NO329956B1 - Nye insulinanaloger med okt sinkbinding og forloper til denne, fremgangsmate for fremstilling, DNA sekvens, ekspresjonsvektor og isolert vertscelle, insulin-sink-kompleks, farmasoytisk preparat, injiserbar opplosning og anvendelse av insulinanalogene. - Google Patents
Nye insulinanaloger med okt sinkbinding og forloper til denne, fremgangsmate for fremstilling, DNA sekvens, ekspresjonsvektor og isolert vertscelle, insulin-sink-kompleks, farmasoytisk preparat, injiserbar opplosning og anvendelse av insulinanalogene. Download PDFInfo
- Publication number
- NO329956B1 NO329956B1 NO20006177A NO20006177A NO329956B1 NO 329956 B1 NO329956 B1 NO 329956B1 NO 20006177 A NO20006177 A NO 20006177A NO 20006177 A NO20006177 A NO 20006177A NO 329956 B1 NO329956 B1 NO 329956B1
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- Prior art keywords
- insulin
- gly
- leu
- ala
- glu
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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
- 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
-
- 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
-
- 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)
- Life Sciences & Earth Sciences (AREA)
- Organic Chemistry (AREA)
- Diabetes (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Endocrinology (AREA)
- Biophysics (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Molecular Biology (AREA)
- Genetics & Genomics (AREA)
- Biochemistry (AREA)
- Gastroenterology & Hepatology (AREA)
- Zoology (AREA)
- Toxicology (AREA)
- Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Veterinary Medicine (AREA)
- Emergency Medicine (AREA)
- Obesity (AREA)
- Hematology (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
- Micro-Organisms Or Cultivation Processes Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19825447A DE19825447A1 (de) | 1998-06-06 | 1998-06-06 | Neue Insulinanaloga mit erhöhter Zinkbildung |
| PCT/EP1999/003490 WO1999064598A2 (de) | 1998-06-06 | 1999-05-21 | Neue insulinanaloga mit erhöhter zinkbindung |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| NO20006177L NO20006177L (no) | 2000-12-05 |
| NO20006177D0 NO20006177D0 (no) | 2000-12-05 |
| NO329956B1 true NO329956B1 (no) | 2011-01-31 |
Family
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO20006177A NO329956B1 (no) | 1998-06-06 | 2000-12-05 | Nye insulinanaloger med okt sinkbinding og forloper til denne, fremgangsmate for fremstilling, DNA sekvens, ekspresjonsvektor og isolert vertscelle, insulin-sink-kompleks, farmasoytisk preparat, injiserbar opplosning og anvendelse av insulinanalogene. |
Country Status (23)
| Country | Link |
|---|---|
| US (1) | US6686177B1 (cs) |
| EP (1) | EP1084248B1 (cs) |
| JP (1) | JP4402296B2 (cs) |
| KR (1) | KR100649339B1 (cs) |
| CN (1) | CN1304450B (cs) |
| AR (1) | AR019852A1 (cs) |
| AT (1) | ATE334201T1 (cs) |
| AU (1) | AU757275B2 (cs) |
| BR (1) | BR9910978A (cs) |
| CA (1) | CA2330183C (cs) |
| CZ (1) | CZ301377B6 (cs) |
| DE (2) | DE19825447A1 (cs) |
| DK (1) | DK1084248T3 (cs) |
| ES (1) | ES2268871T3 (cs) |
| HU (1) | HU228908B1 (cs) |
| MX (1) | MXPA00011456A (cs) |
| NO (1) | NO329956B1 (cs) |
| PL (1) | PL198190B1 (cs) |
| PT (1) | PT1084248E (cs) |
| RU (1) | RU2225723C2 (cs) |
| TR (1) | TR200003606T2 (cs) |
| WO (1) | WO1999064598A2 (cs) |
| ZA (1) | ZA200006835B (cs) |
Families Citing this family (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE19825447A1 (de) * | 1998-06-06 | 1999-12-09 | Hoechst Marion Roussel De Gmbh | Neue Insulinanaloga mit erhöhter Zinkbildung |
| WO2002067969A2 (en) | 2001-02-21 | 2002-09-06 | Medtronic Minimed, Inc. | Stabilized insulin formulations |
| US20040038864A1 (en) * | 2002-06-27 | 2004-02-26 | Per Balschmidt | Use of dimethyl sulfone as isotonicity agent |
| US7875700B2 (en) | 2004-07-19 | 2011-01-25 | Biocon Limited | Cation complexes of insulin compound conjugates, formulation and uses thereof |
| US7833513B2 (en) | 2004-12-03 | 2010-11-16 | Rhode Island Hospital | Treatment of Alzheimer's Disease |
| AU2008313248B2 (en) * | 2007-10-16 | 2012-04-26 | Biocon Limited | An orally administerable solid pharmaceutical composition and a process thereof |
| PL2209800T3 (pl) * | 2007-11-16 | 2013-12-31 | Novo Nordisk As | Stabilne kompozycje farmaceutyczne zawierające liraglutyd i degludec |
| PL219335B1 (pl) * | 2008-07-04 | 2015-04-30 | Inst Biotechnologii I Antybiotyków | Pochodna insuliny lub jej farmaceutycznie dopuszczalna sól, jej zastosowanie oraz zawierająca ją kompozycja farmaceutyczna |
| JP5780958B2 (ja) * | 2008-07-31 | 2015-09-16 | ケイス、ウエスタン、リザーブ、ユニバーシティ | ハロゲン安定化インスリン |
| EA201201164A1 (ru) * | 2010-02-22 | 2013-04-30 | Кейз Вестерн Ризев Юнивесити | Препараты на основе аналогов инсулина пролонгированного действия в растворимой и кристаллической формах |
| PL222975B1 (pl) | 2012-05-23 | 2016-09-30 | Inst Biotechnologii I Antybiotyków | Analog insuliny lub jego farmaceutycznie dopuszczalna sól, kompozycja farmaceutyczna o przedłużonym działaniu terapeutycznym oraz zastosowanie analogu insuliny |
| FR3013049B1 (fr) | 2013-11-14 | 2015-11-13 | You-Ping Chan | Analogue de l'insuline glargine |
| US10562951B2 (en) | 2015-03-10 | 2020-02-18 | Merck Sharp & Dohme Corp. | Process for preparing recombinant insulin using microfiltration |
| UY36870A (es) * | 2015-08-28 | 2017-03-31 | Hanmi Pharm Ind Co Ltd | Análogos de insulina novedosos |
Family Cites Families (30)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FI78616C (fi) | 1982-02-05 | 1989-09-11 | Novo Industri As | Foerfarande foer framstaellning av en foer infusionsaendamaol avsedd stabiliserad insulinloesning, som har en foerhoejd zinkhalt. |
| DE3326472A1 (de) | 1983-07-22 | 1985-02-14 | Hoechst Ag, 6230 Frankfurt | Neue insulin-derivate, verfahren zu deren herstellung und deren verwendung sowie pharmazeutische mittel zur behandlung des diabetes mellitus |
| DE3327709A1 (de) * | 1983-07-29 | 1985-02-07 | Hoechst Ag, 6230 Frankfurt | Insulin-derivat-kristallsuspensionen, verfahren zu deren herstellung und deren verwendung |
| SU1250303A1 (ru) * | 1983-12-30 | 1986-08-15 | Филиал По Разработке Готовых Лекарственных Средств Научно-Исследовательского Института По Биологическим Испытаниям Химических Соединений | Способ стабилизации суспензии цинк-инсулина кристаллического |
| DE3440988A1 (de) | 1984-11-09 | 1986-07-10 | Hoechst Ag, 6230 Frankfurt | Verfahren zur spaltung von peptiden und proteinen an der methionyl-bindung |
| US4569794A (en) * | 1984-12-05 | 1986-02-11 | Eli Lilly And Company | Process for purifying proteins and compounds useful in such process |
| US5008241A (en) | 1985-03-12 | 1991-04-16 | Novo Nordisk A/S | Novel insulin peptides |
| DE3526995A1 (de) | 1985-07-27 | 1987-02-05 | Hoechst Ag | Fusionsproteine, verfahren zu ihrer herstellung und ihre verwendung |
| PH25772A (en) * | 1985-08-30 | 1991-10-18 | Novo Industri As | Insulin analogues, process for their preparation |
| DE3636903A1 (de) | 1985-12-21 | 1987-07-02 | Hoechst Ag | Fusionsproteine mit eukaryotischem ballastanteil |
| DE3541856A1 (de) | 1985-11-27 | 1987-06-04 | Hoechst Ag | Eukaryotische fusionsproteine, ihre herstellung und verwendung sowie mittel zur durchfuehrung des verfahrens |
| RU2104305C1 (ru) * | 1986-08-29 | 1998-02-10 | Ново Нордиск А.С. | Аналоги инсулина человека, способ их получения, раствор для инъекций |
| CA1340522C (en) | 1987-03-10 | 1999-05-04 | Heinz Dobeli | Fusion proteins containing neighbouring histidines for improved purification |
| DE3805150A1 (de) | 1987-04-11 | 1988-10-20 | Hoechst Ag | Gentechnologisches verfahren zur herstellung von polypeptiden |
| DE4012818A1 (de) | 1990-04-21 | 1991-10-24 | Hoechst Ag | Verfahren zur herstellung von fremdproteinen in streptomyceten |
| DE3726655A1 (de) | 1987-08-11 | 1989-02-23 | Hoechst Ag | Verfahren zur isolierung basischer proteine aus proteingemischen, welche solche basischen proteine enthalten |
| DE3739347A1 (de) | 1987-11-20 | 1989-06-01 | Hoechst Ag | Verfahren zur selektiven spaltung von fusionsproteinen |
| DK257988D0 (da) * | 1988-05-11 | 1988-05-11 | Novo Industri As | Nye peptider |
| EP0347781B1 (de) | 1988-06-23 | 1994-02-16 | Hoechst Aktiengesellschaft | Mini-Proinsulin, seine Herstellung und Verwendung |
| DE3827533A1 (de) | 1988-08-13 | 1990-02-15 | Hoechst Ag | Pharmazeutische zubereitung zur behandlung des diabetes mellitus |
| DE3837825A1 (de) | 1988-11-08 | 1990-05-10 | Hoechst Ag | Neue insulinderivate, ihre verwendung und eine sie enthaltende pharmazeutische zubereitung |
| US5358857A (en) | 1989-08-29 | 1994-10-25 | The General Hospital Corp. | Method of preparing fusion proteins |
| US5227293A (en) | 1989-08-29 | 1993-07-13 | The General Hospital Corporation | Fusion proteins, their preparation and use |
| IL95495A (en) | 1989-08-29 | 1996-10-16 | Hoechst Ag | Fusion proteins their preparation and use |
| DE59305396D1 (de) | 1992-12-02 | 1997-03-20 | Hoechst Ag | Verfahren zur Gewinnung von Proinsulin mit korrekt verbundenen Cystinbrücken |
| EP0705275B1 (en) * | 1993-06-21 | 1999-02-03 | Novo Nordisk A/S | Asp-b28 insulin crystals |
| SI0792290T1 (en) * | 1993-09-17 | 2001-12-31 | Novo Nordisk As | Acylated insulin |
| DE4405179A1 (de) | 1994-02-18 | 1995-08-24 | Hoechst Ag | Verfahren zur Gewinnung von Insulin mit korrekt verbundenen Cystinbrücken |
| DE59711533D1 (de) * | 1996-07-26 | 2004-05-27 | Aventis Pharma Gmbh | Insulinderivate mit erhöhter Zinkbindung |
| DE19825447A1 (de) * | 1998-06-06 | 1999-12-09 | Hoechst Marion Roussel De Gmbh | Neue Insulinanaloga mit erhöhter Zinkbildung |
-
1998
- 1998-06-06 DE DE19825447A patent/DE19825447A1/de not_active Withdrawn
-
1999
- 1999-05-21 EP EP99925023A patent/EP1084248B1/de not_active Expired - Lifetime
- 1999-05-21 CZ CZ20004525A patent/CZ301377B6/cs not_active IP Right Cessation
- 1999-05-21 DE DE59913711T patent/DE59913711D1/de not_active Expired - Lifetime
- 1999-05-21 MX MXPA00011456A patent/MXPA00011456A/es not_active IP Right Cessation
- 1999-05-21 WO PCT/EP1999/003490 patent/WO1999064598A2/de active IP Right Grant
- 1999-05-21 RU RU2001101164/15A patent/RU2225723C2/ru not_active IP Right Cessation
- 1999-05-21 BR BR9910978-6A patent/BR9910978A/pt active Search and Examination
- 1999-05-21 JP JP2000553588A patent/JP4402296B2/ja not_active Expired - Fee Related
- 1999-05-21 KR KR1020007013862A patent/KR100649339B1/ko not_active Expired - Fee Related
- 1999-05-21 CA CA002330183A patent/CA2330183C/en not_active Expired - Fee Related
- 1999-05-21 AT AT99925023T patent/ATE334201T1/de active
- 1999-05-21 TR TR2000/03606T patent/TR200003606T2/xx unknown
- 1999-05-21 CN CN998070688A patent/CN1304450B/zh not_active Expired - Fee Related
- 1999-05-21 AU AU41454/99A patent/AU757275B2/en not_active Ceased
- 1999-05-21 PL PL345898A patent/PL198190B1/pl unknown
- 1999-05-21 HU HU0102217A patent/HU228908B1/hu not_active IP Right Cessation
- 1999-05-21 ES ES99925023T patent/ES2268871T3/es not_active Expired - Lifetime
- 1999-05-21 DK DK99925023T patent/DK1084248T3/da active
- 1999-05-21 US US09/701,968 patent/US6686177B1/en not_active Expired - Lifetime
- 1999-05-21 PT PT99925023T patent/PT1084248E/pt unknown
- 1999-06-03 AR ARP990102631A patent/AR019852A1/es active IP Right Grant
-
2000
- 2000-11-22 ZA ZA200006835A patent/ZA200006835B/xx unknown
- 2000-12-05 NO NO20006177A patent/NO329956B1/no not_active IP Right Cessation
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| Date | Code | Title | Description |
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| MM1K | Lapsed by not paying the annual fees |