CN104693302A - 包含额外的二硫键的胰岛素衍生物 - Google Patents
包含额外的二硫键的胰岛素衍生物 Download PDFInfo
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- CN104693302A CN104693302A CN201510007033.3A CN201510007033A CN104693302A CN 104693302 A CN104693302 A CN 104693302A CN 201510007033 A CN201510007033 A CN 201510007033A CN 104693302 A CN104693302 A CN 104693302A
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- insulin
- amino acid
- cysteine
- human insulin
- ethoxy
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- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
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Applications Claiming Priority (8)
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| EP10167046 | 2010-06-23 | ||
| EP10167033 | 2010-06-23 | ||
| EP10167046.1 | 2010-06-23 | ||
| EP10167033.9 | 2010-06-23 | ||
| US35915010P | 2010-06-28 | 2010-06-28 | |
| US61/359150 | 2010-06-28 | ||
| US35950010P | 2010-06-29 | 2010-06-29 | |
| US61/359500 | 2010-06-29 |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201180031021.4A Division CN102985440B (zh) | 2010-06-23 | 2011-06-21 | 包含额外的二硫键的胰岛素衍生物 |
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|---|---|
| CN104693302A true CN104693302A (zh) | 2015-06-10 |
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| Application Number | Title | Priority Date | Filing Date |
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| CN201510007033.3A Pending CN104693302A (zh) | 2010-06-23 | 2011-06-21 | 包含额外的二硫键的胰岛素衍生物 |
| CN201180031021.4A Expired - Fee Related CN102985440B (zh) | 2010-06-23 | 2011-06-21 | 包含额外的二硫键的胰岛素衍生物 |
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| Application Number | Title | Priority Date | Filing Date |
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| CN201180031021.4A Expired - Fee Related CN102985440B (zh) | 2010-06-23 | 2011-06-21 | 包含额外的二硫键的胰岛素衍生物 |
Country Status (13)
| Country | Link |
|---|---|
| US (2) | US8853155B2 (https=) |
| EP (1) | EP2585485A1 (https=) |
| JP (1) | JP5931857B2 (https=) |
| KR (1) | KR20130036290A (https=) |
| CN (2) | CN104693302A (https=) |
| AU (1) | AU2011269000C1 (https=) |
| BR (1) | BR112012033107A2 (https=) |
| CA (1) | CA2802510A1 (https=) |
| IL (1) | IL223288A0 (https=) |
| MX (1) | MX337549B (https=) |
| RU (1) | RU2598273C2 (https=) |
| WO (1) | WO2011161125A1 (https=) |
| ZA (1) | ZA201209345B (https=) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107436311A (zh) * | 2016-05-25 | 2017-12-05 | 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 |
| WO2021129779A1 (zh) * | 2019-12-26 | 2021-07-01 | 李瑛� | 一种新型两亲性蛋白、其制备方法及用途 |
Families Citing this family (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102037008B (zh) | 2008-03-18 | 2016-08-31 | 诺沃-诺迪斯克有限公司 | 蛋白酶稳定化的、酰化胰岛素类似物 |
| EP2686003A2 (en) * | 2011-03-15 | 2014-01-22 | 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 |
| US20150111820A1 (en) | 2012-07-09 | 2015-04-23 | Novo Nordisk A/S | Novel use of insulin derivatives |
| AU2014333979B2 (en) | 2013-10-07 | 2018-02-15 | Novo Nordisk A/S | Novel derivative of an insulin analogue |
| AR099569A1 (es) * | 2014-02-28 | 2016-08-03 | Novo Nordisk As | Derivados de insulina y los usos médicos de estos |
| US20180000742A1 (en) * | 2015-01-29 | 2018-01-04 | Novo Nordisk A/S | Pharmaceutical Composition for Oral Insulin Administration Comprising a Tablet Core and a Polyvinyl Alcohol Coating |
| JP7203415B2 (ja) | 2015-12-23 | 2023-01-13 | ケース ウェスタン リザーブ ユニバーシティ | ポリマー溶融物内の超安定型インスリン類似体のカプセル化 |
| 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 |
| 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 |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1992000321A1 (en) * | 1990-06-28 | 1992-01-09 | Novo Nordisk A/S | Novel, protracted insulin analogues |
| WO2007135117A2 (en) * | 2006-05-24 | 2007-11-29 | Novo Nordisk A/S | Soluble, stable insulin-containing formulations |
| 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 |
Family Cites Families (26)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IE50892B1 (en) | 1980-02-11 | 1986-08-06 | Novo Industri As | Process for preparing insulin esters |
| 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 |
| ZA954983B (en) | 1994-06-17 | 1996-02-14 | Novo Nordisk As | N-terminally extended proteins expressed in yeast |
| DE19726167B4 (de) | 1997-06-20 | 2008-01-24 | Sanofi-Aventis Deutschland Gmbh | Insulin, Verfahren zu seiner Herstellung und es enthaltende pharmazeutische Zubereitung |
| EA200000453A1 (ru) * | 1997-10-24 | 2000-10-30 | Эли Лилли Энд Компани | Композиции нерастворимого инсулина |
| EP1956000B1 (en) | 1999-03-17 | 2016-10-05 | Novo Nordisk A/S | Acylating agents useful for acylating peptides |
| KR20030004317A (ko) | 1999-12-29 | 2003-01-14 | 노보 노르디스크 에이/에스 | 인슐린 선구물질 및 인슐린 선구물질 유사체의 제조 방법 |
| CA2500123A1 (en) | 2002-09-25 | 2004-04-08 | Novo Nordisk A/S | Method for producing acylated peptides |
| AU2003903124A0 (en) * | 2003-06-20 | 2003-07-10 | Mark Del Borgo | Analogues of heteromeric proteins |
| MXPA06001283A (es) * | 2003-08-05 | 2006-04-11 | Novo Nordisk As | Derivados de insulina novedosos. |
| CN1902226A (zh) | 2003-12-03 | 2007-01-24 | 诺和诺德公司 | 单链胰岛素 |
| WO2006008238A1 (en) | 2004-07-16 | 2006-01-26 | Novo Nordisk A/S | Method for selective acylation |
| WO2007081824A2 (en) * | 2006-01-06 | 2007-07-19 | 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 |
| EP2074140B8 (en) | 2006-10-04 | 2015-10-28 | Case Western Reserve University | Fibrillation-resistant insulin and insulin analogues |
| KR20100053561A (ko) * | 2007-08-15 | 2010-05-20 | 노보 노르디스크 에이/에스 | 아실 및 알킬렌 글리콜 부분을 갖는 인슐린 유사체 |
| CN102007143B (zh) * | 2008-01-09 | 2015-08-26 | 塞诺菲-安万特德国有限公司 | 具有超延迟时效特征的新型胰岛素衍生物 |
| WO2009112583A2 (en) * | 2008-03-14 | 2009-09-17 | Novo Nordisk A/S | Protease-stabilized insulin analogues |
| CN102037008B (zh) | 2008-03-18 | 2016-08-31 | 诺沃-诺迪斯克有限公司 | 蛋白酶稳定化的、酰化胰岛素类似物 |
| US8637647B2 (en) | 2008-09-12 | 2014-01-28 | Novo Nordisk A/S | Method of acylating a peptide or protein |
| JP2012511506A (ja) | 2008-12-09 | 2012-05-24 | ノヴォ・ノルディスク・アー／エス | 新規インスリンアナログ |
| WO2011028813A2 (en) | 2009-09-01 | 2011-03-10 | Case Western Reserve University | Insulin analogues of enhanced receptor-binding specificity |
| EP2585484A1 (en) | 2010-06-23 | 2013-05-01 | Novo Nordisk A/S | Insulin analogues containing additional disulfide bonds |
| CN102933599A (zh) | 2010-06-23 | 2013-02-13 | 诺沃—诺迪斯克有限公司 | 包含额外的二硫键的人胰岛素 |
-
2011
- 2011-06-21 RU RU2012157683/10A patent/RU2598273C2/ru not_active IP Right Cessation
- 2011-06-21 JP JP2013515874A patent/JP5931857B2/ja not_active Expired - Fee Related
- 2011-06-21 KR KR1020137001441A patent/KR20130036290A/ko not_active Withdrawn
- 2011-06-21 CN CN201510007033.3A patent/CN104693302A/zh active Pending
- 2011-06-21 CA CA2802510A patent/CA2802510A1/en not_active Withdrawn
- 2011-06-21 WO PCT/EP2011/060383 patent/WO2011161125A1/en not_active Ceased
- 2011-06-21 EP EP11728615.3A patent/EP2585485A1/en not_active Withdrawn
- 2011-06-21 MX MX2012014641A patent/MX337549B/es active IP Right Grant
- 2011-06-21 AU AU2011269000A patent/AU2011269000C1/en not_active Ceased
- 2011-06-21 BR BR112012033107A patent/BR112012033107A2/pt not_active IP Right Cessation
- 2011-06-21 US US13/805,774 patent/US8853155B2/en not_active Expired - Fee Related
- 2011-06-21 CN CN201180031021.4A patent/CN102985440B/zh not_active Expired - Fee Related
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2012
- 2012-11-27 IL IL223288A patent/IL223288A0/en unknown
- 2012-12-10 ZA ZA2012/09345A patent/ZA201209345B/en unknown
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2014
- 2014-08-28 US US14/471,258 patent/US9512195B2/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1992000321A1 (en) * | 1990-06-28 | 1992-01-09 | Novo Nordisk A/S | Novel, protracted insulin analogues |
| WO2007135117A2 (en) * | 2006-05-24 | 2007-11-29 | Novo Nordisk A/S | Soluble, stable insulin-containing formulations |
| 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 |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107436311A (zh) * | 2016-05-25 | 2017-12-05 | 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 |
| WO2021129779A1 (zh) * | 2019-12-26 | 2021-07-01 | 李瑛� | 一种新型两亲性蛋白、其制备方法及用途 |
Also Published As
| Publication number | Publication date |
|---|---|
| BR112012033107A2 (pt) | 2016-10-11 |
| AU2011269000C1 (en) | 2015-10-08 |
| ZA201209345B (en) | 2013-08-28 |
| CN102985440B (zh) | 2016-10-26 |
| US20140371140A1 (en) | 2014-12-18 |
| EP2585485A1 (en) | 2013-05-01 |
| MX2012014641A (es) | 2013-02-07 |
| CA2802510A1 (en) | 2011-12-29 |
| RU2598273C2 (ru) | 2016-09-20 |
| JP2013530974A (ja) | 2013-08-01 |
| US8853155B2 (en) | 2014-10-07 |
| MX337549B (es) | 2016-03-10 |
| KR20130036290A (ko) | 2013-04-11 |
| AU2011269000A1 (en) | 2012-12-13 |
| CN102985440A (zh) | 2013-03-20 |
| US20130157938A1 (en) | 2013-06-20 |
| US9512195B2 (en) | 2016-12-06 |
| IL223288A0 (en) | 2013-02-03 |
| JP5931857B2 (ja) | 2016-06-08 |
| RU2012157683A (ru) | 2014-07-27 |
| AU2011269000B2 (en) | 2015-04-23 |
| WO2011161125A1 (en) | 2011-12-29 |
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