JP5931857B2 - 追加のジスルフィド結合を含有するインスリン誘導体 - Google Patents
追加のジスルフィド結合を含有するインスリン誘導体 Download PDFInfo
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- JP5931857B2 JP5931857B2 JP2013515874A JP2013515874A JP5931857B2 JP 5931857 B2 JP5931857 B2 JP 5931857B2 JP 2013515874 A JP2013515874 A JP 2013515874A JP 2013515874 A JP2013515874 A JP 2013515874A JP 5931857 B2 JP5931857 B2 JP 5931857B2
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- human insulin
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Classifications
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- 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
- 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)
- Endocrinology (AREA)
- General Health & Medical Sciences (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Gastroenterology & Hepatology (AREA)
- Zoology (AREA)
- Biophysics (AREA)
- Molecular Biology (AREA)
- Genetics & Genomics (AREA)
- Toxicology (AREA)
- Biochemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Engineering & Computer Science (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Obesity (AREA)
- Hematology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Emergency Medicine (AREA)
- Immunology (AREA)
- Epidemiology (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
Applications Claiming Priority (9)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP10167033 | 2010-06-23 | ||
| EP10167046.1 | 2010-06-23 | ||
| EP10167046 | 2010-06-23 | ||
| EP10167033.9 | 2010-06-23 | ||
| US35915010P | 2010-06-28 | 2010-06-28 | |
| US61/359,150 | 2010-06-28 | ||
| US35950010P | 2010-06-29 | 2010-06-29 | |
| US61/359,500 | 2010-06-29 | ||
| PCT/EP2011/060383 WO2011161125A1 (en) | 2010-06-23 | 2011-06-21 | Insulin derivatives containing additional disulfide bonds |
Publications (3)
| Publication Number | Publication Date |
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| JP2013530974A JP2013530974A (ja) | 2013-08-01 |
| JP2013530974A5 JP2013530974A5 (cg-RX-API-DMAC7.html) | 2014-07-10 |
| JP5931857B2 true JP5931857B2 (ja) | 2016-06-08 |
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| JP2013515874A Expired - Fee Related JP5931857B2 (ja) | 2010-06-23 | 2011-06-21 | 追加のジスルフィド結合を含有するインスリン誘導体 |
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| JP (1) | JP5931857B2 (cg-RX-API-DMAC7.html) |
| KR (1) | KR20130036290A (cg-RX-API-DMAC7.html) |
| CN (2) | CN104693302A (cg-RX-API-DMAC7.html) |
| AU (1) | AU2011269000C1 (cg-RX-API-DMAC7.html) |
| BR (1) | BR112012033107A2 (cg-RX-API-DMAC7.html) |
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| WO (1) | WO2011161125A1 (cg-RX-API-DMAC7.html) |
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|---|---|---|---|---|
| DK2910570T3 (en) | 2008-03-18 | 2017-01-30 | Novo Nordisk As | Protease-stabilized acylated insulin analogues. |
| WO2012123519A2 (en) * | 2011-03-15 | 2012-09-20 | Novo Nordisk A/S | Human insulin analogues and derivatives comprising cysteine substitutions |
| US20140357838A1 (en) * | 2011-12-21 | 2014-12-04 | Novo Nordisk A/S | N-Terminally Modified Insulin Derivatives |
| US9481721B2 (en) | 2012-04-11 | 2016-11-01 | Novo Nordisk A/S | Insulin formulations |
| WO2014009316A1 (en) | 2012-07-09 | 2014-01-16 | Novo Nordisk A/S | Novel use of insulin derivatives |
| MX366636B (es) | 2013-10-07 | 2019-07-17 | Novo Nordisk As | Nuevo derivado de un análogo de insulina. |
| AR099569A1 (es) * | 2014-02-28 | 2016-08-03 | Novo Nordisk As | Derivados de insulina y los usos médicos de estos |
| WO2016119854A1 (en) * | 2015-01-29 | 2016-08-04 | Novo Nordisk A/S | Pharmaceutical composition for oral insulin administration comprising a tablet core and a polyvinyl alcohol coating |
| HK1255634A1 (zh) * | 2015-12-23 | 2019-08-23 | Case Western Reserve University | 超稳胰岛素类似物在聚合物熔体中的包囊 |
| CN107436311B (zh) * | 2016-05-25 | 2021-11-19 | 正大天晴药业集团股份有限公司 | 一种鉴别胰岛素单体或胰岛素多聚体的方法 |
| TWI700091B (zh) | 2016-12-16 | 2020-08-01 | 丹麥商諾佛 儂迪克股份有限公司 | 含胰島素醫藥組成物 |
| KR102666154B1 (ko) | 2018-08-08 | 2024-05-20 | 주식회사 대웅제약 | 지속형 인슐린 아날로그 및 그 복합체 |
| CN113121649B (zh) * | 2019-12-26 | 2022-10-04 | 李瑛� | 一种新型两亲性蛋白、其制备方法及用途 |
| CN116789801B (zh) * | 2023-08-21 | 2023-11-14 | 南京赛诺生物技术有限公司 | 新型胰岛素衍生物及其用途 |
| US20250154220A1 (en) * | 2023-11-15 | 2025-05-15 | Ambio, Inc. | Insulin analogs for the treatment of human metabolic disorder and disease |
Family Cites Families (29)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4343898A (en) | 1980-02-11 | 1982-08-10 | Novo Industri A/S | Process for preparing esters of human insulin |
| DK58285D0 (da) | 1984-05-30 | 1985-02-08 | Novo Industri As | Peptider samt fremstilling og anvendelse deraf |
| PH25772A (en) * | 1985-08-30 | 1991-10-18 | Novo Industri As | Insulin analogues, process for their preparation |
| DK105489D0 (da) | 1989-03-03 | 1989-03-03 | Novo Nordisk As | Polypeptid |
| DK155690D0 (da) * | 1990-06-28 | 1990-06-28 | Novo Nordisk As | Nye peptider |
| IL114160A (en) | 1994-06-17 | 2006-12-31 | Novo Nordisk As | Dna constructs encoding heterologous proteins and processes for the heterologous protein production in yeast |
| DE19726167B4 (de) | 1997-06-20 | 2008-01-24 | Sanofi-Aventis Deutschland Gmbh | Insulin, Verfahren zu seiner Herstellung und es enthaltende pharmazeutische Zubereitung |
| CA2306905A1 (en) * | 1997-10-24 | 1999-05-06 | Eli Lilly And Company | Fatty acid-acylated insulin analogs |
| HUP0200297A3 (en) | 1999-03-17 | 2002-09-30 | Novo Nordisk As | Method for acylating peptides and the glutaminic acid derivatives as acylating agents |
| KR20030004317A (ko) | 1999-12-29 | 2003-01-14 | 노보 노르디스크 에이/에스 | 인슐린 선구물질 및 인슐린 선구물질 유사체의 제조 방법 |
| KR101131783B1 (ko) | 2002-09-25 | 2012-03-30 | 노보 노르디스크 에이/에스 | 아실화된 펩타이드의 제조방법 |
| AU2003903124A0 (en) * | 2003-06-20 | 2003-07-10 | Mark Del Borgo | Analogues of heteromeric proteins |
| BRPI0413276B8 (pt) * | 2003-08-05 | 2021-05-25 | Novo Nordisk As | derivado de insulina, complexo de zinco do mesmo, e, composição farmacêutica |
| AU2004295023A1 (en) | 2003-12-03 | 2005-06-16 | Novo Nordisk A/S | Single-chain insulin |
| WO2006008238A1 (en) | 2004-07-16 | 2006-01-26 | Novo Nordisk A/S | Method for selective acylation |
| US8343914B2 (en) * | 2006-01-06 | 2013-01-01 | Case Western Reserve University | Fibrillation resistant proteins |
| US20090069216A1 (en) | 2006-02-21 | 2009-03-12 | Novo Nordisk A/S | Single-Chain Insulin Analogues and Pharmaceutical Formulations Thereof |
| WO2007135117A2 (en) * | 2006-05-24 | 2007-11-29 | Novo Nordisk A/S | Soluble, stable insulin-containing formulations |
| KR101729986B1 (ko) | 2006-09-22 | 2017-04-25 | 노보 노르디스크 에이/에스 | 프로테아제 내성 인슐린 유사체 |
| ES2554773T3 (es) | 2006-10-04 | 2015-12-23 | Case Western Reserve University | Insulina y análogos de la insulina resistentes a la fibrilación |
| EP2178912B1 (en) * | 2007-08-15 | 2015-07-08 | Novo Nordisk A/S | Insulin analogues with an acyl and aklylene glycol moiety |
| MY152979A (en) | 2008-01-09 | 2014-12-15 | Sanofi Aventis Deutschland | Novel insulin derivatives having an extremely delayed time-action profile |
| WO2009112583A2 (en) | 2008-03-14 | 2009-09-17 | Novo Nordisk A/S | Protease-stabilized insulin analogues |
| DK2910570T3 (en) | 2008-03-18 | 2017-01-30 | 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 |
| EP2376531A1 (en) | 2008-12-09 | 2011-10-19 | Novo Nordisk A/S | Novel insulin analogues |
| WO2011028813A2 (en) | 2009-09-01 | 2011-03-10 | Case Western Reserve University | Insulin analogues of enhanced receptor-binding specificity |
| 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 |
| EP2585483A1 (en) | 2010-06-23 | 2013-05-01 | Novo Nordisk A/S | Human insulin containing additional disulfide bonds |
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| KR20130036290A (ko) | 2013-04-11 |
| WO2011161125A1 (en) | 2011-12-29 |
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| BR112012033107A2 (pt) | 2016-10-11 |
| RU2598273C2 (ru) | 2016-09-20 |
| US20140371140A1 (en) | 2014-12-18 |
| AU2011269000A1 (en) | 2012-12-13 |
| MX337549B (es) | 2016-03-10 |
| MX2012014641A (es) | 2013-02-07 |
| US8853155B2 (en) | 2014-10-07 |
| US20130157938A1 (en) | 2013-06-20 |
| AU2011269000B2 (en) | 2015-04-23 |
| CN104693302A (zh) | 2015-06-10 |
| IL223288A0 (en) | 2013-02-03 |
| CA2802510A1 (en) | 2011-12-29 |
| ZA201209345B (en) | 2013-08-28 |
| CN102985440B (zh) | 2016-10-26 |
| JP2013530974A (ja) | 2013-08-01 |
| CN102985440A (zh) | 2013-03-20 |
| RU2012157683A (ru) | 2014-07-27 |
| AU2011269000C1 (en) | 2015-10-08 |
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