JP6829928B2 - 二相性単鎖インスリン類似体 - Google Patents
二相性単鎖インスリン類似体 Download PDFInfo
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- JP6829928B2 JP6829928B2 JP2017518189A JP2017518189A JP6829928B2 JP 6829928 B2 JP6829928 B2 JP 6829928B2 JP 2017518189 A JP2017518189 A JP 2017518189A JP 2017518189 A JP2017518189 A JP 2017518189A JP 6829928 B2 JP6829928 B2 JP 6829928B2
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- insulin
- chain insulin
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- amino acid
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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
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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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
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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
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Diabetes (AREA)
- Organic Chemistry (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Endocrinology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Animal Behavior & Ethology (AREA)
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- Molecular Biology (AREA)
- Biophysics (AREA)
- Biochemistry (AREA)
- Pharmacology & Pharmacy (AREA)
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- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
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- Toxicology (AREA)
- Zoology (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Emergency Medicine (AREA)
- Immunology (AREA)
- Epidemiology (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
- Medicinal Preparation (AREA)
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| US62/060,167 | 2014-10-06 | ||
| PCT/US2015/054263 WO2016057529A2 (en) | 2014-10-06 | 2015-10-06 | Biphasic single-chain insulin analogues |
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| JP2017536337A5 JP2017536337A5 (enExample) | 2018-11-08 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN106102763A (zh) | 2014-01-13 | 2016-11-09 | 塞尔玛琳糖尿病有限责任公司 | 速效胰岛素制剂和药物递送系统 |
| AR105616A1 (es) | 2015-05-07 | 2017-10-25 | Lilly Co Eli | Proteínas de fusión |
| AU2016377786A1 (en) * | 2015-12-23 | 2018-06-14 | Case Western Reserve University | Encapsulation of ultra-stable insulin analogues with polymer melts |
| JP7286160B2 (ja) * | 2016-11-21 | 2023-06-05 | ケース ウェスタン リザーブ ユニバーシティ | 安定性が増強された速効性インスリン類似体 |
| SI3892628T1 (sl) * | 2018-06-29 | 2023-01-31 | Akston Biosciences Corporation | Ultra dolgo delujoči inzulin-fc-fuzijski proteini in postopki za uporabo |
| US20210371489A1 (en) * | 2018-09-21 | 2021-12-02 | Case Western Reserve University | Site 2 single-chain insulin analogues |
| US12077568B2 (en) | 2018-10-01 | 2024-09-03 | University Of Houston System | Engineered active single-polypeptide chain insulin analogs |
| WO2020106748A1 (en) * | 2018-11-19 | 2020-05-28 | Case Western Reserve University | Single-chain insulin analogues with poly-alanine c-domain sub-segments |
| EP3969467A4 (en) * | 2019-05-17 | 2023-07-05 | Case Western Reserve University | VARIANT SINGLE STREAM INSULIN ANALOGS |
| TW202434620A (zh) | 2019-07-31 | 2024-09-01 | 美商美國禮來大藥廠 | 鬆弛素(relaxin)類似物及其使用方法 |
| US20220280614A1 (en) * | 2019-08-02 | 2022-09-08 | Case Western Reserve University | Premixed Ultra-Stable Single-Chain Insulin Analogue Formulations |
| IL296090A (en) * | 2020-03-02 | 2022-11-01 | Thermalin Inc | Preparations containing fast-acting analogues of insulin |
| WO2022125587A1 (en) * | 2020-12-07 | 2022-06-16 | Case Western Reserve University | Acylated single-chain insulin analogues |
| CZ310198B6 (cs) * | 2021-07-07 | 2024-11-13 | Ústav organické chemie a biochemie AV ČR, v. v. i. | Deriváty inzulínu se zvýšenou tepelnou stabilitou |
| JP2024531773A (ja) | 2021-09-20 | 2024-08-29 | キュオン バイオテック アー・ゲー | アルギナーゼ－インスリン融合タンパク質 |
Family Cites Families (45)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| PH25772A (en) | 1985-08-30 | 1991-10-18 | Novo Industri As | Insulin analogues, process for their preparation |
| US5149777A (en) | 1988-07-20 | 1992-09-22 | Novo Nordisk A/S | Human insulin analogs and preparations containing them |
| US5716927A (en) | 1988-12-23 | 1998-02-10 | Novo Nordisk A/S | Insulin analogs having a modified B-chain |
| DE3844211A1 (de) | 1988-12-29 | 1990-07-05 | Hoechst Ag | Neue insulinderivate, verfahren zu deren herstellung, ihre verwendung und eine sie enthaltende pharmazeutische zubereitung |
| US5514646A (en) | 1989-02-09 | 1996-05-07 | Chance; Ronald E. | Insulin analogs modified at position 29 of the B chain |
| DE3936876A1 (de) | 1989-11-06 | 1991-05-23 | Hoechst Ag | Neue insulinderivate, verfahren zu deren herstellung, ihre verwendung und eine sie enthaltende pharmazeutische zubereitung |
| DK158390D0 (da) | 1990-07-02 | 1990-07-02 | Novo Nordisk As | Nye peptider |
| US5422339A (en) | 1991-03-19 | 1995-06-06 | Joslin Diabetes Center, Inc. | Peptides having insulin autoantibody but not insulin receptor binding capacity |
| TW224471B (enExample) | 1991-11-26 | 1994-06-01 | Lilly Co Eli | |
| US6011007A (en) | 1993-09-17 | 2000-01-04 | Novo Nordisk A/S | Acylated insulin |
| US5547929A (en) | 1994-09-12 | 1996-08-20 | Eli Lilly And Company | Insulin analog formulations |
| US20030104981A1 (en) | 1995-11-03 | 2003-06-05 | Jelena Mandic | Human insulin analogues |
| DE19652713C2 (de) | 1996-12-18 | 2001-11-22 | Aventis Pharma Gmbh | Verfahren zur Reinigung von Insulin und Insulinderivaten durch Chromatographie an stark saurem Kationenaustauscher |
| DE19726167B4 (de) | 1997-06-20 | 2008-01-24 | Sanofi-Aventis Deutschland Gmbh | Insulin, Verfahren zu seiner Herstellung und es enthaltende pharmazeutische Zubereitung |
| PL340255A1 (en) | 1997-10-24 | 2001-01-29 | Lilly Co Eli | Non-dissolving insulin compositions |
| US6531448B1 (en) | 1997-12-23 | 2003-03-11 | Eli Lilly And Company | Insoluble compositions for controlling blood glucose |
| US7449443B2 (en) | 2000-03-23 | 2008-11-11 | California Institute Of Technology | Method for stabilization of proteins using non-natural amino acids |
| US7316999B2 (en) | 2000-06-02 | 2008-01-08 | Novo Nordisk A/S | Glucose dependent release of insulin from glucose sensing insulin derivatives |
| KR100449454B1 (ko) | 2000-10-02 | 2004-09-21 | 이현철 | 단일사슬 인슐린 유도체의 유전자를 포함하는 당뇨병치료용 벡터 |
| AU2002346491A1 (en) | 2001-12-19 | 2003-07-09 | Eli Lilly And Company | Crystalline compositions for controlling blood glucose |
| JP2005519041A (ja) | 2001-12-20 | 2005-06-30 | イーライ・リリー・アンド・カンパニー | 長期作用を備えたインスリン分子 |
| WO2003080666A2 (en) | 2002-03-26 | 2003-10-02 | Council Of Scientific And Industrial Research | An adipocyte insulin and a method of treating diabetes |
| WO2003093299A2 (en) | 2002-05-06 | 2003-11-13 | Thomas Jefferson University | Insulin-associated peptides with effects on cerebral health |
| WO2004085472A1 (en) * | 2003-03-27 | 2004-10-07 | Novo Nordisk A/S | Method for making human insulin precursors and human insulin |
| US20060217290A1 (en) | 2003-04-29 | 2006-09-28 | Kohn Wayne D | Insulin analogs having protracted time action |
| PL1633876T3 (pl) | 2003-06-17 | 2009-01-30 | Sembiosys Genetics Inc | Sposoby wytwarzania insuliny w roślinach |
| JP5697831B2 (ja) | 2003-12-03 | 2015-04-08 | ノヴォ ノルディスク アー／エス | 単鎖インシュリン |
| CN102660614A (zh) * | 2005-08-16 | 2012-09-12 | 诺沃-诺迪斯克有限公司 | 制备成熟胰岛素多肽的方法 |
| US8343914B2 (en) | 2006-01-06 | 2013-01-01 | 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 |
| US8192857B2 (en) * | 2006-03-04 | 2012-06-05 | Enerdel, Inc. | Battery assembly and method of forming the same |
| WO2008043033A2 (en) * | 2006-10-04 | 2008-04-10 | Case Western Reserve University | Fibrillation-resistant insulin and insulin analogues |
| US7790677B2 (en) | 2006-12-13 | 2010-09-07 | Elona Biotechnologies | Insulin production methods and pro-insulin constructs |
| ES2613152T3 (es) | 2008-01-09 | 2017-05-22 | Sanofi-Aventis Deutschland Gmbh | Nuevos derivados de insulina con perfil tiempo/acción extremadamente retardado |
| WO2009129250A2 (en) | 2008-04-14 | 2009-10-22 | Case Western Reserve University | Meal-time insulin analogues of enhanced stability |
| NZ588857A (en) * | 2008-04-22 | 2012-07-27 | Univ Case Western Reserve | Isoform-specific insulin analogue for control blood sugar levels |
| WO2009133099A2 (en) * | 2008-04-28 | 2009-11-05 | Novo Nordisk A/S | Insulin precursors for diabetes treatment |
| 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 |
| US9060927B2 (en) * | 2009-03-03 | 2015-06-23 | Biodel Inc. | Insulin formulations for rapid uptake |
| WO2011028813A2 (en) | 2009-09-01 | 2011-03-10 | Case Western Reserve University | Insulin analogues of enhanced receptor-binding specificity |
| US8399407B2 (en) | 2009-09-17 | 2013-03-19 | Case Western Reserve University | Non-standard insulin analogues |
| NZ600477A (en) | 2009-12-11 | 2014-07-25 | Univ Case Western Reserve | Insulin analogues with chlorinated amino acids |
| US20130085101A1 (en) | 2010-02-22 | 2013-04-04 | Case Western Reserve University | Long-acting insulin analogue preparations in soluble and crystalline forms |
| AU2011268327B2 (en) | 2010-06-16 | 2016-02-25 | Indiana University Research And Technology Corporation | Single chain insulin agonists exhibiting high activity at the insulin receptor |
| JP6584953B2 (ja) | 2012-11-05 | 2019-10-02 | ケース ウェスタン リザーブ ユニバーシティＣａｓｅ Ｗｅｓｔｅｒｎ Ｒｅｓｅｒｖｅ Ｕｎｉｖｅｒｓｉｔｙ | 長時間作用型単鎖インスリン類似体 |
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2015
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- 2015-10-06 BR BR112017004544A patent/BR112017004544A2/pt not_active IP Right Cessation
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- 2015-10-06 CN CN201580054329.9A patent/CN107108716A/zh active Pending
- 2015-10-06 AU AU2015328222A patent/AU2015328222B9/en active Active
- 2015-10-06 EP EP15849531.7A patent/EP3204410B1/en active Active
- 2015-10-06 WO PCT/US2015/054263 patent/WO2016057529A2/en not_active Ceased
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2017
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2019
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| AU2015328222A1 (en) | 2017-03-16 |
| CN107108716A (zh) | 2017-08-29 |
| AU2015328222B2 (en) | 2020-08-20 |
| WO2016057529A2 (en) | 2016-04-14 |
| EP3204410A4 (en) | 2018-03-07 |
| CA2961037A1 (en) | 2016-04-14 |
| JP2017536337A (ja) | 2017-12-07 |
| EP3204410A2 (en) | 2017-08-16 |
| WO2016057529A3 (en) | 2016-11-03 |
| US20180265560A1 (en) | 2018-09-20 |
| US10392429B2 (en) | 2019-08-27 |
| KR20170064533A (ko) | 2017-06-09 |
| US11142560B2 (en) | 2021-10-12 |
| KR102569743B1 (ko) | 2023-08-23 |
| US20190375814A1 (en) | 2019-12-12 |
| BR112017004544A2 (pt) | 2018-01-23 |
| IL251503A0 (en) | 2017-05-29 |
| EP3204410B1 (en) | 2021-01-20 |
| AU2015328222B9 (en) | 2020-12-24 |
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