CZ295679B6 - Způsob získávání inzulinu nebo derivátů inzulinu se správně spojenými cysteinovými můstky - Google Patents
Způsob získávání inzulinu nebo derivátů inzulinu se správně spojenými cysteinovými můstky Download PDFInfo
- Publication number
- CZ295679B6 CZ295679B6 CZ19982598A CZ259898A CZ295679B6 CZ 295679 B6 CZ295679 B6 CZ 295679B6 CZ 19982598 A CZ19982598 A CZ 19982598A CZ 259898 A CZ259898 A CZ 259898A CZ 295679 B6 CZ295679 B6 CZ 295679B6
- Authority
- CZ
- Czechia
- Prior art keywords
- amino acid
- insulin
- cysteine
- arg
- peptide
- Prior art date
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
- C07K1/12—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length by hydrolysis, i.e. solvolysis in general
-
- 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
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- 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
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- 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
- C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
- C07K1/02—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length in solution
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
- C07K1/14—Extraction; Separation; Purification
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Diabetes (AREA)
- General Health & Medical Sciences (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Genetics & Genomics (AREA)
- Biophysics (AREA)
- Endocrinology (AREA)
- Analytical Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Veterinary Medicine (AREA)
- Toxicology (AREA)
- Zoology (AREA)
- Gastroenterology & Hepatology (AREA)
- General Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Engineering & Computer Science (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Emergency Medicine (AREA)
- Peptides Or Proteins (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Micro-Organisms Or Cultivation Processes Thereof (AREA)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19735711A DE19735711C2 (de) | 1997-08-18 | 1997-08-18 | Verfahren zur Herstellung eines Vorläufers von Insulin oder Insulinderivaten mit korrekt verbundenen Cystinbrücken |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CZ259898A3 CZ259898A3 (cs) | 1999-03-17 |
| CZ295679B6 true CZ295679B6 (cs) | 2005-09-14 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CZ19982598A CZ295679B6 (cs) | 1997-08-18 | 1998-08-17 | Způsob získávání inzulinu nebo derivátů inzulinu se správně spojenými cysteinovými můstky |
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|---|---|
| US (3) | US5986048A (enExample) |
| EP (2) | EP0980874B1 (enExample) |
| JP (1) | JP4291900B2 (enExample) |
| KR (2) | KR100537842B1 (enExample) |
| CN (3) | CN101186940B (enExample) |
| AR (1) | AR016821A1 (enExample) |
| AT (2) | ATE217636T1 (enExample) |
| AU (1) | AU744824B2 (enExample) |
| BR (2) | BR9803755A (enExample) |
| CA (1) | CA2245151C (enExample) |
| CZ (1) | CZ295679B6 (enExample) |
| DE (3) | DE19735711C2 (enExample) |
| DK (2) | DK0980874T3 (enExample) |
| ES (2) | ES2176870T3 (enExample) |
| HU (2) | HU228161B1 (enExample) |
| ID (1) | ID20717A (enExample) |
| PL (1) | PL191901B1 (enExample) |
| PT (2) | PT980874E (enExample) |
| RU (2) | RU2205836C2 (enExample) |
| TR (1) | TR199801587A3 (enExample) |
Families Citing this family (34)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE19735711C2 (de) | 1997-08-18 | 2001-04-26 | Aventis Pharma Gmbh | Verfahren zur Herstellung eines Vorläufers von Insulin oder Insulinderivaten mit korrekt verbundenen Cystinbrücken |
| DE19930676B4 (de) | 1999-07-02 | 2006-01-19 | Sanofi-Aventis Deutschland Gmbh | Verfahren zur Stabilisierung von Insulin, Insulinderivaten und/oder deren Vorläufer in komplexen Mischungen bei deren Lagerung in wäßrigen Lösungsmitteln |
| JP2003530316A (ja) | 1999-12-22 | 2003-10-14 | ノボ ノルディスク アクティーゼルスカブ | スクランブルした一本鎖ポリペプチドの抽出的再生法 |
| AU2001280436A1 (en) * | 2000-07-12 | 2002-01-21 | Eli Lilly And Company | Process to increase protein stability |
| DE10235168A1 (de) * | 2002-08-01 | 2004-02-12 | Aventis Pharma Deutschland Gmbh | Verfahren zur Reinigung von Preproinsulin |
| DE102004015965A1 (de) * | 2004-04-01 | 2005-10-20 | Aventis Pharma Gmbh | Verfahren zur Gewinnung von Insulinen durch verbesserte Luftbegasung der Faltung |
| JP5036727B2 (ja) | 2005-12-22 | 2012-09-26 | ジェネンテック， インコーポレイテッド | ヘパリン結合タンパク質の組み換え体産生 |
| CN101506222B (zh) * | 2006-07-14 | 2013-10-02 | 健泰科生物技术公司 | 重组蛋白的重折叠 |
| CA2692585A1 (en) * | 2007-07-03 | 2010-01-04 | Amgen Inc. | Measurement of protein using inclusion body dry weight |
| RU2451750C2 (ru) * | 2007-09-24 | 2012-05-27 | Общество С Ограниченной Ответственностью "Герофарм" | Способ получения рекомбинантного с-пептида проинсулина человека |
| BRPI0907371A2 (pt) | 2008-01-09 | 2015-11-24 | Sanofi Aventis Deutschland | derivados de insulina com um perfil de tempo-ação muito retardado |
| US9296806B2 (en) * | 2008-04-30 | 2016-03-29 | Wockhardt Limited | Processes for refolding of insulin |
| RS59913B1 (sr) | 2008-10-17 | 2020-03-31 | Sanofi Aventis Deutschland | Kombinacija insulina i glp-1-agonista |
| CA2780043C (en) | 2009-11-13 | 2019-01-29 | Sanofi-Aventis Deutschland Gmbh | Pharmaceutical composition comprising a glp-1 agonist and methionine |
| ES2534191T3 (es) | 2009-11-13 | 2015-04-20 | Sanofi-Aventis Deutschland Gmbh | Composición farmacéutica que comprende un agonista de GLP-1, una insulina y metionina |
| SG187904A1 (en) | 2010-08-30 | 2013-04-30 | Sanofi Aventis Deutschland | Use of ave0010 for the manufacture of a medicament for the treatment of diabetes mellitus type 2 |
| 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 |
| AR087744A1 (es) | 2011-09-01 | 2014-04-16 | Sanofi Aventis Deutschland | Composicion farmaceutica para uso en el tratamiento de una enfermedad neurodegenerativa |
| US12157766B2 (en) * | 2012-08-05 | 2024-12-03 | Absci Corporation | Cytoplasmic expression system |
| US10421795B2 (en) | 2012-12-17 | 2019-09-24 | Merck Sharp & Dohme Corp. | Process for purifying insulin and analogues thereof |
| WO2014133324A1 (ko) * | 2013-02-26 | 2014-09-04 | 한미약품 주식회사 | 신규한 인슐린 아날로그 및 이의 용도 |
| CN103694339B (zh) * | 2013-12-04 | 2017-10-13 | 珠海联邦制药股份有限公司 | 一种甘精胰岛素前体的复性方法 |
| US10407483B2 (en) | 2014-03-14 | 2019-09-10 | Merck Sharp & Dohme Corp. | Purifying insulin using cation exchange and reverse phase chromatography in the presence of an organic modifier and elevated temperature |
| SI3229828T1 (sl) | 2014-12-12 | 2023-06-30 | Sanofi-Aventis Deutschland Gmbh | Formulacija s fiksnim razmerjem inzulin glargin/liksisenatid |
| 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 |
| CN104911203A (zh) * | 2015-06-30 | 2015-09-16 | 成都易胜科生物科技有限公司 | 一种重组人胰岛素的工业制备方法 |
| EP3344651B1 (en) | 2015-09-02 | 2022-03-02 | Merck Sharp & Dohme Corp. | A process for obtaining insulin with correctly formed disulfide bonds |
| US10689430B2 (en) | 2016-05-25 | 2020-06-23 | Merck Sharp & Dohme Corp. | Insulin receptor partial agonists |
| WO2018018613A1 (zh) | 2016-07-29 | 2018-02-01 | 广东东阳光药业有限公司 | 一种提高抗体纯度的细胞培养基和培养方法 |
| CN113773400B (zh) * | 2020-06-09 | 2023-08-18 | 宁波鲲鹏生物科技有限公司 | 一种门冬胰岛素衍生物及其应用 |
| CN113773391B (zh) * | 2020-06-09 | 2023-10-20 | 宁波鲲鹏生物科技有限公司 | 一种门冬胰岛素的制备方法 |
| CN113773396A (zh) * | 2020-06-10 | 2021-12-10 | 宁波鲲鹏生物科技有限公司 | 一种地特胰岛素衍生物及其应用 |
| JP7749397B2 (ja) * | 2021-09-30 | 2025-10-06 | キヤノン株式会社 | 超音波ファントム及び超音波ファントムの製造方法 |
Family Cites Families (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| NZ199391A (en) * | 1981-01-02 | 1985-12-13 | Genentech Inc | Chimeric polypeptides comprising a proinsulin sequence,and preparation by recombinant dna technique;production of human insulin |
| DE3501641A1 (de) * | 1985-01-19 | 1986-07-24 | Hoechst Ag, 6230 Frankfurt | Verfahren zur gewinnung von insulin-vorlaeufern aus reaktionsgemischen, die bei der faltung von insulin-vorlaeufern aus den entsprechenden s-sulfonaten anfallen |
| GR1005153B (el) * | 1989-08-29 | 2006-03-13 | The General Hospital Corporation | Πρωτεινες συντηξεως, παρασκευη τους και χρηση τους. |
| RU2045535C1 (ru) * | 1991-06-18 | 1995-10-10 | Институт биоорганической химии им.М.М.Шемякина и Ю.А.Овчинникова РАН | Способ получения проинсулина человека |
| ES2097426T3 (es) * | 1992-12-02 | 1997-04-01 | Hoechst Ag | Procedimiento para la obtencion de proinsulina con puentes de cistina correctamente unidos. |
| DE4405179A1 (de) * | 1994-02-18 | 1995-08-24 | Hoechst Ag | Verfahren zur Gewinnung von Insulin mit korrekt verbundenen Cystinbrücken |
| RU2081122C1 (ru) * | 1994-06-16 | 1997-06-10 | Институт биоорганической химии им.М.М.Шемякина и Ю.А.Овчинникова РАН | Способ выделения и очистки инсулина или его биотехнологических предшественников |
| PT871474E (pt) * | 1994-12-29 | 2007-02-28 | Ferring Int Ct Sa | Produção de insulina humana |
| DE19735711C2 (de) | 1997-08-18 | 2001-04-26 | Aventis Pharma Gmbh | Verfahren zur Herstellung eines Vorläufers von Insulin oder Insulinderivaten mit korrekt verbundenen Cystinbrücken |
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| PD00 | Pending as of 2000-06-30 in czech republic | ||
| MK4A | Patent expired |
Effective date: 20180817 |