KR20160065126A - 인슐린 유사체의 신규한 유도체 - Google Patents
인슐린 유사체의 신규한 유도체 Download PDFInfo
- Publication number
- KR20160065126A KR20160065126A KR1020167010201A KR20167010201A KR20160065126A KR 20160065126 A KR20160065126 A KR 20160065126A KR 1020167010201 A KR1020167010201 A KR 1020167010201A KR 20167010201 A KR20167010201 A KR 20167010201A KR 20160065126 A KR20160065126 A KR 20160065126A
- Authority
- KR
- South Korea
- Prior art keywords
- compound
- insulin
- hexamer
- nacl
- administered
- 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.)
- Withdrawn
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- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical class N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 title claims description 252
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- 208000004104 gestational diabetes Diseases 0.000 description 1
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- 229960002897 heparin Drugs 0.000 description 1
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- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 1
- 238000003384 imaging method Methods 0.000 description 1
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- 238000001840 matrix-assisted laser desorption--ionisation time-of-flight mass spectrometry Methods 0.000 description 1
- 208000030159 metabolic disease Diseases 0.000 description 1
- XZWYZXLIPXDOLR-UHFFFAOYSA-N metformin Chemical compound CN(C)C(=N)NC(N)=N XZWYZXLIPXDOLR-UHFFFAOYSA-N 0.000 description 1
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- 229910052757 nitrogen Inorganic materials 0.000 description 1
- VOMXSOIBEJBQNF-UTTRGDHVSA-N novorapid Chemical compound C([C@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)[C@H](CS)NC(=O)[C@H]([C@@H](C)CC)NC(=O)[C@H](CO)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CS)NC(=O)[C@H](CS)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](NC(=O)CN)[C@@H](C)CC)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(N)=O)C(O)=O)C1=CC=C(O)C=C1.C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CS)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(O)=O)C(C)C)NC(=O)[C@H](CO)NC(=O)CNC(=O)[C@H](CS)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)CC=1C=CC=CC=1)C(C)C)C1=CN=CN1 VOMXSOIBEJBQNF-UTTRGDHVSA-N 0.000 description 1
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- 239000011734 sodium Substances 0.000 description 1
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- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- HYEKBBUUXFWKKZ-UHFFFAOYSA-K sodium;zinc;trichloride Chemical compound [Na+].[Cl-].[Cl-].[Cl-].[Zn+2] HYEKBBUUXFWKKZ-UHFFFAOYSA-K 0.000 description 1
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- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
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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
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/575—Hormones
- C07K14/62—Insulins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/22—Hormones
- A61K38/28—Insulins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Organic Chemistry (AREA)
- Diabetes (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Endocrinology (AREA)
- Gastroenterology & Hepatology (AREA)
- Zoology (AREA)
- Biophysics (AREA)
- Molecular Biology (AREA)
- Toxicology (AREA)
- Genetics & Genomics (AREA)
- Biochemistry (AREA)
- Engineering & Computer Science (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Epidemiology (AREA)
- Immunology (AREA)
- Obesity (AREA)
- Hematology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Emergency Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
- Medicinal Preparation (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP13187626.0 | 2013-10-07 | ||
| EP13187626 | 2013-10-07 | ||
| PCT/EP2014/071236 WO2015052088A1 (en) | 2013-10-07 | 2014-10-03 | Novel derivative of an insulin analogue |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| KR20160065126A true KR20160065126A (ko) | 2016-06-08 |
Family
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| KR1020167010201A Withdrawn KR20160065126A (ko) | 2013-10-07 | 2014-10-03 | 인슐린 유사체의 신규한 유도체 |
Country Status (21)
| Country | Link |
|---|---|
| US (1) | US9896496B2 (OSRAM) |
| EP (1) | EP3055325B1 (OSRAM) |
| JP (1) | JP6499184B2 (OSRAM) |
| KR (1) | KR20160065126A (OSRAM) |
| CN (1) | CN105636979B (OSRAM) |
| AU (1) | AU2014333979B2 (OSRAM) |
| BR (1) | BR112016007166A2 (OSRAM) |
| CA (1) | CA2926701A1 (OSRAM) |
| DK (1) | DK3055325T3 (OSRAM) |
| ES (1) | ES2676065T3 (OSRAM) |
| HR (1) | HRP20180468T1 (OSRAM) |
| HU (1) | HUE036702T2 (OSRAM) |
| IL (1) | IL244507B (OSRAM) |
| MX (1) | MX366636B (OSRAM) |
| PL (1) | PL3055325T3 (OSRAM) |
| PT (1) | PT3055325T (OSRAM) |
| RS (1) | RS57004B1 (OSRAM) |
| RU (1) | RU2673185C2 (OSRAM) |
| SA (1) | SA516370893B1 (OSRAM) |
| SI (1) | SI3055325T1 (OSRAM) |
| WO (1) | WO2015052088A1 (OSRAM) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20210110349A (ko) * | 2019-01-29 | 2021-09-07 | 일라이 릴리 앤드 캄파니 | Gip/glp1 이중 효능제의 제조 방법 |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| MX2010009850A (es) | 2008-03-18 | 2010-09-30 | Novo Nordisk As | Analogos de insulina acilados y etabilizados contra proteasas. |
| AR105616A1 (es) | 2015-05-07 | 2017-10-25 | Lilly Co Eli | Proteínas de fusión |
| JP7076442B2 (ja) | 2016-11-07 | 2022-05-27 | ノヴォ ノルディスク アー／エス | Ｐｅｇ化合物のｄｃｈｂｓ活性エステル及びその使用 |
| AU2017378102B2 (en) * | 2016-12-16 | 2022-10-13 | Novo Nordisk A/S | Insulin containing pharmaceutical compositions |
| CN111164128A (zh) | 2017-09-29 | 2020-05-15 | 韩美药品株式会社 | 包含作为接头的非肽基聚合物偶联的脂肪酸衍生物化合物的蛋白复合物及其制备方法 |
| CN111909255A (zh) * | 2019-05-10 | 2020-11-10 | 宁波鲲鹏生物科技有限公司 | 胰岛素衍生物及其制备方法 |
| CA3189527A1 (en) | 2020-07-24 | 2022-01-27 | Jiangsu Gensciences Inc. | Insulin-fc fusion protein and application thereof |
| CA3217734A1 (en) | 2021-05-24 | 2022-12-01 | Baoye ZHENG | A novel acylated insulin analog |
| CN117342967A (zh) * | 2023-09-28 | 2024-01-05 | 奥锐特药业(天津)有限公司 | 一种长链脂肪酸化合物的制备方法 |
Family Cites Families (134)
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| US2832685A (en) | 1952-05-24 | 1958-04-29 | Crest Foods Co Inc | Solubilization of milk proteins |
| US3528960A (en) | 1968-10-07 | 1970-09-15 | Lilly Co Eli | N-carboxyaroyl insulins |
| US3719655A (en) | 1969-12-05 | 1973-03-06 | Lilly Co Eli | Process for the crystallization of the ammonium and alkali metal salts in insulin |
| 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 |
| US4179337A (en) | 1973-07-20 | 1979-12-18 | Davis Frank F | Non-immunogenic polypeptides |
| US4033941A (en) | 1975-12-17 | 1977-07-05 | Eli Lilly And Company | Process for purifying glucagon |
| GB1492997A (en) | 1976-07-21 | 1977-11-23 | Nat Res Dev | Insulin derivatives |
| JPS5767548A (en) | 1980-10-14 | 1982-04-24 | Shionogi & Co Ltd | Insulin analog and its preparation |
| PH25772A (en) | 1985-08-30 | 1991-10-18 | Novo Industri As | Insulin analogues, process for their preparation |
| PH23446A (en) | 1986-10-20 | 1989-08-07 | Novo Industri As | Peptide preparations |
| JPH01254699A (ja) | 1988-04-05 | 1989-10-11 | Kodama Kk | インスリン誘導体及びその用途 |
| DK257988D0 (da) | 1988-05-11 | 1988-05-11 | Novo Industri As | Nye peptider |
| KR900701842A (ko) | 1988-07-20 | 1990-12-04 | 헨리 브뢰늄 | 인간 인슐린 동족체와 그를 포함하는 제제 |
| US5225323A (en) | 1988-11-21 | 1993-07-06 | Baylor College Of Medicine | Human high-affinity neurotransmitter uptake system |
| FI913037A7 (fi) | 1988-12-23 | 1991-06-20 | Novo Nordisk As | Ihmisen insuliinianalogit |
| 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 |
| WO1990012814A1 (en) | 1989-04-20 | 1990-11-01 | Mount Sinai School Of Medicine Of The City University Of New York | Hepatospecific insulin analogues |
| CA1340994C (en) | 1989-09-21 | 2000-05-16 | Rudolf Edgar Dr. Falk | Treatment of conditions and disease |
| AU628674B2 (en) | 1989-10-19 | 1992-09-17 | Nippon Oil And Fats Company, Limited | Polymer complexes of a sugar response type |
| US5179189A (en) | 1990-01-19 | 1993-01-12 | Nova Pharmaceutical Corporation | Fatty acid terminated polyanhydrides |
| DK45590D0 (OSRAM) | 1990-02-21 | 1990-02-21 | Novo Nordisk As | |
| DK155690D0 (da) | 1990-06-28 | 1990-06-28 | Novo Nordisk As | Nye peptider |
| DK158390D0 (da) | 1990-07-02 | 1990-07-02 | Novo Nordisk As | Nye peptider |
| 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 |
| 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 |
| US6475795B1 (en) | 1991-07-03 | 2002-11-05 | Meditech Research, Ltd. | Use of hyaluronan in gene therapy |
| US5268453A (en) | 1991-08-08 | 1993-12-07 | Scios Inc. | Tissue-selective insulin analogs |
| ZA928916B (en) | 1991-11-26 | 1994-05-18 | Lilly Co Eli | Tri-arginine insulins |
| AU5171293A (en) | 1992-10-14 | 1994-05-09 | Regents Of The University Of Colorado, The | Ion-pairing of drugs for improved efficacy and delivery |
| US5359030A (en) | 1993-05-10 | 1994-10-25 | Protein Delivery, Inc. | Conjugation-stabilized polypeptide compositions, therapeutic delivery and diagnostic formulations comprising same, and method of making and using the same |
| US5506203C1 (en) | 1993-06-24 | 2001-02-06 | Astra Ab | Systemic administration of a therapeutic preparation |
| CZ287945B6 (cs) | 1993-09-17 | 2001-03-14 | Novo Nordisk A/S | Inzulinový derivát a farmaceutický prostředek s jeho obsahem pro léčení diabetu |
| 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 |
| CA2183577C (en) | 1994-03-07 | 2007-10-30 | John S. Patton | Methods and compositions for pulmonary delivery of insulin |
| US6500645B1 (en) | 1994-06-17 | 2002-12-31 | Novo Nordisk A/S | N-terminally extended proteins expressed in yeast |
| US5693609A (en) | 1994-11-17 | 1997-12-02 | Eli Lilly And Company | Acylated insulin analogs |
| US5646242A (en) | 1994-11-17 | 1997-07-08 | Eli Lilly And Company | Selective acylation of epsilon-amino groups |
| 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 |
| 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 |
| ATE278711T1 (de) | 1996-07-11 | 2004-10-15 | Novo Nordisk As | Verfahren zur selektiven acetylierung |
| DK0821006T3 (da) | 1996-07-26 | 2004-08-16 | Aventis Pharma Gmbh | Insulinderivater med öget zinkbinding |
| 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 |
| CN1240718C (zh) | 1997-10-24 | 2006-02-08 | 诺沃挪第克公司 | 人胰岛素衍生物的聚集体 |
| EP1039920A4 (en) | 1997-10-24 | 2003-05-28 | Lilly Co Eli | INSULIN ANALOGS ACYLATED BY FATTY ACID |
| ZA989744B (en) | 1997-10-31 | 2000-04-26 | Lilly Co Eli | Method for administering acylated insulin. |
| WO1999024015A1 (en) | 1997-11-12 | 1999-05-20 | Alza Corporation | Buffered drug formulations for transdermal electrotransport delivery |
| 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 |
| PT1107743E (pt) | 1998-08-25 | 2007-10-01 | Advanced Inhalation Res Inc | Formulações proteicas estáveis secas por pulverização |
| 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 |
| EP1121144B1 (en) | 1998-10-16 | 2002-06-05 | Novo Nordisk A/S | Stable concentrated insulin preparations for pulmonary delivery |
| US6660715B2 (en) | 1998-11-19 | 2003-12-09 | Massachusetts Institute Of Technology | Nonaqueous solutions and suspensions of macromolecules for pulmonary delivery |
| DK1146896T3 (da) | 1999-01-26 | 2002-09-02 | Lilly Co Eli | Formuleringer, som indeholder monodisperse hexamere acylerede insulin-analoger |
| WO2000061178A1 (en) | 1999-04-13 | 2000-10-19 | Inhale Therapeutics Systems, Inc. | Pulmonary administration of dry powder formulations for treating infertility |
| EP1173482A1 (en) | 1999-04-27 | 2002-01-23 | Eli Lilly And Company | Insulin crystals for pulmonary administration |
| AU5144400A (en) | 1999-05-19 | 2000-12-05 | Xencor, Inc. | Novel proteins with insulin-like activity useful in the treatment of diabetes |
| US6746853B1 (en) | 1999-05-19 | 2004-06-08 | Xencor, Inc. | Proteins with insulin-like activity useful in the treatment of diabetes |
| US6309633B1 (en) | 1999-06-19 | 2001-10-30 | Nobex Corporation | Amphiphilic drug-oligomer conjugates with hydroyzable lipophile components and methods for making and using the same |
| CN1141974C (zh) | 2000-06-07 | 2004-03-17 | 张昊 | 结肠定位释放的口服生物制剂 |
| US6867183B2 (en) | 2001-02-15 | 2005-03-15 | Nobex Corporation | Pharmaceutical compositions of insulin drug-oligomer conjugates and methods of treating diseases therewith |
| CN1160122C (zh) | 2001-04-20 | 2004-08-04 | 清华大学 | 一种制备口服胰岛素油相制剂的方法 |
| AR033903A1 (es) | 2001-05-21 | 2004-01-07 | Inhale Therapeutic Syst | Una composicion de insulina modificada quimicamente para la administracion pulmonar |
| US6828297B2 (en) | 2001-06-04 | 2004-12-07 | Nobex Corporation | Mixtures of insulin drug-oligomer conjugates comprising polyalkylene glycol, uses thereof, and methods of making same |
| US6858580B2 (en) | 2001-06-04 | 2005-02-22 | Nobex Corporation | Mixtures of drug-oligomer conjugates comprising polyalkylene glycol, uses thereof, and methods of making same |
| 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 |
| ES2333781T3 (es) | 2001-09-07 | 2010-03-01 | Biocon Limited | Procedimientos de sintesis de conjugados de polipeptido insulina-oligomero y conjugados de polipeptido proinsulina-oligomero, y procedimientos de sintesis de los mismos. |
| US6770625B2 (en) | 2001-09-07 | 2004-08-03 | Nobex Corporation | Pharmaceutical compositions of calcitonin drug-oligomer conjugates and methods of treating diseases therewith |
| JP2005526009A (ja) | 2001-12-02 | 2005-09-02 | ノボ ノルディスク アクティーゼルスカブ | 新規グルコース依存性インスリン |
| WO2003047493A2 (en) | 2001-12-03 | 2003-06-12 | Dor Biopharma Inc. | Stabilized reverse micelle compositions and uses thereof |
| EP1456371A1 (en) | 2001-12-05 | 2004-09-15 | Dow Global Technologies Inc. | Method for immobilizing a biologic in a polyurethane-hydrogel composition, a composition prepared from the method, and biomedical applications |
| CZ2004710A3 (cs) | 2001-12-20 | 2005-02-16 | Eli Lilly And Company | Inzulínová sloučenina s protrahovaným účinkem |
| ES2360182T3 (es) | 2002-05-07 | 2011-06-01 | Novo Nordisk A/S | Formulaciones solubles que comprenden insulina monomérica e insulina acilada. |
| AU2003218635A1 (en) | 2002-05-07 | 2003-11-11 | Novo Nordisk A/S | Soluble formulations comprising insulin aspart and insulin detemir |
| 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 |
| EP1633391B1 (en) | 2003-06-03 | 2011-10-19 | Novo Nordisk A/S | Stabilized pharmaceutical peptide compositions |
| EP1644411A2 (en) | 2003-07-11 | 2006-04-12 | Novo Nordisk A/S | Stabilised insulin compositions |
| PL1648933T3 (pl) | 2003-07-25 | 2010-01-29 | Conjuchem Biotechnologies Inc | Długo działające pochodne insuliny i związane z tym sposoby |
| JP4463814B2 (ja) | 2003-08-05 | 2010-05-19 | ノボ ノルディスク アクティーゼルスカブ | 新規のインスリン誘導体 |
| PT1660047E (pt) | 2003-08-13 | 2014-02-27 | Biocon Ltd | Formulação de dosagem sólida de sais de ácidos gordos em micropartículas para agentes terapêuticos |
| TW200526254A (en) * | 2003-09-19 | 2005-08-16 | Novo Nordisk As | Novel GLP-1 derivatives |
| WO2005047508A1 (en) | 2003-11-14 | 2005-05-26 | Novo Nordisk A/S | Processes for making acylated insulin |
| CN1882356B (zh) | 2003-11-20 | 2015-02-25 | 诺沃挪第克公司 | 对于生产和用于注射装置中是最佳的含有丙二醇的肽制剂 |
| WO2005058961A2 (en) | 2003-12-12 | 2005-06-30 | Amgen Inc. | Antibodies specific for human galanin, and uses thereof |
| DE10358387A1 (de) | 2003-12-13 | 2005-07-07 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Pulver enthaltend niedermolekulares Dextran und Verfahren zu deren Herstellung |
| US7625865B2 (en) | 2004-03-26 | 2009-12-01 | Universita Degli Studi Di Parma | Insulin highly respirable microparticles |
| RU2006143544A (ru) | 2004-05-10 | 2008-06-20 | Нэстек Фармасьютикал Кампани Инк. (Us) | Композиции и способ для облегченной чресслизистой доставки паратиреоидного гормона |
| CN103223160B (zh) | 2004-07-19 | 2015-02-18 | 比奥孔有限公司 | 胰岛素-低聚物共轭物,制剂及其用途 |
| BR122019022692B1 (pt) | 2004-08-23 | 2023-01-10 | Mannkind Corporation | Composição terapêutica em pó seco contendo dicetopiperazina, pelo menos um tipo de cátion e um agente biologicamente ativo |
| JP5921052B2 (ja) | 2004-12-03 | 2016-05-24 | ロード アイランド ホスピタル | アルツハイマー病の検査 |
| US20090036353A1 (en) | 2005-01-27 | 2009-02-05 | Novo Nordisk A/S | Insulin Derivatives Conjugated with Structurally Well Defined Branched Polymers |
| EP1846447B1 (en) | 2005-02-02 | 2013-08-21 | Novo Nordisk A/S | Insulin derivatives |
| ES2438145T3 (es) | 2005-02-02 | 2014-01-16 | Novo Nordisk A/S | Nuevos derivados de insulina |
| WO2006097521A1 (en) | 2005-03-18 | 2006-09-21 | Novo Nordisk A/S | Pegylated single-chain insulin |
| WO2007006320A1 (en) | 2005-07-12 | 2007-01-18 | Sherine Hassan Abbas Helmy | Drinkable oral insulin liquid and capsules |
| WO2007041481A1 (en) | 2005-09-29 | 2007-04-12 | Biodel, Inc. | Rapid acting and prolonged acting insulin preparations |
| JP4710533B2 (ja) | 2005-10-07 | 2011-06-29 | 株式会社豊田自動織機 | 牽引車両のドローバー装置 |
| WO2007047948A2 (en) | 2005-10-20 | 2007-04-26 | Nastech Pharmaceutical Company Inc. | Intranasal administration of rapid acting insulin |
| US20090074882A1 (en) | 2005-12-28 | 2009-03-19 | Novo Nordisk A/S | Insulin compositions and method of making a composition |
| US8343914B2 (en) | 2006-01-06 | 2013-01-01 | Case Western Reserve University | Fibrillation resistant proteins |
| WO2007096332A1 (en) | 2006-02-21 | 2007-08-30 | Novo Nordisk A/S | Single-chain insulin analogues and pharmaceutical formulations thereof |
| WO2007096431A1 (en) | 2006-02-27 | 2007-08-30 | Novo Nordisk A/S | Insulin derivatives |
| EP1996223A1 (en) | 2006-03-13 | 2008-12-03 | Novo Nordisk A/S | Acylated single chain insulin |
| AU2007247109B2 (en) | 2006-05-09 | 2012-03-15 | Novo Nordisk A/S | Insulin derivative |
| JP5269766B2 (ja) * | 2006-05-09 | 2013-08-21 | ノボ・ノルデイスク・エー／エス | インスリン誘導体 |
| ES2542146T3 (es) | 2006-07-31 | 2015-07-31 | Novo Nordisk A/S | Insulinas extendidas PEGiladas. |
| RU2524150C2 (ru) | 2006-09-22 | 2014-07-27 | Ново Нордиск А/С | Аналоги инсулина, устойчивые к протеазам |
| WO2008132229A2 (en) | 2007-04-30 | 2008-11-06 | Novo Nordisk A/S | Highly concentrated insulin solutions and compositions |
| CA2716159A1 (en) | 2007-06-01 | 2008-12-04 | Novo Nordisk A/S | Stable non-aqueous pharmaceutical compositions |
| WO2008152106A1 (en) * | 2007-06-13 | 2008-12-18 | Novo Nordisk A/S | Pharmaceutical formulation comprising an insulin derivative |
| EP2170945A1 (en) | 2007-07-16 | 2010-04-07 | Novo Nordisk A/S | Protease stabilized, pegylated insulin analogues |
| WO2009022013A1 (en) | 2007-08-15 | 2009-02-19 | Novo Nordisk A/S | Insulin analogues with an acyl and aklylene glycol moiety |
| EP2178910B1 (en) | 2007-08-15 | 2014-10-08 | Novo Nordisk A/S | Insulins with an acyl moiety comprising repeating units of alkylene glycol containing amino acids |
| JP5715418B2 (ja) * | 2007-11-08 | 2015-05-07 | ノボ・ノルデイスク・エー／エス | インスリン誘導体 |
| ES2618073T3 (es) | 2008-03-14 | 2017-06-20 | Novo Nordisk A/S | Análogos de insulina estabilizados frente a proteasas |
| MX2010009850A (es) | 2008-03-18 | 2010-09-30 | Novo Nordisk As | Analogos de insulina acilados y etabilizados contra proteasas. |
| ES2607003T3 (es) | 2008-10-30 | 2017-03-28 | Novo Nordisk A/S | Tratamiento de diabetes mellitus utilizando inyecciones de insulina con una frecuencia de inyección inferior a la diaria |
| WO2011141407A1 (en) * | 2010-05-10 | 2011-11-17 | Novo Nordisk A/S | Process for the preparation of insulin-zinc complexes |
| CN102947331B (zh) * | 2010-06-23 | 2016-08-03 | 诺沃—诺迪斯克有限公司 | 包含额外的二硫键的胰岛素类似物 |
| CN104693302A (zh) | 2010-06-23 | 2015-06-10 | 诺沃—诺迪斯克有限公司 | 包含额外的二硫键的胰岛素衍生物 |
| PL2632478T3 (pl) * | 2010-10-27 | 2020-03-31 | Novo Nordisk A/S | Leczenie cukrzycy z zastosowaniem zastrzyków insuliny podawanych w różnych odstępach czasu |
| EP2836508B1 (en) | 2012-04-11 | 2016-06-29 | Novo Nordisk A/S | Insulin formulations |
-
2014
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- 2014-10-03 HR HRP20180468TT patent/HRP20180468T1/hr unknown
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20210110349A (ko) * | 2019-01-29 | 2021-09-07 | 일라이 릴리 앤드 캄파니 | Gip/glp1 이중 효능제의 제조 방법 |
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| MX366636B (es) | 2019-07-17 |
| AU2014333979A1 (en) | 2016-03-24 |
| WO2015052088A1 (en) | 2015-04-16 |
| BR112016007166A2 (pt) | 2017-09-12 |
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| US20160215037A1 (en) | 2016-07-28 |
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| SA516370893B1 (ar) | 2018-08-13 |
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| RU2673185C2 (ru) | 2018-11-22 |
| CA2926701A1 (en) | 2015-04-16 |
| ES2676065T3 (es) | 2018-07-16 |
| RU2016114098A3 (OSRAM) | 2018-05-21 |
| JP6499184B2 (ja) | 2019-04-10 |
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| IL244507A0 (en) | 2016-04-21 |
| US9896496B2 (en) | 2018-02-20 |
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| CN105636979A (zh) | 2016-06-01 |
| IL244507B (en) | 2018-05-31 |
| EP3055325B1 (en) | 2018-01-03 |
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