CN102219851B - 甘精胰岛素结晶的制备方法 - Google Patents
甘精胰岛素结晶的制备方法 Download PDFInfo
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- CN102219851B CN102219851B CN2011101180262A CN201110118026A CN102219851B CN 102219851 B CN102219851 B CN 102219851B CN 2011101180262 A CN2011101180262 A CN 2011101180262A CN 201110118026 A CN201110118026 A CN 201110118026A CN 102219851 B CN102219851 B CN 102219851B
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- lantus
- reorganization
- zinc
- crystal solution
- crystallization
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- C—CHEMISTRY; METALLURGY
- C30—CRYSTAL GROWTH
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- C30B7/00—Single-crystal growth from solutions using solvents which are liquid at normal temperature, e.g. aqueous solutions
- C30B7/14—Single-crystal growth from solutions using solvents which are liquid at normal temperature, e.g. aqueous solutions the crystallising materials being formed by chemical reactions in the solution
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Claims (2)
Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN2011101180262A CN102219851B (zh) | 2011-05-09 | 2011-05-09 | 甘精胰岛素结晶的制备方法 |
PCT/CN2012/074392 WO2012152175A1 (zh) | 2011-05-09 | 2012-04-19 | 甘精胰岛素结晶的制备方法 |
EP12782610.5A EP2708550B1 (en) | 2011-05-09 | 2012-04-19 | Preparation method for insulin glargine crystal |
US14/116,556 US9187520B2 (en) | 2011-05-09 | 2012-04-19 | Method for preparing insulin glargine crystal |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN2011101180262A CN102219851B (zh) | 2011-05-09 | 2011-05-09 | 甘精胰岛素结晶的制备方法 |
Publications (2)
Publication Number | Publication Date |
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CN102219851A CN102219851A (zh) | 2011-10-19 |
CN102219851B true CN102219851B (zh) | 2012-05-30 |
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CN2011101180262A Active CN102219851B (zh) | 2011-05-09 | 2011-05-09 | 甘精胰岛素结晶的制备方法 |
Country Status (4)
Country | Link |
---|---|
US (1) | US9187520B2 (zh) |
EP (1) | EP2708550B1 (zh) |
CN (1) | CN102219851B (zh) |
WO (1) | WO2012152175A1 (zh) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2015084694A3 (en) * | 2013-12-04 | 2015-10-22 | Merck Sharp & Dohme Corp. | Method for preparing crystalline insulin |
CN105585628B (zh) * | 2016-01-28 | 2019-02-01 | 通化东宝药业股份有限公司 | 一种甘精胰岛素的制备方法及其制备的甘精胰岛素 |
Families Citing this family (15)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102219851B (zh) * | 2011-05-09 | 2012-05-30 | 甘李药业有限公司 | 甘精胰岛素结晶的制备方法 |
CN103342746B (zh) * | 2013-07-26 | 2014-07-30 | 珠海联邦制药股份有限公司 | 一种制备稳定的门冬胰岛素结晶的方法 |
WO2016032869A1 (en) | 2014-08-26 | 2016-03-03 | Merck Sharp & Dohme Corp. | Method for preparing crystalline insulin or insulin analog compositions |
CN104761632A (zh) * | 2015-04-14 | 2015-07-08 | 珠海联邦制药股份有限公司 | 一种地特胰岛素结晶的制备方法及应用 |
CN104892749B (zh) * | 2015-06-16 | 2019-02-05 | 珠海联邦制药股份有限公司 | 一种德谷胰岛素结晶的制备方法及应用 |
MX2020004042A (es) | 2017-09-26 | 2021-01-15 | Biocon Biologics India Ltd | Filtracion automatizada integrada para separacion, lavado y secado de cristales de peptidos. |
CN109957001B (zh) * | 2017-12-26 | 2022-11-18 | 甘李药业股份有限公司 | 甘赖脯胰岛素结晶的制备方法 |
PL239258B1 (pl) * | 2018-07-06 | 2021-11-22 | Bioton Spolka Akcyjna | Krystaliczna postać insuliny glargine o stechiometrycznej zawartości cynku i sposób jej otrzymywania |
PL238016B1 (pl) * | 2018-07-06 | 2021-06-28 | Bioton Spolka Akcyjna | Krystaliczna, bezcynkowa postać insuliny glargine i sposób jej otrzymywania |
CN112584853B (zh) * | 2018-09-12 | 2021-12-10 | 美药星(南京)制药有限公司 | 一种新型门冬胰岛素原的结构和制备门冬胰岛素的方法 |
EP3908599A4 (en) * | 2019-01-10 | 2022-11-09 | Biocon Limited | PREPARATIVE CRYSTALLIZATION OF RECOMBINANT HUMAN INSULIN |
CN111304271A (zh) * | 2020-02-28 | 2020-06-19 | 东莞市东阳光生物药研发有限公司 | 一种含脂肪酸侧链的胰岛素类似物的制备方法 |
CN111234001B (zh) * | 2020-03-27 | 2022-04-26 | 宜昌东阳光长江药业股份有限公司 | 一种甘精胰岛素晶体的制备方法 |
CN113896784B (zh) * | 2021-10-18 | 2024-04-16 | 合肥天麦生物科技发展有限公司 | 一种胰岛素结晶的制备方法及其产品 |
CN114933647B (zh) * | 2022-06-01 | 2023-06-06 | 重庆宸安生物制药有限公司 | 一种胰岛素结晶的制备方法及产品 |
Family Cites Families (14)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2143590A (en) * | 1936-09-26 | 1939-01-10 | Univ Alberta | Insulin preparation and process of producing crystals of insulin |
US2920104A (en) | 1958-07-01 | 1960-01-05 | Vanderbilt Co R T | Stabilized solutions of a dithiocarbamate |
US3719655A (en) * | 1969-12-05 | 1973-03-06 | Lilly Co Eli | Process for the crystallization of the ammonium and alkali metal salts in insulin |
DE3327709A1 (de) * | 1983-07-29 | 1985-02-07 | Hoechst Ag, 6230 Frankfurt | Insulin-derivat-kristallsuspensionen, verfahren zu deren herstellung und deren verwendung |
US4764592A (en) | 1987-04-23 | 1988-08-16 | Eli Lilly And Company | Crystalline human proinsulin and process for its production |
DE3837825A1 (de) | 1988-11-08 | 1990-05-10 | Hoechst Ag | Neue insulinderivate, ihre verwendung und eine sie enthaltende pharmazeutische zubereitung |
US5504188A (en) * | 1994-06-16 | 1996-04-02 | Eli Lilly And Company | Preparation of stable zinc insulin analog crystals |
CO4970787A1 (es) * | 1997-12-23 | 2000-11-07 | Lilly Co Eli | Composiciones insolubles de insulina y derivados de insulina que controlan la glucosa sanguinea |
DE10235168A1 (de) * | 2002-08-01 | 2004-02-12 | Aventis Pharma Deutschland Gmbh | Verfahren zur Reinigung von Preproinsulin |
ES2779957T3 (es) * | 2004-10-05 | 2020-08-20 | Novo Nordisk As | Preparación farmacéutica que contiene insulina en forma cristalina así como también solubilizada |
DE102006031962A1 (de) * | 2006-07-11 | 2008-01-17 | Sanofi-Aventis Deutschland Gmbh | Amidiertes Insulin Glargin |
WO2008065138A1 (en) * | 2006-11-29 | 2008-06-05 | Novo Nordisk A/S | Novel insulin crystal and method for preparing the crystal |
BRPI0822775A2 (pt) * | 2008-02-19 | 2015-06-30 | Biocon Ltd | Método de obtenção de uma proteína heteróloga, purificada, biologicamente ativa. |
CN102219851B (zh) * | 2011-05-09 | 2012-05-30 | 甘李药业有限公司 | 甘精胰岛素结晶的制备方法 |
-
2011
- 2011-05-09 CN CN2011101180262A patent/CN102219851B/zh active Active
-
2012
- 2012-04-19 EP EP12782610.5A patent/EP2708550B1/en not_active Not-in-force
- 2012-04-19 WO PCT/CN2012/074392 patent/WO2012152175A1/zh active Application Filing
- 2012-04-19 US US14/116,556 patent/US9187520B2/en not_active Expired - Fee Related
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2015084694A3 (en) * | 2013-12-04 | 2015-10-22 | Merck Sharp & Dohme Corp. | Method for preparing crystalline insulin |
EP3077414A4 (en) * | 2013-12-04 | 2017-06-21 | Merck Sharp & Dohme Corp. | Method for preparing crystalline insulin |
US9822158B2 (en) | 2013-12-04 | 2017-11-21 | Merck Sharp & Dohme Corp. | Method for preparing crystalline insulin |
CN105585628B (zh) * | 2016-01-28 | 2019-02-01 | 通化东宝药业股份有限公司 | 一种甘精胰岛素的制备方法及其制备的甘精胰岛素 |
Also Published As
Publication number | Publication date |
---|---|
EP2708550A1 (en) | 2014-03-19 |
EP2708550A4 (en) | 2014-10-08 |
US20140155574A1 (en) | 2014-06-05 |
EP2708550B1 (en) | 2016-03-09 |
WO2012152175A1 (zh) | 2012-11-15 |
CN102219851A (zh) | 2011-10-19 |
US9187520B2 (en) | 2015-11-17 |
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