US20180169190A1 - Insulin containing pharmaceutical compositions - Google Patents
Insulin containing pharmaceutical compositions Download PDFInfo
- Publication number
- US20180169190A1 US20180169190A1 US15/843,016 US201715843016A US2018169190A1 US 20180169190 A1 US20180169190 A1 US 20180169190A1 US 201715843016 A US201715843016 A US 201715843016A US 2018169190 A1 US2018169190 A1 US 2018169190A1
- Authority
- US
- United States
- Prior art keywords
- pharmaceutical composition
- compound
- formulation
- phenol
- cresol
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 title claims abstract description 110
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 102
- 102000004877 Insulin Human genes 0.000 title abstract description 46
- 108090001061 Insulin Proteins 0.000 title abstract description 46
- 229940125396 insulin Drugs 0.000 title abstract description 25
- 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 49
- RLSSMJSEOOYNOY-UHFFFAOYSA-N m-cresol Chemical compound CC1=CC=CC(O)=C1 RLSSMJSEOOYNOY-UHFFFAOYSA-N 0.000 claims description 131
- 229940125904 compound 1 Drugs 0.000 claims description 107
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 87
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims description 83
- 239000004026 insulin derivative Substances 0.000 claims description 77
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 76
- PTFCDOFLOPIGGS-UHFFFAOYSA-N Zinc dication Chemical compound [Zn+2] PTFCDOFLOPIGGS-UHFFFAOYSA-N 0.000 claims description 57
- 101000976075 Homo sapiens Insulin Proteins 0.000 claims description 43
- DLSWIYLPEUIQAV-UHFFFAOYSA-N Semaglutide Chemical compound CCC(C)C(NC(=O)C(Cc1ccccc1)NC(=O)C(CCC(O)=O)NC(=O)C(CCCCNC(=O)COCCOCCNC(=O)COCCOCCNC(=O)CCC(NC(=O)CCCCCCCCCCCCCCCCC(O)=O)C(O)=O)NC(=O)C(C)NC(=O)C(C)NC(=O)C(CCC(N)=O)NC(=O)CNC(=O)C(CCC(O)=O)NC(=O)C(CC(C)C)NC(=O)C(Cc1ccc(O)cc1)NC(=O)C(CO)NC(=O)C(CO)NC(=O)C(NC(=O)C(CC(O)=O)NC(=O)C(CO)NC(=O)C(NC(=O)C(Cc1ccccc1)NC(=O)C(NC(=O)CNC(=O)C(CCC(O)=O)NC(=O)C(C)(C)NC(=O)C(N)Cc1cnc[nH]1)C(C)O)C(C)O)C(C)C)C(=O)NC(C)C(=O)NC(Cc1c[nH]c2ccccc12)C(=O)NC(CC(C)C)C(=O)NC(C(C)C)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CCCNC(N)=N)C(=O)NCC(O)=O DLSWIYLPEUIQAV-UHFFFAOYSA-N 0.000 claims description 42
- 229950011186 semaglutide Drugs 0.000 claims description 42
- 108010060325 semaglutide Proteins 0.000 claims description 42
- 239000011780 sodium chloride Substances 0.000 claims description 38
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 14
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 claims description 10
- 238000000034 method Methods 0.000 claims description 10
- 150000001875 compounds Chemical class 0.000 claims description 5
- 208000030159 metabolic disease Diseases 0.000 claims description 5
- 229940125782 compound 2 Drugs 0.000 claims description 3
- 229940126214 compound 3 Drugs 0.000 claims description 3
- 239000000203 mixture Substances 0.000 abstract description 227
- 206010012601 diabetes mellitus Diseases 0.000 abstract description 5
- 238000002560 therapeutic procedure Methods 0.000 abstract description 4
- 238000009472 formulation Methods 0.000 description 222
- 239000011701 zinc Substances 0.000 description 52
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 37
- 229910052725 zinc Inorganic materials 0.000 description 37
- 238000002347 injection Methods 0.000 description 28
- 239000007924 injection Substances 0.000 description 28
- 239000000872 buffer Substances 0.000 description 23
- 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 17
- 230000003247 decreasing effect Effects 0.000 description 13
- 239000000126 substance Substances 0.000 description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- 238000009826 distribution Methods 0.000 description 12
- 238000002474 experimental method Methods 0.000 description 11
- 238000005259 measurement Methods 0.000 description 11
- 239000000243 solution Substances 0.000 description 10
- 230000002829 reductive effect Effects 0.000 description 9
- 241000894007 species Species 0.000 description 9
- 238000003556 assay Methods 0.000 description 7
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 7
- 108010092217 Long-Acting Insulin Proteins 0.000 description 6
- 102000016261 Long-Acting Insulin Human genes 0.000 description 6
- 229940100066 Long-acting insulin Drugs 0.000 description 6
- 230000009471 action Effects 0.000 description 6
- 230000010354 integration Effects 0.000 description 6
- 238000004062 sedimentation Methods 0.000 description 6
- FYZPCMFQCNBYCY-WIWKJPBBSA-N Insulin degludec 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)N2CCC[C@H]2C(=O)N[C@@H](CCCCNC(=O)CC[C@H](NC(=O)CCCCCCCCCCCCCCC(O)=O)C(O)=O)C(O)=O)NC1=O)[C@@H](C)O)[C@@H](C)CC FYZPCMFQCNBYCY-WIWKJPBBSA-N 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- 230000008859 change Effects 0.000 description 5
- 230000001419 dependent effect Effects 0.000 description 5
- 238000002296 dynamic light scattering Methods 0.000 description 5
- 230000008030 elimination Effects 0.000 description 5
- 238000003379 elimination reaction Methods 0.000 description 5
- 238000005755 formation reaction Methods 0.000 description 5
- 108010050259 insulin degludec Proteins 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 4
- DTHNMHAUYICORS-KTKZVXAJSA-N Glucagon-like peptide 1 Chemical class 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 4
- 238000013103 analytical ultracentrifugation Methods 0.000 description 4
- 201000010099 disease Diseases 0.000 description 4
- 239000003446 ligand Substances 0.000 description 4
- 229940100630 metacresol Drugs 0.000 description 4
- 239000000178 monomer Substances 0.000 description 4
- 206010033675 panniculitis Diseases 0.000 description 4
- 239000003755 preservative agent Substances 0.000 description 4
- 108090000765 processed proteins & peptides Proteins 0.000 description 4
- 239000000523 sample Substances 0.000 description 4
- 102000001049 Amyloid Human genes 0.000 description 3
- 108010094108 Amyloid Proteins 0.000 description 3
- 102100025101 GATA-type zinc finger protein 1 Human genes 0.000 description 3
- 101710198884 GATA-type zinc finger protein 1 Proteins 0.000 description 3
- 230000007423 decrease Effects 0.000 description 3
- 208000035475 disorder Diseases 0.000 description 3
- 210000003722 extracellular fluid Anatomy 0.000 description 3
- -1 hexamers Chemical compound 0.000 description 3
- 230000002335 preservative effect Effects 0.000 description 3
- 230000002035 prolonged effect Effects 0.000 description 3
- 238000000235 small-angle X-ray scattering Methods 0.000 description 3
- 125000002435 L-phenylalanyl group Chemical group O=C([*])[C@](N([H])[H])([H])C([H])([H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 2
- 108010019598 Liraglutide Proteins 0.000 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 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- 208000001145 Metabolic Syndrome Diseases 0.000 description 2
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 230000003941 amyloidogenesis Effects 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000010828 elution Methods 0.000 description 2
- 125000001207 fluorophenyl group Chemical group 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 230000002473 insulinotropic effect Effects 0.000 description 2
- 229960002701 liraglutide Drugs 0.000 description 2
- 230000014759 maintenance of location Effects 0.000 description 2
- 235000012054 meals Nutrition 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 238000004448 titration Methods 0.000 description 2
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 2
- 238000001195 ultra high performance liquid chromatography Methods 0.000 description 2
- 238000000825 ultraviolet detection Methods 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 1
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 1
- 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 1
- 102000009027 Albumins Human genes 0.000 description 1
- 108010088751 Albumins Proteins 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- 241001313846 Calypso Species 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 208000032928 Dyslipidaemia Diseases 0.000 description 1
- 101800004266 Glucagon-like peptide 1(7-37) Proteins 0.000 description 1
- 208000002705 Glucose Intolerance Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 208000031773 Insulin resistance syndrome Diseases 0.000 description 1
- 208000017170 Lipid metabolism disease Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 125000000729 N-terminal amino-acid group Chemical group 0.000 description 1
- 208000008589 Obesity Diseases 0.000 description 1
- 241000282887 Suidae Species 0.000 description 1
- 201000000690 abdominal obesity-metabolic syndrome Diseases 0.000 description 1
- 201000010390 abdominal obesity-metabolic syndrome 1 Diseases 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 238000000149 argon plasma sintering Methods 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 235000011148 calcium chloride Nutrition 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 230000004087 circulation Effects 0.000 description 1
- 229930003836 cresol Natural products 0.000 description 1
- 239000000539 dimer Substances 0.000 description 1
- 239000000428 dust Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000011067 equilibration Methods 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 201000001421 hyperglycemia Diseases 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 229960004225 insulin degludec Drugs 0.000 description 1
- 230000003914 insulin secretion Effects 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 208000011661 metabolic syndrome X Diseases 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- BAPROVDXKNPHAM-UHFFFAOYSA-N n-(2-aminoethyl)-3-(3,5-ditert-butyl-4-hydroxyphenyl)propanamide Chemical compound CC(C)(C)C1=CC(CCC(=O)NCCN)=CC(C(C)(C)C)=C1O BAPROVDXKNPHAM-UHFFFAOYSA-N 0.000 description 1
- 235000020824 obesity Nutrition 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 201000009104 prediabetes syndrome Diseases 0.000 description 1
- 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 description 1
- 230000008569 process Effects 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 239000012925 reference material Substances 0.000 description 1
- 239000013074 reference sample Substances 0.000 description 1
- 238000004007 reversed phase HPLC Methods 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 239000012146 running buffer Substances 0.000 description 1
- 229910052594 sapphire Inorganic materials 0.000 description 1
- 239000010980 sapphire Substances 0.000 description 1
- 238000001542 size-exclusion chromatography Methods 0.000 description 1
- 238000001464 small-angle X-ray scattering data Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 238000001370 static light scattering Methods 0.000 description 1
- 238000011146 sterile filtration Methods 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 230000001502 supplementing effect Effects 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 230000009897 systematic effect Effects 0.000 description 1
- 230000001839 systemic circulation Effects 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/22—Hormones
- A61K38/28—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
- A61K38/26—Glucagons
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/02—Inorganic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
-
- 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
- A61P3/04—Anorexiants; Antiobesity agents
-
- 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
- A61P3/06—Antihyperlipidemics
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
Definitions
- the present invention is in the field of pharmaceutical compositions for the treatment of medical conditions relating to diabetes. More specifically the invention provides pharmaceutical compositions comprising a long-acting acylated derivative of a human insulin analogue, and to the medical use of such compositions for basal insulin administration therapy.
- the primary objective of insulin therapy in the treatment of metabolic disorders is to produce sustained near-normal glycemia by replacing or supplementing endogenous insulin secretion in as physiological a manner as possible, post-prandially as well as between meals and overnight. Separating basal and meal-related (bolus) insulin requirements represents a systematic approach to subcutaneous insulin therapy.
- Non-covalent zinc mediated oligomerisation is a well-described property of insulin products. Under physiological pH, human insulin is soluble but has a tendency to self-associate into well-defined hexamers (i.e. a unit of six insulin molecules), by coordination of two zinc ions (Zn ++ ) to high affinity (B10His) binding sites. It is also well-known that phenolic ligands, especially phenol, bind specifically to the insulin hexamer and promote R-state hexamer formation. Upon injection, phenolic ligands diffuses quickly from the injection site. In the absence of phenol at the injection site, the conformation and size of the insulin oligomer may change, as well as the viscosity of the insulin-containing solution, contributing to a prolonged action profile.
- WO 2009/115469 describes various long-acting insulin derivatives with acylated fatty di-acid chains.
- WO 2013/153000 describes the formulation of those long-acting insulin derivatives for subcutaneous administration, which contains high level of zinc (no less than 3.5 Zn ++ /six moles of insulin derivatives). It was designed in order to obtain the prolonged duration of action commensurate with a once-weekly administration profile. High content of Zn ++ in the formulations described in WO 2009/115469 lead to a prolonged PK profile.
- WO 2009/063072 discloses pharmaceutical compositions for parenteral administration comprising a basal insulin derivative (e.g. degludec) and a GLP-1 derivative (e.g, liraglutid). Because liraglutide monomer binds with zinc to form di-heptmer, zinc level higher than the degludec mono formulation is necessary in the combo formulation, to achieve comparable PK profile of degludec, and achieve acceptable physical stability.
- a basal insulin derivative e.g. degludec
- GLP-1 derivative e.g, liraglutid
- a new formulation of the long-acting insulin derivatives has been developed, which is capable of promoting a conformational state and oligomerisation pattern more closely resembling that of human insulin, i.e. hexamers, especially R6 hexamers.
- the invention provides a pharmaceutical composition comprising a selected long-acting insulin derivative in a unique combination of excipients carefully formulated in order to reduce formation of oligomers at the injection site, while still showing PK/PD properties suited for a once-weekly administration.
- the invention provides a pharmaceutical composition with decreased viscosity upon injection and accordingly decreased propensity to create any discomfort upon injection.
- the invention provides a pharmaceutical composition with improved stability.
- the invention provides a pharmaceutical composition for use as a medicament for the treatment of a metabolic disorder.
- the invention provides pharmaceutical composition comprising an insulin derivative selected from the group consisting of
- A14E, B25H, desB27, B29K(N ⁇ -Octadecandioyl- ⁇ Glu), desB30 human insulin (Compound 4); and further comprising of from about 1 to about 2% (weight/weight) of glycerol; of from about 45 to about 75 mM of phenol; of from about 0 to about 19 mM of m-cresol; of from about 1.5 to about 2.5 moles of zinc ions per six moles of said insulin derivative; not more than about 75 mM of sodium chloride; and having a pH value in the range of from 7.2 to 8.0.
- the invention provides pharmaceutical compositions further comprising an insulinotropic GLP-1 compound, and in particular the insulinotropic GLP-1 compound known as semaglutide.
- Semaglutide may be described by the structure Aib8,Lys26(OEG-OEG-gamma-Glu-C18-diacid),Arg34)GLP-1 H(7-37)-OH, which may also be designated as (N-epsilon26-[2-(2- ⁇ 2-[2-(2- ⁇ 2-[(S)-4-Carboxy-4-(17-carboxyheptadecanoylamino) butyrylamino]ethoxy ⁇ ethoxy)acetylamino]ethoxy ⁇ ethoxy)-acetyl] [Aib8,Arg34]GLP-1-(7-37), c.f. disclosure in WO 2006/097537.
- a pharmaceutical composition of the invention comprising an insulin derivative, which is A14E, B16H, B25H, B29K((N ⁇ -Eicosanedioyl- ⁇ Glu-[2-(2- ⁇ 2-[2-(2-aminoethoxy)ethoxy]acetylamino ⁇ ethoxy)ethoxy]acetyl)), desB30 human insulin (Compound 1).
- a pharmaceutical composition of the invention comprising an insulin derivative, which is A14E, B16H, B25H, B29K(N ⁇ -Hexadecandioyl- ⁇ Glu), desB30 human insulin (Compound 2).
- a pharmaceutical composition of the invention comprising an insulin derivative, which is A14E, B16H, B25H, B29K(N ⁇ -Eicosanedioyl- ⁇ Glu), desB30 human insulin (Compound 3).
- a pharmaceutical composition of the invention comprising an insulin derivative, which is A14E, B25H, desB27, B29K(N ⁇ -Octadecandioyl- ⁇ Glu), desB30 human insulin (Compound 4).
- composition of the previous embodiments comprising of from about 1 to about 2% (weight/weight) of glycerol.
- composition of the previous embodiments comprising of from about 1.4 to about 1.8% (weight/weight) of glycerol.
- composition of the previous embodiments comprising about 1.5% or 1.6% (weight/weight) of glycerol.
- composition of the previous embodiments comprising of from about 45 to about 75 mM of phenol.
- composition of previous embodiments comprising of from about 50 to about 70 mM of phenol.
- composition of previous embodiments comprising of from about 55 to about 65 mM of phenol.
- composition of the previous embodiments comprising about 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, or 70 mM of phenol.
- composition of the previous embodiments comprising of from about 0 to about 19 mM of m-cresol.
- composition of the previous embodiments comprising 0 mM, 1 mM, 2 mM, 3 mM, 4 mM of m-cresol.
- composition of the previous embodiments comprising of from about 0 to about 15 mM of m-cresol.
- composition of the previous embodiments comprising about 5 mM, 6 mM, 7 mM, 8 mM, 9 mM, 10 mM, 11 mM, 12 mM, 13 mM, 14 mM, 15 mM, 16 mM, 17 mM, 18 mM or 19 mM of m-cresol.
- composition of the previous embodiments comprising of from about 1.5 to about 2.5 moles of zinc ions per six moles of insulin derivative.
- composition of the previous embodiments comprising of from about 2.0 to about 2.4 moles of zinc ions per six moles of insulin derivative.
- composition of the previous embodiments comprising about 2.0 or 2.1 moles of zinc ions per six moles of insulin derivative.
- composition of the previous embodiments comprising about 2.2 or 2.3 moles of zinc ions per six moles of insulin derivative.
- composition of the previous embodiments comprising about 2.4 or 2.5 moles of zinc ions per six moles of insulin derivative.
- composition of the previous embodiments comprising less than about 75 mM of sodium chloride.
- composition of the previous embodiments comprising of from about 5 to about 50 mM of sodium chloride.
- composition of the previous embodiments comprising of from about 10 to about 25 mM of sodium chloride.
- composition of the previous embodiments comprising of from about 15 to about 25 mM of sodium chloride.
- composition of the previous embodiments comprising about 20 mM, 50 mM or 75 mM of sodium chloride.
- composition of the previous embodiments which has a pH value in the range of from 7.2 to 8.0.
- composition of the previous embodiments which has a pH value in the range of from 7.2 to 7.6.
- composition of the previous embodiments which has a pH value about 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, or 7.9.
- composition of the previous embodiments comprising of about 4.2 mM of insulin derivative; of from about 1 to about 2% (weight/weight) of glycerol; of from about 45 to about 75 mM of phenol; of from about 0 to about 15 mM of m-cresol; of from about 1.5 to about 2.5 moles of zinc ions per six moles of said insulin derivative; not more than about 50 mM of sodium chloride; and having a pH value in the range of from 7.2 to 8.0.
- composition of the previous embodiments comprising about 0 mM of m-cresol.
- composition of the previous embodiments comprising of from about 5 to about 10 mM of m-cresol.
- composition of the previous embodiments comprising about 10 mM of m-cresol.
- a pharmaceutical composition comprising A14E, B16H, B25H, B29K((N ⁇ -Eicosanedioyl- ⁇ Glu-[2-(2- ⁇ 2-[2-(2-aminoethoxy)ethoxy]acetylamino ⁇ ethoxy)ethoxy]-acetyl)), desB30 human insulin (Compound 1); and semaglutide; and further comprising of from about 1 to about 2% (weight/weight) of glycerol; of from about 45 to about 75 mM of phenol; of from 0-15 mM of m-cresol; of from about 1.5 to about 2.5 moles of zinc ions per six moles of said insulin derivative; not more than about 25 mM of sodium chloride; and having a pH value in the range of from 7.2 to 8.0
- composition according to the previous embodiments comprising from about 0.20 to about 0.70 mM semaglutide.
- composition according to the previous embodiments comprising from about 0.30 to about 0.70 mM semaglutide.
- composition comprising from about 3.5 mM to about 5.0 mM A14E, B16H, B25H, B29K((N ⁇ -Eicosanedioyl- ⁇ Glu-[2-(2- ⁇ 2-[2-(2-aminoethoxy)ethoxy]acetylamino ⁇ ethoxy)ethoxy]-acetyl)), desB30 human insulin (Compound 1).
- composition comprising from about 0.30 to about 0.70 mM semaglutide, and from about 3.5 mM to about 5.0 mM A14E, B16H, B25H, B29K((N ⁇ -Eicosanedioyl- ⁇ Glu-[2-(2- ⁇ 2-[2-(2-aminoethoxy)ethoxy]acetylamino ⁇ ethoxy)ethoxy]acetyl)), desB30 human insulin (Compound 1).
- composition comprising about 0.30 mM semaglutide, and from about 3.5 mM to about 5.0 mM A14E, B16H, B25H, B29K((N ⁇ -Eicosanedioyl- ⁇ Glu-[2-(2- ⁇ 2-[2-(2-aminoethoxy)ethoxy]acetylamino ⁇ ethoxy)ethoxy]acetyl)), desB30 human insulin (Compound 1).
- composition comprising about 0.40 mM semaglutide, and 4.2 mM A14E, B16H, B25H, B29K((N ⁇ -Eicosanedioyl- ⁇ Glu-[2-(2- ⁇ 2-[2-(2-aminoethoxy)ethoxy]acetylamino ⁇ ethoxy)ethoxy]-acetyl)), desB30 human insulin (Compound 1).
- composition according to the previous embodiments comprising about 0.49 mM or 0.50 mM semaglutide, and 4.2 mM A14E, B16H, B25H, B29K((N ⁇ -Eicosanedioyl- ⁇ Glu-[2-(2- ⁇ 2-[2-(2-aminoethoxy)ethoxy]acetylamino ⁇ ethoxy)-ethoxy]acetyl)), desB30 human insulin (Compound 1).
- composition comprising about 0.60 mM semaglutide, and 4.2 mM A14E, B16H, B25H, B29K((N ⁇ -Eicosanedioyl- ⁇ Glu-[2-(2- ⁇ 2-[2-(2-aminoethoxy)ethoxy]acetylamino ⁇ ethoxy)ethoxy]-acetyl)), desB30 human insulin (Compound 1).
- a pharmaceutical (coformulation) composition comprising A14E, B16H, B25H, B29K((N ⁇ -Eicosanedioyl- ⁇ Glu-[2-(2- ⁇ 2-[2-(2-aminoethoxy)ethoxy]acetylamino ⁇ -ethoxy)ethoxy]acetyl)), desB30 human insulin (Compound 1); and semaglutide; and further comprising about 1.5% (weight/weight) of glycerol; of about 60 mM of phenol; about 0 mM of m-cresol; about 2.2 moles of zinc ions per six moles of said insulin derivative; about 20 mM of sodium chloride; and having a pH value of about 7.4.
- a pharmaceutical (coformulation) composition comprising A14E, B16H, B25H, B29K((N ⁇ -Eicosanedioyl- ⁇ Glu-[2-(2- ⁇ 2-[2-(2-aminoethoxy)ethoxy]acetylamino ⁇ -ethoxy)ethoxy]acetyl)), desB30 human insulin (Compound 1); and semaglutide; and further comprising about 1.5% (weight/weight) of glycerol; of about 60 mM of phenol; about 10 mM of m-cresol; about 2.2 moles of zinc ions per six moles of said insulin derivative; about 20 mM of sodium chloride; and having a pH value of about 7.4.
- composition of the previous embodiments for administration to a subject in need hereof at intervals less frequent than once-daily (i.e. at intervals longer than 24 hours), during a period of time of at least 3 months, at least 6 months, or of at least 1 year.
- composition of the previous embodiments for administration to a subject in need for administration to the subject with a frequency in the range of from every 2 nd day to every 11 th day, on average.
- composition of the previous embodiments for administration to a subject in need for administration to the subject with a frequency in the range of from every 3 rd day to every 10 th day, on average.
- composition of the previous embodiments for administration to a subject in need for administration to the subject with a frequency in the range of from every 4 th day to every 9 th day, on average.
- composition of the previous embodiments for administration to a subject in need for administration to the subject with a frequency in the range of from every 5 th day to every 8 th day, on average.
- composition of the previous embodiments for administration to a subject in need for administration to the subject with a frequency in the range of from every 6 th day to every 7 th day, on average.
- composition of the previous embodiments for administration to a subject in need for administration to the subject once a week, i.e. on every 7 th day, on average, during a period of time of at least 3 months, at least 6 months, or of at least 1 year.
- a method for making injectable pharmaceutical composition comprises:
- the invention provides pharmaceutical compositions useful as medicaments for the treatment of metabolic diseases, disorders or conditions, and, in particular, diseases, disorders or conditions relating to diabetes.
- the pharmaceutical composition of the invention is for use in the treatment or alleviation of a disease, disorder or condition relating to diabetes, Type 1 diabetes, Type 2 diabetes, impaired glucose tolerance, hyperglycemia, dyslipidemia, obesity, or metabolic syndrome (metabolic syndrome X, insulin resistance syndrome).
- a disease, disorder or condition relating to diabetes Type 1 diabetes, Type 2 diabetes, impaired glucose tolerance, hyperglycemia, dyslipidemia, obesity, or metabolic syndrome (metabolic syndrome X, insulin resistance syndrome).
- the pharmaceutical composition of the invention is for use in the treatment or alleviation of a disease, disorder or condition relating to diabetes, and in particular Type 1 diabetes, or Type 2 diabetes.
- the actual dosage depends on the nature and severity of the disease being treated, and is within the discretion of the physician, and may be varied by titration of the dosage to the particular circumstances of this invention to produce the desired therapeutic effect.
- FIG. 1A , FIG. 1B and FIG. 1C show oligomerisation of Compound 1 mono Formulations A, B, and C at simulated injection site conditions:
- FIG. 1A Apparent average hydrodynamic radius (rH) [nm] measured by DLS;
- FIG. 1B Apparent average molecular weight measured by CG-MALS
- FIG. 1C Apparent average sedimentation coefficient (S) measured by AUC;
- Black bars Compound 1, Formulation A containing 4.5 Zn++ per six insulins (mol:mol);
- FIG. 2A and FIG. 2B show oligomerisation of Compound 1 mono Formulations 01-06 at simulated injection site conditions:
- FIG. 2A Apparent average hydrodynamic radius (Rh, avg) [nm] measured by DLS;
- FIG. 2B Apparent average sedimentation coefficient (S*) measured by AUC
- FIG. 3A - FIG. 3D show apparent dynamic viscosity [cP] ( FIG. 3A , and FIG. 3C ) and specific viscosity [ ⁇ spec] ( FIG. 3B , FIG. 3D ) of different buffer-exchanged formulations of Compound 1 and interstitial fluid buffer (ISF), as a function of temperature [° C.];
- FIG. 3A and FIG. 3B Formulation A; Formulation B; Formulation C; ISF buffer;
- FIG. 3C and FIG. 3D Formulation 02; Formulation 03; Formulation 04; ISF buffer;
- FIG. 4A and FIG. 4B show conformational state of Compound 1 in formulations:
- FIG. 4A near-UV CD [ ⁇ 251 nm(M-1 cm-1)] showing conformational changes (T-state; mixed TR state; R-state) as a function of Zn++ per six insulins (mol:mol) for Formulations 01-06;
- FIG. 4B near-UV CD [ ⁇ 251 nm(M-1 cm-1)] showing conformational changes (T-state; mixed TR state; R-state) as a function of Zn++ per six insulins (mol:mol) for Formulations B1-B6, D1-D7, and human insulin formulations with various zinc level:
- Human insulin 600 nmol/ml human insulin, 30 mM phenol, 150 mM NaCl, pH 7.4.
- Black squares Compound 1 formulated with 25 mM phenol, 25 mM m-cresol and 20 mM NaCl;
- FIG. 5A and FIG. 5B show oligomer distribution of Compound 1 in formulations by SEC:
- FIG. 5A shows native SEC chromatogram of Formulations 01, 02, 03, 04, 05, and 06;
- FIG. 5B shows native SEC chromatogram of formulations A and B1-B6
- FIG. 6A and FIG. 6B show SAXS scattering data [Intensity (a.u.) vs. s( ⁇ -1)] of Compound 1 and human insulin in the formulated state:
- FIG. 6A Scattering curves of Compound 1 Formulation A shown in black and of human insulin shown in grey (Compound 1, 4.2 mM, 4.5 Zn/hexamer; Human insulin 0.6 mM, 2.2 Zn/hexamer);
- FIG. 6B Scattering curves of Compound 1 Formulation C shown in black and of human insulin shown in grey (Compound 1, 4.2 mM, 2.2 Zn/hexamer; Human insulin 0.6 mM, 2.2 Zn/hexamer (R6-hexamer));
- FIG. 7A and FIG. 7B show purity of Compound 1 in formulations:
- FIG. 7A shows purity (% of total peptide) at 30° C. storage [Time Point (Month)] for Compound 1 Formulation A (black line), Formulation B (grey line) and Formulation C (dotted line);
- FIG. 7B shows purity (% of total peptide) at 37° C. storage [Time Point (weeks)] for Compound 1 for Formulations 01, 04, 05 and 06;
- FIG. 8 shows purity of Compound 1 (% of total Compound 1) at 37° C. storage [Time Point (weeks)] in combo formulations with semaglutide:
- FIG. 9A and FIG. 9B show oligomerisation of combo formulations at simulated injection site conditions:
- FIG. 9A Apparent average hydrodynamic radius (rH) [nm] measured by DLS;
- FIG. 9B shows the oligomer size of combo formulations after buffer exchanged as observed by AUC (S*).
- the API of the formulations is A14E, B16H, B25H, B29K((N ⁇ -Eicosanedioyl- ⁇ Glu-[2-(2- ⁇ 2-[2-(2-aminoethoxy)ethoxy]acetylamino ⁇ ethoxy)ethoxy]acetyl)), desB30 human insulin (Compound 1), obtained as described in e.g. WO 2009/115469, see Example 33.
- Oligomerisation of Compound 1 was determined at simulated injection site conditions. Simulated injection site conditions were achieved by depletion of phenol and/or metacresol, respectively, and buffer exchange into simulated interstitial fluid buffer. This procedure virtually removed all phenolic ligands but maintained the zinc/insulin ratio of the parent formulation.
- Formulations are buffer-exchanged into interstitial fluid (ISF-) buffer via PD-MidiTrap G-25 column according to the manufacturers protocol.
- ISF- interstitial fluid
- the columns are equilibrated with the target buffer by washing the column with a sufficient volume of target buffer, and the formulation is applied in a suitable volume and eluted with target buffer.
- the ISF buffer consists of 140 mM NaCl, 4 mM KCl, 1 mM MgSO4, 2 mM CaCl2, 10 mM Hepes, pH 7.4.
- r H Apparent average hydrodynamic radius was measured by Dynamic Light Scattering (DLS), using a DynaPro PRTM (Wyatt technology, Santa Barbara, Calif., USA). Before analysis samples were centrifuged for 5 minutes at 1200 rpm to remove any dust particles in the solution. Measurements were conducted at 25° C. using 40 acquisitions and 2 sec acquisition time.
- CG-MALS Composition-Gradient, Multi-Angle Static Light Scattering
- Sedimentation velocity (SV) experiments were performed with an XL-I Analytical Ultracentrifuge (BeckmanCoulter, Brea, Calif.) in 12-mm or 3-mm double-sector centrepieces capped with sapphire windows. Samples were spun at 40000 rpm and 20° C. until sedimentation was completed and monitored with the interference optics of the instrument. Sedimentation Coefficient Distributions (SCD) were calculated with SedFit, version 11.8 (www.analyticalultracentrifugation.com) using the c(s) model with a grid of 100 s-values over a range sufficient to describe all sedimenting material, as judged by the rmsd and the residual run pattern.
- SCD Sedimentation Coefficient Distributions
- the frictional ratio f/fo was treated as a variable to be optimized during fitting (P Schuck, M A Perugini, N R Gonzales, G J Howlett and D Schubert: Size-distribution analysis of proteins by analytical ultracentrifugation: strategies and application to model systems; ( Biophys. J. 2002 82:1096). Average sedimentation coefficient values were obtained via integration of the resulting c(s)-distributions.
- Temperature-dependent dynamic viscosities were measured with a Lovis2000 rolling-ball type viscosimeter (Anton Paar, Graz, Austria). The temperature was decreased from 40° C. to 4° C. in 2° C. steps, allowing 5 minutes of temperature equilibration between steps. The density of the buffer was simultaneously measured with a DMA5000 densitometer, also from Anton Paar.
- Formulation A representative of the prior art (see e.g. WO 2013/153000), and Formulations B, C representative of the invention (60 mM phenol/10 mM m-cresol), were prepared.
- Formulation 01 (same as Formulation A), and Formulations 02, 03, 04, 05 and 06 representative of the invention, were made (Table 1B).
- the zinc content has been varied from 4.5 Zn ++ /six insulins to 2.4, 2.2, and 2.0 Zn ++ /six insulins.
- preservative systems of either 25/25 mM phenol/m-cresol or 60/0 mM phenol/m-cresol have been tested.
- the zinc content was decreased from 4.5 Zn++/six insulins in Formulation A to 2.4 and 2.2 Zn ++ /six insulins in formulations B and C (with increased phenol and decreased metacresol) respectively.
- This decrease in zinc was accompanied by a reduction of oligomer size (see FIGS. 1A, 1B and 1C ) as determined at simulated injection site conditions by the method described above.
- Results from formulation 01-06 further confirm that the oligomer size is reduced when Zn is reduced from 4.5 Zn++/six insulins to 2.2 ⁇ 0.2 Zn++/six insulins.
- the oligomer size is further reduced when phenol/cresol is reduced from 25 mM/25 mM to 60 mM/0 mM. See FIGS. 2A and 2B .
- t max represents the time to maximum concentration (maximal plasma exposure)
- t 1/2 represents the elimination half-life in which half of the compound disappears from plasma following administration.
- Example 1 The altered biophysical properties described in Example 1 are consistent with a PK profile exhibiting earlier t max in pigs (see Table 3). This indicates that the residence time of Compound 1 in the sub-cutis is reduced when formulated according to the invention, and in contrast to the same compound being provided in a formulation according to the prior art.
- the reduced zinc level almost has no impact on the duration of action (i.e. elimination t 112 is not affected), which makes the formulation according to the invention and the formulation of the prior art equally suited for once-weekly administration.
- Compound 1 when formulated according to the invention, forms smaller oligomers at the site of injection resulting in a PK/PD profile with a shorter residence time in the sub-cutis (decreased t max ).
- human insulin exists as hexamers in formulation.
- Human insulin hexamers can adopt two different conformational states depending on the conformation of the monomers.
- the eight N-terminal amino acid residues of the insulin monomer B-chain can be in either an extended conformation (T-state) or an ⁇ -helical conformation (R-state).
- T-state extended conformation
- R-state ⁇ -helical conformation
- human insulin adopts the R conformation, which is the favourable conformation with regards to physical and chemical stability (Dunn M F. Zinc-ligand interactions modulate assembly and stability of the insulin hexamer: A review. Biometals 2005; 18; 295-303).
- FIG. 4A shows the conformational changes (T-state; mixed TR state; R-state) as a function of Zn ++ per six insulins (mol:mol) for formulations 01-06.
- FIG. 4B shows conformational changes (T-state; mixed TR state; R-state) as a function of Zn++ per six insulins (mol:mol) for Series B and Series D formulations, and human insulin formulatoins.
- formulations 01-06 show that R-state of Compound 1 in the formulations is are further enriched by decreasing Zn from 4.5 to 2.2Zn ⁇ 0.2Zn/6 Compound 1 and by omitting m-cresol ( FIG. 4A ).
- Size Exclusion Chromatography is a sensitive method for quantifying the non-covalent oligomer distribution of insulin formulations.
- SEC was conducted using a BEH200 column, 1.7 ⁇ m 4.6 ⁇ 150 mm with a running buffer consisting of 8.0 mM phenol, 140 mM NaCl, 10 mM Tris-HCl, pH 7.4. Chromatography was conducted at 22 C using 2 ⁇ L injection volume and a flow of 0.3 ml/min.
- molecular weight standards albumin, a covalent insulin hexamer, and a monomeric insulin were used.
- Chromatograms were analysed by integration to represent species larger than hexamer (3.0-3.8 min), hexamer (3.8-4.3 min), and species smaller than hexamer (4.3-5.5 min). Please note that exact integration limits for each data set will vary slightly due to variations in column performance.
- SAXS Small angle X-ray scattering
- SEC data of Formulations 01-06 show that the oligomer distribution of Compound 1 Formulation 01 is characterised by broad bands with no clear dominant oligomer species.
- the oligomer distribution of Compound 1 in Formulations 03-06 is narrower compared to Formulations 01 and 02.
- the retention time of the main peak Formulations 03-06 is consistent with a hexamer and the small peak with a retention time of 5 minutes is consistent with a monomer or dimer.
- SEC data of Formulations B1-B6 and A (Table 7, FIG. 5B ) also show that with 2.0-2.5 zinc/6 insulins, the hexamer peak is enriched, compared to 4.0 or 4.5 Zn.
- the hexamer peak is enriched at low zinc (e.g., 2.0Zn to 2.5Zn) compared to high zinc (e.g. 4.0 or 4.5Zn).
- low zinc e.g. 2.0Zn to 2.5Zn
- high zinc e.g. 4.0 or 4.5Zn
- the hexamer is enriched at 60 mM/0 or 10 mM phenol/m-cresol relative to 25/25 mM phenol/m-cresol.
- the hexamer content is increased and the oligomerisation becomes more well-defined.
- SAXS data also confirm that the oligomerisation pattern of Compound 1 Formulation A with 4.5 Zn++/hexamer does not resemble the classical human insulin hexamer while a hexamer-based structure of the Compound 1 is dominant in Formulation C ( FIG. 6 ).
- Formulation C When formulated according to the invention (Formulation C) the oligomerisation pattern becomes more well-defined and consistent with a hexamer based structure similar to human insulin.
- Purity was determined by reversed phase ultra-high performance liquid chromatography (RP-UHPLC) where the samples were analysed using a Acquity CSH Fluoro Phenyl, 130 ⁇ , 1.7 ⁇ m, 2.1 ⁇ 150 mm column, gradient elution by acetonitrile in a mobile phase of acetonitrile and phosphoric buffer in water with subsequent UV detection (215 nm) under a flow of 0.30 ml/min with a sample injection volume of 2-3 ⁇ l. Purity was evaluated as the area of the main peak divided by the area of all peaks ⁇ 100%.
- the stability measured as (%) purity of total peptide with RP-UHPLC shows an significantly increased stability of Compound 1 in Formulation B and Formulation C, which comprised 60 mM phenol and 10 mM m-cresol, compared to Compound 1 Formulation A, which comprised 25 mM phenol and 25 mM m-cresol. See Table 8 and FIG. 7A .
- the stability of formulations presented in table 9 measured as % purity of total peptide with RP-UHPLC further confirms that the chemical stability of Compound 1 increases as a function of zinc concentration in formulations with relatively high level of phenol and low level of m-cresol.
- the results show an increased stability of Compound 1 when zinc was decreased from 4.5 Zn ++ /six insulins to 2.4, 2.2 and 2.0 Zn ++ /six insulins in formulations with a change in preservative system from 25/25 mM phenol/m-cresol to 60 mM phenol and 0 m-cresol. See Table 9 and FIG. 7B .
- the Compound 1 formulations were tested in a 96-well microtiter plate with 4 replica of 200 ⁇ l.
- ThT thioflavin T
- Thioflavin T (ThT) assay for propensity to form amyloid fibrils was performed on Thermo Fluoroskan, 960 rpm shaking, 37° C., for 45 hours.
- ThT emission was scanned before and after assay. The lag time until on-set of ThT fluorescence emission is a measurement of physical stability. Lag times were determined from fluorescence curves averaged over 4 replica. A longer lag-time is indicative of higher physical stability.
- ThT results obtained from the described protocol may vary between experiments. Therefore it is desirable that measurements for a given set of formulations be compared within the same experiment and not across experiments.
- the same reference formulation was tested together with various formulations of the invention in different experiments. For example, Formulation A vs. Formulation C; Formulation 01 vs. Formulations 04-06.
- the lag-times obtained in the ThT assay indicates that the physical stability of Compound 1 is improved in formulations with low level of zinc, high level of phenol, and low level of m-cresol.
- the data showed that when decreasing zinc from 4.5Zn/6Ins to 2.2 ⁇ 0.2Zn/6Ins and concomitant increasing phenol from 25 mM to 60 mM and decreasing m-cresol from 25 mM to 10 mM lead to longer lag time and thus improved physical stability. With m-cresol being removed, the physical stability of Compound 1 was further improved in formulations with low zinc level (see Table 10B).
- Compound 1 may be co-formulated together with the once-weekly GLP-1 analogue semaglutide for a fixed-ratio combination.
- ThT thioflavin T
- Thioflavin T (ThT) assay for propensity to form amyloid fibrils was performed on Thermo Fluoroskan, 960 rpm shaking, 37° C., for 45 hours. ThT emission was scanned before and after assay. The lag time until on-set of ThT fluorescence emission (formation of amyloid fibrils) is a measurement of physical stability. Lag times were determined from fluorescence curves averaged over 8 replica. Lag times were tested twice for combo formulations 1-4 and combo formulations 5 and 6, respectively; and each with mono formulation tested as a reference, to make the results comparable. A longer lag-time is indicative of higher physical stability.
- the Compound 1 mono-formulation reference and the combo-formulations were tested in a 96-well microtiter plate Thioflavin T (ThT) assay for propensity to form amyloid fibrils.
- Thioflavin T Thioflavin T
- the ThT assay indicated that without increasing zinc level, combo formulations of Compound 1 and semaglutide did not compromise the physical stability of Compound 1 compared to that of the Compound 1 mono-formulation. In fact, the lag times of the combo-formulations were much longer than that of the Compound 1 mono-formulation, showing the co-formulating of Compound 1 with semaglutide in fact stabilizes the formulation towards the unwanted amyloid fibril formation. Compared with combo-formulation of other long acting insulin derivative and GLP-1 derivative (e.g. degludec and liraglutide), this finding is unexpected and surprising.
- other long acting insulin derivative and GLP-1 derivative e.g. degludec and liraglutide
- Table 14C results show that lowering the level of m-cresol can further improve the physical stability of the combo-formulation of Compound 1 and semaglutide; and increasing the level of phenol also improves the physical stability of the combo-formulation of Compound 1 and semaglutide.
- Table 14C results also show that when co-formulating Compound 1 with semaglutide in a formulation according to the invention, the physical stability of Compound 1 increases, compared to using prior art formulation (Formulation I) for combo-formulation of Compound 1 and semaglutide.
- Purity was determined by reversed phase ultra-high performance liquid chromatography (RP-UHPLC) where the samples were analysed using a Acquity CSH Fluoro Phenyl, 130 ⁇ , 1.7 um, 2.1 ⁇ 150 mm column, gradient elution by acetonitrile in a mobile phase of acetonitrile and phosphoric buffer in water with subsequent UV detection (215 nm) under a flow of 0.30 ml/min with a sample injection volume of 2-3 ⁇ l. Purity was evaluated as the area of the main peak divided by the area of all peaks ⁇ 100%.
- the PK parameters for Compound 1 when co-formulated with semaglutide in Combo 1 and Combo 2 were not significantly changed compared to Compound 1 administrated as a mono-formulation.
- the t max values were slightly lower for the co-formulations, but with the standard deviation for the Compound 1 reference the values are overlapping.
- the t 1/2 and MRT were very similar for Compound 1 in the co-formulations compared to the reference mono-formulation. In conclusion the PK properties of Compound 1 were not significantly impacted by the co-formulation with semaglutide.
- the average size of oligomers formed from combo-formulations at simulated injection site conditions is significantly reduced in formulations with low level of zinc (e.g., 2.4 and 2.2 Zn++/six insulins) compared to formulations with high level zinc (e.g. 4.5 Zn++/six insulin).
- low level of zinc e.g., 2.4 and 2.2 Zn++/six insulins
- high level zinc e.g. 4.5 Zn++/six insulin
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Diabetes (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Epidemiology (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Endocrinology (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Zoology (AREA)
- Gastroenterology & Hepatology (AREA)
- Immunology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Inorganic Chemistry (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Dermatology (AREA)
- Emergency Medicine (AREA)
- Child & Adolescent Psychology (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicinal Preparation (AREA)
- Peptides Or Proteins (AREA)
- Manipulator (AREA)
Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US16/023,328 US10265385B2 (en) | 2016-12-16 | 2018-06-29 | Insulin containing pharmaceutical compositions |
US16/280,603 US10596231B2 (en) | 2016-12-16 | 2019-02-20 | Insulin containing pharmaceutical compositions |
US16/984,990 US20200384088A1 (en) | 2016-12-16 | 2020-08-04 | Insulin containing pharmaceutical compositions |
US17/692,238 US20220202909A1 (en) | 2016-12-16 | 2022-03-11 | Insulin containing pharmaceutical compositions |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP16204688 | 2016-12-16 | ||
EP16204688.2 | 2016-12-16 |
Related Child Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US16/023,328 Continuation US10265385B2 (en) | 2016-12-16 | 2018-06-29 | Insulin containing pharmaceutical compositions |
US16/984,990 Continuation US20200384088A1 (en) | 2016-12-16 | 2020-08-04 | Insulin containing pharmaceutical compositions |
Publications (1)
Publication Number | Publication Date |
---|---|
US20180169190A1 true US20180169190A1 (en) | 2018-06-21 |
Family
ID=57570394
Family Applications (5)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US15/843,016 Abandoned US20180169190A1 (en) | 2016-12-16 | 2017-12-15 | Insulin containing pharmaceutical compositions |
US16/023,328 Active US10265385B2 (en) | 2016-12-16 | 2018-06-29 | Insulin containing pharmaceutical compositions |
US16/280,603 Active US10596231B2 (en) | 2016-12-16 | 2019-02-20 | Insulin containing pharmaceutical compositions |
US16/984,990 Abandoned US20200384088A1 (en) | 2016-12-16 | 2020-08-04 | Insulin containing pharmaceutical compositions |
US17/692,238 Pending US20220202909A1 (en) | 2016-12-16 | 2022-03-11 | Insulin containing pharmaceutical compositions |
Family Applications After (4)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US16/023,328 Active US10265385B2 (en) | 2016-12-16 | 2018-06-29 | Insulin containing pharmaceutical compositions |
US16/280,603 Active US10596231B2 (en) | 2016-12-16 | 2019-02-20 | Insulin containing pharmaceutical compositions |
US16/984,990 Abandoned US20200384088A1 (en) | 2016-12-16 | 2020-08-04 | Insulin containing pharmaceutical compositions |
US17/692,238 Pending US20220202909A1 (en) | 2016-12-16 | 2022-03-11 | Insulin containing pharmaceutical compositions |
Country Status (28)
Country | Link |
---|---|
US (5) | US20180169190A1 (es) |
EP (2) | EP3821905B1 (es) |
JP (2) | JP6690062B2 (es) |
KR (2) | KR102374354B1 (es) |
CN (2) | CN115154591B (es) |
AU (2) | AU2017378102B2 (es) |
BR (1) | BR112019011761A2 (es) |
CA (1) | CA3046583A1 (es) |
CL (1) | CL2019001586A1 (es) |
CO (1) | CO2019006017A2 (es) |
DK (2) | DK3821905T3 (es) |
ES (2) | ES2886837T3 (es) |
HR (2) | HRP20221324T1 (es) |
HU (2) | HUE055231T2 (es) |
IL (2) | IL267224B2 (es) |
MA (1) | MA49116A (es) |
MX (2) | MX2019006463A (es) |
MY (1) | MY194504A (es) |
PE (2) | PE20210857A1 (es) |
PH (1) | PH12019501363A1 (es) |
PL (2) | PL3554534T3 (es) |
PT (1) | PT3554534T (es) |
RS (2) | RS62295B1 (es) |
RU (1) | RU2758367C2 (es) |
SA (2) | SA520420276B1 (es) |
SI (1) | SI3554534T1 (es) |
TW (2) | TWI700091B (es) |
WO (1) | WO2018109162A1 (es) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US10259856B2 (en) | 2008-03-18 | 2019-04-16 | Novo Nordisk A/S | Protease stabilized acylated insulin analogues |
US10265385B2 (en) | 2016-12-16 | 2019-04-23 | Novo Nordisk A/S | Insulin containing pharmaceutical compositions |
Families Citing this family (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CA3122637A1 (en) | 2018-12-11 | 2020-06-18 | Sanofi | Peptide binder |
MX2022007034A (es) | 2019-12-10 | 2022-06-23 | Sanofi Sa | Un metodo para formar un conjugado de una sulfonamida y un polipeptido. |
CN118420744A (zh) * | 2019-12-30 | 2024-08-02 | 甘李药业股份有限公司 | 胰岛素衍生物 |
JP7424918B2 (ja) * | 2020-06-18 | 2024-01-30 | 株式会社平和 | 遊技機 |
WO2022268208A1 (zh) * | 2021-06-25 | 2022-12-29 | 甘李药业股份有限公司 | 含酰化胰岛素的药物组合物 |
JP7437833B1 (ja) | 2023-09-21 | 2024-02-26 | 俊二 二宮 | 検体検査用のカラー濾紙及びその製造方法 |
Family Cites Families (224)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2832685A (en) | 1952-05-24 | 1958-04-29 | Crest Foods Co Inc | Solubilization of milk proteins |
GB894095A (en) | 1960-02-08 | 1962-04-18 | Tanaka Shoichi | A therapeutic device for personal wear |
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 |
JPS6030650B2 (ja) | 1979-10-26 | 1985-07-17 | 日本油脂株式会社 | 座薬基剤組成物 |
JPS5767548A (en) | 1980-10-14 | 1982-04-24 | Shionogi & Co Ltd | Insulin analog and its preparation |
NL193099C (nl) | 1981-10-30 | 1998-11-03 | Novo Industri As | Gestabiliseerde insuline-oplossing. |
US4839341A (en) | 1984-05-29 | 1989-06-13 | Eli Lilly And Company | Stabilized insulin formulations |
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 |
US4849227A (en) | 1986-03-21 | 1989-07-18 | Eurasiam Laboratories, Inc. | Pharmaceutical compositions |
PH23446A (en) | 1986-10-20 | 1989-08-07 | Novo Industri As | Peptide preparations |
US5266310A (en) | 1987-09-17 | 1993-11-30 | Boehringer Ingelheim International Gmbh | Stabilization of therapeutically active proteins in pharmaceutical 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 |
EP0425482B1 (en) | 1988-07-20 | 1993-08-18 | Novo Nordisk A/S | Human insulin analogs and preparations containing them |
GB2222770B (en) | 1988-09-16 | 1992-07-29 | Sandoz Ltd | Pharmaceutical compositions containing cyclosporins |
US5225323A (en) | 1988-11-21 | 1993-07-06 | Baylor College Of Medicine | Human high-affinity neurotransmitter uptake system |
WO1990007522A1 (en) | 1988-12-23 | 1990-07-12 | Novo Nordisk A/S | Human insulin analogues |
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 |
US5514646A (en) | 1989-02-09 | 1996-05-07 | Chance; Ronald E. | Insulin analogs modified at position 29 of the B chain |
HU210142B (en) | 1989-04-20 | 1995-02-28 | Sinai School Medicine | Process for producing hepatospecific insulin-analogues and pharmaceutical compositions containing them |
CA1340994C (en) | 1989-09-21 | 2000-05-16 | Rudolf Edgar Dr. Falk | Treatment of conditions and disease |
AU6417790A (en) | 1989-09-22 | 1991-04-18 | Tsi-Madison Research Institute | Method and compositions for one-step cryopreservation of embryos |
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 (es) | 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 |
AU8091091A (en) | 1990-07-26 | 1992-02-18 | University Of Iowa Research Foundation, The | Novel drug delivery systems for proteins and peptides using albumin as a carrier molecule |
JPH06501003A (ja) | 1990-09-13 | 1994-01-27 | スミスクライン・ビーチャム・コーポレイション | 非水性液状経口懸濁液 |
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 |
EP0952855B1 (en) | 1991-07-03 | 2005-07-27 | Meditech Research Limited | Use of hyaluronan in gene therapy |
JPH06509796A (ja) | 1991-07-26 | 1994-11-02 | スミスクライン・ビーチャム・コーポレイション | W/oミクロエマルジョン |
US5268453A (en) | 1991-08-08 | 1993-12-07 | Scios Inc. | Tissue-selective insulin analogs |
US5206219A (en) | 1991-11-25 | 1993-04-27 | Applied Analytical Industries, Inc. | Oral compositions of proteinaceous medicaments |
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 |
ES2099193T3 (es) | 1991-12-18 | 1997-05-16 | Hoechst Ag | Procedimiento para la obtencion de soluciones con contenido en insulina. |
WO1994008599A1 (en) | 1992-10-14 | 1994-04-28 | The Regents Of The University Of Colorado | Ion-pairing of drugs for improved efficacy and delivery |
EP0666752A4 (en) | 1992-10-16 | 1996-09-11 | Smithkline Beecham Corp | THERAPEUTIC MICROEMULSIONS. |
JPH08502490A (ja) | 1992-10-16 | 1996-03-19 | スミスクライン・ビーチャム・コーポレイション | 組成物 |
WO1994019001A1 (en) | 1993-02-17 | 1994-09-01 | Smithkline Beecham Corporation | Microemulsions comprising therapeutic peptides |
EP0684834A4 (en) | 1993-02-17 | 1996-09-25 | Smithkline Beecham Corp | MICROEMULSIONS CONTAINING THERAPEUTIC PEPTIDES. |
DE69426292T2 (de) | 1993-02-23 | 2001-05-17 | Genentech, Inc. | Stabilisierung von mit organischen lösungsmittel behandelten polypeptiden mit einem hilfsstoff |
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 |
KR100310122B1 (ko) | 1993-09-17 | 2002-04-24 | 한센 핀 베네드, 안네 제헤르, 웨이콥 마리안느 | 아실화된인슐린 |
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 |
PL179443B1 (pl) | 1994-03-07 | 2000-09-29 | Inhale Therapeutic Syst | Kompozycja insuliny, sposób wytwarzania kompozycji insuliny i sposób wytwarzania dawki insuliny w postaci aerozolu PL PL PL PL |
US6500645B1 (en) | 1994-06-17 | 2002-12-31 | Novo Nordisk A/S | N-terminally extended proteins expressed in yeast |
US5646242A (en) | 1994-11-17 | 1997-07-08 | Eli Lilly And Company | Selective acylation of epsilon-amino groups |
US5693609A (en) | 1994-11-17 | 1997-12-02 | Eli Lilly And Company | Acylated insulin analogs |
GB2296712B (en) | 1995-01-05 | 1999-02-24 | British Gas Plc | Absorbents for separating nitrogen from a feed gas |
CZ289343B6 (cs) | 1995-03-17 | 2002-01-16 | Novo Nordisk A/S | Inzulinový derivát a farmaceutický prostředek pro léčení diabetes |
US6251856B1 (en) | 1995-03-17 | 2001-06-26 | Novo Nordisk A/S | Insulin derivatives |
US5824638A (en) | 1995-05-22 | 1998-10-20 | Shire Laboratories, Inc. | Oral insulin delivery |
US20010041786A1 (en) | 1995-06-07 | 2001-11-15 | Mark L. Brader | Stabilized acylated insulin formulations |
DE69630527T2 (de) | 1995-06-30 | 2004-08-05 | Novo Nordisk A/S | Vorbeugung einer krankheit mit diabetes charakter |
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 |
US5981489A (en) | 1996-07-18 | 1999-11-09 | Alza Corporation | Non-aqueous protic peptide formulations |
DK0821006T3 (da) | 1996-07-26 | 2004-08-16 | Aventis Pharma Gmbh | Insulinderivater med öget zinkbinding |
IL119029A0 (en) | 1996-08-07 | 1996-11-14 | Yeda Res & Dev | Long-acting drugs and pharamaceutical compositions comprising them |
US6160541A (en) | 1997-01-21 | 2000-12-12 | Lear Automotive Dearborn Inc. | Power consumption control for a visual screen display by utilizing a total number of pixels to be energized in the image to determine an order of pixel energization in a manner that conserves power |
SK285019B6 (sk) | 1997-01-30 | 2006-04-06 | Novartis Ag | Tvrdá želatínová tobolka |
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 |
PE79099A1 (es) | 1997-06-13 | 1999-08-24 | Lilly Co Eli | Formulaciones de insulina estables |
US20020155994A1 (en) * | 1997-10-24 | 2002-10-24 | Svend Havelund | Aggregates of human insulin derivatives |
EP1025125B1 (en) | 1997-10-24 | 2003-06-25 | Novo Nordisk A/S | Aggregates of human insulin derivatives |
PE123799A1 (es) | 1997-10-24 | 1999-12-13 | Lilly Co Eli | Composiciones insolubles de insulina |
ZA989744B (en) | 1997-10-31 | 2000-04-26 | Lilly Co Eli | Method for administering acylated insulin. |
WO1999024071A1 (en) | 1997-11-12 | 1999-05-20 | Alza Corporation | Method for decreasing self-association of polypeptides |
US6531448B1 (en) | 1997-12-23 | 2003-03-11 | Eli Lilly And Company | Insoluble compositions for controlling blood glucose |
JP2002518408A (ja) | 1998-06-12 | 2002-06-25 | キングス・カレツジ・ロンドン | インスリン類似体 |
GB9814172D0 (en) | 1998-06-30 | 1998-08-26 | Andaris Ltd | Formulation for inhalation |
DK1107743T3 (da) | 1998-08-25 | 2007-10-22 | Advanced Inhalation Res Inc | Stabile, spraytörrede proteinformuleringer |
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 |
ATE277630T1 (de) | 1998-10-16 | 2004-10-15 | Novo Nordisk As | Stabile konzentrierte insulin präparationen zur pulmonaren verabreichung |
US6660715B2 (en) | 1998-11-19 | 2003-12-09 | Massachusetts Institute Of Technology | Nonaqueous solutions and suspensions of macromolecules for pulmonary delivery |
US7425541B2 (en) | 1998-12-11 | 2008-09-16 | Medarex, Inc. | Enzyme-cleavable prodrug compounds |
ES2180511T3 (es) * | 1999-01-26 | 2003-02-16 | Lilly Co Eli | Formulaciones monodispersas de analogos de insulina acilados hexamericos. |
AU2879100A (en) | 1999-02-12 | 2000-08-29 | Miles A. Libbey Iii | Formulation and system for intra-oral delivery of pharmaceutical agents |
US6267985B1 (en) | 1999-06-30 | 2001-07-31 | Lipocine Inc. | Clear oil-containing pharmaceutical compositions |
WO2000061178A1 (en) | 1999-04-13 | 2000-10-19 | Inhale Therapeutics Systems, Inc. | Pulmonary administration of dry powder formulations for treating infertility |
CA2370302A1 (en) | 1999-04-27 | 2000-11-02 | Benjamin Lee Hughes | Insulin crystals for pulmonary administration |
US6746853B1 (en) | 1999-05-19 | 2004-06-08 | Xencor, Inc. | Proteins with insulin-like activity useful in the treatment of diabetes |
AU5144400A (en) | 1999-05-19 | 2000-12-05 | Xencor, Inc. | Novel 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 |
AU5453300A (en) | 1999-06-29 | 2001-01-31 | Eli Lilly And Company | Insulin crystals for pulmonary administration |
EA004631B1 (ru) | 1999-12-16 | 2004-06-24 | Эли Лилли Энд Компани | Полипептидные композиции, обладающие повышенной стабильностью |
WO2001052937A1 (en) | 2000-01-24 | 2001-07-26 | Medtronic Minimed, Inc. | Mixed buffer system for stabilizing polypeptide formulations |
WO2001072323A2 (en) | 2000-03-24 | 2001-10-04 | Genentech, Inc. | Use of insulin for the treatment of cartilagenous disorders |
AU2001263775A1 (en) | 2000-06-02 | 2001-12-11 | Novo-Nordisk A/S | Glucose dependent release of insulin from glucose sensing insulin derivatives |
CN1141974C (zh) | 2000-06-07 | 2004-03-17 | 张昊 | 结肠定位释放的口服生物制剂 |
KR100508695B1 (ko) | 2001-02-13 | 2005-08-17 | 한국과학기술연구원 | 인슐린의 경구투여용 제형과 그의 제조방법 |
US6867183B2 (en) | 2001-02-15 | 2005-03-15 | Nobex Corporation | Pharmaceutical compositions of insulin drug-oligomer conjugates and methods of treating diseases therewith |
US7060675B2 (en) | 2001-02-15 | 2006-06-13 | Nobex Corporation | Methods of treating diabetes mellitus |
WO2002067969A2 (en) | 2001-02-21 | 2002-09-06 | Medtronic Minimed, Inc. | Stabilized insulin formulations |
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 |
MXPA03010649A (es) | 2001-05-21 | 2005-10-05 | Nektar Therapeutics | Administracion pulmonar de insulina modificada quimicamente. |
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 |
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 |
US7186797B2 (en) | 2001-08-10 | 2007-03-06 | Epix Pharmaceuticals, Inc. | Polypeptide conjugates with extended circulating half-lives |
US7030082B2 (en) | 2001-09-07 | 2006-04-18 | Nobex Corporation | Pharmaceutical compositions of drug-oligomer conjugates and methods of treating disease therewith |
ATE446971T1 (de) | 2001-09-07 | 2009-11-15 | Biocon Ltd | Verfahren zur synthese von insulinpolypeptid- oligomer-konjugaten und proinsulinpolypeptid- oligomer-konjugaten und verfahren zu deren synthese |
US6770625B2 (en) | 2001-09-07 | 2004-08-03 | Nobex Corporation | Pharmaceutical compositions of calcitonin drug-oligomer conjugates and methods of treating diseases therewith |
US7312192B2 (en) | 2001-09-07 | 2007-12-25 | Biocon Limited | Insulin polypeptide-oligomer conjugates, proinsulin polypeptide-oligomer conjugates and methods of synthesizing same |
AU2002349295A1 (en) | 2001-12-02 | 2003-06-17 | Novo Nordisk A/S | Glucose dependant release of insulin from glucose sensing insulin derivatives |
US7317000B2 (en) | 2001-12-02 | 2008-01-08 | Novo Nordisk A/S | Glucose-dependent insulins |
ATE424815T1 (de) | 2001-12-03 | 2009-03-15 | Dor Biopharma Inc | Stabilisierte umkehr-mizellen-zusammensetzungen und ihre verwendung |
WO2003050276A1 (en) | 2001-12-05 | 2003-06-19 | Dow Global Technologies Inc. | Method for immobilizing a biologic in a polyurethane-hydrogel composition, a composition prepared from the method, and biomedical applications |
AU2002346491A1 (en) | 2001-12-19 | 2003-07-09 | Eli Lilly And Company | Crystalline compositions for controlling blood glucose |
US20050014679A1 (en) | 2001-12-20 | 2005-01-20 | Beals John Michael | Insulin molecule having protracted time action |
UA46669C2 (uk) | 2001-12-29 | 2005-12-15 | Товариство З Обмеженою Відповідальністю "Мако" | Спосіб приготування готової лікарської форми інсуліну пролонгованої дії |
US8003605B2 (en) | 2002-03-13 | 2011-08-23 | Novo Nordisk A/S | Minimising body weight gain in insulin treatment |
JP2005526126A (ja) | 2002-05-07 | 2005-09-02 | ノボ ノルディスク アクティーゼルスカブ | インスリンアスパルト及びインスリンデテミアを含む可溶性製剤 |
JP5599543B2 (ja) | 2002-05-07 | 2014-10-01 | ノヴォ ノルディスク アー/エス | 単量体インスリン及びアシル化インスリンを含む可溶性製剤 |
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 |
AU2003272347A1 (en) | 2002-09-17 | 2004-04-08 | Merck And Co., Inc. | Removal of aldehyde impurity by reactive polystyrene resin |
US20050065066A1 (en) * | 2002-12-20 | 2005-03-24 | Kaarsholm Niels Christian | Stabilised insulin compositions |
US20060258561A1 (en) * | 2003-03-13 | 2006-11-16 | Novo Nordisk A/S | Novel NPH insulin preparations |
US20040185068A1 (en) | 2003-03-18 | 2004-09-23 | Zhi-Jian Yu | Self-emulsifying compositions, methods of use and preparation |
EP1633391B1 (en) | 2003-06-03 | 2011-10-19 | Novo Nordisk A/S | Stabilized pharmaceutical peptide compositions |
EP2292253A3 (en) | 2003-06-03 | 2011-12-14 | Novo Nordisk A/S | Stabilized pharmaceutical peptide compositions |
BRPI0411479A (pt) | 2003-06-17 | 2006-07-25 | Sembiosys Genetics Inc | métodos para a produção de insulina em plantas |
US20050054818A1 (en) | 2003-07-02 | 2005-03-10 | Brader Mark Laurence | Crystalline compositions for controlling blood glucose |
EP1644411A2 (en) | 2003-07-11 | 2006-04-12 | Novo Nordisk A/S | Stabilised insulin compositions |
WO2005012346A1 (en) | 2003-07-25 | 2005-02-10 | Conjuchem, Inc. | Long lasting insulin derivatives and methods thereof |
EP2264065B1 (en) | 2003-08-05 | 2017-03-08 | Novo Nordisk A/S | Novel insulin derivatives |
US20060198819A1 (en) | 2003-08-08 | 2006-09-07 | Novo Nordisk Healthcare A/G | Use of galactose oxidase for selective chemical conjugation of protractor molecules to proteins of therapeutic interest |
US7635675B2 (en) | 2003-08-13 | 2009-12-22 | Biocon Limited | Micro-particle fatty acid salt solid dosage formulations for therapeutic agents |
BRPI0414539B8 (pt) | 2003-09-19 | 2021-05-25 | Novo Nordisk As | composto, composição farmacêutica, e, uso de um composto |
EP1687428A1 (en) | 2003-11-14 | 2006-08-09 | Novo Nordisk A/S | Processes for making acylated insulin |
US20050118206A1 (en) | 2003-11-14 | 2005-06-02 | Luk Andrew S. | Surfactant-based gel as an injectable, sustained drug delivery vehicle |
CN102784386A (zh) | 2003-11-20 | 2012-11-21 | 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 |
US7371381B2 (en) | 2003-12-12 | 2008-05-13 | Amgen Inc. | Anti-galanin antibodies 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 |
KR20070044805A (ko) | 2004-04-15 | 2007-04-30 | 키아스마, 인코포레이티드 | 생물학적 장벽 투과를 촉진시킬 수 있는 조성물 |
CN101151048A (zh) | 2004-05-10 | 2008-03-26 | 纳斯泰克制药公司 | 增强甲状旁腺激素粘膜递送的组合物和方法 |
JP2008505866A (ja) | 2004-07-09 | 2008-02-28 | ノボ ノルディスク アクティーゼルスカブ | インスリンを含有する薬学的製剤 |
UA103758C2 (ru) | 2004-07-19 | 2013-11-25 | Биокон Лимитед | Конъюгаты олигомеров инсулина, их композиции и применение |
JP2008513356A (ja) | 2004-08-09 | 2008-05-01 | アリオス バイオファーマ インク. | 合成高度糖鎖付加プロテアーゼ耐性ポリペプチド変異体、それを使用する経口製剤および方法 |
ES2540886T3 (es) | 2004-08-23 | 2015-07-14 | Mannkind Corporation | Sales de dicetopiperazina para la administración de fármacos |
WO2006035418A2 (en) | 2004-09-27 | 2006-04-06 | Sigmoid Biotechnologies Limited | Microcapsules comprising a methylxanthine and a corticosteroid |
CN101060856B (zh) * | 2004-11-22 | 2011-01-19 | 诺和诺德公司 | 可溶、稳定的含胰岛素制剂 |
CA2587601C (en) | 2004-12-03 | 2017-11-07 | 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 |
WO2006082205A1 (en) | 2005-02-02 | 2006-08-10 | Novo Nordisk A/S | Insulin derivatives |
ES2438145T3 (es) | 2005-02-02 | 2014-01-16 | Novo Nordisk A/S | Nuevos derivados de insulina |
WO2006082245A1 (en) | 2005-02-07 | 2006-08-10 | Novo Nordisk A/S | Pharmaceutical preparations comprising insulin, zinc ions and a zinc-binding ligand |
EP2242489A1 (en) | 2005-02-15 | 2010-10-27 | Jallal Messadek | Combination therapeutic compositions and method of use |
JP2008533100A (ja) | 2005-03-18 | 2008-08-21 | ノボ ノルディスク アクティーゼルスカブ | Peg化された単鎖インスリン |
TWI362392B (en) | 2005-03-18 | 2012-04-21 | Novo Nordisk As | Acylated glp-1 compounds |
WO2006103657A2 (en) | 2005-03-31 | 2006-10-05 | Dexcel Pharma Technologies Ltd. | A solid composition for intra-oral delivery of insulin |
EP1909824B1 (en) | 2005-04-08 | 2011-05-18 | Amylin Pharmaceuticals, Inc. | Pharmaceutical formulations comprising incretin peptide and aprotic polar solvent |
CN101180081B (zh) | 2005-05-25 | 2015-08-26 | 诺沃-诺迪斯克有限公司 | 稳定的多肽制剂 |
WO2007006320A1 (en) | 2005-07-12 | 2007-01-18 | Sherine Hassan Abbas Helmy | Drinkable oral insulin liquid and capsules |
US20070086952A1 (en) | 2005-09-29 | 2007-04-19 | Biodel, Inc. | Rapid Acting and Prolonged Acting Inhalable 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 |
WO2007047948A2 (en) | 2005-10-20 | 2007-04-26 | Nastech Pharmaceutical Company Inc. | Intranasal administration of rapid acting insulin |
PT1969004E (pt) | 2005-12-28 | 2011-11-25 | Novo Nordisk As | Composições que compreendem uma insulina acilada e zinco e método para criar tais composições |
WO2007081824A2 (en) | 2006-01-06 | 2007-07-19 | Case Western Reserve University | Fibrillation resistant proteins |
JP2009527526A (ja) | 2006-02-21 | 2009-07-30 | ノボ・ノルデイスク・エー/エス | 単鎖インスリンのアナログとその製薬的製剤 |
ATE557037T1 (de) | 2006-02-27 | 2012-05-15 | Novo Nordisk As | Insulin derivate |
JP2009530243A (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 |
EP1996223A1 (en) | 2006-03-13 | 2008-12-03 | Novo Nordisk A/S | Acylated single chain insulin |
ES2548393T3 (es) | 2006-05-09 | 2015-10-16 | Novo Nordisk A/S | Derivado de insulina |
ES2553154T3 (es) | 2006-05-09 | 2015-12-04 | Novo Nordisk A/S | Derivado de la insulina |
JP5550338B2 (ja) | 2006-07-31 | 2014-07-16 | ノボ・ノルデイスク・エー/エス | ペグ化持続型インスリン |
CN101541830A (zh) | 2006-09-22 | 2009-09-23 | 诺沃-诺迪斯克有限公司 | 蛋白酶抗性的胰岛素类似物 |
WO2008043033A2 (en) | 2006-10-04 | 2008-04-10 | Case Western Reserve University | Fibrillation-resistant insulin and insulin analogues |
ES2563038T3 (es) | 2007-04-30 | 2016-03-10 | Novo Nordisk A/S | Método para secar una composición proteica, una composición proteica seca y una composición farmacéutica que comprende la proteína seca |
EP2152243A2 (en) * | 2007-04-30 | 2010-02-17 | Novo Nordisk A/S | Highly concentrated insulin solutions and compositions |
JP2011504871A (ja) | 2007-06-01 | 2011-02-17 | ノボ・ノルデイスク・エー/エス | 固体又は半固体担体中にペプチド薬剤を含む自然に分散可能なプレコンセントレイト |
JP5675347B2 (ja) | 2007-06-01 | 2015-02-25 | ノボ・ノルデイスク・エー/エス | 安定した非水性薬学的組成物 |
ES2744384T3 (es) | 2007-06-13 | 2020-02-24 | Novo Nordisk As | Formulación farmacéutica que comprende un derivado de insulina |
EP2170945A1 (en) | 2007-07-16 | 2010-04-07 | Novo Nordisk A/S | Protease stabilized, pegylated insulin analogues |
EP2178909B1 (en) | 2007-08-13 | 2015-10-21 | Novo Nordisk A/S | Rapid acting insulin analogues |
WO2009022006A1 (en) | 2007-08-15 | 2009-02-19 | Novo Nordisk A/S | Insulins with an acyl moiety comprising repeating units of alkylene glycol containing amino acids |
CN101784562B (zh) | 2007-08-15 | 2016-07-13 | 诺沃-诺迪斯克有限公司 | 具有酰基和亚烷基二醇部分的胰岛素类似物 |
US20090087484A1 (en) | 2007-09-28 | 2009-04-02 | Alza Corporation | Formulation and dosage form for increasing oral bioavailability of hydrophilic macromolecules |
PL2209800T3 (pl) * | 2007-11-16 | 2013-12-31 | Novo Nordisk As | Stabilne kompozycje farmaceutyczne zawierające liraglutyd i degludec |
ES2618073T3 (es) | 2008-03-14 | 2017-06-20 | Novo Nordisk A/S | Análogos de insulina estabilizados frente a proteasas |
EP2910571B1 (en) | 2008-03-18 | 2016-10-05 | Novo Nordisk A/S | Protease stabilized, acylated insulin analogues |
US8993516B2 (en) | 2008-04-14 | 2015-03-31 | Case Western Reserve University | Meal-time insulin analogues of enhanced stability |
TWI451876B (zh) | 2008-06-13 | 2014-09-11 | Lilly Co Eli | 聚乙二醇化之離脯胰島素化合物 |
US9603904B2 (en) | 2008-10-30 | 2017-03-28 | Novo Nordisk A/S | Treating diabetes melitus using insulin injections with less than daily injection frequency |
US20110293714A1 (en) | 2008-11-28 | 2011-12-01 | Novo Nordisk A/S | Pharmaceutical compositions suitable for oral administration of derivatized insulin peptides |
CN102245633A (zh) | 2008-12-09 | 2011-11-16 | 诺沃—诺迪斯克有限公司 | 新的胰岛素类似物 |
WO2010092163A2 (en) | 2009-02-13 | 2010-08-19 | Boehringer Ingelheim International Gmbh | Antidiabetic medications |
JP2013504610A (ja) | 2009-09-16 | 2013-02-07 | ノヴォ ノルディスク アー/エス | インスリンを含む安定な非水性液体医薬組成物 |
EP2496213B1 (en) | 2009-11-02 | 2015-08-12 | Novo Nordisk A/S | Pharmaceutical solution of non covalently bound albumin and acylated insulin |
EP2523655A2 (en) | 2010-01-12 | 2012-11-21 | Novo Nordisk A/S | Pharmaceutical compositions for oral administration of insulin peptides |
BR112012033107A2 (pt) * | 2010-06-23 | 2016-10-11 | Novo Nordisk As | derivados de insulina contendo ligações dissulfeto adicionais. |
JP5973427B2 (ja) | 2010-06-23 | 2016-08-23 | ノヴォ ノルディスク アー/エス | 追加のジスルフィド結合を含有するインスリン類似体 |
EP2627670A2 (en) | 2010-10-15 | 2013-08-21 | Novo Nordisk A/S | Novel n-terminally modified insulin derivatives |
US20130331320A1 (en) * | 2010-12-14 | 2013-12-12 | Novo Nordisk A/S | Fast-acting insulin in combination with long-acting insulin |
WO2012171994A1 (en) | 2011-06-15 | 2012-12-20 | Novo Nordisk A/S | Multi substituted insulins |
CA2870313A1 (en) | 2012-04-11 | 2013-10-17 | Novo Nordisk A/S | Insulin formulations |
WO2014009316A1 (en) | 2012-07-09 | 2014-01-16 | Novo Nordisk A/S | Novel use of insulin derivatives |
EP2991672A1 (en) | 2013-04-30 | 2016-03-09 | Novo Nordisk A/S | Novel administration regime |
CN105324126A (zh) | 2013-06-21 | 2016-02-10 | 诺和诺德股份有限公司 | Glp-1受体激动剂在用胰岛素治疗的和/或患有1型糖尿病的患者中的新用途 |
WO2015052088A1 (en) * | 2013-10-07 | 2015-04-16 | Novo Nordisk A/S | Novel derivative of an insulin analogue |
CN104587455A (zh) * | 2013-10-31 | 2015-05-06 | 江苏万邦生化医药股份有限公司 | 一种胰岛素制剂 |
FR3013049B1 (fr) | 2013-11-14 | 2015-11-13 | You-Ping Chan | Analogue de l'insuline glargine |
CN105899191B (zh) * | 2014-01-09 | 2020-06-16 | 赛诺菲 | 胰岛素类似物和/或胰岛素衍生物的稳定化不含甘油的药物制剂 |
EP3113791B1 (en) | 2014-03-07 | 2018-12-26 | Jørgensen, Klavs Holger | Novel fast acting insulin preparations |
JO3624B1 (ar) | 2014-05-08 | 2020-08-27 | Lilly Co Eli | تركيبات إنسولين سريعة المفعول |
AR102869A1 (es) | 2014-12-16 | 2017-03-29 | Lilly Co Eli | Composiciones de insulina de rápida acción |
MX2019006463A (es) | 2016-12-16 | 2019-08-14 | Novo Nordisk As | Composiciones farmaceuticas que contienen insulina. |
-
2017
- 2017-12-15 MX MX2019006463A patent/MX2019006463A/es unknown
- 2017-12-15 KR KR1020197016684A patent/KR102374354B1/ko active IP Right Grant
- 2017-12-15 AU AU2017378102A patent/AU2017378102B2/en active Active
- 2017-12-15 HR HRP20221324TT patent/HRP20221324T1/hr unknown
- 2017-12-15 US US15/843,016 patent/US20180169190A1/en not_active Abandoned
- 2017-12-15 ES ES17832941T patent/ES2886837T3/es active Active
- 2017-12-15 EP EP20208962.9A patent/EP3821905B1/en active Active
- 2017-12-15 KR KR1020217021581A patent/KR102580007B1/ko active IP Right Grant
- 2017-12-15 PL PL17832941T patent/PL3554534T3/pl unknown
- 2017-12-15 TW TW106144072A patent/TWI700091B/zh active
- 2017-12-15 DK DK20208962.9T patent/DK3821905T3/da active
- 2017-12-15 EP EP17832941.3A patent/EP3554534B1/en active Active
- 2017-12-15 TW TW108137665A patent/TWI700092B/zh active
- 2017-12-15 CN CN202210905188.9A patent/CN115154591B/zh active Active
- 2017-12-15 RS RS20211060A patent/RS62295B1/sr unknown
- 2017-12-15 MY MYPI2019003286A patent/MY194504A/en unknown
- 2017-12-15 PE PE2020002022A patent/PE20210857A1/es unknown
- 2017-12-15 PT PT178329413T patent/PT3554534T/pt unknown
- 2017-12-15 PL PL20208962.9T patent/PL3821905T3/pl unknown
- 2017-12-15 HU HUE17832941A patent/HUE055231T2/hu unknown
- 2017-12-15 RS RS20221009A patent/RS63773B1/sr unknown
- 2017-12-15 PE PE2019001239A patent/PE20191205A1/es unknown
- 2017-12-15 JP JP2019531948A patent/JP6690062B2/ja active Active
- 2017-12-15 CN CN201780077665.4A patent/CN110087674B/zh active Active
- 2017-12-15 IL IL267224A patent/IL267224B2/en unknown
- 2017-12-15 IL IL300839A patent/IL300839B2/en unknown
- 2017-12-15 SI SI201730873T patent/SI3554534T1/sl unknown
- 2017-12-15 BR BR112019011761-0A patent/BR112019011761A2/pt unknown
- 2017-12-15 WO PCT/EP2017/083013 patent/WO2018109162A1/en active Application Filing
- 2017-12-15 CA CA3046583A patent/CA3046583A1/en active Pending
- 2017-12-15 DK DK17832941.3T patent/DK3554534T3/da active
- 2017-12-15 HU HUE20208962A patent/HUE060149T2/hu unknown
- 2017-12-15 RU RU2019118696A patent/RU2758367C2/ru active
- 2017-12-15 ES ES20208962T patent/ES2930149T3/es active Active
- 2017-12-15 MA MA049116A patent/MA49116A/fr unknown
-
2018
- 2018-06-29 US US16/023,328 patent/US10265385B2/en active Active
-
2019
- 2019-02-20 US US16/280,603 patent/US10596231B2/en active Active
- 2019-06-03 MX MX2021002083A patent/MX2021002083A/es unknown
- 2019-06-05 SA SA520420276A patent/SA520420276B1/ar unknown
- 2019-06-05 SA SA519401933A patent/SA519401933B1/ar unknown
- 2019-06-10 CL CL2019001586A patent/CL2019001586A1/es unknown
- 2019-06-10 CO CO2019006017A patent/CO2019006017A2/es unknown
- 2019-06-14 PH PH12019501363A patent/PH12019501363A1/en unknown
-
2020
- 2020-04-07 JP JP2020068954A patent/JP6788139B2/ja active Active
- 2020-08-04 US US16/984,990 patent/US20200384088A1/en not_active Abandoned
-
2021
- 2021-08-10 HR HRP20211281TT patent/HRP20211281T1/hr unknown
-
2022
- 2022-03-11 US US17/692,238 patent/US20220202909A1/en active Pending
- 2022-08-19 AU AU2022218612A patent/AU2022218612B2/en active Active
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US10259856B2 (en) | 2008-03-18 | 2019-04-16 | Novo Nordisk A/S | Protease stabilized acylated insulin analogues |
US10265385B2 (en) | 2016-12-16 | 2019-04-23 | Novo Nordisk A/S | Insulin containing pharmaceutical compositions |
US10596231B2 (en) | 2016-12-16 | 2020-03-24 | Novo Nordisk A/S | Insulin containing pharmaceutical compositions |
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US10596231B2 (en) | Insulin containing pharmaceutical compositions | |
EP2340033B1 (en) | PREPARATION COMPRISING INSULIN, NICOTINAMIDE AND Arginine | |
RU2691059C2 (ru) | Стабильный состав инсулина глулизин | |
WO2012080320A1 (en) | Fast-acting insulin in combination with long-acting insulin | |
KR20140030125A (ko) | 인슐린, 니코틴아미드 및 아미노산을 포함하는 제제 | |
WO2024112231A1 (ru) | Композиция быстродействующего инсулина (варианты) |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AS | Assignment |
Owner name: NOVO NORDISK A/S, DENMARK Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:NORRMAN, MATHIAS;HOSTRUP, SUSANNE;STEENSGAARD, DORTE BJERRE;AND OTHERS;SIGNING DATES FROM 20180122 TO 20180129;REEL/FRAME:044945/0399 |
|
STPP | Information on status: patent application and granting procedure in general |
Free format text: DOCKETED NEW CASE - READY FOR EXAMINATION |
|
STPP | Information on status: patent application and granting procedure in general |
Free format text: NON FINAL ACTION MAILED |
|
STPP | Information on status: patent application and granting procedure in general |
Free format text: RESPONSE TO NON-FINAL OFFICE ACTION ENTERED AND FORWARDED TO EXAMINER |
|
STPP | Information on status: patent application and granting procedure in general |
Free format text: NON FINAL ACTION MAILED |
|
STCB | Information on status: application discontinuation |
Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION |