AU777564B2 - Novel exendin agonist formulations and methods of administration thereof - Google Patents
Novel exendin agonist formulations and methods of administration thereof Download PDFInfo
- Publication number
- AU777564B2 AU777564B2 AU35819/00A AU3581900A AU777564B2 AU 777564 B2 AU777564 B2 AU 777564B2 AU 35819/00 A AU35819/00 A AU 35819/00A AU 3581900 A AU3581900 A AU 3581900A AU 777564 B2 AU777564 B2 AU 777564B2
- Authority
- AU
- Australia
- Prior art keywords
- solvent
- peptide
- exendin
- formulation
- tfa
- 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, expires
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Classifications
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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
-
- 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
- A61K38/2278—Vasoactive intestinal peptide [VIP]; Related peptides (e.g. Exendin)
-
- 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
- A61P3/04—Anorexiants; Antiobesity agents
-
- 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
- A61P5/50—Drugs for disorders of the endocrine system of the pancreatic hormones for increasing or potentiating the activity of insulin
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical & Material Sciences (AREA)
- Diabetes (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Endocrinology (AREA)
- Zoology (AREA)
- Epidemiology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Immunology (AREA)
- Organic Chemistry (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Gastroenterology & Hepatology (AREA)
- Vascular Medicine (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Child & Adolescent Psychology (AREA)
- Emergency Medicine (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Compounds Of Unknown Constitution (AREA)
- Peptides Or Proteins (AREA)
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US11638099P | 1999-01-14 | 1999-01-14 | |
| US60/116380 | 1999-01-14 | ||
| US17536500P | 2000-01-10 | 2000-01-10 | |
| US60/175365 | 2000-01-10 | ||
| PCT/US2000/000902 WO2000041546A2 (en) | 1999-01-14 | 2000-01-14 | Novel exendin agonist formulations and methods of administration thereof |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU2005200206A Division AU2005200206B2 (en) | 1999-01-14 | 2005-01-17 | Novel exendin agonist formulations and methods of administration thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| AU3581900A AU3581900A (en) | 2000-08-01 |
| AU777564B2 true AU777564B2 (en) | 2004-10-21 |
Family
ID=26814176
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU35819/00A Expired AU777564B2 (en) | 1999-01-14 | 2000-01-14 | Novel exendin agonist formulations and methods of administration thereof |
| AU2005200206A Expired AU2005200206B2 (en) | 1999-01-14 | 2005-01-17 | Novel exendin agonist formulations and methods of administration thereof |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU2005200206A Expired AU2005200206B2 (en) | 1999-01-14 | 2005-01-17 | Novel exendin agonist formulations and methods of administration thereof |
Country Status (21)
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|---|---|
| US (1) | US6902744B1 (enExample) |
| EP (2) | EP1140145B2 (enExample) |
| JP (1) | JP4426727B2 (enExample) |
| KR (1) | KR100675711B1 (enExample) |
| CN (2) | CN100356978C (enExample) |
| AT (1) | ATE299031T2 (enExample) |
| AU (2) | AU777564B2 (enExample) |
| BR (1) | BRPI0007820B8 (enExample) |
| CA (1) | CA2356706C (enExample) |
| CY (1) | CY2007013I2 (enExample) |
| DE (3) | DE60021166T3 (enExample) |
| DK (1) | DK1140145T4 (enExample) |
| ES (1) | ES2244416T5 (enExample) |
| HK (1) | HK1040635B (enExample) |
| LU (1) | LU91343I2 (enExample) |
| NL (1) | NL300282I1 (enExample) |
| NO (2) | NO331382B1 (enExample) |
| NZ (1) | NZ512663A (enExample) |
| PT (1) | PT1140145E (enExample) |
| RU (1) | RU2242244C2 (enExample) |
| WO (1) | WO2000041546A2 (enExample) |
Families Citing this family (149)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1998005351A1 (en) * | 1996-08-08 | 1998-02-12 | Amylin Pharmaceuticals, Inc. | Methods for regulating gastrointestinal motility |
| DE69831673C5 (de) * | 1997-01-07 | 2015-01-22 | Amylin Pharmaceuticals, Llc | Verwendung von exedinen und deren antagonisten zur verminderung der lebensmittelaufnahme |
| US7399489B2 (en) | 1999-01-14 | 2008-07-15 | Amylin Pharmaceuticals, Inc. | Exendin analog formulations |
| BRPI0007823A8 (pt) | 1999-01-14 | 2017-03-21 | Amylin Pharmaceuticals Inc | Métodos de supressão do glucagon |
| US20030087820A1 (en) * | 1999-01-14 | 2003-05-08 | Young Andrew A. | Novel exendin agonist formulations and methods of administration thereof |
| US6514500B1 (en) * | 1999-10-15 | 2003-02-04 | Conjuchem, Inc. | Long lasting synthetic glucagon like peptide {GLP-!} |
| US20090175821A1 (en) * | 1999-05-17 | 2009-07-09 | Bridon Dominique P | Modified therapeutic peptides with extended half-lives in vivo |
| US6528486B1 (en) | 1999-07-12 | 2003-03-04 | Zealand Pharma A/S | Peptide agonists of GLP-1 activity |
| US7022674B2 (en) | 1999-12-16 | 2006-04-04 | Eli Lilly And Company | Polypeptide compositions with improved stability |
| CA2430934C (en) | 2000-12-01 | 2011-06-21 | Takeda Chemical Industries, Ltd. | A method of producing sustained-release preparations of a bioactive substance using high-pressure gas |
| JP5562510B2 (ja) | 2001-06-28 | 2014-07-30 | ノヴォ ノルディスク アー/エス | 修飾glp−1の安定な処方剤 |
| JP2005501058A (ja) * | 2001-07-31 | 2005-01-13 | ザ ガバメント オブ ザ ユナイテッドステイツ オブ アメリカ アズ リプレゼンテッド バイ ザ セクレタリー デパートメント オブ ヘルス アンド ヒューマン サービシーズ ザ ナショナル インステ | Glp−1、exendin−4、そのペプチド・アナログ及びその使用 |
| RU2353625C2 (ru) * | 2001-10-18 | 2009-04-27 | Бристол-Маерс Сквибб Компани | Миметики человеческого глюканоподобного пептида-1 и их применение в лечении диабета и родственных состояний |
| DE10238931C1 (de) * | 2002-08-24 | 2003-07-31 | Fh Hildesheim Holzminden Goe | Verfahren und Vorrichtung zur Vorbereitung eines Finger- oder Fußnagels für eine Beschichtung, insbesondere Lackierung |
| CA2501677A1 (en) * | 2002-10-22 | 2004-05-06 | Waratah Pharmaceuticals, Inc. | Treatment of diabetes |
| US7731947B2 (en) | 2003-11-17 | 2010-06-08 | Intarcia Therapeutics, Inc. | Composition and dosage form comprising an interferon particle formulation and suspending vehicle |
| KR101198346B1 (ko) | 2003-04-08 | 2012-11-06 | 노보 노르디스크 에이/에스 | 크로마토그래피 고정상의 재생 |
| WO2004089985A1 (en) | 2003-04-11 | 2004-10-21 | Novo Nordisk A/S | Stable pharmaceutical compositions |
| WO2005000222A2 (en) * | 2003-05-30 | 2005-01-06 | Amylin Pharmaceuticals, Inc. | Novel methods and compositions for enhanced transmucosal delivery of peptides and proteins |
| EP1633391B1 (en) | 2003-06-03 | 2011-10-19 | Novo Nordisk A/S | Stabilized pharmaceutical peptide compositions |
| CN102940879B (zh) | 2003-06-03 | 2017-06-06 | 诺沃挪第克公司 | 稳定化的药物肽组合物 |
| EP2292253A3 (en) | 2003-06-03 | 2011-12-14 | Novo Nordisk A/S | Stabilized pharmaceutical peptide compositions |
| DE10329324A1 (de) * | 2003-06-30 | 2005-02-03 | Toximed Gmbh | Pharmarzeutischer Schlankmacher |
| JP5518282B2 (ja) * | 2003-09-01 | 2014-06-11 | ノヴォ ノルディスク アー/エス | 安定なペプチドの製剤 |
| PL3300721T5 (pl) | 2003-11-20 | 2025-11-17 | Novo Nordisk A/S | Preparaty peptydowe zawierające glikol propylenowy, które są optymalne do produkcji i do zastosowania w urządzeniu do wstrzykiwania |
| WO2005058252A2 (en) * | 2003-12-16 | 2005-06-30 | Societe De Conseils De Recherches Et D'applications Scientifiques S.A.S. | Glp-1 pharmaceutical compositions |
| WO2005072045A2 (en) * | 2004-01-30 | 2005-08-11 | Waratah Pharmaceuticals, Inc. | The combined use of glp-1 agonists and gastrin for regulating blood glucose levels |
| DK1745078T3 (da) * | 2004-04-23 | 2009-10-26 | Conjuchem Biotechnologies Inc | Fremgangsmåde til oprensning af albuminkonjugater |
| WO2005117584A2 (en) * | 2004-05-28 | 2005-12-15 | Amylin Pharmaceuticals, Inc | Improved transmucosal delivery of peptides and proteins |
| EP1789434B1 (en) | 2004-08-31 | 2013-11-20 | Novo Nordisk A/S | Use of tris(hydroxymethyl) aminomethane for the stabilization of peptides, polypeptides and proteins |
| ES2735533T3 (es) | 2004-11-12 | 2019-12-19 | Novo Nordisk As | Formulaciones estables de GLP-1 |
| EP1841448A2 (en) * | 2004-12-30 | 2007-10-10 | Diakine Therapeutics, Inc. | Pharmaceutical compositions and methods for restoring beta-cell mass and function |
| WO2006083761A2 (en) | 2005-02-03 | 2006-08-10 | Alza Corporation | Solvent/polymer solutions as suspension vehicles |
| US11246913B2 (en) | 2005-02-03 | 2022-02-15 | Intarcia Therapeutics, Inc. | Suspension formulation comprising an insulinotropic peptide |
| US20090227493A1 (en) * | 2005-05-27 | 2009-09-10 | Daiichi Sankyo Company, Limited | Combined drug for treating diabetes |
| PL2347762T3 (pl) | 2005-08-19 | 2019-09-30 | Amylin Pharmaceuticals, Llc | Eksendyna do leczenia cukrzycy i zmniejszania masy ciała |
| US8039432B2 (en) * | 2005-11-09 | 2011-10-18 | Conjuchem, Llc | Method of treatment of diabetes and/or obesity with reduced nausea side effect |
| RU2426530C2 (ru) | 2005-12-22 | 2011-08-20 | Такеда Фармасьютикал Компани Лимитед | Твердый препарат |
| CN101384623B (zh) * | 2005-12-22 | 2013-07-24 | 常山凯捷健生物药物研发(河北)有限公司 | 白蛋白与治疗剂的预成型偶联物的制备方法 |
| BRPI0712559A2 (pt) * | 2006-05-26 | 2012-11-20 | Amylin Pharmaceuticals Inc | composiÇÕes e mÉtodos para o tratamento de insuficiÊncia cardÍaca congestiva |
| DE602007009377D1 (de) | 2006-05-30 | 2010-11-04 | Intarcia Therapeutics Inc | Zweiteiliger flussmodulator mit einem internen kanal für ein osmotisches ausgabesystem |
| EP2359808B1 (en) | 2006-08-09 | 2013-05-22 | Intarcia Therapeutics, Inc | Osmotic delivery systems and piston assemblies |
| MX2009001763A (es) * | 2006-08-17 | 2009-02-25 | Wellstat Therapeutics Corp | Tratamiento combinado para trastornos metabolicos. |
| CN102827284B (zh) * | 2006-11-14 | 2015-07-29 | 上海仁会生物制药股份有限公司 | 带有聚乙二醇基团的Exendin或其类似物及其制剂和用途 |
| RU2413528C2 (ru) | 2007-01-18 | 2011-03-10 | Открытое Акционерное Общество "Валента Фармацевтика" | Лекарственный препарат для лечения сахарного диабета на основе экзенатида и даларгина, применение и способ лечения |
| KR100805208B1 (ko) | 2007-03-27 | 2008-02-21 | 주식회사 펩트론 | 엑센딘 함유 서방성 제제 조성물, 엑센딘 함유 서방성미립구 및 이의 제조 방법 |
| CN104000779A (zh) | 2007-04-23 | 2014-08-27 | 精达制药公司 | 促胰岛素释放肽的混悬制剂及其应用 |
| JP5496082B2 (ja) * | 2007-04-30 | 2014-05-21 | ノボ・ノルデイスク・エー/エス | タンパク質組成物を乾燥させる方法、乾燥タンパク質組成物、及び乾燥タンパク質を含有する薬学的組成物 |
| CN101366692A (zh) * | 2007-08-15 | 2009-02-18 | 江苏豪森药业股份有限公司 | 一种稳定的艾塞那肽制剂 |
| CN101444618B (zh) * | 2007-11-26 | 2012-06-13 | 杭州九源基因工程有限公司 | 含有艾塞那肽的药物制剂 |
| CN102026666B (zh) * | 2007-12-11 | 2013-10-16 | 常山凯捷健生物药物研发(河北)有限公司 | 促胰岛素肽缀合物制剂 |
| CA2726861C (en) | 2008-02-13 | 2014-05-27 | Intarcia Therapeutics, Inc. | Devices, formulations, and methods for delivery of multiple beneficial agents |
| EP2280993A1 (en) | 2008-05-15 | 2011-02-09 | Novo Nordisk A/S | Purification of peptides prepared by solid phase synthesis |
| US20110263496A1 (en) | 2008-05-21 | 2011-10-27 | Amylin Pharmaceuticals, Inc. | Exendins to lower cholesterol and triglycerides |
| MX2011001734A (es) * | 2008-08-14 | 2011-06-20 | Nestec Sa | Composiciones y metodos para influenciar la saciedad, metabolismo de lipidos y utilizacion de grasas. |
| LT2349324T (lt) | 2008-10-17 | 2017-12-27 | Sanofi-Aventis Deutschland Gmbh | Insulino ir glp-1 agonisto derinys |
| CN101870728A (zh) | 2009-04-23 | 2010-10-27 | 派格生物医药(苏州)有限公司 | 新型Exendin变体及其缀合物 |
| WO2010138671A1 (en) | 2009-05-28 | 2010-12-02 | Amylin Pharmaceuticals, Inc. | Glp-1 receptor agonist compounds for sleep enhancement |
| CN101642562A (zh) * | 2009-08-28 | 2010-02-10 | 江苏万邦生化医药股份有限公司 | 艾塞那肽药用制剂及注射液的制备方法 |
| NO2462246T3 (enExample) | 2009-09-28 | 2018-02-03 | ||
| JP5832439B2 (ja) | 2009-11-13 | 2015-12-16 | サノフィ−アベンティス・ドイチュラント・ゲゼルシャフト・ミット・ベシュレンクテル・ハフツング | Glp−1アゴニスト、インスリン及びメチオニンを含む薬学的組成物 |
| CN102711804B (zh) | 2009-11-13 | 2015-09-16 | 赛诺菲-安万特德国有限公司 | 包含glp-1激动剂和甲硫氨酸的药物组合物 |
| EP2504019A2 (en) | 2009-11-25 | 2012-10-03 | ArisGen SA | Mucosal delivery composition comprising a peptide complexed with a crown compound and/or a counter ion |
| CN102100912B (zh) * | 2009-12-16 | 2015-04-22 | 上海蓝心医药科技有限公司 | 一种给药组合物及其制备和使用方法 |
| WO2011123943A1 (en) | 2010-04-09 | 2011-10-13 | Mount Sinai Hospital | Methods for treating disorders of the gastrointestinal tract using a glp-1 agonist |
| WO2011134471A1 (en) | 2010-04-27 | 2011-11-03 | Zealand Pharma A/S | Peptide conjugates of glp-1 receptor agonists and gastrin and their use |
| NZ603399A (en) * | 2010-05-17 | 2014-09-26 | Cebix Inc | Pegylated c-peptide |
| CN103179978A (zh) | 2010-08-30 | 2013-06-26 | 赛诺菲-安万特德国有限公司 | Ave0010用于制造供治疗2型糖尿病用的药物的用途 |
| CN102397558B (zh) * | 2010-09-09 | 2013-08-14 | 中国人民解放军军事医学科学院毒物药物研究所 | Exendin-4类似物的定位聚乙二醇化修饰物及其用途 |
| EP2438930A1 (en) * | 2010-09-17 | 2012-04-11 | Sanofi-Aventis Deutschland GmbH | Prodrugs comprising an exendin linker conjugate |
| ES2563091T3 (es) | 2010-09-28 | 2016-03-10 | Amylin Pharmaceuticals, Llc | Polipéptidos modificados genéticamente que tienen duración de acción potenciada |
| WO2012088157A2 (en) | 2010-12-22 | 2012-06-28 | Amylin Pharmaceuticals, Inc. | Glp-1 receptor agonists for islet cell transplantation |
| US20120208755A1 (en) | 2011-02-16 | 2012-08-16 | Intarcia Therapeutics, Inc. | Compositions, Devices and Methods of Use Thereof for the Treatment of Cancers |
| CN102100906A (zh) * | 2011-02-18 | 2011-06-22 | 深圳翰宇药业股份有限公司 | 一种艾塞那肽的药用制剂及其制备方法 |
| 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 |
| US20140221282A1 (en) | 2011-05-25 | 2014-08-07 | Astrazeneca Pharmaceuticals Lp | Long duration dual hormone conjugates |
| EP2526971A1 (en) | 2011-05-25 | 2012-11-28 | ArisGen SA | Mucosal delivery of drugs |
| DK2713722T3 (en) | 2011-05-31 | 2017-07-03 | Celgene Int Ii Sarl | Newly known GLP-1 receptor stabilizers and modulators |
| JP6006309B2 (ja) | 2011-07-08 | 2016-10-12 | アミリン・ファーマシューティカルズ, リミテッド・ライアビリティ・カンパニーAmylin Pharmaceuticals, Llc | 作用持続期間が増大し、免疫原性が減少した操作されたポリペプチド |
| WO2013030160A1 (en) | 2011-08-29 | 2013-03-07 | Sanofi-Aventis Deutschland Gmbh | Pharmaceutical combination for use in glycemic control in diabetes type 2 patients |
| TWI559929B (en) | 2011-09-01 | 2016-12-01 | Sanofi Aventis Deutschland | Pharmaceutical composition for use in the treatment of a neurodegenerative disease |
| CN104144704B (zh) | 2011-11-03 | 2018-03-23 | 西兰制药公司 | Glp‑1受体激动剂肽胃泌素缀合物 |
| CN104220086A (zh) | 2011-11-17 | 2014-12-17 | 塞比克斯股份公司 | Peg化的c-肽 |
| HK1202119A1 (en) | 2011-12-12 | 2015-09-18 | Celgene International Ii Sàrl | Novel glp-1 receptor modulators |
| WO2013182217A1 (en) * | 2012-04-27 | 2013-12-12 | Sanofi-Aventis Deutschland Gmbh | Quantification of impurities for release testing of peptide products |
| WO2013170636A1 (zh) | 2012-05-18 | 2013-11-21 | 爱德迪安(北京)生物技术有限公司 | 用于糖尿病治疗的蛋白、蛋白缀合物及其应用 |
| CN109456400A (zh) | 2012-07-23 | 2019-03-12 | 西兰制药公司 | 胰高血糖素类似物 |
| TWI608013B (zh) | 2012-09-17 | 2017-12-11 | 西蘭製藥公司 | 升糖素類似物 |
| UA116217C2 (uk) | 2012-10-09 | 2018-02-26 | Санофі | Пептидна сполука як подвійний агоніст рецепторів glp1-1 та глюкагону |
| WO2014067084A1 (zh) | 2012-10-31 | 2014-05-08 | 深圳翰宇药业股份有限公司 | 一种艾塞那肽的制备方法 |
| CN102977204A (zh) * | 2012-11-14 | 2013-03-20 | 吉林省敖腾生物科技有限责任公司 | 一种固相合成glp-1类似物的方法 |
| SG10201705097PA (en) | 2012-12-21 | 2017-07-28 | Sanofi Sa | Functionalized exendin-4 derivatives |
| SG11201506888VA (en) | 2013-04-03 | 2015-09-29 | Sanofi Sa | Treatment of diabetes mellitus by long-acting formulations of insulins |
| CN105593225B (zh) | 2013-06-11 | 2019-04-16 | 赛尔基因第二国际有限公司 | 新型glp-1受体调节剂 |
| CN103405753B (zh) * | 2013-08-13 | 2016-05-11 | 上海仁会生物制药股份有限公司 | 稳定的促胰岛素分泌肽水针药物组合物 |
| RS57632B1 (sr) | 2013-10-17 | 2018-11-30 | Zealand Pharma As | Acilovani analozi glukagona |
| US9988429B2 (en) | 2013-10-17 | 2018-06-05 | Zealand Pharma A/S | Glucagon analogues |
| JP2017503474A (ja) | 2013-11-06 | 2017-02-02 | ジーランド ファーマ アクティーゼルスカブ | グルカゴン−glp−1−gipトリプルアゴニスト化合物 |
| CN105849122B (zh) | 2013-11-06 | 2021-04-30 | 西兰制药公司 | Gip-glp-1双重激动剂化合物及方法 |
| CN105934257B (zh) | 2013-12-06 | 2020-10-09 | 韩捷 | 用于含氮和羟基的药物的生物可逆引入基团 |
| TW201609796A (zh) | 2013-12-13 | 2016-03-16 | 賽諾菲公司 | 非醯化之艾塞那肽-4(exendin-4)胜肽類似物 |
| EP3080154B1 (en) | 2013-12-13 | 2018-02-07 | Sanofi | Dual glp-1/gip receptor agonists |
| WO2015086728A1 (en) | 2013-12-13 | 2015-06-18 | Sanofi | Exendin-4 peptide analogues as dual glp-1/gip receptor agonists |
| TW201609797A (zh) | 2013-12-13 | 2016-03-16 | 賽諾菲公司 | 雙重glp-1/升糖素受體促效劑 |
| TW201625668A (zh) | 2014-04-07 | 2016-07-16 | 賽諾菲公司 | 作為胜肽性雙重glp-1/昇糖素受體激動劑之艾塞那肽-4衍生物 |
| TW201625669A (zh) | 2014-04-07 | 2016-07-16 | 賽諾菲公司 | 衍生自艾塞那肽-4(Exendin-4)之肽類雙重GLP-1/升糖素受體促效劑 |
| TW201625670A (zh) | 2014-04-07 | 2016-07-16 | 賽諾菲公司 | 衍生自exendin-4之雙重glp-1/升糖素受體促效劑 |
| US9932381B2 (en) | 2014-06-18 | 2018-04-03 | Sanofi | Exendin-4 derivatives as selective glucagon receptor agonists |
| CN107074820B (zh) | 2014-07-25 | 2021-05-18 | 赛尔基因第二国际有限公司 | Glp-1受体调节剂 |
| GB201415598D0 (en) | 2014-09-03 | 2014-10-15 | Univ Birmingham | Elavated Itercranial Pressure Treatment |
| US12071516B2 (en) | 2014-09-04 | 2024-08-27 | Nano Precision Medical, Inc. | Polymeric stabilizing formulations |
| WO2016037128A1 (en) * | 2014-09-04 | 2016-03-10 | Nano Precision Medical, Inc. | Polymeric stabilizing formulations |
| US9889085B1 (en) | 2014-09-30 | 2018-02-13 | Intarcia Therapeutics, Inc. | Therapeutic methods for the treatment of diabetes and related conditions for patients with high baseline HbA1c |
| TWI705973B (zh) | 2014-10-29 | 2020-10-01 | 丹麥商西蘭製藥公司 | Gip促效劑化合物及方法 |
| KR102497644B1 (ko) | 2014-12-10 | 2023-02-08 | 리셉토스 엘엘씨 | Glp-1 수용체 조절제 |
| MA41138B1 (fr) | 2014-12-12 | 2023-07-31 | Sanofi Aventis Deutschland | Formulation à rapport fixe d'insuline glargine/lixisenatide |
| MX386778B (es) | 2015-03-09 | 2025-03-19 | Intekrin Therapeutics Inc | Métodos para el tratamiento de enfermedad de hígado graso no alcohólico y/o lipodistrofia. |
| 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 |
| PL3283507T3 (pl) | 2015-04-16 | 2020-05-18 | Zealand Pharma A/S | Acylowany analog glukagonu |
| BR112017025000A2 (pt) | 2015-05-22 | 2018-08-07 | The Bot Of The Leland Stanford Junior University | tratamento de hipoglicemia pós-bariátrica com exendina (9-39) |
| US10925639B2 (en) | 2015-06-03 | 2021-02-23 | Intarcia Therapeutics, Inc. | Implant placement and removal systems |
| AR105319A1 (es) | 2015-06-05 | 2017-09-27 | Sanofi Sa | Profármacos que comprenden un conjugado agonista dual de glp-1 / glucagón conector ácido hialurónico |
| AR105284A1 (es) | 2015-07-10 | 2017-09-20 | Sanofi Sa | Derivados de exendina-4 como agonistas peptídicos duales específicos de los receptores de glp-1 / glucagón |
| CN106554403B (zh) | 2015-09-25 | 2021-08-31 | 博瑞生物医药(苏州)股份有限公司 | 艾塞那肽修饰物及其用途 |
| CN109715662B (zh) | 2015-12-23 | 2023-07-21 | 美国安进公司 | 使用gipr结合蛋白与glp-1激动剂的组合来治疗或改善代谢病症的方法 |
| WO2017152014A1 (en) | 2016-03-04 | 2017-09-08 | Eiger Biopharmaceuticals, Inc. | Treatment of hyperinsulinemic hypoglycemia with exendin-4 derivatives |
| TWI754643B (zh) | 2016-05-16 | 2022-02-11 | 美商因塔希亞治療公司 | 升糖素受體選擇性多肽和彼之使用方法 |
| USD860451S1 (en) | 2016-06-02 | 2019-09-17 | Intarcia Therapeutics, Inc. | Implant removal tool |
| USD840030S1 (en) | 2016-06-02 | 2019-02-05 | Intarcia Therapeutics, Inc. | Implant placement guide |
| WO2018057977A1 (en) | 2016-09-23 | 2018-03-29 | Delpor, Inc. | Stable compositions for incretin mimetic compounds |
| CN107952064B (zh) * | 2016-10-14 | 2023-10-20 | 江苏豪森药业集团有限公司 | 含有聚乙二醇洛塞那肽的药物制剂及其制备方法 |
| DK3541366T3 (da) * | 2016-11-21 | 2025-03-03 | Amylyx Pharmaceuticals Inc | Bufferformuleringer af exendin (9-39) |
| US11285180B2 (en) | 2016-12-06 | 2022-03-29 | Inserm (Institut National De La Sante Et De La Recherche Medicale) | Methods of enhancing the potency of incretin-based drugs in subjects in need thereof |
| EP3551651B1 (en) | 2016-12-09 | 2024-03-06 | Zealand Pharma A/S | Acylated glp-1/glp-2 dual agonists |
| WO2018129058A1 (en) | 2017-01-03 | 2018-07-12 | Intarcia Therapeutics, Inc. | Methods comprising continuous administration of a glp-1 receptor agonist and co-adminstration of a drug |
| JOP20190177A1 (ar) | 2017-01-17 | 2019-07-16 | Amgen Inc | طريقة لعلاج أو تحسين اضطرابات أيضية باستخدام مساعدات مستقبل glp-1 مقترنة بمناهضات لمستقبل ببتيد مثبط معوي (gipr) |
| CA3058806A1 (en) | 2017-04-03 | 2018-10-11 | Coherus Biosciences Inc. | Ppar.gamma. agonist for treatment of progressive supranuclear palsy |
| WO2018237097A1 (en) | 2017-06-20 | 2018-12-27 | Amgen Inc. | METHOD OF TREATING OR REDUCING METABOLIC DISORDERS USING GASTRIC INHIBITING PEPTIDE RECEPTOR BINDING PROTEINS (GIPR) IN ASSOCIATION WITH GLP-1 AGONISTS |
| EP3642238A1 (en) | 2017-06-21 | 2020-04-29 | Amgen Inc. | Method of treating or ameliorating metabolic disorders using antagonistic binding proteins for gastric inhibitory peptide receptor (gipr)/glp-1 receptor agonist fusion proteins |
| HRP20240485T1 (hr) | 2017-08-24 | 2024-07-05 | Novo Nordisk A/S | Pripravci glp-1 i njihova upotreba |
| RU2666148C1 (ru) * | 2017-10-05 | 2018-09-06 | Общество с ограниченной ответственностью "Новые Антибиотики" | Способ получения водорастворимой лиофилизированной формы соли бис(2-тио-4,6-диоксо-1,2,3,4,5,6-гексагидропиримидин-5-ил)-(4-нитрофенил)метана |
| WO2020185533A1 (en) | 2019-03-08 | 2020-09-17 | Amgen Inc. | Growth differentiation factor 15 combination therapy |
| AU2020234718A1 (en) | 2019-03-13 | 2023-05-18 | Tearsolutions, Inc. | Compositions and methods for promoting islet viability and enhancing insulin secretion |
| CN110151980B (zh) * | 2019-06-30 | 2022-12-09 | 中国药科大学 | Glp-1受体激动剂融合蛋白在制备预防或治疗高血脂药物中的应用 |
| MX2022009844A (es) | 2020-02-18 | 2022-09-05 | Novo Nordisk As | Composiciones y usos del peptido similar al glucagon-1 (glp-1). |
| WO2022157747A2 (en) | 2021-01-25 | 2022-07-28 | Mylan Ireland Limited | Pharmaceutical peptide compositions and methods of preparation thereof |
| CN114028537B (zh) * | 2021-11-27 | 2024-03-29 | 上海万锦医药科技有限公司 | 一种含有svhrsp蝎毒肽的药物组合物及其制备方法 |
| WO2024123812A1 (en) | 2022-12-05 | 2024-06-13 | Shattuck Labs, Inc. | Fusion proteins for the treatment of cardiometabolic diseases |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1997046584A1 (de) * | 1996-06-05 | 1997-12-11 | Boehringer Mannheim Gmbh | Exendin-analoga, verfahren zu deren herstellung und diese enthaltende arzneimittel |
| WO1998030231A1 (en) * | 1997-01-07 | 1998-07-16 | Amylin Pharmaceuticals, Inc. | Use of exendins and agonists thereof for the reduction of food intake |
Family Cites Families (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5424286A (en) | 1993-05-24 | 1995-06-13 | Eng; John | Exendin-3 and exendin-4 polypeptides, and pharmaceutical compositions comprising same |
| WO1995007098A1 (en) | 1993-09-07 | 1995-03-16 | Amylin Pharmaceuticals, Inc. | Methods for regulating gastrointestinal motility |
| WO1998005351A1 (en) | 1996-08-08 | 1998-02-12 | Amylin Pharmaceuticals, Inc. | Methods for regulating gastrointestinal motility |
| ES2283025T3 (es) * | 1996-08-30 | 2007-10-16 | Novo Nordisk A/S | Derivados de glp-1.1. |
| RU2114617C1 (ru) * | 1996-09-27 | 1998-07-10 | Юрий Георгиевич Каминский | Антидиабетическое средство на основе янтарной кислоты |
| CA2299425A1 (en) | 1997-08-08 | 1999-02-18 | Amylin Pharmaceuticals, Inc. | Novel exendin agonist compounds |
| CA2309356C (en) | 1997-11-14 | 2010-09-21 | Amylin Pharmaceuticals, Inc. | Novel exendin agonist compounds |
| EP1066314B1 (en) | 1997-11-14 | 2007-12-26 | Amylin Pharmaceuticals, Inc. | Novel exendin agonist compounds |
| CA2320371C (en) | 1998-02-13 | 2012-01-17 | Amylin Pharmaceuticals, Inc. | Inotropic and diuretic effects of exendin and glp-1 |
| WO1999043708A1 (en) | 1998-02-27 | 1999-09-02 | Novo Nordisk A/S | Glp-1 derivatives of glp-1 and exendin with protracted profile of action |
| US6506724B1 (en) * | 1999-06-01 | 2003-01-14 | Amylin Pharmaceuticals, Inc. | Use of exendins and agonists thereof for the treatment of gestational diabetes mellitus |
| US6528486B1 (en) * | 1999-07-12 | 2003-03-04 | Zealand Pharma A/S | Peptide agonists of GLP-1 activity |
-
2000
- 2000-01-14 BR BRPI0007820A patent/BRPI0007820B8/pt not_active IP Right Cessation
- 2000-01-14 HK HK02102346.5A patent/HK1040635B/en not_active IP Right Cessation
- 2000-01-14 WO PCT/US2000/000902 patent/WO2000041546A2/en not_active Ceased
- 2000-01-14 PT PT00914425T patent/PT1140145E/pt unknown
- 2000-01-14 ES ES00914425T patent/ES2244416T5/es not_active Expired - Lifetime
- 2000-01-14 DK DK00914425.4T patent/DK1140145T4/da active
- 2000-01-14 RU RU2001122722/15A patent/RU2242244C2/ru active Protection Beyond IP Right Term
- 2000-01-14 EP EP00914425.4A patent/EP1140145B2/en not_active Expired - Lifetime
- 2000-01-14 JP JP2000593167A patent/JP4426727B2/ja not_active Expired - Lifetime
- 2000-01-14 DE DE60021166.5T patent/DE60021166T3/de not_active Expired - Lifetime
- 2000-01-14 CA CA2356706A patent/CA2356706C/en not_active Expired - Lifetime
- 2000-01-14 DE DE2000621166 patent/DE122007000001I1/de active Pending
- 2000-01-14 NZ NZ512663A patent/NZ512663A/en not_active IP Right Cessation
- 2000-01-14 DE DE122007000042C patent/DE122007000042I2/de active Active
- 2000-01-14 AU AU35819/00A patent/AU777564B2/en not_active Expired
- 2000-01-14 US US09/889,330 patent/US6902744B1/en not_active Expired - Lifetime
- 2000-01-14 EP EP05009873A patent/EP1609478A1/en not_active Withdrawn
- 2000-01-14 CN CNB008048479A patent/CN100356978C/zh not_active Expired - Lifetime
- 2000-01-14 AT AT00914425T patent/ATE299031T2/de active
- 2000-01-14 KR KR1020017008904A patent/KR100675711B1/ko not_active Expired - Lifetime
- 2000-01-14 CN CNA2007101658564A patent/CN101181236A/zh active Pending
-
2001
- 2001-07-12 NO NO20013468A patent/NO331382B1/no not_active IP Right Cessation
-
2005
- 2005-01-17 AU AU2005200206A patent/AU2005200206B2/en not_active Expired
-
2007
- 2007-05-18 NL NL300282C patent/NL300282I1/nl unknown
- 2007-05-18 LU LU91343C patent/LU91343I2/fr unknown
- 2007-05-18 CY CY2007013C patent/CY2007013I2/el unknown
-
2012
- 2012-05-09 NO NO2012008C patent/NO2012008I1/no unknown
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1997046584A1 (de) * | 1996-06-05 | 1997-12-11 | Boehringer Mannheim Gmbh | Exendin-analoga, verfahren zu deren herstellung und diese enthaltende arzneimittel |
| WO1998030231A1 (en) * | 1997-01-07 | 1998-07-16 | Amylin Pharmaceuticals, Inc. | Use of exendins and agonists thereof for the reduction of food intake |
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