DE69631996T2 - Verfahren zur Herstellung von acylierten Proteinpuder - Google Patents
Verfahren zur Herstellung von acylierten Proteinpuder Download PDFInfo
- Publication number
- DE69631996T2 DE69631996T2 DE69631996T DE69631996T DE69631996T2 DE 69631996 T2 DE69631996 T2 DE 69631996T2 DE 69631996 T DE69631996 T DE 69631996T DE 69631996 T DE69631996 T DE 69631996T DE 69631996 T2 DE69631996 T2 DE 69631996T2
- Authority
- DE
- Germany
- Prior art keywords
- protein
- insulin
- acylated
- fatty acid
- filtration
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- 238000000034 method Methods 0.000 title claims abstract description 34
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- 108091005647 acylated proteins Proteins 0.000 title abstract description 27
- 230000008569 process Effects 0.000 title description 7
- 238000002360 preparation method Methods 0.000 title description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 58
- 102000004169 proteins and genes Human genes 0.000 claims abstract description 52
- 108090000623 proteins and genes Proteins 0.000 claims abstract description 52
- 239000007864 aqueous solution Substances 0.000 claims abstract description 20
- 238000001556 precipitation Methods 0.000 claims abstract description 16
- 239000002245 particle Substances 0.000 claims abstract description 8
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical class N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 claims description 109
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- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 3
- 239000004472 Lysine Substances 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 229940053200 antiepileptics fatty acid derivative Drugs 0.000 description 3
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- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
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Classifications
-
- 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
-
- 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
- C07K1/30—Extraction; Separation; Purification by precipitation
-
- 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
-
- 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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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Biophysics (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Biochemistry (AREA)
- Zoology (AREA)
- Diabetes (AREA)
- Endocrinology (AREA)
- Gastroenterology & Hepatology (AREA)
- Toxicology (AREA)
- Analytical Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Immunology (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Peptides Or Proteins (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US484220 | 1995-06-07 | ||
| US08/484,220 US5700904A (en) | 1995-06-07 | 1995-06-07 | Preparation of an acylated protein powder |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| DE69631996D1 DE69631996D1 (de) | 2004-05-06 |
| DE69631996T2 true DE69631996T2 (de) | 2005-01-27 |
Family
ID=23923252
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DE69631996T Expired - Fee Related DE69631996T2 (de) | 1995-06-07 | 1996-05-31 | Verfahren zur Herstellung von acylierten Proteinpuder |
Country Status (21)
| Country | Link |
|---|---|
| US (1) | US5700904A (enExample) |
| EP (1) | EP0747391B1 (enExample) |
| JP (1) | JP3844504B2 (enExample) |
| KR (1) | KR19990022590A (enExample) |
| CN (1) | CN1192218A (enExample) |
| AT (1) | ATE263185T1 (enExample) |
| AU (1) | AU703032B2 (enExample) |
| BR (1) | BR9608729A (enExample) |
| CA (1) | CA2223389A1 (enExample) |
| CZ (1) | CZ388197A3 (enExample) |
| DE (1) | DE69631996T2 (enExample) |
| DK (1) | DK0747391T3 (enExample) |
| EA (1) | EA199800042A1 (enExample) |
| ES (1) | ES2216039T3 (enExample) |
| HU (1) | HUP9900877A3 (enExample) |
| IL (1) | IL122460A0 (enExample) |
| NO (1) | NO975583D0 (enExample) |
| NZ (1) | NZ309371A (enExample) |
| PL (1) | PL323994A1 (enExample) |
| TR (1) | TR199701528T1 (enExample) |
| WO (1) | WO1996040730A1 (enExample) |
Families Citing this family (68)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB9316895D0 (en) | 1993-08-13 | 1993-09-29 | Guy S And St Thomas Hospitals | Hepatoselective insulin analogues |
| US5986050A (en) * | 1996-12-26 | 1999-11-16 | Poly-Med, Inc. | Peracylated proteins and synthetic polypeptides and process for making the same |
| US5898067A (en) * | 1997-02-07 | 1999-04-27 | Novo Nordisk A/S | Crystallization of proteins |
| AU5749198A (en) * | 1997-02-07 | 1998-08-26 | Novo Nordisk A/S | Crystallisation of proteins |
| US5898028A (en) * | 1997-03-20 | 1999-04-27 | Novo Nordisk A/S | Method for producing powder formulation comprising an insulin |
| US6310038B1 (en) * | 1997-03-20 | 2001-10-30 | Novo Nordisk A/S | Pulmonary insulin crystals |
| RU2198181C2 (ru) * | 1997-03-20 | 2003-02-10 | Ново Нордиск А/С | Не содержащие цинк кристаллы инсулина для применения в легочных композициях |
| TR200001050T2 (tr) * | 1997-10-24 | 2000-08-21 | Eli Lilly And Company | Çözünmez insülin bileşimleri |
| ZA989644B (en) * | 1997-10-24 | 2000-04-25 | Lilly Co Eli | Insoluble insulen compositions. |
| ZA989744B (en) * | 1997-10-31 | 2000-04-26 | Lilly Co Eli | Method for administering acylated insulin. |
| CO4970787A1 (es) | 1997-12-23 | 2000-11-07 | Lilly Co Eli | Composiciones insolubles de insulina y derivados de insulina que controlan la glucosa sanguinea |
| EP1396272A1 (en) * | 1997-12-23 | 2004-03-10 | Eli Lilly & Company | Insoluble Insulin Compositions for Controlling Blood Glucose |
| US6526675B1 (en) * | 1999-06-07 | 2003-03-04 | Roe-Hoan Yoon | Methods of using natural products as dewatering aids for fine particles |
| US6855260B1 (en) * | 1999-06-07 | 2005-02-15 | Roe-Hoan Yoon | Methods of enhancing fine particle dewatering |
| US7169889B1 (en) | 1999-06-19 | 2007-01-30 | Biocon Limited | Insulin prodrugs hydrolyzable in vivo to yield peglylated insulin |
| US6799682B1 (en) | 2000-05-16 | 2004-10-05 | Roe-Hoan Yoon | Method of increasing flotation rate |
| US6663602B2 (en) | 2000-06-16 | 2003-12-16 | Novo Nordisk A/S | Injection device |
| US6867183B2 (en) | 2001-02-15 | 2005-03-15 | Nobex Corporation | Pharmaceutical compositions of insulin drug-oligomer conjugates and methods of treating diseases therewith |
| US7060675B2 (en) | 2001-02-15 | 2006-06-13 | Nobex Corporation | Methods of treating diabetes mellitus |
| US6828297B2 (en) | 2001-06-04 | 2004-12-07 | Nobex Corporation | Mixtures of insulin drug-oligomer conjugates comprising polyalkylene glycol, uses thereof, and methods of making same |
| US6828305B2 (en) | 2001-06-04 | 2004-12-07 | Nobex Corporation | Mixtures of growth hormone drug-oligomer conjugates comprising polyalkylene glycol, uses thereof, and methods of making same |
| US6713452B2 (en) * | 2001-06-04 | 2004-03-30 | Nobex Corporation | Mixtures of calcitonin drug-oligomer conjugates comprising polyalkylene glycol, uses thereof, and methods of making same |
| US6835802B2 (en) * | 2001-06-04 | 2004-12-28 | Nobex Corporation | Methods of synthesizing substantially monodispersed mixtures of polymers having polyethylene glycol moieties |
| US6858580B2 (en) * | 2001-06-04 | 2005-02-22 | Nobex Corporation | Mixtures of drug-oligomer conjugates comprising polyalkylene glycol, uses thereof, and methods of making same |
| US7713932B2 (en) | 2001-06-04 | 2010-05-11 | Biocon Limited | Calcitonin drug-oligomer conjugates, and uses thereof |
| US6913903B2 (en) | 2001-09-07 | 2005-07-05 | Nobex Corporation | Methods of synthesizing insulin polypeptide-oligomer conjugates, and proinsulin polypeptide-oligomer conjugates and methods of synthesizing same |
| US6770625B2 (en) | 2001-09-07 | 2004-08-03 | Nobex Corporation | Pharmaceutical compositions of calcitonin drug-oligomer conjugates and methods of treating diseases therewith |
| US7166571B2 (en) | 2001-09-07 | 2007-01-23 | Biocon Limited | Insulin polypeptide-oligomer conjugates, proinsulin polypeptide-oligomer conjugates and methods of synthesizing same |
| US7030082B2 (en) * | 2001-09-07 | 2006-04-18 | Nobex Corporation | Pharmaceutical compositions of drug-oligomer conjugates and methods of treating disease therewith |
| US7196059B2 (en) | 2001-09-07 | 2007-03-27 | Biocon Limited | Pharmaceutical compositions of insulin drug-oligomer conjugates and methods of treating diseases therewith |
| US7312192B2 (en) | 2001-09-07 | 2007-12-25 | Biocon Limited | Insulin polypeptide-oligomer conjugates, proinsulin polypeptide-oligomer conjugates and methods of synthesizing same |
| TWI329105B (en) | 2002-02-01 | 2010-08-21 | Rigel Pharmaceuticals Inc | 2,4-pyrimidinediamine compounds and their uses |
| WO2003088961A1 (en) * | 2002-04-19 | 2003-10-30 | Yissum Research Development Company Of The Hebrew University Of Jerusalem | Beta-agonist compounds comprising nitric oxide donor groups and reactive oxygen species scavenger groups and their use in the treatment of respiratory disorders |
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| US20060247216A1 (en) * | 2002-10-25 | 2006-11-02 | Haj-Yehia Abdullah I | Steroid compounds comprising superoxide dismutase mimic groups and nitric oxide donor groups, and their use in the preparation of medicaments |
| CA2820537C (en) | 2003-04-23 | 2015-10-20 | Valeritas, Inc. | Hydraulically actuated pump for fluid administration |
| US7122542B2 (en) | 2003-07-30 | 2006-10-17 | Rigel Pharmaceuticals, Inc. | Methods of treating or preventing autoimmune diseases with 2,4-pyrimidinediamine compounds |
| US9089636B2 (en) | 2004-07-02 | 2015-07-28 | Valeritas, Inc. | Methods and devices for delivering GLP-1 and uses thereof |
| WO2006014673A2 (en) | 2004-07-19 | 2006-02-09 | Nobex Corporation | Insulin-oligomer conjugates, formulations and uses thereof |
| PL1804865T3 (pl) | 2004-10-21 | 2010-03-31 | Novo Nordisk As | Mechanizm wkręcania dla nawijanych penów |
| JP4022595B2 (ja) * | 2004-10-26 | 2007-12-19 | コニカミノルタオプト株式会社 | 撮影装置 |
| CA2597176C (en) | 2005-02-04 | 2013-10-22 | Mineral And Coal Technologies, Inc. | Improving the separation of diamond from gangue minerals |
| US20090043264A1 (en) | 2005-04-24 | 2009-02-12 | Novo Nordisk A/S | Injection Device |
| US20070203161A1 (en) | 2006-02-24 | 2007-08-30 | Rigel Pharmaceuticals, Inc. | Compositions and methods for inhibition of the jak pathway |
| RU2485106C2 (ru) * | 2005-06-08 | 2013-06-20 | Райджел Фамэсьютикэлз, Инк. | Соединения, проявляющие активность в отношении jak-киназы (варианты), способ лечения заболеваний, опосредованных jak-киназой, способ ингибирования активности jak-киназы (варианты), фармацевтическая композиция на основе указанных соединений |
| US7741281B2 (en) * | 2005-11-03 | 2010-06-22 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
| US8962643B2 (en) * | 2006-02-24 | 2015-02-24 | Rigel Pharmaceuticals, Inc. | Compositions and methods for inhibition of the JAK pathway |
| US8361036B2 (en) | 2006-03-10 | 2013-01-29 | Novo Nordisk A/S | Injection device having a gearing arrangement |
| JP5062768B2 (ja) | 2006-03-10 | 2012-10-31 | ノボ・ノルデイスク・エー／エス | 注射装置および該装置のカートリッジを交換する方法 |
| EP2004671B1 (en) | 2006-03-30 | 2015-12-09 | Novo Nordisk A/S | Two-phase precipitation of proteins |
| ES2656675T3 (es) | 2006-03-30 | 2018-02-28 | Valeritas, Inc. | Dispositivo de suministro de fluidos de múltiples cartuchos |
| US7714025B2 (en) * | 2006-05-10 | 2010-05-11 | Arizona Biomedical Research Commission | Modified chalcone compounds as antimitotic agents |
| US8226618B2 (en) | 2006-05-16 | 2012-07-24 | Novo Nordisk A/S | Gearing mechanism for an injection device |
| AU2007253481B2 (en) | 2006-05-18 | 2013-01-17 | Novo Nordisk A/S | An injection device with mode locking means |
| CA2681023C (en) | 2007-03-23 | 2015-11-03 | Novo Nordisk A/S | An injection device comprising a locking nut |
| KR101234540B1 (ko) | 2007-10-16 | 2013-02-19 | 바이오콘 리미티드 | 경구 투여가능한 고형 약제학적 조성물 및 그 제조방법 |
| HRP20151325T1 (hr) | 2009-01-23 | 2016-01-01 | Rigel Pharmaceuticals, Inc. | Pripravci i postupci za inhibiciju jak puta |
| CN102770152B (zh) | 2009-11-25 | 2016-07-06 | 阿瑞斯根股份有限公司 | 肽类的粘膜递送 |
| WO2012015972A1 (en) | 2010-07-28 | 2012-02-02 | Rigel Pharmaceuticals, Inc. | Compositions and methods for inhibition of the jak pathway |
| EP2797650A2 (en) | 2011-12-29 | 2014-11-05 | Novo Nordisk A/S | Torsion-spring based wind-up autoinjector pen with dial-up/dial-down dosing mechanism |
| WO2013142038A2 (en) | 2012-03-23 | 2013-09-26 | Oxigene, Inc. | Compositions and methods for inhibition of cathepsins |
| US11206846B2 (en) * | 2017-05-02 | 2021-12-28 | Leprino Foods Company | High purity alpha lactalbumin and methods of making |
| WO2019064125A1 (en) | 2017-09-26 | 2019-04-04 | Biocon Limited | INTEGRATED AUTOMATED FILTRATION FOR THE SEPARATION, WASHING AND DRYING OF PEPTIDE CRYSTALS |
| US20220000880A1 (en) | 2018-11-01 | 2022-01-06 | Rigel Pharmaceuticals, Inc. | Method and composition embodiments for treating acute myeloid leukemia |
| US20200377518A1 (en) | 2019-05-29 | 2020-12-03 | Rigel Pharmaceuticals, Inc. | Method of preventing and treating thrombosis |
| CA3147443A1 (en) | 2019-08-08 | 2021-02-11 | Rigel Pharmaceuticals, Inc. | Compounds and method for treating cytokine release syndrome |
| ES2970382T3 (es) | 2019-08-14 | 2024-05-28 | Rigel Pharmaceuticals Inc | Método para bloquear o mejorar el síndrome de liberación de citocinas |
| JP2025513716A (ja) | 2022-03-23 | 2025-04-30 | ライジェル・ファーマシューティカルズ・インコーポレイテッド | Ｉｒａｋ阻害剤としてのピリミド－２－イル－ピラゾール化合物 |
Family Cites Families (29)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR1468831A (fr) * | 1965-10-05 | 1967-02-10 | Roussel Uclaf | Procédé de préparation de nouveaux composés polypeptidiques et produits en résultant |
| DE1902865A1 (de) * | 1968-02-01 | 1969-09-11 | American Home Prod | Substituierte Insulin-Derivate,Verfahren zu ihrer Herstellung und ihre Verwendung in pharmazeutischen Zubereitungen |
| US3591574A (en) * | 1968-05-29 | 1971-07-06 | American Home Prod | Tri-n-phenylglycyl derivatives of insulin |
| US3528960A (en) * | 1968-10-07 | 1970-09-15 | Lilly Co Eli | N-carboxyaroyl insulins |
| US3823125A (en) * | 1969-10-14 | 1974-07-09 | American Home Prod | N-aminoacyl-substituted insulins |
| US3752798A (en) * | 1969-12-02 | 1973-08-14 | G Amird | Tris-na1,nb1,nepsilonb29 - (3-x-3-oxo - 1-y-prop-1-en-1-yl)(ndelta-(4-z-6-r-pyrimidin - 2 - yl) ornithine b22)-insulins and their preparation |
| US3869437A (en) * | 1970-05-08 | 1975-03-04 | Nat Res Dev | Mono-, di, and N{HD A1{B , N{HU B1{B , N{HU B29{B -tri-acylated insulin |
| US3950517A (en) * | 1970-05-08 | 1976-04-13 | National Research Development Corporation | Insulin derivatives |
| GB1381273A (en) * | 1971-01-28 | 1975-01-22 | Nat Res Dev | Insulin derivatives |
| GB1381274A (en) * | 1971-01-28 | 1975-01-22 | Nat Res Dev | Insulin derivatives |
| US3864325A (en) * | 1971-11-18 | 1975-02-04 | Nat Res Dev | (N{HU Al{b , N{HU Bl{b , N{HU B29{B , carbamoyl)-(O{HU A14{B , O{HU B16{B , O{HU B26{B aryl) insulin derivatives |
| BE791949A (fr) * | 1971-11-27 | 1973-05-28 | Schering Ag | Derives d'insuline, leur preparation et leur utilisation |
| US3843815A (en) * | 1972-02-10 | 1974-10-22 | Gen Foods Corp | Inhibiting gel formation in meat-in-gravy products |
| US3755569A (en) * | 1972-07-25 | 1973-08-28 | American Home Prod | Acyl substituted insulins |
| DE2252157C3 (de) * | 1972-10-25 | 1976-03-18 | Hoechst Ag | Zwischenprodukte zur herstellung von insulin, insulin-analogen und -derivaten und verfahren zur herstellung von insulin, insulin analogen und derivaten |
| NL7314766A (enExample) * | 1972-10-31 | 1974-05-02 | ||
| DE2253327A1 (de) * | 1972-10-31 | 1974-05-09 | Hoechst Ag | Verfahren zur herstellung von insulin, insulin-analogen und -derivaten |
| DE2428412A1 (de) * | 1974-06-12 | 1976-01-15 | Hoechst Ag | Verfahren zur herstellung von insulin, insulin-analogen und -derivaten |
| DE2439296A1 (de) * | 1974-08-16 | 1976-02-26 | Hoechst Ag | Verfahren zur herstellung von insulin, insulin-analogen und -derivaten |
| GB1492997A (en) * | 1976-07-21 | 1977-11-23 | Nat Res Dev | Insulin derivatives |
| EP0014815A3 (de) * | 1978-12-20 | 1980-10-29 | Ciba-Geigy Ag | Peptidderivate, Verfahren zu deren Herstellung und Zwischenprodukte sowie pharmazeutische Präparate mit einer dieser Verbindungen |
| US4486458A (en) * | 1982-09-07 | 1984-12-04 | A. E. Staley Manufacturing Company | Non-gelling corn steep liquor |
| PH25772A (en) * | 1985-08-30 | 1991-10-18 | Novo Industri As | Insulin analogues, process for their preparation |
| JPS6255096A (ja) * | 1986-06-12 | 1987-03-10 | Nippon Shinyaku Co Ltd | 新規な脂肪酸アシル化合物 |
| JPH01254699A (ja) * | 1988-04-05 | 1989-10-11 | Kodama Kk | インスリン誘導体及びその用途 |
| PT93057B (pt) * | 1989-02-09 | 1995-12-29 | Lilly Co Eli | Processo para a preparacao de analogos da insulina |
| WO1992001476A1 (en) * | 1990-07-26 | 1992-02-06 | University Of Iowa Research Foundation | Novel drug delivery systems for proteins and peptides using albumin as a carrier molecule |
| US5304473A (en) * | 1991-06-11 | 1994-04-19 | Eli Lilly And Company | A-C-B proinsulin, method of manufacturing and using same, and intermediates in insulin production |
| AU5574094A (en) * | 1992-11-30 | 1994-06-22 | Biosignal Kutato-Fejleszto Kft. | Polyunsaturated fatty acyl-peptide composition |
-
1995
- 1995-06-07 US US08/484,220 patent/US5700904A/en not_active Expired - Fee Related
-
1996
- 1996-05-31 AT AT96303974T patent/ATE263185T1/de not_active IP Right Cessation
- 1996-05-31 ES ES96303974T patent/ES2216039T3/es not_active Expired - Lifetime
- 1996-05-31 DE DE69631996T patent/DE69631996T2/de not_active Expired - Fee Related
- 1996-05-31 EP EP96303974A patent/EP0747391B1/en not_active Expired - Lifetime
- 1996-05-31 DK DK96303974T patent/DK0747391T3/da active
- 1996-06-04 CN CN96195951A patent/CN1192218A/zh active Pending
- 1996-06-04 HU HU9900877A patent/HUP9900877A3/hu unknown
- 1996-06-04 PL PL96323994A patent/PL323994A1/xx unknown
- 1996-06-04 EA EA199800042A patent/EA199800042A1/ru unknown
- 1996-06-04 AU AU59513/96A patent/AU703032B2/en not_active Ceased
- 1996-06-04 BR BR9608729A patent/BR9608729A/pt not_active Application Discontinuation
- 1996-06-04 IL IL12246096A patent/IL122460A0/xx unknown
- 1996-06-04 CZ CZ973881A patent/CZ388197A3/cs unknown
- 1996-06-04 JP JP50083297A patent/JP3844504B2/ja not_active Expired - Fee Related
- 1996-06-04 CA CA002223389A patent/CA2223389A1/en not_active Abandoned
- 1996-06-04 NZ NZ309371A patent/NZ309371A/en unknown
- 1996-06-04 KR KR1019970709071A patent/KR19990022590A/ko not_active Ceased
- 1996-06-04 WO PCT/US1996/007963 patent/WO1996040730A1/en not_active Ceased
- 1996-06-04 TR TR97/01528T patent/TR199701528T1/xx unknown
-
1997
- 1997-12-03 NO NO975583A patent/NO975583D0/no not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| IL122460A0 (en) | 1998-06-15 |
| EA199800042A1 (ru) | 1998-08-27 |
| DE69631996D1 (de) | 2004-05-06 |
| CA2223389A1 (en) | 1996-12-19 |
| KR19990022590A (ko) | 1999-03-25 |
| ATE263185T1 (de) | 2004-04-15 |
| HUP9900877A3 (en) | 1999-11-29 |
| HUP9900877A2 (hu) | 1999-07-28 |
| WO1996040730A1 (en) | 1996-12-19 |
| US5700904A (en) | 1997-12-23 |
| AU5951396A (en) | 1996-12-30 |
| ES2216039T3 (es) | 2004-10-16 |
| AU703032B2 (en) | 1999-03-11 |
| TR199701528T1 (xx) | 1998-03-21 |
| JP3844504B2 (ja) | 2006-11-15 |
| NO975583L (no) | 1997-12-03 |
| EP0747391B1 (en) | 2004-03-31 |
| EP0747391A2 (en) | 1996-12-11 |
| MX9709657A (es) | 1998-07-31 |
| PL323994A1 (en) | 1998-04-27 |
| DK0747391T3 (da) | 2004-07-19 |
| JPH11506738A (ja) | 1999-06-15 |
| NO975583D0 (no) | 1997-12-03 |
| BR9608729A (pt) | 1999-06-29 |
| NZ309371A (en) | 1999-09-29 |
| CZ388197A3 (cs) | 1998-05-13 |
| CN1192218A (zh) | 1998-09-02 |
| EP0747391A3 (en) | 1997-05-21 |
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