHFFFAOYSA-N 0.000 description 2
- 210000003462 vein Anatomy 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- 239000011592 zinc chloride Substances 0.000 description 2
- 235000005074 zinc chloride Nutrition 0.000 description 2
- XYGVIBXOJOOCFR-BTJKTKAUSA-N (z)-but-2-enedioic acid;8-chloro-6-(2-fluorophenyl)-1-methyl-4h-imidazo[1,5-a][1,4]benzodiazepine Chemical compound OC(=O)\C=C/C(O)=O.C12=CC(Cl)=CC=C2N2C(C)=NC=C2CN=C1C1=CC=CC=C1F XYGVIBXOJOOCFR-BTJKTKAUSA-N 0.000 description 1
- UGBLISDIHDMHJX-UHFFFAOYSA-N 1-(4-fluorophenyl)-4-[4-(2-methoxyphenyl)piperazin-1-yl]butan-1-one;hydrochloride Chemical compound [Cl-].COC1=CC=CC=C1N1CC[NH+](CCCC(=O)C=2C=CC(F)=CC=2)CC1 UGBLISDIHDMHJX-UHFFFAOYSA-N 0.000 description 1
- QYIHXUIVNJZLLN-UHFFFAOYSA-N 2,2-dimethyldocosane Chemical compound CCCCCCCCCCCCCCCCCCCCC(C)(C)C QYIHXUIVNJZLLN-UHFFFAOYSA-N 0.000 description 1
- JUCDAUSILDWYOA-UHFFFAOYSA-N 20-[(2-methylpropan-2-yl)oxy]-20-oxoicosanoic acid Chemical compound CC(C)(C)OC(=O)CCCCCCCCCCCCCCCCCCC(O)=O JUCDAUSILDWYOA-UHFFFAOYSA-N 0.000 description 1
- VZHNAVSRNGLHRD-UHFFFAOYSA-N 5-[(2-methylpropan-2-yl)oxy]-5-oxopentanoic acid Chemical compound CC(C)(C)OC(=O)CCCC(O)=O VZHNAVSRNGLHRD-UHFFFAOYSA-N 0.000 description 1
- UQXNEWQGGVUVQA-UHFFFAOYSA-N 8-aminooctanoic acid Chemical compound NCCCCCCCC(O)=O UQXNEWQGGVUVQA-UHFFFAOYSA-N 0.000 description 1
- 241000590035 Achromobacter lyticus Species 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-M Acrylate Chemical compound [O-]C(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-M 0.000 description 1
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- 101001011741 Bos taurus Insulin Proteins 0.000 description 1
- QQTNHRRMPBAEJO-UHFFFAOYSA-N C(C)(C)N(CC)C(C)C.C(C)(C)NCC Chemical compound C(C)(C)N(CC)C(C)C.C(C)(C)NCC QQTNHRRMPBAEJO-UHFFFAOYSA-N 0.000 description 1
- 206010006895 Cachexia Diseases 0.000 description 1
- 239000004429 Calibre Substances 0.000 description 1
- 102000000496 Carboxypeptidases A Human genes 0.000 description 1
- 108010080937 Carboxypeptidases A Proteins 0.000 description 1
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 description 1
- 108090000317 Chymotrypsin Proteins 0.000 description 1
- 241000195493 Cryptophyta Species 0.000 description 1
- 125000004077 D-glutamic acid group Chemical group [H]N([H])[C@@]([H])(C(=O)[*])C([H])([H])C([H])([H])C(N([H])[H])=O 0.000 description 1
- 241001649081 Dina Species 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 208000002705 Glucose Intolerance Diseases 0.000 description 1
- 206010018429 Glucose tolerance impaired Diseases 0.000 description 1
- 239000007995 HEPES buffer Substances 0.000 description 1
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 108010073961 Insulin Aspart Proteins 0.000 description 1
- 229940122254 Intermediate acting insulin Drugs 0.000 description 1
- 208000001145 Metabolic Syndrome Diseases 0.000 description 1
- 102000029749 Microtubule Human genes 0.000 description 1
- 108091022875 Microtubule Proteins 0.000 description 1
- 102100026933 Myelin-associated neurite-outgrowth inhibitor Human genes 0.000 description 1
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 1
- 208000008589 Obesity Diseases 0.000 description 1
- 240000002390 Pandanus odoratissimus Species 0.000 description 1
- 235000005311 Pandanus odoratissimus Nutrition 0.000 description 1
- 239000005662 Paraffin oil Substances 0.000 description 1
- 102000057297 Pepsin A Human genes 0.000 description 1
- 108090000284 Pepsin A Proteins 0.000 description 1
- 102000035195 Peptidases Human genes 0.000 description 1
- 102000015731 Peptide Hormones Human genes 0.000 description 1
- 108010038988 Peptide Hormones Proteins 0.000 description 1
- 108010005991 Pork Regular Insulin Proteins 0.000 description 1
- 239000004365 Protease Substances 0.000 description 1
- 101710118538 Protease Proteins 0.000 description 1
- 229940123452 Rapid-acting insulin Drugs 0.000 description 1
- 241000700157 Rattus norvegicus Species 0.000 description 1
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 description 1
- 108010026951 Short-Acting Insulin Proteins 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- RHQDFWAXVIIEBN-UHFFFAOYSA-N Trifluoroethanol Chemical compound OCC(F)(F)F RHQDFWAXVIIEBN-UHFFFAOYSA-N 0.000 description 1
- LEHOTFFKMJEONL-UHFFFAOYSA-N Uric Acid Chemical compound N1C(=O)NC(=O)C2=C1NC(=O)N2 LEHOTFFKMJEONL-UHFFFAOYSA-N 0.000 description 1
- SAHIZENKTPRYSN-UHFFFAOYSA-N [2-[3-(phenoxymethyl)phenoxy]-6-(trifluoromethyl)pyridin-4-yl]methanamine Chemical compound O(C1=CC=CC=C1)CC=1C=C(OC2=NC(=CC(=C2)CN)C(F)(F)F)C=CC=1 SAHIZENKTPRYSN-UHFFFAOYSA-N 0.000 description 1
- 201000000690 abdominal obesity-metabolic syndrome Diseases 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000035508 accumulation Effects 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 description 1
- 238000010306 acid treatment Methods 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 238000005054 agglomeration Methods 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 230000003444 anaesthetic effect Effects 0.000 description 1
- 238000005349 anion exchange Methods 0.000 description 1
- 230000036528 appetite Effects 0.000 description 1
- 235000019789 appetite Nutrition 0.000 description 1
- 238000000149 argon plasma sintering Methods 0.000 description 1
- 210000000227 basophil cell of anterior lobe of hypophysis Anatomy 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- QRUDEWIWKLJBPS-UHFFFAOYSA-N benzotriazole Chemical compound C1=CC=C2N[N][N]C2=C1 QRUDEWIWKLJBPS-UHFFFAOYSA-N 0.000 description 1
- 239000012964 benzotriazole Substances 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 239000012148 binding buffer Substances 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
- 125000004744 butyloxycarbonyl group Chemical group 0.000 description 1
- 210000004899 c-terminal region Anatomy 0.000 description 1
- LEMUFSYUPGXXCM-JNEQYSBXSA-N caninsulin Chemical compound [Zn].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](CC3N=CN=C3)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)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)C1C=NC=N1 LEMUFSYUPGXXCM-JNEQYSBXSA-N 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 125000002843 carboxylic acid group Chemical group 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 239000002738 chelating agent Substances 0.000 description 1
- 238000002144 chemical decomposition reaction Methods 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 229960002376 chymotrypsin Drugs 0.000 description 1
- 239000004927 clay Substances 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 230000009089 cytolysis Effects 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 238000013480 data collection Methods 0.000 description 1
- 230000006240 deamidation Effects 0.000 description 1
- 230000009615 deamination Effects 0.000 description 1
- 238000006481 deamination reaction Methods 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- GHVNFZFCNZKVNT-UHFFFAOYSA-N decanoic acid Chemical compound CCCCCCCCCC(O)=O GHVNFZFCNZKVNT-UHFFFAOYSA-N 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 238000011033 desalting Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 125000003963 dichloro group Chemical group Cl* 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- ZMXDDKWLCZADIW-UHFFFAOYSA-N dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 1
- OKBPCTLSPGDQBO-UHFFFAOYSA-L disodium;dichloride Chemical compound [Na+].[Na+].[Cl-].[Cl-] OKBPCTLSPGDQBO-UHFFFAOYSA-L 0.000 description 1
- 239000003651 drinking water Substances 0.000 description 1
- 235000020188 drinking water Nutrition 0.000 description 1
- 210000001198 duodenum Anatomy 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 208000026500 emaciation Diseases 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 125000004672 ethylcarbonyl group Chemical group [H]C([H])([H])C([H])([H])C(*)=O 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 238000003958 fumigation Methods 0.000 description 1
- 230000002538 fungal effect Effects 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 238000010353 genetic engineering Methods 0.000 description 1
- 208000004104 gestational diabetes Diseases 0.000 description 1
- 239000007902 hard capsule Substances 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 229960002897 heparin Drugs 0.000 description 1
- 229920000669 heparin Polymers 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 1
- 201000001421 hyperglycemia Diseases 0.000 description 1
- 238000003018 immunoassay Methods 0.000 description 1
- 239000005414 inactive ingredient Substances 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 230000003914 insulin secretion Effects 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- 210000004731 jugular vein Anatomy 0.000 description 1
- 238000002372 labelling Methods 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- FXBYOMANNHFNQV-UHFFFAOYSA-L magnesium;hydrogen sulfate Chemical compound [Mg+2].OS([O-])(=O)=O.OS([O-])(=O)=O FXBYOMANNHFNQV-UHFFFAOYSA-L 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 238000001840 matrix-assisted laser desorption--ionisation time-of-flight mass spectrometry Methods 0.000 description 1
- 230000002503 metabolic effect Effects 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
- 238000012008 microflow imaging Methods 0.000 description 1
- 210000004688 microtubule Anatomy 0.000 description 1
- 230000003278 mimic effect Effects 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000004899 motility Effects 0.000 description 1
- 239000003471 mutagenic agent Substances 0.000 description 1
- 231100000707 mutagenic chemical Toxicity 0.000 description 1
- 230000003505 mutagenic effect Effects 0.000 description 1
- UPXAZUFKXWLNMF-UHFFFAOYSA-N n'-propan-2-ylmethanediimine Chemical compound CC(C)N=C=N UPXAZUFKXWLNMF-UHFFFAOYSA-N 0.000 description 1
- HWYHDWGGACRVEH-UHFFFAOYSA-N n-methyl-n-(4-pyrrolidin-1-ylbut-2-ynyl)acetamide Chemical compound CC(=O)N(C)CC#CCN1CCCC1 HWYHDWGGACRVEH-UHFFFAOYSA-N 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 235000020925 non fasting Nutrition 0.000 description 1
- 235000020824 obesity Nutrition 0.000 description 1
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 229940111202 pepsin Drugs 0.000 description 1
- 239000000813 peptide hormone Substances 0.000 description 1
- 238000010647 peptide synthesis reaction Methods 0.000 description 1
- 230000037081 physical activity Effects 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 229920005990 polystyrene resin Polymers 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 201000009104 prediabetes syndrome Diseases 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 238000001814 protein method Methods 0.000 description 1
- 230000001603 reducing effect Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000003252 repetitive effect Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical compound CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 description 1
- 238000004062 sedimentation Methods 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000001542 size-exclusion chromatography Methods 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000010344 sodium nitrate Nutrition 0.000 description 1
- ZUNUXLMUHUHCOC-UHFFFAOYSA-L sodium zinc acetate chloride Chemical compound C(C)(=O)[O-].[Na+].[Cl-].[Zn+2] ZUNUXLMUHUHCOC-UHFFFAOYSA-L 0.000 description 1
- DFIWJEVKLWMZBI-UHFFFAOYSA-M sodium;dihydrogen phosphate;phosphoric acid Chemical compound [Na+].OP(O)(O)=O.OP(O)([O-])=O DFIWJEVKLWMZBI-UHFFFAOYSA-M 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 238000010532 solid phase synthesis reaction Methods 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- NQRYJNQNLNOLGT-UHFFFAOYSA-N tetrahydropyridine hydrochloride Natural products C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- JADVWWSKYZXRGX-UHFFFAOYSA-M thioflavine T Chemical compound [Cl-].C1=CC(N(C)C)=CC=C1C1=[N+](C)C2=CC=C(C)C=C2S1 JADVWWSKYZXRGX-UHFFFAOYSA-M 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
- 238000000825 ultraviolet detection Methods 0.000 description 1
- 230000002485 urinary effect Effects 0.000 description 1
- 239000013598 vector Substances 0.000 description 1
- 239000012905 visible particle Substances 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
- 239000000080 wetting agent Substances 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
-
- 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
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Organic Chemistry (AREA)
- Diabetes (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Endocrinology (AREA)
- Gastroenterology & Hepatology (AREA)
- Zoology (AREA)
- Biophysics (AREA)
- Molecular Biology (AREA)
- Toxicology (AREA)
- Genetics & Genomics (AREA)
- Biochemistry (AREA)
- Engineering & Computer Science (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Epidemiology (AREA)
- Immunology (AREA)
- Obesity (AREA)
- Hematology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Emergency Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
- Medicinal Preparation (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP13187626 | 2013-10-07 | ||
| PCT/EP2014/071236 WO2015052088A1 (en) | 2013-10-07 | 2014-10-03 | Novel derivative of an insulin analogue |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| SA516370893B1 true SA516370893B1 (ar) | 2018-08-13 |
Family
ID=49301382
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| SA516370893A SA516370893B1 (ar) | 2013-10-07 | 2016-04-07 | مشتق جديد من نظير إنسولين |
Country Status (21)
| Country | Link |
|---|---|
| US (1) | US9896496B2 (OSRAM) |
| EP (1) | EP3055325B1 (OSRAM) |
| JP (1) | JP6499184B2 (OSRAM) |
| KR (1) | KR20160065126A (OSRAM) |
| CN (1) | CN105636979B (OSRAM) |
| AU (1) | AU2014333979B2 (OSRAM) |
| BR (1) | BR112016007166A2 (OSRAM) |
| CA (1) | CA2926701A1 (OSRAM) |
| DK (1) | DK3055325T3 (OSRAM) |
| ES (1) | ES2676065T3 (OSRAM) |
| HR (1) | HRP20180468T1 (OSRAM) |
| HU (1) | HUE036702T2 (OSRAM) |
| IL (1) | IL244507B (OSRAM) |
| MX (1) | MX366636B (OSRAM) |
| PL (1) | PL3055325T3 (OSRAM) |
| PT (1) | PT3055325T (OSRAM) |
| RS (1) | RS57004B1 (OSRAM) |
| RU (1) | RU2673185C2 (OSRAM) |
| SA (1) | SA516370893B1 (OSRAM) |
| SI (1) | SI3055325T1 (OSRAM) |
| WO (1) | WO2015052088A1 (OSRAM) |
Families Citing this family (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DK2254906T3 (en) | 2008-03-18 | 2017-01-23 | Novo Nordisk As | Protease-stabilized acylated insulin analogues |
| AR105616A1 (es) | 2015-05-07 | 2017-10-25 | Lilly Co Eli | Proteínas de fusión |
| MA46780A (fr) | 2016-11-07 | 2019-09-11 | Novo Nordisk As | Esters à dchbs actif de composés peg et leur utilisation |
| HUE060149T2 (hu) * | 2016-12-16 | 2023-02-28 | Novo Nordisk As | Inzulint tartalmazó gyógyászati készítmények |
| EP3689942B1 (en) | 2017-09-29 | 2024-06-19 | Hanmi Pharm. Co., Ltd. | Protein complex comprising non-peptidyl polymer-coupled fatty acid derivative compound as linker and preparation method therefor |
| TWI799680B (zh) * | 2019-01-29 | 2023-04-21 | 美商美國禮來大藥廠 | 製備gip/glp1雙重促效劑之方法 |
| CN111909255A (zh) * | 2019-05-10 | 2020-11-10 | 宁波鲲鹏生物科技有限公司 | 胰岛素衍生物及其制备方法 |
| WO2022017309A1 (zh) | 2020-07-24 | 2022-01-27 | 江苏晟斯生物制药有限公司 | 胰岛素-Fc融合蛋白及其应用 |
| US20240374692A1 (en) * | 2021-05-24 | 2024-11-14 | Sunshine Lake Pharma Co., Ltd. | A novel acylated insulin analog |
| CN117342967A (zh) * | 2023-09-28 | 2024-01-05 | 奥锐特药业(天津)有限公司 | 一种长链脂肪酸化合物的制备方法 |
Family Cites Families (134)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2832685A (en) | 1952-05-24 | 1958-04-29 | Crest Foods Co Inc | Solubilization of milk proteins |
| US3528960A (en) | 1968-10-07 | 1970-09-15 | Lilly Co Eli | N-carboxyaroyl insulins |
| US3719655A (en) | 1969-12-05 | 1973-03-06 | Lilly Co Eli | Process for the crystallization of the ammonium and alkali metal salts in insulin |
| US3950517A (en) | 1970-05-08 | 1976-04-13 | National Research Development Corporation | Insulin derivatives |
| US3869437A (en) | 1970-05-08 | 1975-03-04 | Nat Res Dev | Mono-, di, and N{HD A1{B , N{HU B1{B , N{HU B29{B -tri-acylated insulin |
| US4179337A (en) | 1973-07-20 | 1979-12-18 | Davis Frank F | Non-immunogenic polypeptides |
| US4033941A (en) | 1975-12-17 | 1977-07-05 | Eli Lilly And Company | Process for purifying glucagon |
| GB1492997A (en) | 1976-07-21 | 1977-11-23 | Nat Res Dev | Insulin derivatives |
| JPS5767548A (en) | 1980-10-14 | 1982-04-24 | Shionogi & Co Ltd | Insulin analog and its preparation |
| PH25772A (en) | 1985-08-30 | 1991-10-18 | Novo Industri As | Insulin analogues, process for their preparation |
| PH23446A (en) | 1986-10-20 | 1989-08-07 | Novo Industri As | Peptide preparations |
| JPH01254699A (ja) | 1988-04-05 | 1989-10-11 | Kodama Kk | インスリン誘導体及びその用途 |
| DK257988D0 (da) | 1988-05-11 | 1988-05-11 | Novo Industri As | Nye peptider |
| AU616205B2 (en) | 1988-07-20 | 1991-10-24 | Novo Nordisk A/S | Human insulin analogs and preparations containing them |
| US5225323A (en) | 1988-11-21 | 1993-07-06 | Baylor College Of Medicine | Human high-affinity neurotransmitter uptake system |
| KR910700262A (ko) | 1988-12-23 | 1991-03-14 | 안네 제케르 | 사람 인슐린 유사체 |
| US5716927A (en) | 1988-12-23 | 1998-02-10 | Novo Nordisk A/S | Insulin analogs having a modified B-chain |
| DE3844211A1 (de) | 1988-12-29 | 1990-07-05 | Hoechst Ag | Neue insulinderivate, verfahren zu deren herstellung, ihre verwendung und eine sie enthaltende pharmazeutische zubereitung |
| ATE120762T1 (de) | 1989-04-20 | 1995-04-15 | Sinai School Medicine | Hepatospezifische insulin-analoga. |
| CA1340994C (en) | 1989-09-21 | 2000-05-16 | Rudolf Edgar Dr. Falk | Treatment of conditions and disease |
| CA2027930C (en) | 1989-10-19 | 1998-06-30 | Tsuyoshi Miyazaki | Polymer complexes of a sugar response type |
| US5179189A (en) | 1990-01-19 | 1993-01-12 | Nova Pharmaceutical Corporation | Fatty acid terminated polyanhydrides |
| DK45590D0 (OSRAM) | 1990-02-21 | 1990-02-21 | Novo Nordisk As | |
| DK155690D0 (da) | 1990-06-28 | 1990-06-28 | Novo Nordisk As | Nye peptider |
| DK158390D0 (da) | 1990-07-02 | 1990-07-02 | Novo Nordisk As | Nye peptider |
| WO1992001476A1 (en) | 1990-07-26 | 1992-02-06 | University Of Iowa Research Foundation | Novel drug delivery systems for proteins and peptides using albumin as a carrier molecule |
| DK10191D0 (da) | 1991-01-22 | 1991-01-22 | Novo Nordisk As | Hidtil ukendte peptider |
| US5336782A (en) | 1991-04-24 | 1994-08-09 | Kuraray Co., Ltd. | Long chain carboxylic acid imide ester |
| WO1998017320A1 (en) | 1991-07-03 | 1998-04-30 | Hyal Pharmaceutical Corporation | Use of hyaluronan in gene therapy |
| US5268453A (en) | 1991-08-08 | 1993-12-07 | Scios Inc. | Tissue-selective insulin analogs |
| CZ342492A3 (en) | 1991-11-26 | 1993-06-16 | Lilly Co Eli | Derivatives of tri-arginine insulin, process of their preparation and a pharmaceutical composition in which said derivatives are comprised |
| WO1994008599A1 (en) | 1992-10-14 | 1994-04-28 | The Regents Of The University Of Colorado | Ion-pairing of drugs for improved efficacy and delivery |
| US5359030A (en) | 1993-05-10 | 1994-10-25 | Protein Delivery, Inc. | Conjugation-stabilized polypeptide compositions, therapeutic delivery and diagnostic formulations comprising same, and method of making and using the same |
| US5506203C1 (en) | 1993-06-24 | 2001-02-06 | Astra Ab | Systemic administration of a therapeutic preparation |
| DE69428134T2 (de) * | 1993-09-17 | 2002-05-02 | Novo Nordisk A/S, Bagsvaerd | Acyliertes insulin |
| US6869930B1 (en) | 1993-09-17 | 2005-03-22 | Novo Nordisk A/S | Acylated insulin |
| GB9323588D0 (en) | 1993-11-16 | 1994-01-05 | Cortecs Ltd | Hydrophobic preparation |
| ATE264096T1 (de) | 1994-03-07 | 2004-04-15 | Nektar Therapeutics | Verfahren und mittel zur verabreichung von insulin über die lunge |
| US6500645B1 (en) | 1994-06-17 | 2002-12-31 | Novo Nordisk A/S | N-terminally extended proteins expressed in yeast |
| US5693609A (en) | 1994-11-17 | 1997-12-02 | Eli Lilly And Company | Acylated insulin analogs |
| US5646242A (en) | 1994-11-17 | 1997-07-08 | Eli Lilly And Company | Selective acylation of epsilon-amino groups |
| US6251856B1 (en) | 1995-03-17 | 2001-06-26 | Novo Nordisk A/S | Insulin derivatives |
| CA2215694A1 (en) | 1995-03-17 | 1996-09-26 | Novo Nordisk A/S | Insulin derivatives |
| US5824638A (en) | 1995-05-22 | 1998-10-20 | Shire Laboratories, Inc. | Oral insulin delivery |
| US20030104981A1 (en) | 1995-11-03 | 2003-06-05 | Jelena Mandic | Human insulin analogues |
| US6451970B1 (en) | 1996-02-21 | 2002-09-17 | Novo Nordisk A/S | Peptide derivatives |
| WO1998001473A1 (en) | 1996-07-05 | 1998-01-15 | Novo Nordisk A/S | Method for the production of precursors of insulin, precursors of insulin analogues, and insulin like peptides |
| EP0938502B1 (en) | 1996-07-11 | 2004-10-06 | Novo Nordisk A/S | Selective acylation method |
| EP0821006B1 (de) | 1996-07-26 | 2004-04-21 | Aventis Pharma Deutschland GmbH | Insulinderivate mit erhöhter Zinkbindung |
| US5898067A (en) | 1997-02-07 | 1999-04-27 | Novo Nordisk A/S | Crystallization of proteins |
| US6310038B1 (en) | 1997-03-20 | 2001-10-30 | Novo Nordisk A/S | Pulmonary insulin crystals |
| TR200001050T2 (tr) | 1997-10-24 | 2000-08-21 | Eli Lilly And Company | Çözünmez insülin bileşimleri |
| JP2003525846A (ja) | 1997-10-24 | 2003-09-02 | ノボ ノルディスク アクティーゼルスカブ | ヒトインスリン誘導体の集合体 |
| ZA989744B (en) | 1997-10-31 | 2000-04-26 | Lilly Co Eli | Method for administering acylated insulin. |
| AU1375199A (en) | 1997-11-12 | 1999-05-31 | Alza Corporation | Method for decreasing self-association of polypeptides |
| CO4970787A1 (es) | 1997-12-23 | 2000-11-07 | Lilly Co Eli | Composiciones insolubles de insulina y derivados de insulina que controlan la glucosa sanguinea |
| CA2334859A1 (en) | 1998-06-12 | 1999-12-23 | Kings College London | Insulin analogue |
| GB9814172D0 (en) | 1998-06-30 | 1998-08-26 | Andaris Ltd | Formulation for inhalation |
| EP1107743B1 (en) | 1998-08-25 | 2007-06-27 | Advanced Inhalation Research, Inc. | Stable spray-dried protein formulations |
| TW570805B (en) | 1998-09-01 | 2004-01-11 | Hoffmann La Roche | Water-soluble pharmaceutical composition in an ionic complex |
| US7030083B2 (en) | 1998-09-09 | 2006-04-18 | University Of Washington | Treatment of eclampsia and preeclampsia |
| PL197504B1 (pl) | 1998-10-16 | 2008-04-30 | Novo Nordisk As | Trwałe stężone preparaty insulinowe do podawania do płuc |
| US6660715B2 (en) | 1998-11-19 | 2003-12-09 | Massachusetts Institute Of Technology | Nonaqueous solutions and suspensions of macromolecules for pulmonary delivery |
| ATE220917T1 (de) | 1999-01-26 | 2002-08-15 | Lilly Co Eli | Monodisperse formulierungen, die hexamere acylierte insulinanaloge enthalten |
| WO2000061178A1 (en) | 1999-04-13 | 2000-10-19 | Inhale Therapeutics Systems, Inc. | Pulmonary administration of dry powder formulations for treating infertility |
| JP2002543092A (ja) | 1999-04-27 | 2002-12-17 | イーライ・リリー・アンド・カンパニー | 肺投与用インスリン結晶 |
| JP2003518917A (ja) | 1999-05-19 | 2003-06-17 | ゼンコー | 糖尿病の処置に有用なインシュリン様活性を有する新規タンパク質 |
| US6746853B1 (en) | 1999-05-19 | 2004-06-08 | Xencor, Inc. | Proteins with insulin-like activity useful in the treatment of diabetes |
| US6309633B1 (en) | 1999-06-19 | 2001-10-30 | Nobex Corporation | Amphiphilic drug-oligomer conjugates with hydroyzable lipophile components and methods for making and using the same |
| CN1141974C (zh) | 2000-06-07 | 2004-03-17 | 张昊 | 结肠定位释放的口服生物制剂 |
| US6867183B2 (en) | 2001-02-15 | 2005-03-15 | Nobex Corporation | Pharmaceutical compositions of insulin drug-oligomer conjugates and methods of treating diseases therewith |
| CN1160122C (zh) | 2001-04-20 | 2004-08-04 | 清华大学 | 一种制备口服胰岛素油相制剂的方法 |
| MY137181A (en) | 2001-05-21 | 2009-01-30 | Nektar Therapeutics | Pulmonary administration of chemically modified insulin |
| US6828297B2 (en) | 2001-06-04 | 2004-12-07 | Nobex Corporation | Mixtures of insulin drug-oligomer conjugates comprising polyalkylene glycol, uses thereof, and methods of making same |
| US6858580B2 (en) | 2001-06-04 | 2005-02-22 | Nobex Corporation | Mixtures of drug-oligomer conjugates comprising polyalkylene glycol, uses thereof, and methods of making same |
| EP1423136A4 (en) | 2001-08-10 | 2007-07-25 | Epix Pharm Inc | POLYPEPTIDE CONJUGATES HAVING INCREASED CIRCULATION HALF-VIES |
| US6770625B2 (en) | 2001-09-07 | 2004-08-03 | Nobex Corporation | Pharmaceutical compositions of calcitonin drug-oligomer conjugates and methods of treating diseases therewith |
| PT1430082E (pt) | 2001-09-07 | 2010-01-15 | Biocon Ltd | Métodos de síntese de conjugados de polipéptido de insulina-oligómero, e conjugados de polipéptido de pró-insulina-oligómero e método de síntese dos mesmos |
| US7030082B2 (en) | 2001-09-07 | 2006-04-18 | Nobex Corporation | Pharmaceutical compositions of drug-oligomer conjugates and methods of treating disease therewith |
| WO2003048195A2 (en) | 2001-12-02 | 2003-06-12 | Novo Nordisk A/S | Glucose dependant release of insulin from glucose sensing insulin derivatives |
| US8535650B2 (en) | 2001-12-03 | 2013-09-17 | Soligenix, Inc. | Stabilized reverse micelle compositions and uses thereof |
| EP1456371A1 (en) | 2001-12-05 | 2004-09-15 | Dow Global Technologies Inc. | Method for immobilizing a biologic in a polyurethane-hydrogel composition, a composition prepared from the method, and biomedical applications |
| EP1545460A4 (en) | 2001-12-20 | 2005-11-16 | Lilly Co Eli | INSULIN MOLECULE WITH TEMPORARY EFFECT |
| EP1506003A1 (en) | 2002-05-07 | 2005-02-16 | Novo Nordisk A/S | Soluble formulations comprising insulin aspart and insulin detemir |
| ATE496064T1 (de) | 2002-05-07 | 2011-02-15 | Novo Nordisk As | Lösliche formulierungen, die monomeres insulin und acyliertes insulin enthalten |
| US7601688B2 (en) | 2002-06-13 | 2009-10-13 | Biocon Limited | Methods of reducing hypoglycemic episodes in the treatment of diabetes mellitus |
| CN1165549C (zh) | 2002-06-15 | 2004-09-08 | 江苏万邦生化医药股份有限公司 | 胰岛素的纯化方法 |
| PL1633391T3 (pl) | 2003-06-03 | 2012-03-30 | Novo Nordisk As | Stabilizowane farmaceutycznie kompozycje peptydowe |
| EP1644411A2 (en) | 2003-07-11 | 2006-04-12 | Novo Nordisk A/S | Stabilised insulin compositions |
| AU2004261319B2 (en) | 2003-07-25 | 2010-12-23 | Conjuchem Biotechnologies Inc. | Long lasting insulin derivatives and methods thereof |
| BRPI0413276B8 (pt) | 2003-08-05 | 2021-05-25 | Novo Nordisk As | derivado de insulina, complexo de zinco do mesmo, e, composição farmacêutica |
| WO2005016312A1 (en) | 2003-08-13 | 2005-02-24 | Nobex Corporation | Micro-particle fatty acid salt solid dosage formulations for therapeutic agents |
| TW200526254A (en) * | 2003-09-19 | 2005-08-16 | Novo Nordisk As | Novel GLP-1 derivatives |
| EP1687428A1 (en) | 2003-11-14 | 2006-08-09 | Novo Nordisk A/S | Processes for making acylated insulin |
| CN104826116A (zh) | 2003-11-20 | 2015-08-12 | 诺沃挪第克公司 | 对于生产和用于注射装置中是最佳的含有丙二醇的肽制剂 |
| WO2005058961A2 (en) | 2003-12-12 | 2005-06-30 | Amgen Inc. | Antibodies specific for human galanin, and uses thereof |
| DE10358387A1 (de) | 2003-12-13 | 2005-07-07 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Pulver enthaltend niedermolekulares Dextran und Verfahren zu deren Herstellung |
| JP4792457B2 (ja) | 2004-03-26 | 2011-10-12 | ユニヴァーシタ’デグリ ステュディ ディ パルマ | 高度に呼吸に適したインスリンのマイクロ粒子 |
| MXPA06012980A (es) | 2004-05-10 | 2007-06-12 | Nastech Pharm Co | Composiciones y metodos para el suministro mucosal mejorado de la hormona paratiroidea. |
| WO2006014673A2 (en) | 2004-07-19 | 2006-02-09 | Nobex Corporation | Insulin-oligomer conjugates, formulations and uses thereof |
| EP2314298B1 (en) | 2004-08-23 | 2015-05-27 | MannKind Corporation | Microparticles comprising diketopiperazine salts for drug delivery |
| EP1817050B1 (en) | 2004-12-03 | 2015-04-15 | Rhode Island Hospital | Diagnosis and treatment of alzheimer's disease |
| WO2006079641A2 (en) | 2005-01-27 | 2006-08-03 | Novo Nordisk A/S | Insulin derivatives conjugated with structurally well defined branched polymers |
| JP4933455B2 (ja) | 2005-02-02 | 2012-05-16 | ノヴォ ノルディスク アー／エス | 新規のインスリン誘導体 |
| EP2292653B1 (en) | 2005-02-02 | 2014-05-21 | Novo Nordisk A/S | Novel insulin derivatives |
| WO2006097521A1 (en) | 2005-03-18 | 2006-09-21 | Novo Nordisk A/S | Pegylated single-chain insulin |
| WO2007006320A1 (en) | 2005-07-12 | 2007-01-18 | Sherine Hassan Abbas Helmy | Drinkable oral insulin liquid and capsules |
| WO2007041481A1 (en) | 2005-09-29 | 2007-04-12 | Biodel, Inc. | Rapid acting and prolonged acting insulin preparations |
| JP4710533B2 (ja) | 2005-10-07 | 2011-06-29 | 株式会社豊田自動織機 | 牽引車両のドローバー装置 |
| JP2009512709A (ja) | 2005-10-20 | 2009-03-26 | エムディーアールエヌエー，インコーポレイテッド | 速効型インスリンの経鼻投与 |
| PL1969004T3 (pl) | 2005-12-28 | 2012-01-31 | Novo Nordisk As | Kompozycje zawierające acylowaną insulinę i cynk oraz sposób wytwarzania tych kompozycji |
| WO2007081824A2 (en) | 2006-01-06 | 2007-07-19 | Case Western Reserve University | Fibrillation resistant proteins |
| US20090069216A1 (en) | 2006-02-21 | 2009-03-12 | Novo Nordisk A/S | Single-Chain Insulin Analogues and Pharmaceutical Formulations Thereof |
| DE602007009496D1 (de) | 2006-02-27 | 2010-11-11 | Novo Nordisk As | Insulinderivate |
| JP2009530242A (ja) | 2006-03-13 | 2009-08-27 | ノボ・ノルデイスク・エー／エス | アシル化単鎖インスリン |
| EP2386572B1 (en) | 2006-05-09 | 2015-07-08 | Novo Nordisk A/S | Insulin derivative |
| EP2024390B1 (en) | 2006-05-09 | 2015-08-19 | Novo Nordisk A/S | Insulin derivative |
| WO2008015099A2 (en) | 2006-07-31 | 2008-02-07 | Novo Nordisk A/S | Pegylated, extended insulins |
| ES2601839T3 (es) | 2006-09-22 | 2017-02-16 | Novo Nordisk A/S | Análogos de insulina resistentes a proteasas |
| EP2152243A2 (en) | 2007-04-30 | 2010-02-17 | Novo Nordisk A/S | Highly concentrated insulin solutions and compositions |
| EP2497462A1 (en) | 2007-06-01 | 2012-09-12 | Novo Nordisk A/S | Stable non-aqueous pharmaceutical compositions |
| WO2008152106A1 (en) | 2007-06-13 | 2008-12-18 | Novo Nordisk A/S | Pharmaceutical formulation comprising an insulin derivative |
| WO2009010428A1 (en) | 2007-07-16 | 2009-01-22 | Novo Nordisk A/S | Protease stabilized, pegylated insulin analogues |
| US8962794B2 (en) | 2007-08-15 | 2015-02-24 | Novo Nordisk A/S | Insulins with an acyl moiety comprising repeating units of alkylene glycol containing amino acids |
| AU2008288413B2 (en) | 2007-08-15 | 2013-09-26 | Novo Nordisk A/S | Insulin analogues with an acyl and aklylene glycol moiety |
| WO2009060071A1 (en) * | 2007-11-08 | 2009-05-14 | Novo Nordisk A/S | Insulin derivative |
| EP2254905B1 (en) | 2008-03-14 | 2016-12-14 | Novo Nordisk A/S | Protease-stabilized insulin analogues |
| DK2254906T3 (en) * | 2008-03-18 | 2017-01-23 | Novo Nordisk As | Protease-stabilized acylated insulin analogues |
| WO2010049488A1 (en) * | 2008-10-30 | 2010-05-06 | Novo Nordisk A/S | Treating diabetes melitus using insulin injections with less than daily injection frequency |
| AU2011252127B2 (en) * | 2010-05-10 | 2014-02-20 | Novo Nordisk A/S | Process for the preparation of insulin-zinc complexes |
| CN102947331B (zh) | 2010-06-23 | 2016-08-03 | 诺沃—诺迪斯克有限公司 | 包含额外的二硫键的胰岛素类似物 |
| AU2011269000C1 (en) * | 2010-06-23 | 2015-10-08 | Novo Nordisk A/S | Insulin derivatives containing additional disulfide bonds |
| RS59423B1 (sr) * | 2010-10-27 | 2019-11-29 | Novo Nordisk As | Lečenje dijabetesa melitusa korišćenjem insulinskih injekcija davanih u različitim intervalima ubrizgavanja |
| CA2870313A1 (en) | 2012-04-11 | 2013-10-17 | Novo Nordisk A/S | Insulin formulations |
-
2014
- 2014-10-03 AU AU2014333979A patent/AU2014333979B2/en not_active Ceased
- 2014-10-03 JP JP2016546167A patent/JP6499184B2/ja not_active Expired - Fee Related
- 2014-10-03 CA CA2926701A patent/CA2926701A1/en not_active Withdrawn
- 2014-10-03 BR BR112016007166A patent/BR112016007166A2/pt not_active IP Right Cessation
- 2014-10-03 EP EP14780512.1A patent/EP3055325B1/en not_active Not-in-force
- 2014-10-03 RS RS20180322A patent/RS57004B1/sr unknown
- 2014-10-03 HU HUE14780512A patent/HUE036702T2/hu unknown
- 2014-10-03 US US15/023,872 patent/US9896496B2/en not_active Expired - Fee Related
- 2014-10-03 ES ES14780512.1T patent/ES2676065T3/es active Active
- 2014-10-03 MX MX2016004325A patent/MX366636B/es active IP Right Grant
- 2014-10-03 PT PT147805121T patent/PT3055325T/pt unknown
- 2014-10-03 CN CN201480055375.6A patent/CN105636979B/zh not_active Expired - Fee Related
- 2014-10-03 HR HRP20180468TT patent/HRP20180468T1/hr unknown
- 2014-10-03 DK DK14780512.1T patent/DK3055325T3/en active
- 2014-10-03 PL PL14780512T patent/PL3055325T3/pl unknown
- 2014-10-03 WO PCT/EP2014/071236 patent/WO2015052088A1/en not_active Ceased
- 2014-10-03 KR KR1020167010201A patent/KR20160065126A/ko not_active Withdrawn
- 2014-10-03 SI SI201430644T patent/SI3055325T1/en unknown
- 2014-10-03 RU RU2016114098A patent/RU2673185C2/ru not_active IP Right Cessation
-
2016
- 2016-03-08 IL IL244507A patent/IL244507B/en not_active IP Right Cessation
- 2016-04-07 SA SA516370893A patent/SA516370893B1/ar unknown
Also Published As
| Publication number | Publication date |
|---|---|
| HRP20180468T1 (hr) | 2018-05-04 |
| DK3055325T3 (en) | 2018-04-16 |
| IL244507A0 (en) | 2016-04-21 |
| HUE036702T2 (hu) | 2018-07-30 |
| AU2014333979B2 (en) | 2018-02-15 |
| JP2017502074A (ja) | 2017-01-19 |
| BR112016007166A2 (pt) | 2017-09-12 |
| CN105636979A (zh) | 2016-06-01 |
| RU2673185C2 (ru) | 2018-11-22 |
| CA2926701A1 (en) | 2015-04-16 |
| EP3055325A1 (en) | 2016-08-17 |
| US9896496B2 (en) | 2018-02-20 |
| EP3055325B1 (en) | 2018-01-03 |
| AU2014333979A1 (en) | 2016-03-24 |
| SI3055325T1 (en) | 2018-05-31 |
| JP6499184B2 (ja) | 2019-04-10 |
| CN105636979B (zh) | 2020-01-10 |
| ES2676065T3 (es) | 2018-07-16 |
| RS57004B1 (sr) | 2018-05-31 |
| PL3055325T3 (pl) | 2018-06-29 |
| PT3055325T (pt) | 2018-04-06 |
| US20160215037A1 (en) | 2016-07-28 |
| MX2016004325A (es) | 2016-07-11 |
| WO2015052088A1 (en) | 2015-04-16 |
| KR20160065126A (ko) | 2016-06-08 |
| IL244507B (en) | 2018-05-31 |
| RU2016114098A (ru) | 2017-11-15 |
| MX366636B (es) | 2019-07-17 |
| RU2016114098A3 (OSRAM) | 2018-05-21 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| SA516370893B1 (ar) | مشتق جديد من نظير إنسولين | |
| US8192957B2 (en) | Fibrillation-resistant insulin and insulin analogues | |
| US8343914B2 (en) | Fibrillation resistant proteins | |
| RU2598273C2 (ru) | Производные инсулина, содержащие дополнительные дисульфидные связи | |
| EP3509615A1 (en) | Stable peptides and methods of use thereof | |
| CN103249427A (zh) | 速效胰岛素联合长效胰岛素 | |
| TW201620930A (zh) | 新穎胰島素衍生物及其醫療用途 | |
| US20250367265A1 (en) | Pharmaceutical parenteral composition of dual glp1/2 agonist | |
| JP2018008955A (ja) | Ｓｈｋベースの薬学的組成物とその製造方法および使用方法 | |
| US8883722B2 (en) | Human insulin containing additional disulfide bonds | |
| US20210040171A1 (en) | Pharmaceutical composition comprising acylated derivative of human insulin analog and preparation method thereof | |
| TW202535919A (zh) | 類升糖素肽2(glp-2)類似物之調配物及其用途 |