ES2390286T3 - Conjugados poliméricos de GLP-1 - Google Patents
Conjugados poliméricos de GLP-1 Download PDFInfo
- Publication number
- ES2390286T3 ES2390286T3 ES06847728T ES06847728T ES2390286T3 ES 2390286 T3 ES2390286 T3 ES 2390286T3 ES 06847728 T ES06847728 T ES 06847728T ES 06847728 T ES06847728 T ES 06847728T ES 2390286 T3 ES2390286 T3 ES 2390286T3
- Authority
- ES
- Spain
- Prior art keywords
- glp
- moiety
- conjugate
- polymer
- mpeg
- 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.)
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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
- C07K14/605—Glucagons
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K17/00—Carrier-bound or immobilised peptides; Preparation thereof
- C07K17/02—Peptides being immobilised on, or in, an organic carrier
- C07K17/08—Peptides being immobilised on, or in, an organic carrier the carrier being a synthetic polymer
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
- A61K47/59—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
- A61K47/60—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
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- Biochemistry (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
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- Engineering & Computer Science (AREA)
- Diabetes (AREA)
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- Public Health (AREA)
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- Bioinformatics & Cheminformatics (AREA)
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- Toxicology (AREA)
- Emergency Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Hematology (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Obesity (AREA)
- Medicinal Preparation (AREA)
- Peptides Or Proteins (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Other Resins Obtained By Reactions Not Involving Carbon-To-Carbon Unsaturated Bonds (AREA)
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US75108205P | 2005-12-16 | 2005-12-16 | |
| US75112105P | 2005-12-16 | 2005-12-16 | |
| US751121P | 2005-12-16 | ||
| US751082P | 2005-12-16 | ||
| PCT/US2006/048181 WO2007075534A2 (en) | 2005-12-16 | 2006-12-18 | Polymer conjugates of glp-1 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| ES2390286T3 true ES2390286T3 (es) | 2012-11-08 |
Family
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ES06847728T Active ES2390286T3 (es) | 2005-12-16 | 2006-12-18 | Conjugados poliméricos de GLP-1 |
Country Status (5)
| Country | Link |
|---|---|
| US (2) | US8293869B2 (enExample) |
| EP (2) | EP1968644B1 (enExample) |
| JP (1) | JP5096363B2 (enExample) |
| ES (1) | ES2390286T3 (enExample) |
| WO (1) | WO2007075534A2 (enExample) |
Families Citing this family (109)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9006175B2 (en) | 1999-06-29 | 2015-04-14 | Mannkind Corporation | Potentiation of glucose elimination |
| SI1494732T1 (sl) | 2002-03-20 | 2008-08-31 | Mannking Corp | Inhalacijski aparat |
| US7731947B2 (en) | 2003-11-17 | 2010-06-08 | Intarcia Therapeutics, Inc. | Composition and dosage form comprising an interferon particle formulation and suspending vehicle |
| US20060182692A1 (en) * | 2003-12-16 | 2006-08-17 | Fishburn C S | Chemically modified small molecules |
| JP5078014B2 (ja) | 2004-08-20 | 2012-11-21 | マンカインド コーポレイション | ジケトピペラジン合成の触媒反応 |
| JP4990142B2 (ja) | 2004-08-23 | 2012-08-01 | マンカインド コーポレイション | 薬物送達のためのジケトピペラジン塩、ジケトモルホリン塩、又はジケトジオキサン塩 |
| AU2005318984B2 (en) | 2004-12-21 | 2011-12-01 | Nektar Therapeutics | Stabilized polymeric thiol reagents |
| WO2006083761A2 (en) | 2005-02-03 | 2006-08-10 | Alza Corporation | Solvent/polymer solutions as suspension vehicles |
| US8299025B2 (en) | 2005-02-03 | 2012-10-30 | Intarcia Therapeutics, Inc. | Suspension formulations of insulinotropic peptides and uses thereof |
| US11246913B2 (en) | 2005-02-03 | 2022-02-15 | Intarcia Therapeutics, Inc. | Suspension formulation comprising an insulinotropic peptide |
| EP1937219B1 (en) | 2005-09-14 | 2015-11-11 | MannKind Corporation | Method of drug formulation based on increasing the affinity of crystalline microparticle surfaces for active agents |
| US8293869B2 (en) | 2005-12-16 | 2012-10-23 | Nektar Therapeutics | Polymer conjugates of GLP-1 |
| CN104383546B (zh) | 2006-02-22 | 2021-03-02 | 曼金德公司 | 用于改善包含二酮哌嗪和活性剂的微粒的药物性质的方法 |
| LT1988910T (lt) | 2006-02-28 | 2018-01-10 | Kodiak Sciences Inc. | Akriloiloksietilfosforilcholiną turintys polimero konjugatai ir jų gavimo būdas |
| EP2020990B1 (en) | 2006-05-30 | 2010-09-22 | Intarcia Therapeutics, Inc | Two-piece, internal-channel osmotic delivery system flow modulator |
| ES2422864T3 (es) | 2006-08-09 | 2013-09-16 | Intarcia Therapeutics, Inc | Sistemas de liberación osmótica y unidades de pistón |
| NZ577397A (en) | 2006-12-27 | 2012-01-12 | Nektar Therapeutics | Factor ix moiety-polymer conjugates having a releasable linkage |
| WO2008082669A2 (en) | 2006-12-27 | 2008-07-10 | Nektar Therapeutics Al, Corporation | Von willebrand factor- and factor viii-polymer conjugates having a releasable linkage |
| EP2164519A2 (en) * | 2007-06-08 | 2010-03-24 | Ascendis Pharma AS | Long-acting polymeric prodrugs of exendin |
| AU2008316634B2 (en) * | 2007-10-24 | 2014-02-27 | Mannkind Corporation | Method of preventing adverse effects by GLP-1 |
| DK2240155T3 (da) | 2008-02-13 | 2012-09-17 | Intarcia Therapeutics Inc | Indretninger, formuleringer og fremgangsmåder til levering af flere gavnlige midler |
| SI2279007T1 (sl) | 2008-04-29 | 2016-09-30 | Ascendis Pharma Growth Disorders Division A/S | Spojine pegiliranega rekombinantnega humanega rastnega hormona |
| CN109568740B (zh) | 2008-06-13 | 2022-05-27 | 曼金德公司 | 干粉吸入器和用于药物输送的系统 |
| US9358352B2 (en) | 2008-06-13 | 2016-06-07 | Mannkind Corporation | Dry powder drug delivery system and methods |
| US8485180B2 (en) | 2008-06-13 | 2013-07-16 | Mannkind Corporation | Dry powder drug delivery system |
| TWI451876B (zh) * | 2008-06-13 | 2014-09-11 | Lilly Co Eli | 聚乙二醇化之離脯胰島素化合物 |
| MX336361B (es) | 2008-06-20 | 2015-12-03 | Mannkind Corp | Un metodo y un aparato interactivo para perfilar en tiempo real esfuerzos de inhalacion. |
| US8575102B2 (en) | 2008-08-01 | 2013-11-05 | Nektar Therapeutics | Conjugates having a releasable linkage |
| TWI614024B (zh) | 2008-08-11 | 2018-02-11 | 曼凱公司 | 超快起作用胰島素之用途 |
| US20110166063A1 (en) * | 2008-09-19 | 2011-07-07 | Nektar Therapeutics | Polymer conjugates of therapeutic peptides |
| WO2010033221A1 (en) | 2008-09-19 | 2010-03-25 | Nektar Therapeutics | Polymer conjugates of protegrin peptides |
| CA3016451A1 (en) | 2008-10-17 | 2010-04-22 | Sanofi-Aventis Deutschland Gmbh | Combination of an insulin and a glp-1 agonist |
| US8314106B2 (en) | 2008-12-29 | 2012-11-20 | Mannkind Corporation | Substituted diketopiperazine analogs for use as drug delivery agents |
| EP2405963B1 (en) | 2009-03-11 | 2013-11-06 | MannKind Corporation | Apparatus, system and method for measuring resistance of an inhaler |
| TWI547487B (zh) | 2009-06-12 | 2016-09-01 | 曼凱公司 | 具限定比表面積之二酮基哌微粒子 |
| CN104323981B (zh) | 2009-09-28 | 2019-03-12 | 精达制药公司 | 基本稳态药物递送的快速建立和/或终止 |
| WO2011056889A1 (en) | 2009-11-03 | 2011-05-12 | Mannkind Corporation | An apparatus and method for simulating inhalation efforts |
| DK2498802T3 (en) | 2009-11-13 | 2015-04-13 | Sanofi Aventis Deutschland | Pharmaceutical composition comprising a GLP-1 agonist, insulin and a methionine |
| PL3345593T3 (pl) | 2009-11-13 | 2024-04-08 | Sanofi-Aventis Deutschland Gmbh | Kompozycja farmaceutyczna zawierająca desPro36-eksendynę-4(1-39)-Lys6-NH2 i metioninę |
| JP5980466B2 (ja) * | 2009-11-13 | 2016-08-31 | 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 | インスリングラルギン及びメトホルミンへの付加療法を含む２型糖尿病の治療方法 |
| WO2011073234A2 (en) | 2009-12-15 | 2011-06-23 | Ascendis Pharma As | Growth hormone composition |
| US8765432B2 (en) | 2009-12-18 | 2014-07-01 | Oligasis, Llc | Targeted drug phosphorylcholine polymer conjugates |
| AU2011274474B2 (en) | 2010-07-09 | 2015-06-18 | Dana-Farber Cancer Institute, Inc. | Stabilized insulinotropic peptides and methods of use |
| PT2611458T (pt) | 2010-08-30 | 2016-12-16 | Sanofi Aventis Deutschland | Utilização de ave0010 para o fabrico de um medicamento para o tratamento da diabetes mellitus tipo 2 |
| WO2012054861A1 (en) * | 2010-10-22 | 2012-04-26 | Nektar Therapeutics | Glp-1 polymer conjugates having a releasable linkage |
| WO2012054822A1 (en) | 2010-10-22 | 2012-04-26 | Nektar Therapeutics | Pharmacologically active polymer-glp-1 conjugates |
| CN103517718A (zh) | 2010-11-12 | 2014-01-15 | 尼克塔治疗公司 | Il-2部分与聚合物的缀合物 |
| BR112013011967A2 (pt) | 2010-11-24 | 2016-08-30 | Durect Corp | composição biodegradável para distribuição de fármaco |
| US20120208755A1 (en) | 2011-02-16 | 2012-08-16 | Intarcia Therapeutics, Inc. | Compositions, Devices and Methods of Use Thereof for the Treatment of Cancers |
| SG10201606220QA (en) | 2011-04-01 | 2016-09-29 | Mannkind Corp | Blister package for pharmaceutical cartridges |
| 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 |
| CN102786590A (zh) * | 2011-05-19 | 2012-11-21 | 江苏豪森药业股份有限公司 | 分枝型peg修饰的glp-1类似物及其可药用盐 |
| WO2012174472A1 (en) | 2011-06-17 | 2012-12-20 | Mannkind Corporation | High capacity diketopiperazine microparticles |
| KR101357117B1 (ko) * | 2011-06-28 | 2014-02-06 | 비앤엘델리팜 주식회사 | 폴리에틸렌글라이콜 또는 이의 유도체로 페길화된 엑센딘-4 유사체, 이의 제조방법 및 이를 유효성분으로 함유하는 당뇨병 예방 또는 치료용 약학적 조성물 |
| DK2750699T3 (en) | 2011-08-29 | 2015-10-26 | Sanofi Aventis Deutschland | A pharmaceutical combination for use in glycemic control in diabetes type 2 patients |
| AU2012301793A1 (en) * | 2011-08-30 | 2014-03-20 | Quanta Biodesign, Ltd. | Branched discrette PEG constructs |
| TWI559929B (en) | 2011-09-01 | 2016-12-01 | Sanofi Aventis Deutschland | Pharmaceutical composition for use in the treatment of a neurodegenerative disease |
| MX2014004983A (es) | 2011-10-24 | 2014-09-22 | Mannkid Corp | Metodos y composiciones para tratar dolor. |
| WO2013078396A2 (en) | 2011-11-23 | 2013-05-30 | Durect Corporation | Radiation-sterilized biodegradable drug delivery compositions |
| SG10201605800UA (en) | 2012-07-12 | 2016-09-29 | Mannkind Corp | Dry powder drug delivery system and methods |
| UA116217C2 (uk) | 2012-10-09 | 2018-02-26 | Санофі | Пептидна сполука як подвійний агоніст рецепторів glp1-1 та глюкагону |
| US10159644B2 (en) | 2012-10-26 | 2018-12-25 | Mannkind Corporation | Inhalable vaccine compositions and methods |
| WO2014093640A1 (en) | 2012-12-12 | 2014-06-19 | Mersana Therapeutics,Inc. | Hydroxy-polmer-drug-protein conjugates |
| WO2014096149A1 (en) | 2012-12-21 | 2014-06-26 | Sanofi | Exendin-4 Derivatives |
| BR112015023168B1 (pt) | 2013-03-15 | 2021-08-10 | Mannkind Corporation | Composição de 3,6-bis(n-fumaril-4-aminobutil)-2,5-dicetopiperazina cristalina, método de produção de partículas de 3,6-bis(n-fumaril-4-aminobutil)-2,5-dicetopiperazina e uso de uma composição de dicetopiperazina cristalina |
| US9925144B2 (en) | 2013-07-18 | 2018-03-27 | Mannkind Corporation | Heat-stable dry powder pharmaceutical compositions and methods |
| CN105517607A (zh) | 2013-08-05 | 2016-04-20 | 曼金德公司 | 吹入设备和方法 |
| JP6463361B2 (ja) | 2013-09-08 | 2019-01-30 | コディアック サイエンシーズ インコーポレイテッドＫｏｄｉａｋ Ｓｃｉｅｎｃｅｓ Ｉｎｃ． | 第ｖｉｉｉ因子両性イオンポリマーコンジュゲート |
| US20160303242A1 (en) | 2013-12-09 | 2016-10-20 | Durect Corporation | Pharmaceutically Active Agent Complexes, Polymer Complexes, and Compositions and Methods Involving the Same |
| WO2015086730A1 (en) | 2013-12-13 | 2015-06-18 | Sanofi | Non-acylated exendin-4 peptide analogues |
| WO2015086733A1 (en) | 2013-12-13 | 2015-06-18 | Sanofi | Dual glp-1/glucagon receptor agonists |
| WO2015086729A1 (en) | 2013-12-13 | 2015-06-18 | Sanofi | Dual glp-1/gip receptor agonists |
| TW201609795A (zh) | 2013-12-13 | 2016-03-16 | 賽諾菲公司 | 作為雙重ｇｌｐ－１／ｇｉｐ受體促效劑的艾塞那肽－４（ｅｘｅｎｄｉｎ－４）胜肽類似物 |
| WO2015138638A1 (en) | 2014-03-11 | 2015-09-17 | Theraly Pharmaceuticals, Inc. | Long acting trail receptor agonists for treatment of autoimmune diseases |
| WO2015148905A1 (en) | 2014-03-28 | 2015-10-01 | Mannkind Corporation | Use of ultrarapid acting insulin |
| 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 |
| 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 |
| 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 |
| US9840553B2 (en) | 2014-06-28 | 2017-12-12 | Kodiak Sciences Inc. | Dual PDGF/VEGF antagonists |
| 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 |
| US10561806B2 (en) | 2014-10-02 | 2020-02-18 | Mannkind Corporation | Mouthpiece cover for an inhaler |
| KR20210013299A (ko) | 2014-10-17 | 2021-02-03 | 코디악 사이언시스 인코포레이티드 | 부티릴콜린에스테라제 양성이온성 중합체 컨쥬게이트 |
| MX394222B (es) | 2014-11-18 | 2025-03-24 | Ascendis Pharma Endocrinology Div A/S | Nuevos profarmacos polimericos de la hormona del crecimiento humana (hgh). |
| SI3220892T1 (sl) | 2014-11-21 | 2022-01-31 | Ascendis Pharma Endocrinology Division A/S | Oblike odmerjanja dolgotrajno delujočega rastnega hormona |
| ES2949095T3 (es) | 2014-12-12 | 2023-09-25 | Sanofi Aventis Deutschland | Formulación de relación fija de insulina glargina/lixisenatida |
| 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 |
| EP4278996A3 (en) | 2015-06-03 | 2024-01-24 | i2o Therapeutics, Inc. | Implant placement 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 |
| TW201706291A (zh) | 2015-07-10 | 2017-02-16 | 賽諾菲公司 | 作為選擇性肽雙重ｇｌｐ－１／升糖素受體促效劑之新毒蜥外泌肽（ｅｘｅｎｄｉｎ－４）衍生物 |
| WO2017062832A1 (en) | 2015-10-08 | 2017-04-13 | Nektar Therapeutics | Combination of an il-2rbeta-selective agonist and a long-acting il-15 agonist |
| WO2017106627A1 (en) | 2015-12-17 | 2017-06-22 | The Johns Hopkins University | Ameliorating systemic sclerosis with death receptor agonists |
| WO2017112889A1 (en) | 2015-12-23 | 2017-06-29 | The Johns Hopkins University | Long-acting glp-1r agonist as a therapy of neurological and neurodegenerative conditions |
| NZ744185A (en) | 2015-12-30 | 2025-09-26 | Kodiak Sciences Inc | Antibodies and conjugates thereof |
| EP3439687A1 (en) | 2016-04-07 | 2019-02-13 | The Johns Hopkins University | Compositions and methods for treating pancreatitis and pain with death receptor agonists |
| WO2017200943A1 (en) | 2016-05-16 | 2017-11-23 | Intarcia Therapeutics, Inc. | Glucagon-receptor selective polypeptides and methods of use thereof |
| USD840030S1 (en) | 2016-06-02 | 2019-02-05 | Intarcia Therapeutics, Inc. | Implant placement guide |
| USD860451S1 (en) | 2016-06-02 | 2019-09-17 | Intarcia Therapeutics, Inc. | Implant removal tool |
| EP3565580B1 (en) | 2017-01-03 | 2024-03-06 | i2o Therapeutics, Inc. | Continuous administration of exenatide and co-adminstration of acetaminophen, ethinylestradiol or levonorgestrel |
| JP7152408B2 (ja) | 2017-03-10 | 2022-10-12 | キアペグ ファーマシューティカルズ アクチエボラグ | 遊離可能コンジュゲート |
| MX2020009152A (es) | 2018-03-02 | 2020-11-09 | Kodiak Sciences Inc | Anticuerpos de il-6 y constructos de fusion y conjugados de los mismos. |
| CN112955216A (zh) * | 2018-09-12 | 2021-06-11 | 奎亚培格制药公司 | 可释放glp-1缀合物 |
| KR20210077677A (ko) * | 2018-10-11 | 2021-06-25 | 넥타르 테라퓨틱스 | 방출 가능한 중합체성 시약의 제조 방법 |
| CN111269309B (zh) * | 2018-12-04 | 2022-03-08 | 翰宇药业（武汉）有限公司 | 一种glp-1类似多肽的纯化方法 |
| KR20210126088A (ko) * | 2019-02-11 | 2021-10-19 | 옵코 바이오로직스 리미티드 | 지속성 glp-2 유사체 |
| US12303553B2 (en) | 2019-03-04 | 2025-05-20 | Ascendis Pharma Endocrinology Division A/S | Long-acting growth hormone dosage forms with superior efficacy to daily somatropin |
| WO2021072265A1 (en) | 2019-10-10 | 2021-04-15 | Kodiak Sciences Inc. | Methods of treating an eye disorder |
| CA3182260A1 (en) * | 2020-06-09 | 2021-12-16 | Gleb Feldman | Manufacture, formulation and dosing of apraglutide |
Family Cites Families (97)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SE438261B (sv) * | 1981-07-08 | 1985-04-15 | Draco Ab | Anvendning i dosinhalator av ett perforerat membran |
| GB8314308D0 (en) | 1983-05-24 | 1983-06-29 | Matburn Holdings Ltd | Medical administration devices |
| US4805811A (en) * | 1985-03-29 | 1989-02-21 | Aktiebolaget Draco | Dosage device |
| SE448277B (sv) * | 1985-04-12 | 1987-02-09 | Draco Ab | Indikeringsanordning vid en doseringsanordning for lekemedel |
| US6849708B1 (en) * | 1986-05-05 | 2005-02-01 | The General Hospital Corporation | Insulinotropic hormone and uses thereof |
| US5118666A (en) * | 1986-05-05 | 1992-06-02 | The General Hospital Corporation | Insulinotropic hormone |
| US5120712A (en) | 1986-05-05 | 1992-06-09 | The General Hospital Corporation | Insulinotropic hormone |
| AT387234B (de) | 1987-03-05 | 1988-12-27 | Vogelbusch Gmbh | Vorrichtung zur zuechtung von dauerformen insbesondere filamentoeser mikroorganismen |
| US5324844A (en) * | 1989-04-19 | 1994-06-28 | Enzon, Inc. | Active carbonates of polyalkylene oxides for modification of polypeptides |
| GB8909891D0 (en) | 1989-04-28 | 1989-06-14 | Riker Laboratories Inc | Device |
| EP0512042B1 (en) | 1990-01-24 | 1998-04-08 | BUCKLEY, Douglas I. | Glp-1 analogs useful for diabetes treatment |
| IT1243344B (it) | 1990-07-16 | 1994-06-10 | Promo Pack Sa | Inalatore plurimonodose per medicamenti in polvere |
| US6565841B1 (en) * | 1991-03-15 | 2003-05-20 | Amgen, Inc. | Pulmonary administration of granulocyte colony stimulating factor |
| DE69230613T2 (de) * | 1991-07-02 | 2000-12-28 | Inhale Inc | Verfahren und vorrichtung zum abgeben von medikamenten in aerosolform |
| US5320094A (en) * | 1992-01-10 | 1994-06-14 | The Johns Hopkins University | Method of administering insulin |
| US5785049A (en) * | 1994-09-21 | 1998-07-28 | Inhale Therapeutic Systems | Method and apparatus for dispersion of dry powder medicaments |
| US6582728B1 (en) | 1992-07-08 | 2003-06-24 | Inhale Therapeutic Systems, Inc. | Spray drying of macromolecules to produce inhaleable dry powders |
| US5470949A (en) | 1992-12-15 | 1995-11-28 | The Arizona Board Of Regents On Behalf Of The University Of Arizona | Method for making amino acid glycosides and glycopeptides |
| US5672581A (en) * | 1993-01-29 | 1997-09-30 | Aradigm Corporation | Method of administration of insulin |
| US6284727B1 (en) * | 1993-04-07 | 2001-09-04 | Scios, Inc. | Prolonged delivery of peptides |
| NZ250844A (en) | 1993-04-07 | 1996-03-26 | Pfizer | Treatment of non-insulin dependant diabetes with peptides; composition |
| WO1995000162A1 (en) | 1993-06-21 | 1995-01-05 | Enzon, Inc. | Site specific synthesis of conjugated peptides |
| US5512459A (en) * | 1993-07-20 | 1996-04-30 | Bionebraska, Inc. | Enzymatic method for modification or recombinant polypeptides |
| US5880131A (en) * | 1993-10-20 | 1999-03-09 | Enzon, Inc. | High molecular weight polymer-based prodrugs |
| US5840900A (en) * | 1993-10-20 | 1998-11-24 | Enzon, Inc. | High molecular weight polymer-based prodrugs |
| US5388572A (en) * | 1993-10-26 | 1995-02-14 | Tenax Corporation (A Connecticut Corp.) | Dry powder medicament inhalator having an inhalation-activated piston to aerosolize dose and deliver same |
| US5446090A (en) | 1993-11-12 | 1995-08-29 | Shearwater Polymers, Inc. | Isolatable, water soluble, and hydrolytically stable active sulfones of poly(ethylene glycol) and related polymers for modification of surfaces and molecules |
| US6051256A (en) | 1994-03-07 | 2000-04-18 | Inhale Therapeutic Systems | Dispersible macromolecule compositions and methods for their preparation and use |
| US5523549A (en) | 1994-05-25 | 1996-06-04 | Ceramic Powders, Inc. | Ferrite compositions for use in a microwave oven |
| GB9413202D0 (en) | 1994-06-30 | 1994-08-24 | Univ Bradford | Method and apparatus for the formation of particles |
| US5574008A (en) | 1994-08-30 | 1996-11-12 | Eli Lilly And Company | Biologically active fragments of glucagon-like insulinotropic peptide |
| US5522385A (en) * | 1994-09-27 | 1996-06-04 | Aradigm Corporation | Dynamic particle size control for aerosolized drug delivery |
| US5932462A (en) | 1995-01-10 | 1999-08-03 | Shearwater Polymers, Inc. | Multiarmed, monofunctional, polymer for coupling to molecules and surfaces |
| US5826633A (en) | 1996-04-26 | 1998-10-27 | Inhale Therapeutic Systems | Powder filling systems, apparatus and methods |
| DE122009000079I2 (de) * | 1996-08-30 | 2011-06-16 | Novo Nordisk As Novo Alle | Glp-1 derivate |
| US6214966B1 (en) | 1996-09-26 | 2001-04-10 | Shearwater Corporation | Soluble, degradable poly(ethylene glycol) derivatives for controllable release of bound molecules into solution |
| US5908830A (en) * | 1996-10-31 | 1999-06-01 | Merck & Co., Inc. | Combination therapy for the treatment of diabetes and obesity |
| UA65549C2 (uk) | 1996-11-05 | 2004-04-15 | Елі Ліллі Енд Компані | Спосіб регулювання ожиріння шляхом периферійного введення аналогів та похідних glp-1 (варіанти) та фармацевтична композиція |
| ATE289517T1 (de) | 1996-11-12 | 2005-03-15 | Novo Nordisk As | Verwendung von glp-1 peptiden |
| JP4526702B2 (ja) | 1997-09-29 | 2010-08-18 | ネクター セラピューティックス | 安定化生物活性処方物およびその使用方法 |
| US6565885B1 (en) | 1997-09-29 | 2003-05-20 | Inhale Therapeutic Systems, Inc. | Methods of spray drying pharmaceutical compositions |
| AU1617399A (en) | 1997-12-05 | 1999-06-28 | Eli Lilly And Company | Glp-1 formulations |
| AU2610899A (en) * | 1998-02-27 | 1999-09-15 | Novo Nordisk A/S | N-terminally modified glp-1 derivatives |
| EP1411075B1 (en) * | 1998-03-12 | 2008-07-02 | Nektar Therapeutics Al, Corporation | Method for preparing polymer conjugates |
| US6257233B1 (en) * | 1998-06-04 | 2001-07-10 | Inhale Therapeutic Systems | Dry powder dispersing apparatus and methods for their use |
| US6720407B1 (en) * | 1998-08-28 | 2004-04-13 | Eli Lilly And Company | Method for administering insulinotropic peptides |
| HRP20010141A2 (en) | 1998-08-28 | 2002-02-28 | Lilly Co Eli | Method for administering insulinotropic peptides |
| CA2343268A1 (en) * | 1998-09-17 | 2000-03-23 | Eli Lilly And Company | Protein formulations |
| ES2302390T3 (es) | 1998-12-07 | 2008-07-01 | Societe De Conseils De Recherches Et D'applications Scientifiques S.A.S. | Analogos de glp-1. |
| DE60044041D1 (de) | 1999-01-14 | 2010-04-29 | Amylin Pharmaceuticals Inc | Exendine zur Glucagon Suppression |
| NZ514916A (en) | 1999-04-30 | 2004-06-25 | Amylin Pharmaceuticals Inc | Exendins and exendin agonists linked to polyethylene glycol polymers |
| KR100345214B1 (ko) | 1999-08-17 | 2002-07-25 | 이강춘 | 생체적합성 고분자가 수식된 펩타이드의 비점막 전달 |
| US6376470B1 (en) * | 1999-09-23 | 2002-04-23 | Enzon, Inc. | Polymer conjugates of ara-C and ara-C derivatives |
| EP1223915B1 (en) | 1999-10-29 | 2005-12-21 | Nektar Therapeutics | Dry powder compositions having improved dispersivity |
| US6348558B1 (en) | 1999-12-10 | 2002-02-19 | Shearwater Corporation | Hydrolytically degradable polymers and hydrogels made therefrom |
| AU2001238595A1 (en) | 2000-02-22 | 2001-09-03 | Shearwater Corporation | N-maleimidyl polymer derivatives |
| DK1724284T3 (da) | 2000-12-07 | 2009-11-02 | Lilly Co Eli | GLP-1 fusionsproteiner |
| JP4142569B2 (ja) | 2001-06-22 | 2008-09-03 | 協和醗酵工業株式会社 | 軟膏剤 |
| EP1432430A4 (en) * | 2001-08-28 | 2006-05-10 | Lilly Co Eli | PREMIXTURES OF GLP-1 AND BASALINSULIN |
| EP1446438A2 (en) * | 2001-11-07 | 2004-08-18 | Nektar Therapeutics Al, Corporation | Branched polymers and their conjugates |
| EP1461070B1 (en) * | 2001-12-29 | 2007-01-24 | Novo Nordisk A/S | Combined use of a glp-1 compound and an aldose reductase inhibitor |
| JP4282485B2 (ja) | 2002-01-08 | 2009-06-24 | イーライ リリー アンド カンパニー | 伸長グルカゴン様ペプチド−１アナログ |
| ES2304501T3 (es) | 2002-02-15 | 2008-10-16 | Nektar Therapeutics Al, Corporation | Polimeros a base de oxido de alquileno degradables hidroliticamente. |
| US20050260259A1 (en) * | 2004-04-23 | 2005-11-24 | Bolotin Elijah M | Compositions for treatment with glucagon-like peptide, and methods of making and using the same |
| US20030191056A1 (en) * | 2002-04-04 | 2003-10-09 | Kenneth Walker | Use of transthyretin peptide/protein fusions to increase the serum half-life of pharmacologically active peptides/proteins |
| AU2002950136A0 (en) | 2002-07-11 | 2002-09-12 | La Trobe University | N-methyl amino acids |
| EP1539210A4 (en) | 2002-09-06 | 2006-06-07 | Bayer Pharmaceuticals Corp | GLP-1 RECEPTOR MODIFIED AGONISTS AND THEIR PHARMACOLOGICAL METHODS OF USE |
| EP1546235B1 (en) | 2002-09-09 | 2021-10-20 | Nektar Therapeutics | Water-soluble polymer alkanals |
| ES2315526T3 (es) | 2002-09-09 | 2009-04-01 | Nektar Therapeutics Al, Corporation | Metodo para preparar derivados polimericos solubles en agua que llevan un acido carboxilico terminal. |
| WO2004029081A2 (en) | 2002-09-25 | 2004-04-08 | Theratechnologies Inc. | Modified glp-1 peptides with increased biological potency |
| GB0223424D0 (en) | 2002-10-09 | 2002-11-13 | Imp College Innovations Ltd | Disease-associated gene |
| JP4975966B2 (ja) | 2002-12-31 | 2012-07-11 | ネクター セラピューティクス | ケトンまたは関連する官能基を含むポリマー試薬 |
| AU2003300139B2 (en) | 2002-12-31 | 2008-08-28 | Nektar Therapeutics | Maleamic acid polymer derivatives and their bioconjugates |
| ATE444984T1 (de) | 2002-12-31 | 2009-10-15 | Nektar Therapeutics Al Corp | Hydrolysestabile maleimidendgruppen-enthaltende polymere |
| AU2003300140A1 (en) | 2002-12-31 | 2004-07-29 | Nektar Therapeutics Al, Corporation | Methods for the formation of hydrogels using thiosulfonate compositions and uses thereof |
| DE602004029646D1 (en) * | 2003-01-06 | 2010-12-02 | Nektar Therapeutics San Carlos | Thiolselektive wasserlösliche polymerderivate |
| CN1750842A (zh) | 2003-02-19 | 2006-03-22 | 研究及应用科学协会股份有限公司 | Glp－1的类似物 |
| WO2004078777A2 (en) | 2003-03-04 | 2004-09-16 | Biorexis Pharmaceutical Corporation | Dipeptidyl-peptidase protected proteins |
| AU2004231461B2 (en) | 2003-03-19 | 2009-11-12 | Eli Lilly And Company | Polyethelene glycol linked GLP-1 compounds |
| EP1620118B1 (en) * | 2003-04-08 | 2014-06-18 | Yeda Research And Development Co., Ltd. | Reversible pegylated drugs |
| KR101128320B1 (ko) * | 2003-05-23 | 2012-04-12 | 넥타르 테라퓨틱스 | 아미도카르보네이트 연결기를 갖는 ｐｅｇ 유도체 |
| JP2007501811A (ja) * | 2003-08-08 | 2007-02-01 | ノボ ノルディスク ヘルス ケア アクチェンゲゼルシャフト | 治療的な関心対象のタンパク質に対する遅延分子の選択的な化学物質接合のためのガラクトースオキシダーゼの使用。 |
| EP2932981B1 (en) | 2003-09-19 | 2021-06-16 | Novo Nordisk A/S | Albumin-binding derivatives of GLP-1 |
| US20050118718A1 (en) * | 2003-09-22 | 2005-06-02 | University Of Utah Research Foundation | Stabilization and controlled delivery of ionic biopharmaceuticals |
| JP2007536214A (ja) | 2003-12-16 | 2007-12-13 | ソシエテ・ドゥ・コンセイユ・ドゥ・ルシェルシュ・エ・ダプリカーション・シャンティフィック・エス・ア・エス | Ｇｌｐ−１類似体 |
| CA2549582A1 (en) | 2003-12-18 | 2005-06-30 | Novo Nordisk A/S | Novel glp-1 compounds |
| US20050143303A1 (en) | 2003-12-26 | 2005-06-30 | Nastech Pharmaceutical Company Inc. | Intranasal administration of glucose-regulating peptides |
| CA2940803A1 (en) | 2004-03-23 | 2005-10-27 | Ascendis Pharma Gmbh | Prodrug linker |
| US7803764B2 (en) | 2004-03-29 | 2010-09-28 | The Arizona Board Of Regents On Behalf Of The University Of Arizona | Amphipathic glycopeptides |
| US20080300173A1 (en) | 2004-07-13 | 2008-12-04 | Defrees Shawn | Branched Peg Remodeling and Glycosylation of Glucagon-Like Peptides-1 [Glp-1] |
| KR101276754B1 (ko) | 2004-07-19 | 2013-06-19 | 바이오콘 리미티드 | 인슐린―올리고머 접합체，제형 및 이들의 용도 |
| WO2006037810A2 (en) | 2004-10-07 | 2006-04-13 | Novo Nordisk A/S | Protracted glp-1 compounds |
| WO2006091506A2 (en) | 2005-02-24 | 2006-08-31 | Bayer Pharmaceuticals Corporation | Neuropeptide y4 receptor agonists |
| BRPI0609676A2 (pt) * | 2005-05-13 | 2011-10-18 | Lilly Co Eli | composto de glp-1 peguilado,e, uso do mesmo |
| WO2006138572A2 (en) * | 2005-06-16 | 2006-12-28 | Nektar Therapeutics Al, Corporation | Conjugates having a degradable linkage and polymeric reagents useful in preparing such conjugates |
| WO2007061148A1 (en) * | 2005-11-24 | 2007-05-31 | Pegsphere Co., Ltd. | Site-specific peg conjugates of glp-1 and methods for production thereof |
| US8293869B2 (en) | 2005-12-16 | 2012-10-23 | Nektar Therapeutics | Polymer conjugates of GLP-1 |
-
2006
- 2006-12-18 US US12/086,687 patent/US8293869B2/en not_active Expired - Fee Related
- 2006-12-18 JP JP2008545882A patent/JP5096363B2/ja not_active Expired - Fee Related
- 2006-12-18 EP EP06847728A patent/EP1968644B1/en active Active
- 2006-12-18 EP EP11165922A patent/EP2364735A3/en not_active Withdrawn
- 2006-12-18 ES ES06847728T patent/ES2390286T3/es active Active
- 2006-12-18 WO PCT/US2006/048181 patent/WO2007075534A2/en not_active Ceased
-
2012
- 2012-09-14 US US13/617,756 patent/US8580919B2/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| US8580919B2 (en) | 2013-11-12 |
| WO2007075534A3 (en) | 2007-11-08 |
| US20100210505A1 (en) | 2010-08-19 |
| EP1968644A2 (en) | 2008-09-17 |
| EP2364735A2 (en) | 2011-09-14 |
| JP2009519961A (ja) | 2009-05-21 |
| WO2007075534A2 (en) | 2007-07-05 |
| US20130096258A1 (en) | 2013-04-18 |
| JP5096363B2 (ja) | 2012-12-12 |
| US8293869B2 (en) | 2012-10-23 |
| EP1968644B1 (en) | 2012-06-27 |
| EP2364735A3 (en) | 2012-04-11 |
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