HRP20000236A2 - Insoluble insulin compositions - Google Patents
Insoluble insulin compositions Download PDFInfo
- Publication number
- HRP20000236A2 HRP20000236A2 HR20000236A HRP20000236A HRP20000236A2 HR P20000236 A2 HRP20000236 A2 HR P20000236A2 HR 20000236 A HR20000236 A HR 20000236A HR P20000236 A HRP20000236 A HR P20000236A HR P20000236 A2 HRP20000236 A2 HR P20000236A2
- Authority
- HR
- Croatia
- Prior art keywords
- insulin
- acylated
- human insulin
- fatty acid
- acid
- Prior art date
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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 352
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- 101000976075 Homo sapiens Insulin Proteins 0.000 claims description 445
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- 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 description 303
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- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- WGIWBXUNRXCYRA-UHFFFAOYSA-H trizinc;2-hydroxypropane-1,2,3-tricarboxylate Chemical compound [Zn+2].[Zn+2].[Zn+2].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O.[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O WGIWBXUNRXCYRA-UHFFFAOYSA-H 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- 229940072651 tylenol Drugs 0.000 description 1
- 238000000870 ultraviolet spectroscopy Methods 0.000 description 1
- 125000000297 undecanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 239000004246 zinc acetate Substances 0.000 description 1
- 229960000314 zinc acetate Drugs 0.000 description 1
- 235000013904 zinc acetate Nutrition 0.000 description 1
- 229960001939 zinc chloride Drugs 0.000 description 1
- 239000011746 zinc citrate Substances 0.000 description 1
- 235000006076 zinc citrate Nutrition 0.000 description 1
- 229940068475 zinc citrate Drugs 0.000 description 1
- 229960001296 zinc oxide Drugs 0.000 description 1
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
- 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
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
- A61P5/50—Drugs for disorders of the endocrine system of the pancreatic hormones for increasing or potentiating the activity of insulin
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Diabetes (AREA)
- General Health & Medical Sciences (AREA)
- Endocrinology (AREA)
- Medicinal Chemistry (AREA)
- Organic Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Gastroenterology & Hepatology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Zoology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Immunology (AREA)
- Epidemiology (AREA)
- Toxicology (AREA)
- Biochemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Molecular Biology (AREA)
- Genetics & Genomics (AREA)
- Biophysics (AREA)
- Obesity (AREA)
- Emergency Medicine (AREA)
- Hematology (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
- Medicinal Preparation (AREA)
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US6310497P | 1997-10-24 | 1997-10-24 | |
US8893098P | 1998-06-11 | 1998-06-11 | |
PCT/US1998/022434 WO1999021578A1 (en) | 1997-10-24 | 1998-10-22 | Insoluble insulin compositions |
Publications (1)
Publication Number | Publication Date |
---|---|
HRP20000236A2 true HRP20000236A2 (en) | 2001-02-28 |
Family
ID=26743043
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
HR20000236A HRP20000236A2 (en) | 1997-10-24 | 2000-04-21 | Insoluble insulin compositions |
Country Status (21)
Country | Link |
---|---|
US (3) | US6268335B1 (hu) |
EP (1) | EP1039920A4 (hu) |
JP (2) | JP2001521004A (hu) |
KR (1) | KR20010024556A (hu) |
CN (1) | CN1276731A (hu) |
AR (1) | AR020047A1 (hu) |
AU (2) | AU1111799A (hu) |
BR (1) | BR9813111A (hu) |
CA (2) | CA2306905A1 (hu) |
CO (1) | CO4970769A1 (hu) |
EA (1) | EA200000453A1 (hu) |
HR (1) | HRP20000236A2 (hu) |
HU (1) | HUP0004169A3 (hu) |
ID (1) | ID24890A (hu) |
IL (1) | IL134901A0 (hu) |
NO (1) | NO20002038L (hu) |
PE (1) | PE123799A1 (hu) |
PL (1) | PL340255A1 (hu) |
SV (1) | SV1998000125A (hu) |
TR (1) | TR200001050T2 (hu) |
WO (2) | WO1999021573A1 (hu) |
Families Citing this family (109)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6444641B1 (en) | 1997-10-24 | 2002-09-03 | Eli Lilly Company | Fatty acid-acylated insulin analogs |
US6531448B1 (en) | 1997-12-23 | 2003-03-11 | Eli Lilly And Company | Insoluble compositions for controlling blood glucose |
US7169889B1 (en) * | 1999-06-19 | 2007-01-30 | Biocon Limited | Insulin prodrugs hydrolyzable in vivo to yield peglylated insulin |
CN1406131A (zh) * | 2000-12-25 | 2003-03-26 | 株式会社资生堂 | 活化交感神经的香料组合物 |
US7060675B2 (en) * | 2001-02-15 | 2006-06-13 | Nobex Corporation | Methods of treating diabetes mellitus |
US20020155614A1 (en) * | 2001-02-21 | 2002-10-24 | Tomlinson Andrew J. | Peptide esterification |
US6835802B2 (en) | 2001-06-04 | 2004-12-28 | Nobex Corporation | Methods of synthesizing substantially monodispersed mixtures of polymers having polyethylene glycol moieties |
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 |
US7713932B2 (en) | 2001-06-04 | 2010-05-11 | Biocon Limited | Calcitonin drug-oligomer conjugates, and uses thereof |
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 |
MXPA04001560A (es) * | 2001-08-28 | 2004-05-17 | Lilly Co Eli | Premezclas de glp-1 e insulina basal. |
US7312192B2 (en) * | 2001-09-07 | 2007-12-25 | Biocon Limited | Insulin polypeptide-oligomer conjugates, proinsulin polypeptide-oligomer conjugates and methods of synthesizing same |
US7030082B2 (en) * | 2001-09-07 | 2006-04-18 | Nobex Corporation | Pharmaceutical compositions of drug-oligomer conjugates and methods of treating disease therewith |
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 |
US6770625B2 (en) | 2001-09-07 | 2004-08-03 | Nobex Corporation | Pharmaceutical compositions of calcitonin 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 |
WO2003024425A1 (en) * | 2001-09-19 | 2003-03-27 | Elan Pharma International, Ltd. | Nanoparticulate insulin formulations |
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 |
US20040038864A1 (en) * | 2002-06-27 | 2004-02-26 | Per Balschmidt | Use of dimethyl sulfone as isotonicity agent |
WO2004080481A1 (en) * | 2003-03-13 | 2004-09-23 | Novo Nordisk A/S | Novel nph insulin preparations |
US20060258561A1 (en) * | 2003-03-13 | 2006-11-16 | Novo Nordisk A/S | Novel NPH insulin preparations |
US20050054818A1 (en) * | 2003-07-02 | 2005-03-10 | Brader Mark Laurence | Crystalline compositions for controlling blood glucose |
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 |
ATE517119T1 (de) * | 2003-12-03 | 2011-08-15 | Novo Nordisk As | Einzelketteninsulin |
UA103758C2 (ru) | 2004-07-19 | 2013-11-25 | Биокон Лимитед | Конъюгаты олигомеров инсулина, их композиции и применение |
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 |
EP1679065A1 (en) * | 2005-01-07 | 2006-07-12 | OctoPlus Sciences B.V. | Controlled release compositions for interferon based on PEGT/PBT block copolymers |
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 |
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 |
US8927015B2 (en) * | 2006-04-12 | 2015-01-06 | Emisphere Technologies, Inc. | Formulations for delivering insulin |
EP2023947A4 (en) * | 2006-05-10 | 2009-11-25 | Smithkline Beecham Corp | COMPOSITION AND METHOD IMPROVING THE CELL PERMEABILITY OF A COMPOUND |
WO2007135118A1 (en) * | 2006-05-24 | 2007-11-29 | Novo Nordisk A/S | Soluble, stable insulin-containing formulations |
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 |
ES2744384T3 (es) | 2007-06-13 | 2020-02-24 | Novo Nordisk As | Formulación farmacéutica que comprende un derivado de insulina |
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 |
BRPI0818004B8 (pt) | 2007-10-16 | 2021-05-25 | Biocon Ltd | composição farmacêutica sólida administrável por via oral e o processo da mesma. |
BRPI0907371A2 (pt) | 2008-01-09 | 2015-11-24 | Sanofi Aventis Deutschland | derivados de insulina com um perfil de tempo-ação muito retardado |
DE102008003566A1 (de) * | 2008-01-09 | 2009-07-16 | Sanofi-Aventis Deutschland Gmbh | Neue Insulinderivate mit extrem verzögertem Zeit-/ Wirkungsprofil |
NZ586589A (en) | 2008-01-09 | 2012-04-27 | Sanofi Aventis Deutschland | Novel insulin analogues having an extremely delayed time-action profile |
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 |
AU2009240636A1 (en) * | 2008-04-22 | 2009-10-29 | Case Western Reserve University | Isoform-specific insulin analogues |
US9200053B2 (en) | 2008-07-31 | 2015-12-01 | Case Western Reserve University | Insulin analogues containing penta-fluoro-Phenylalanine at position B24 |
KR20120129875A (ko) | 2008-07-31 | 2012-11-28 | 케이스 웨스턴 리저브 유니버시티 | 염소화 아미노산을 갖는 인슐린 유사체 |
DK2349324T3 (en) | 2008-10-17 | 2017-12-11 | Sanofi Aventis Deutschland | COMBINATION OF AN INSULIN AND A GLP-1 AGONIST |
US9603904B2 (en) | 2008-10-30 | 2017-03-28 | Novo Nordisk A/S | Treating diabetes melitus using insulin injections with less than daily injection frequency |
MA33064B1 (fr) | 2009-01-28 | 2012-02-01 | Smartcells Inc | Systemes à base de conjugués pour administration contrôlée de médicaments |
WO2010088286A1 (en) | 2009-01-28 | 2010-08-05 | Smartcells, Inc. | Synthetic conjugates and uses thereof |
US20100198188A1 (en) * | 2009-02-05 | 2010-08-05 | Abbott Diabetes Care Inc. | Devices and Methods for Metering Insoluble Active Agent Particles |
WO2010107519A1 (en) | 2009-03-20 | 2010-09-23 | Smartcells, Inc. | Terminally-functionalized conjugates and uses thereof |
US20120241356A1 (en) * | 2009-07-06 | 2012-09-27 | Sanofi-Aventis Deutschland Gmbh | Heat- and vibration-stable insulin preparations |
TW201113032A (en) * | 2009-07-06 | 2011-04-16 | Sanofi Aventis Deutschland | Slow-acting insulin preparations |
US8399407B2 (en) * | 2009-09-17 | 2013-03-19 | Case Western Reserve University | Non-standard insulin analogues |
KR101836070B1 (ko) | 2009-11-13 | 2018-03-09 | 사노피-아벤티스 도이칠란트 게엠베하 | Glp-1 작용제, 인슐린 및 메티오닌을 포함하는 약제학적 조성물 |
JP5973918B2 (ja) | 2009-11-13 | 2016-08-23 | サノフィ−アベンティス・ドイチュラント・ゲゼルシャフト・ミット・ベシュレンクテル・ハフツング | Glp−1アゴニスト及びメチオニンを含む薬学的組成物 |
WO2011064316A2 (en) | 2009-11-25 | 2011-06-03 | Paolo Botti | Mucosal delivery of peptides |
CN102762589A (zh) * | 2009-12-11 | 2012-10-31 | 卡斯西部储备大学 | 带有氯化氨基酸的胰岛素类似物 |
AU2011202239C1 (en) | 2010-05-19 | 2017-03-16 | Sanofi | Long-acting formulations of insulins |
BR112012033107A2 (pt) | 2010-06-23 | 2016-10-11 | Novo Nordisk As | derivados de insulina contendo ligações dissulfeto adicionais. |
PT2611458T (pt) | 2010-08-30 | 2016-12-16 | Sanofi Aventis Deutschland | Utilização de ave0010 para o fabrico de um medicamento para o tratamento da diabetes mellitus tipo 2 |
BR112013010345A2 (pt) | 2010-10-27 | 2017-07-25 | Novo Nordisk As | tratamento de diabetes melitus usando as injeções de insulina administradas com intervalos de variação da injeção |
US9821032B2 (en) | 2011-05-13 | 2017-11-21 | Sanofi-Aventis Deutschland Gmbh | Pharmaceutical combination for improving glycemic control as add-on therapy to basal insulin |
WO2012171994A1 (en) | 2011-06-15 | 2012-12-20 | Novo Nordisk A/S | Multi substituted insulins |
CN108079281A (zh) | 2011-08-29 | 2018-05-29 | 赛诺菲-安万特德国有限公司 | 用于2型糖尿病患者中的血糖控制的药物组合 |
AR087744A1 (es) | 2011-09-01 | 2014-04-16 | Sanofi Aventis Deutschland | Composicion farmaceutica para uso en el tratamiento de una enfermedad neurodegenerativa |
CA2870313A1 (en) | 2012-04-11 | 2013-10-17 | Novo Nordisk A/S | Insulin formulations |
EP2925345B1 (en) | 2012-12-03 | 2018-09-05 | Merck Sharp & Dohme Corp. | Method for making o-glycosylated carboxy terminal portion (ctp) peptide-based insulin and insulin analogues |
TWI641381B (zh) | 2013-02-04 | 2018-11-21 | 法商賽諾菲公司 | 胰島素類似物及/或胰島素衍生物之穩定化醫藥調配物 |
EP3517122A1 (en) | 2013-04-03 | 2019-07-31 | Sanofi | Treatment of diabetes mellitus by long-acting formulations of insulins |
EP2991672A1 (en) | 2013-04-30 | 2016-03-09 | Novo Nordisk A/S | Novel administration regime |
WO2015052088A1 (en) | 2013-10-07 | 2015-04-16 | Novo Nordisk A/S | Novel derivative of an insulin analogue |
SG11201604710XA (en) | 2014-01-09 | 2016-07-28 | Sanofi Sa | Stabilized pharmaceutical formulations of insulin analogues and/or insulin derivatives |
CN114939156A (zh) | 2014-01-09 | 2022-08-26 | 赛诺菲 | 门冬胰岛素的稳定化药物制剂 |
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 |
AR099569A1 (es) | 2014-02-28 | 2016-08-03 | Novo Nordisk As | Derivados de insulina y los usos médicos de estos |
WO2016025459A2 (en) * | 2014-08-11 | 2016-02-18 | Albany Medical College | Myristoylated leptin-related peptides and uses thereof |
BR112017004544A2 (pt) | 2014-10-06 | 2018-01-23 | Univ Case Western Reserve | insulina de cadeia simples, composição farmacêutica e método para tratar diabetes mellitus |
CN107206058A (zh) | 2014-12-12 | 2017-09-26 | 赛诺菲-安万特德国有限公司 | 甘精胰岛素/利西拉来固定比率配制剂 |
CN105884879A (zh) * | 2015-01-26 | 2016-08-24 | 漳州博欣生物技术有限公司 | 一种胰岛素类似物的化学合成方法 |
TWI748945B (zh) | 2015-03-13 | 2021-12-11 | 德商賽諾菲阿凡提斯德意志有限公司 | 第2型糖尿病病患治療 |
TW201705975A (zh) | 2015-03-18 | 2017-02-16 | 賽諾菲阿凡提斯德意志有限公司 | 第2型糖尿病病患之治療 |
JP2018531900A (ja) | 2015-08-25 | 2018-11-01 | ノヴォ ノルディスク アー/エス | 新規インスリン誘導体及びその医学的使用 |
CN105597087B (zh) * | 2016-01-06 | 2019-04-26 | 山东新时代药业有限公司 | 一种甘精胰岛素注射液及其制备方法 |
US11230585B2 (en) | 2016-09-06 | 2022-01-25 | Chemical & Biopharmaceutical Laboratories Of Patra | Proinsulin derivatives |
ES2932498T3 (es) | 2016-12-05 | 2023-01-20 | Nuritas Ltd | Composiciones que comprenden el péptido WKDEAGKPLVK |
EP3329930A1 (en) | 2016-12-05 | 2018-06-06 | Nuritas Limited | Pharmaceuctical compositions |
MX2019006463A (es) | 2016-12-16 | 2019-08-14 | Novo Nordisk As | Composiciones farmaceuticas que contienen insulina. |
WO2018200462A1 (en) * | 2017-04-24 | 2018-11-01 | Friedman Simon H | Drug conjugates with photocleavable solubility modulators |
JOP20190273A1 (ar) * | 2017-05-26 | 2019-11-24 | Lilly Co Eli | مركب إنسولين معالج بأسيل |
WO2019125879A2 (en) | 2017-12-18 | 2019-06-27 | Merck Sharp & Dohme Corp. | Conjugate based systems for controlled insulin delivery |
EP3727424A4 (en) | 2017-12-18 | 2021-10-27 | Merck Sharp & Dohme Corp. | CONJUGATE-BASED SYSTEMS FOR CONTROLLED INSULIN RELEASE |
US20190343768A1 (en) * | 2018-05-14 | 2019-11-14 | Dance Biopharm Inc. | Insulin formulations for reconstitution into high concentration liquid solutions |
US10335464B1 (en) | 2018-06-26 | 2019-07-02 | Novo Nordisk A/S | Device for titrating basal insulin |
CA3122637A1 (en) | 2018-12-11 | 2020-06-18 | Sanofi | Peptide binder |
CN110063932A (zh) * | 2019-04-12 | 2019-07-30 | 浙江大学 | 一种多肽蛋白类药物的缓释组合物制剂及其制备方法 |
BR112022009510A2 (pt) | 2019-12-11 | 2022-08-16 | Novo Nordisk As | Análogo de insulina, composição farmacêutica, e, método de tratamento, prevenção ou alívio de uma doença ou distúrbio ou condição |
AU2021247169A1 (en) | 2020-03-31 | 2022-10-20 | Protomer Technologies Inc. | Conjugates for selective responsiveness to vicinal diols |
CN115867308A (zh) * | 2020-05-15 | 2023-03-28 | 伊莱利利公司 | 延时作用的酰化胰岛素化合物 |
CA3198757A1 (en) | 2020-11-19 | 2022-05-27 | Protomer Technologies Inc. | Aromatic boron-containing compounds and insulin analogs |
US20240043493A1 (en) * | 2020-12-07 | 2024-02-08 | Case Western Reserve University | Acylated single-chain insulin analogues |
TW202409070A (zh) | 2022-05-18 | 2024-03-01 | 美商普羅托莫科技公司 | 芳族含硼化合物及相關胰島素類似物 |
Family Cites Families (45)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2538018A (en) | 1944-04-04 | 1951-01-16 | Nordisk Insulinlab | Crystalline product of insulin and alkaline protein and process of making it |
US2801953A (en) | 1952-02-28 | 1957-08-06 | Hoechst Ag | Process of preparing crystallized insulin preparations |
US2849370A (en) | 1953-06-04 | 1958-08-26 | Novo Terapeutisk Labortorium A | Injectable insulin preparations with protracted effect and process of producing same |
US3102077A (en) | 1953-08-19 | 1963-08-27 | Christensen Henry Marinus | Preparation of insulin containing 2.75 to 8 percent zinc content |
US3060093A (en) | 1957-07-18 | 1962-10-23 | Nordisk Insulinlab | Slowly acting insulin preparation in crystalline form and method of preparation |
DE1793517C3 (de) | 1968-09-28 | 1974-12-05 | Farbwerke Hoechst Ag, Vormals Meister Lucius & Bruening, 6000 Frankfurt | N(Al),N(B29>Bis-(tert.-butyloxycarbonyl)-insulin und Verfahren zu seiner Herstellung |
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 |
US3950517A (en) | 1970-05-08 | 1976-04-13 | National Research Development Corporation | Insulin derivatives |
GB1381274A (en) | 1971-01-28 | 1975-01-22 | Nat Res Dev | Insulin derivatives |
US3868358A (en) | 1971-04-30 | 1975-02-25 | Lilly Co Eli | Protamine-insulin product |
US3865325A (en) | 1971-07-02 | 1975-02-11 | Dylaker Computer Systems Inc | Flexible tape reel |
US3907763A (en) | 1972-03-01 | 1975-09-23 | Bayer Ag | Insulin derivatives crosslinked by a dicarboxylic acid moiety |
US4183849A (en) | 1975-01-15 | 1980-01-15 | Nordisk Insulinlaboratorium | Therapeutic insulin preparation and a process for the production of a stable insulin preparation with protracted effect |
JPS55138391A (en) | 1979-04-13 | 1980-10-29 | Shionogi & Co Ltd | New synthetic method of peptide derivative |
JPS55138393A (en) | 1979-04-13 | 1980-10-29 | Shionogi & Co Ltd | Semisynthesis of insulin |
US4343898A (en) | 1980-02-11 | 1982-08-10 | Novo Industri A/S | Process for preparing esters of human insulin |
DE3101382A1 (de) | 1981-01-17 | 1982-09-02 | Hoechst Ag, 6000 Frankfurt | "verfahren zur herstellung von humanisulin oder dessen derivaten aus schweineinsulin oder dessen derivaten" |
DK353781A (da) | 1981-08-10 | 1983-02-11 | Novo Industri As | Fremgangsmaade til fremstilling af insulinderivater |
IT1189353B (it) | 1982-06-07 | 1988-02-04 | Nordisk Insulinlab | Procedimento per la preparazione di insulina umana e suoi esteri |
DE3326473A1 (de) | 1983-07-22 | 1985-01-31 | Hoechst Ag, 6230 Frankfurt | Pharmazeutisches mittel zur behandlung des diabetes mellitus |
DE3327709A1 (de) * | 1983-07-29 | 1985-02-07 | Hoechst Ag, 6230 Frankfurt | Insulin-derivat-kristallsuspensionen, verfahren zu deren herstellung und deren verwendung |
US4946828A (en) * | 1985-03-12 | 1990-08-07 | Novo Nordisk A/S | Novel insulin peptides |
PH25772A (en) | 1985-08-30 | 1991-10-18 | Novo Industri As | Insulin analogues, process for their preparation |
JPH01254699A (ja) | 1988-04-05 | 1989-10-11 | Kodama Kk | インスリン誘導体及びその用途 |
EP0425482B1 (en) | 1988-07-20 | 1993-08-18 | Novo Nordisk A/S | Human insulin analogs and preparations containing them |
DE3837825A1 (de) * | 1988-11-08 | 1990-05-10 | Hoechst Ag | Neue insulinderivate, ihre verwendung und eine sie enthaltende pharmazeutische zubereitung |
WO1990007522A1 (en) | 1988-12-23 | 1990-07-12 | Novo Nordisk A/S | Human insulin analogues |
NZ232375A (en) | 1989-02-09 | 1992-04-28 | Lilly Co Eli | Insulin analogues modified at b29 |
US5514646A (en) | 1989-02-09 | 1996-05-07 | Chance; Ronald E. | Insulin analogs modified at position 29 of the B chain |
DK134189D0 (da) | 1989-03-20 | 1989-03-20 | Nordisk Gentofte | Insulinforbindelser |
DK72793D0 (da) | 1993-06-21 | 1993-06-21 | Novo Nordisk As | Nyt produkt |
DE122006000015I1 (de) | 1993-06-21 | 2006-06-29 | Novo Nordisk As | Asp-B28-Insulinkristalle |
KR100310122B1 (ko) * | 1993-09-17 | 2002-04-24 | 한센 핀 베네드, 안네 제헤르, 웨이콥 마리안느 | 아실화된인슐린 |
US5474978A (en) | 1994-06-16 | 1995-12-12 | Eli Lilly And Company | Insulin analog formulations |
US5461031A (en) * | 1994-06-16 | 1995-10-24 | Eli Lilly And Company | Monomeric insulin analog formulations |
US5597893A (en) | 1994-10-31 | 1997-01-28 | Eli Lilly And Company | Preparation of stable insulin analog crystals |
US5693609A (en) * | 1994-11-17 | 1997-12-02 | Eli Lilly And Company | Acylated insulin analogs |
US5646242A (en) * | 1994-11-17 | 1997-07-08 | Eli Lilly And Company | Selective acylation of epsilon-amino groups |
CZ289343B6 (cs) * | 1995-03-17 | 2002-01-16 | Novo Nordisk A/S | Inzulinový derivát a farmaceutický prostředek pro léčení diabetes |
US5700904A (en) * | 1995-06-07 | 1997-12-23 | Eli Lilly And Company | Preparation of an acylated protein powder |
US5877153A (en) | 1996-06-11 | 1999-03-02 | Commonwealth Biotechnologies Inc. | Heparin-binding peptides |
CA2258099A1 (en) | 1996-06-20 | 1997-12-24 | Novo Nordisk A/S | Insulin preparations containing carbohydrates |
US5948751A (en) | 1996-06-20 | 1999-09-07 | Novo Nordisk A/S | X14-mannitol |
JP3343129B2 (ja) | 1997-02-07 | 2002-11-11 | ノボ ノルディスク アクティーゼルスカブ | タンパク質の結晶化 |
ZA989744B (en) | 1997-10-31 | 2000-04-26 | Lilly Co Eli | Method for administering acylated insulin. |
-
1998
- 1998-10-22 PE PE1998000996A patent/PE123799A1/es not_active Application Discontinuation
- 1998-10-22 US US09/177,685 patent/US6268335B1/en not_active Expired - Lifetime
- 1998-10-22 BR BR9813111-7A patent/BR9813111A/pt not_active IP Right Cessation
- 1998-10-22 CA CA002306905A patent/CA2306905A1/en not_active Abandoned
- 1998-10-22 CA CA002306877A patent/CA2306877A1/en not_active Abandoned
- 1998-10-22 SV SV1998000125A patent/SV1998000125A/es unknown
- 1998-10-22 CN CN98810334A patent/CN1276731A/zh active Pending
- 1998-10-22 AU AU11117/99A patent/AU1111799A/en not_active Abandoned
- 1998-10-22 IL IL13490198A patent/IL134901A0/xx unknown
- 1998-10-22 ID IDW20000748A patent/ID24890A/id unknown
- 1998-10-22 CO CO98061475A patent/CO4970769A1/es unknown
- 1998-10-22 HU HU0004169A patent/HUP0004169A3/hu unknown
- 1998-10-22 TR TR2000/01050T patent/TR200001050T2/xx unknown
- 1998-10-22 JP JP2000517731A patent/JP2001521004A/ja not_active Withdrawn
- 1998-10-22 AR ARP980105267A patent/AR020047A1/es unknown
- 1998-10-22 WO PCT/US1998/022313 patent/WO1999021573A1/en not_active Application Discontinuation
- 1998-10-22 WO PCT/US1998/022434 patent/WO1999021578A1/en not_active Application Discontinuation
- 1998-10-22 JP JP2000517736A patent/JP2001521006A/ja not_active Withdrawn
- 1998-10-22 KR KR1020007004395A patent/KR20010024556A/ko not_active Application Discontinuation
- 1998-10-22 EP EP98953852A patent/EP1039920A4/en not_active Withdrawn
- 1998-10-22 EA EA200000453A patent/EA200000453A1/ru unknown
- 1998-10-22 PL PL98340255A patent/PL340255A1/xx not_active Application Discontinuation
- 1998-10-22 AU AU11166/99A patent/AU747926B2/en not_active Ceased
-
2000
- 2000-04-18 NO NO20002038A patent/NO20002038L/no not_active Application Discontinuation
- 2000-04-21 HR HR20000236A patent/HRP20000236A2/hr not_active Application Discontinuation
-
2001
- 2001-01-17 US US09/761,903 patent/US6465426B2/en not_active Expired - Fee Related
- 2001-12-06 US US10/010,038 patent/US20020082199A1/en not_active Abandoned
Also Published As
Publication number | Publication date |
---|---|
WO1999021578A1 (en) | 1999-05-06 |
ID24890A (id) | 2000-08-31 |
BR9813111A (pt) | 2000-08-15 |
SV1998000125A (es) | 1999-05-24 |
EP1039920A1 (en) | 2000-10-04 |
CA2306905A1 (en) | 1999-05-06 |
PL340255A1 (en) | 2001-01-29 |
JP2001521006A (ja) | 2001-11-06 |
KR20010024556A (ko) | 2001-03-26 |
US20010036916A1 (en) | 2001-11-01 |
HUP0004169A3 (en) | 2001-06-28 |
HUP0004169A2 (hu) | 2001-05-28 |
CO4970769A1 (es) | 2000-11-07 |
AR020047A1 (es) | 2002-04-10 |
EP1039920A4 (en) | 2003-05-28 |
AU1111799A (en) | 1999-05-17 |
IL134901A0 (en) | 2001-05-20 |
WO1999021573A1 (en) | 1999-05-06 |
US6465426B2 (en) | 2002-10-15 |
JP2001521004A (ja) | 2001-11-06 |
AU747926B2 (en) | 2002-05-30 |
US6268335B1 (en) | 2001-07-31 |
CA2306877A1 (en) | 1999-05-06 |
EA200000453A1 (ru) | 2000-10-30 |
PE123799A1 (es) | 1999-12-13 |
NO20002038L (no) | 2000-06-26 |
CN1276731A (zh) | 2000-12-13 |
US20020082199A1 (en) | 2002-06-27 |
NO20002038D0 (no) | 2000-04-18 |
TR200001050T2 (tr) | 2000-08-21 |
AU1116699A (en) | 1999-05-17 |
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