DE69535031T2 - Selektive Acylierung von Epsilon-Aminogruppen in Insulin - Google Patents
Selektive Acylierung von Epsilon-Aminogruppen in Insulin Download PDFInfo
- Publication number
- DE69535031T2 DE69535031T2 DE69535031T DE69535031T DE69535031T2 DE 69535031 T2 DE69535031 T2 DE 69535031T2 DE 69535031 T DE69535031 T DE 69535031T DE 69535031 T DE69535031 T DE 69535031T DE 69535031 T2 DE69535031 T2 DE 69535031T2
- Authority
- DE
- Germany
- Prior art keywords
- insulin
- fatty acid
- amino group
- proinsulin
- ester
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
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- 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 description 117
- 108090001061 Insulin Proteins 0.000 title claims description 48
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- 229940125396 insulin Drugs 0.000 title claims description 48
- 230000010933 acylation Effects 0.000 title claims description 46
- 238000005917 acylation reaction Methods 0.000 title claims description 46
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 73
- 238000006243 chemical reaction Methods 0.000 claims description 44
- 235000014113 dietary fatty acids Nutrition 0.000 claims description 34
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- 101000976075 Homo sapiens Insulin Proteins 0.000 claims description 29
- PBGKTOXHQIOBKM-FHFVDXKLSA-N insulin (human) Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@H]1CSSC[C@H]2C(=O)N[C@H](C(=O)N[C@@H](CO)C(=O)N[C@H](C(=O)N[C@H](C(N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=3C=CC(O)=CC=3)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=3C=CC(O)=CC=3)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=3C=CC(O)=CC=3)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=3NC=NC=3)NC(=O)[C@H](CO)NC(=O)CNC1=O)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(O)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O)=O)CSSC[C@@H](C(N2)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](NC(=O)CN)[C@@H](C)CC)[C@@H](C)CC)[C@@H](C)O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)CC=1C=CC=CC=1)C(C)C)C1=CN=CN1 PBGKTOXHQIOBKM-FHFVDXKLSA-N 0.000 claims description 29
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- WSXGQYDHJZKQQB-UHFFFAOYSA-N 3-pyridin-4-ylpropanoic acid Chemical compound OC(=O)CCC1=CC=NC=C1 WSXGQYDHJZKQQB-UHFFFAOYSA-N 0.000 claims description 17
- 239000004026 insulin derivative Substances 0.000 claims description 16
- 150000004665 fatty acids Chemical class 0.000 claims description 14
- 239000002904 solvent Substances 0.000 claims description 10
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- 102000004169 proteins and genes Human genes 0.000 claims description 8
- 108090000623 proteins and genes Proteins 0.000 claims description 8
- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 claims description 6
- WQEPLUUGTLDZJY-UHFFFAOYSA-N n-Pentadecanoic acid Natural products CCCCCCCCCCCCCCC(O)=O WQEPLUUGTLDZJY-UHFFFAOYSA-N 0.000 claims description 5
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- NMHMNPHRMNGLLB-UHFFFAOYSA-N phloretic acid Chemical group OC(=O)CCC1=CC=C(O)C=C1 NMHMNPHRMNGLLB-UHFFFAOYSA-N 0.000 claims 6
- WWZKQHOCKIZLMA-UHFFFAOYSA-M octanoate Chemical compound CCCCCCCC([O-])=O WWZKQHOCKIZLMA-UHFFFAOYSA-M 0.000 claims 1
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- 150000002148 esters Chemical class 0.000 description 29
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 26
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- 125000003277 amino group Chemical group 0.000 description 18
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- 239000013078 crystal Substances 0.000 description 12
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- 238000011179 visual inspection Methods 0.000 description 8
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 7
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 7
- 239000004472 Lysine Substances 0.000 description 7
- 125000000539 amino acid group Chemical group 0.000 description 7
- 239000003795 chemical substances by application Substances 0.000 description 7
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- KYVBNYUBXIEUFW-UHFFFAOYSA-N 1,1,3,3-tetramethylguanidine Chemical group CN(C)C(=N)N(C)C KYVBNYUBXIEUFW-UHFFFAOYSA-N 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
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- 230000037430 deletion Effects 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 230000008451 emotion Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 125000003630 glycyl group Chemical group [H]N([H])C([H])([H])C(*)=O 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 238000007040 multi-step synthesis reaction Methods 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 230000006855 networking Effects 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 238000010647 peptide synthesis reaction Methods 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 230000009145 protein modification Effects 0.000 description 1
- 230000017854 proteolysis Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000036647 reaction Effects 0.000 description 1
- 238000004366 reverse phase liquid chromatography Methods 0.000 description 1
- 238000004007 reversed phase HPLC Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 235000003441 saturated fatty acids Nutrition 0.000 description 1
- 150000004671 saturated fatty acids Chemical class 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 238000010532 solid phase synthesis reaction Methods 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 238000000108 ultra-filtration Methods 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/575—Hormones
- C07K14/62—Insulins
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
- C07K1/107—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length by chemical modification of precursor peptides
- C07K1/1072—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length by chemical modification of precursor peptides by covalent attachment of residues or functional groups
- C07K1/1077—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length by chemical modification of precursor peptides by covalent attachment of residues or functional groups by covalent attachment of residues other than amino acids or peptide residues, e.g. sugars, polyols, fatty acids
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Medicinal Chemistry (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- Genetics & Genomics (AREA)
- Endocrinology (AREA)
- Toxicology (AREA)
- Zoology (AREA)
- Gastroenterology & Hepatology (AREA)
- Diabetes (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Analytical Chemistry (AREA)
- Peptides Or Proteins (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US341231 | 1994-11-17 | ||
| US08/341,231 US5646242A (en) | 1994-11-17 | 1994-11-17 | Selective acylation of epsilon-amino groups |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| DE69535031D1 DE69535031D1 (de) | 2006-07-20 |
| DE69535031T2 true DE69535031T2 (de) | 2006-12-28 |
Family
ID=23336740
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DE69535031T Expired - Lifetime DE69535031T2 (de) | 1994-11-17 | 1995-11-14 | Selektive Acylierung von Epsilon-Aminogruppen in Insulin |
Country Status (27)
| Country | Link |
|---|---|
| US (2) | US5646242A (https=) |
| EP (2) | EP0712862B1 (https=) |
| JP (1) | JP4312828B2 (https=) |
| CN (1) | CN1171742A (https=) |
| AR (1) | AR003915A1 (https=) |
| AT (1) | ATE328902T1 (https=) |
| AU (2) | AU691066B2 (https=) |
| BR (1) | BR9509652A (https=) |
| CA (1) | CA2205061A1 (https=) |
| CO (1) | CO4520285A1 (https=) |
| CZ (1) | CZ287731B6 (https=) |
| DE (1) | DE69535031T2 (https=) |
| DK (1) | DK0712862T3 (https=) |
| ES (1) | ES2264124T3 (https=) |
| HU (2) | HU9903007D0 (https=) |
| IL (1) | IL115972A (https=) |
| IN (1) | IN179820B (https=) |
| NO (1) | NO972185L (https=) |
| NZ (1) | NZ297256A (https=) |
| PL (1) | PL320556A1 (https=) |
| PT (1) | PT712862E (https=) |
| RU (1) | RU2155773C2 (https=) |
| SI (1) | SI0712862T1 (https=) |
| TR (1) | TR199501421A2 (https=) |
| WO (1) | WO1996015803A1 (https=) |
| YU (1) | YU71495A (https=) |
| ZA (1) | ZA959680B (https=) |
Families Citing this family (76)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB9316895D0 (en) | 1993-08-13 | 1993-09-29 | Guy S And St Thomas Hospitals | Hepatoselective insulin analogues |
| US6869930B1 (en) | 1993-09-17 | 2005-03-22 | Novo Nordisk A/S | Acylated insulin |
| US5951974A (en) * | 1993-11-10 | 1999-09-14 | Enzon, Inc. | Interferon polymer conjugates |
| US6251856B1 (en) | 1995-03-17 | 2001-06-26 | Novo Nordisk A/S | Insulin derivatives |
| US5631347A (en) * | 1995-06-07 | 1997-05-20 | Eli Lilly And Company | Reducing gelation of a fatty acid-acylated protein |
| US6451970B1 (en) * | 1996-02-21 | 2002-09-17 | Novo Nordisk A/S | Peptide derivatives |
| ATE278711T1 (de) * | 1996-07-11 | 2004-10-15 | Novo Nordisk As | Verfahren zur selektiven acetylierung |
| US5905140A (en) * | 1996-07-11 | 1999-05-18 | Novo Nordisk A/S, Novo Alle | Selective acylation method |
| JP2001521006A (ja) * | 1997-10-24 | 2001-11-06 | イーライ・リリー・アンド・カンパニー | 不溶性インシュリン組成物 |
| US6444641B1 (en) | 1997-10-24 | 2002-09-03 | Eli Lilly Company | Fatty acid-acylated insulin analogs |
| US5985263A (en) * | 1997-12-19 | 1999-11-16 | Enzon, Inc. | Substantially pure histidine-linked protein polymer conjugates |
| US5981709A (en) * | 1997-12-19 | 1999-11-09 | Enzon, Inc. | α-interferon-polymer-conjugates having enhanced biological activity and methods of preparing the same |
| US6451974B1 (en) | 1999-03-17 | 2002-09-17 | Novo Nordisk A/S | Method of acylating peptides and novel acylating agents |
| WO2000073793A2 (en) * | 1999-05-27 | 2000-12-07 | Cecil Yip | Identification of compounds modulating insulin receptor activity |
| US7169889B1 (en) | 1999-06-19 | 2007-01-30 | Biocon Limited | Insulin prodrugs hydrolyzable in vivo to yield peglylated insulin |
| JP2003532691A (ja) * | 2000-05-05 | 2003-11-05 | ノボ ノルディスク アクティーゼルスカブ | 重症疾患神経障害 |
| US7316999B2 (en) | 2000-06-02 | 2008-01-08 | Novo Nordisk A/S | Glucose dependent release of insulin from glucose sensing insulin derivatives |
| US20030054015A1 (en) * | 2000-12-25 | 2003-03-20 | Shinichiro Haze | Sympathetic-activating perfume composition |
| 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 |
| 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 |
| US6713452B2 (en) * | 2001-06-04 | 2004-03-30 | Nobex Corporation | Mixtures of calcitonin drug-oligomer conjugates comprising polyalkylene glycol, uses thereof, and methods of making same |
| US6835802B2 (en) * | 2001-06-04 | 2004-12-28 | Nobex Corporation | Methods of synthesizing substantially monodispersed mixtures of polymers having polyethylene glycol moieties |
| US7713932B2 (en) | 2001-06-04 | 2010-05-11 | Biocon Limited | Calcitonin drug-oligomer conjugates, and uses thereof |
| US6828305B2 (en) * | 2001-06-04 | 2004-12-07 | Nobex Corporation | Mixtures of growth hormone 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 |
| ATE411337T1 (de) * | 2001-07-24 | 2008-10-15 | Novo Nordisk As | Verfahren zur herstellung acylierter polypeptide |
| US7595172B2 (en) | 2001-07-24 | 2009-09-29 | Novo Nordisk A/S | Method for making acylated polypeptides |
| JP2005503141A (ja) * | 2001-07-24 | 2005-02-03 | ノボ ノルディスク アクティーゼルスカブ | アシル化ポリペプチドを作出するための方法 |
| US20030082671A1 (en) | 2001-07-24 | 2003-05-01 | Thomas Hoeg-Jensen | Method for making acylated polypeptides |
| US6770625B2 (en) | 2001-09-07 | 2004-08-03 | Nobex Corporation | Pharmaceutical compositions of calcitonin drug-oligomer conjugates and methods of treating diseases therewith |
| US7030082B2 (en) * | 2001-09-07 | 2006-04-18 | Nobex Corporation | Pharmaceutical compositions of drug-oligomer conjugates and methods of treating disease therewith |
| UY27439A1 (es) | 2001-09-07 | 2003-04-30 | Nobex Corp | Procedimiento para sintetizar un conjunto de oligomero-polipeptido insulina, conjugado oligomero-polipeptido de proinsulina, composicion de conjugado oligomero-insulina, procedimiento para sintetizar un conjugado oligomero-polipeptido c-peptido, conj |
| US6913903B2 (en) | 2001-09-07 | 2005-07-05 | Nobex Corporation | Methods of synthesizing insulin polypeptide-oligomer conjugates, and proinsulin polypeptide-oligomer conjugates and methods of synthesizing same |
| US7312192B2 (en) | 2001-09-07 | 2007-12-25 | Biocon Limited | Insulin polypeptide-oligomer conjugates, proinsulin polypeptide-oligomer conjugates and methods of synthesizing same |
| US7196059B2 (en) | 2001-09-07 | 2007-03-27 | Biocon Limited | Pharmaceutical compositions of insulin drug-oligomer conjugates and methods of treating diseases therewith |
| US7166571B2 (en) * | 2001-09-07 | 2007-01-23 | Biocon Limited | Insulin polypeptide-oligomer conjugates, proinsulin polypeptide-oligomer conjugates and methods of synthesizing same |
| US20030199445A1 (en) * | 2002-02-07 | 2003-10-23 | Knudsen Lotte Bjerre | Use of GLP-1 compound for treatment of critically ill patients |
| AU2003236521A1 (en) | 2002-06-13 | 2003-12-31 | Nobex Corporation | Methods of reducing hypoglycemic episodes in the treatment of diabetes mellitus |
| US7273921B2 (en) | 2002-09-25 | 2007-09-25 | Novo Nordisk A/S | Method for producing acylated peptides |
| EP1546090B1 (en) * | 2002-09-25 | 2009-06-24 | Novo Nordisk A/S | Method for producing acylated peptides |
| CA2531988C (en) * | 2003-08-05 | 2016-06-28 | Novo Nordisk A/S | Novel insulin derivatives |
| EP1687428A1 (en) | 2003-11-14 | 2006-08-09 | Novo Nordisk A/S | Processes for making acylated insulin |
| RU2527893C2 (ru) | 2004-07-19 | 2014-09-10 | Биокон Лимитед | Инсулин-олигомерные конъюгаты, их препараты и применения |
| CN102660614A (zh) | 2005-08-16 | 2012-09-12 | 诺沃-诺迪斯克有限公司 | 制备成熟胰岛素多肽的方法 |
| ES2371361T3 (es) * | 2005-12-28 | 2011-12-30 | Novo Nordisk A/S | Composiciones que comprenden una insulina acilada y zinc y método de producción de dichas composiciones. |
| DE602007009496D1 (de) * | 2006-02-27 | 2010-11-11 | Novo Nordisk As | Insulinderivate |
| WO2007121318A2 (en) * | 2006-04-12 | 2007-10-25 | Emisphere Technologies, Inc. | Formulations for delivering insulin |
| CN101573133B (zh) | 2006-07-31 | 2014-08-27 | 诺沃-诺迪斯克有限公司 | Peg化延长的胰岛素 |
| RU2524150C2 (ru) | 2006-09-22 | 2014-07-27 | Ново Нордиск А/С | Аналоги инсулина, устойчивые к протеазам |
| EP2069502B1 (en) | 2006-09-27 | 2014-02-26 | Novo Nordisk A/S | Method for making maturated insulin polypeptides |
| JP5496082B2 (ja) | 2007-04-30 | 2014-05-21 | ノボ・ノルデイスク・エー／エス | タンパク質組成物を乾燥させる方法、乾燥タンパク質組成物、及び乾燥タンパク質を含有する薬学的組成物 |
| JP5552046B2 (ja) | 2007-06-13 | 2014-07-16 | ノボ・ノルデイスク・エー／エス | インスリン誘導体を含有する薬学的製剤 |
| RU2453332C2 (ru) | 2007-10-16 | 2012-06-20 | Байокон Лимитид | Твердая фармацевтическая композиция (варианты) и способ контроля концентрации глюкозы с ее помощью, способ получения твердой фармацевтической композиции (варианты), таблетка (варианты) и способ получения амфорных частиц |
| WO2009112583A2 (en) | 2008-03-14 | 2009-09-17 | Novo Nordisk A/S | Protease-stabilized insulin analogues |
| HUE032284T2 (en) | 2008-03-18 | 2017-09-28 | Novo Nordisk As | Protease-stabilized, acylated insulin analogues |
| ES2561208T3 (es) | 2008-09-12 | 2016-02-25 | Novo Nordisk A/S | Método de acilación de un péptido o una proteína |
| JP4959005B2 (ja) * | 2008-10-30 | 2012-06-20 | ノボ・ノルデイスク・エー／エス | 毎日の注射頻度より少ないインスリン注射での真性糖尿病の治療 |
| CN102325544A (zh) * | 2009-02-20 | 2012-01-18 | 益普生制药股份有限公司 | 具有34位脯氨酸替换的神经肽y的类似物 |
| WO2011064316A2 (en) | 2009-11-25 | 2011-06-03 | Paolo Botti | Mucosal delivery of peptides |
| DK2632478T3 (da) | 2010-10-27 | 2019-10-07 | Novo Nordisk As | Behandling af diabetes melitus under anvendelse af insulinindsprøjtninger indgivet med varierende indsprøjtningsintervaller |
| CN104364260B (zh) | 2012-04-11 | 2017-02-22 | 诺和诺德股份有限公司 | 胰岛素制剂 |
| EP2991672A1 (en) | 2013-04-30 | 2016-03-09 | Novo Nordisk A/S | Novel administration regime |
| JP6499184B2 (ja) | 2013-10-07 | 2019-04-10 | ノヴォ ノルディスク アー／エス | インスリン類似体の新規な誘導体 |
| FR3013049B1 (fr) | 2013-11-14 | 2015-11-13 | You-Ping Chan | Analogue de l'insuline glargine |
| AR099569A1 (es) | 2014-02-28 | 2016-08-03 | Novo Nordisk As | Derivados de insulina y los usos médicos de estos |
| CN104558097A (zh) * | 2014-05-20 | 2015-04-29 | 广东东阳光药业有限公司 | 肽的酰化方法 |
| CN105111305B (zh) * | 2015-10-10 | 2018-12-14 | 山东阿华生物药业有限公司 | 酰化胰岛素的色谱纯化方法 |
| CN105440125B (zh) * | 2015-11-25 | 2019-09-24 | 华润昂德生物药业有限公司 | 地特胰岛素或其类似物的制备方法 |
| US10724025B2 (en) | 2016-05-05 | 2020-07-28 | Codexis, Inc. | Penicillin-G acylases |
| ES2828526T3 (es) | 2016-11-07 | 2021-05-26 | Novo Nordisk As | Esteres activos DCHBS de compuestos PEG y sus usos |
| PE20210857A1 (es) | 2016-12-16 | 2021-05-18 | Novo Nordisk As | Composiciones farmaceuticas que contienen insulina |
| CN107602437A (zh) * | 2017-08-09 | 2018-01-19 | 上海昂德生物科技有限公司 | 活化酯的制备方法 |
| US10335464B1 (en) | 2018-06-26 | 2019-07-02 | Novo Nordisk A/S | Device for titrating basal insulin |
| US12343383B2 (en) | 2019-07-12 | 2025-07-01 | Novo Nordisk A/S | High concentration insulin formulation |
| CN116874585B (zh) * | 2023-09-06 | 2023-12-15 | 杭州湃肽生化科技有限公司 | 一种地特胰岛素的合成方法 |
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| FR1468831A (fr) * | 1965-10-05 | 1967-02-10 | Roussel Uclaf | Procédé de préparation de nouveaux composés polypeptidiques et produits en résultant |
| DE1902865A1 (de) * | 1968-02-01 | 1969-09-11 | American Home Prod | Substituierte Insulin-Derivate,Verfahren zu ihrer Herstellung und ihre Verwendung in pharmazeutischen Zubereitungen |
| US3591574A (en) * | 1968-05-29 | 1971-07-06 | American Home Prod | Tri-n-phenylglycyl derivatives of insulin |
| US3528960A (en) * | 1968-10-07 | 1970-09-15 | Lilly Co Eli | N-carboxyaroyl insulins |
| US3823125A (en) * | 1969-10-14 | 1974-07-09 | American Home Prod | N-aminoacyl-substituted insulins |
| US3752798A (en) * | 1969-12-02 | 1973-08-14 | G Amird | Tris-na1,nb1,nepsilonb29 - (3-x-3-oxo - 1-y-prop-1-en-1-yl)(ndelta-(4-z-6-r-pyrimidin - 2 - yl) ornithine b22)-insulins and their preparation |
| 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 |
| GB1381273A (en) * | 1971-01-28 | 1975-01-22 | Nat Res Dev | Insulin derivatives |
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| BE791949A (fr) * | 1971-11-27 | 1973-05-28 | Schering Ag | Derives d'insuline, leur preparation et leur utilisation |
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| US5905140A (en) | 1996-07-11 | 1999-05-18 | Novo Nordisk A/S, Novo Alle | Selective acylation method |
-
1994
- 1994-11-17 US US08/341,231 patent/US5646242A/en not_active Ceased
-
1995
- 1995-11-14 PT PT95308167T patent/PT712862E/pt unknown
- 1995-11-14 YU YU71495A patent/YU71495A/sh unknown
- 1995-11-14 CZ CZ19971456A patent/CZ287731B6/cs not_active IP Right Cessation
- 1995-11-14 EP EP95308167A patent/EP0712862B1/en not_active Expired - Lifetime
- 1995-11-14 NZ NZ297256A patent/NZ297256A/xx active IP Right Revival
- 1995-11-14 HU HU9903007A patent/HU9903007D0/hu unknown
- 1995-11-14 IN IN1452CA1995 patent/IN179820B/en unknown
- 1995-11-14 WO PCT/US1995/014872 patent/WO1996015803A1/en not_active Ceased
- 1995-11-14 AR ARP950100165A patent/AR003915A1/es not_active Application Discontinuation
- 1995-11-14 PL PL95320556A patent/PL320556A1/xx unknown
- 1995-11-14 RU RU97110075/04A patent/RU2155773C2/ru active
- 1995-11-14 ES ES95308167T patent/ES2264124T3/es not_active Expired - Lifetime
- 1995-11-14 TR TR95/01421A patent/TR199501421A2/xx unknown
- 1995-11-14 DK DK95308167T patent/DK0712862T3/da active
- 1995-11-14 BR BR9509652A patent/BR9509652A/pt not_active Application Discontinuation
- 1995-11-14 CA CA002205061A patent/CA2205061A1/en not_active Abandoned
- 1995-11-14 JP JP51696396A patent/JP4312828B2/ja not_active Expired - Lifetime
- 1995-11-14 ZA ZA959680A patent/ZA959680B/xx unknown
- 1995-11-14 EP EP02000258A patent/EP1227107A1/en not_active Ceased
- 1995-11-14 HU HU9800566A patent/HU217585B/hu not_active IP Right Cessation
- 1995-11-14 IL IL11597295A patent/IL115972A/xx unknown
- 1995-11-14 AT AT95308167T patent/ATE328902T1/de active
- 1995-11-14 CN CN95197224A patent/CN1171742A/zh active Pending
- 1995-11-14 DE DE69535031T patent/DE69535031T2/de not_active Expired - Lifetime
- 1995-11-14 AU AU42372/96A patent/AU691066B2/en not_active Revoked
- 1995-11-14 SI SI9530727T patent/SI0712862T1/sl unknown
- 1995-11-14 CO CO95053590A patent/CO4520285A1/es unknown
-
1997
- 1997-05-13 NO NO972185A patent/NO972185L/no not_active Application Discontinuation
-
1998
- 1998-08-07 AU AU78854/98A patent/AU720820B2/en not_active Ceased
-
1999
- 1999-07-08 US US09/351,103 patent/USRE37971E1/en not_active Expired - Lifetime
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