IL266977B2 - Fracture-targeted bone regeneration using thyroid hormone receptor stimulation - Google Patents
Fracture-targeted bone regeneration using thyroid hormone receptor stimulationInfo
- Publication number
- IL266977B2 IL266977B2 IL266977A IL26697719A IL266977B2 IL 266977 B2 IL266977 B2 IL 266977B2 IL 266977 A IL266977 A IL 266977A IL 26697719 A IL26697719 A IL 26697719A IL 266977 B2 IL266977 B2 IL 266977B2
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Landscapes
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| US201762553313P | 2017-09-01 | 2017-09-01 | |
| PCT/US2017/064081 WO2018102616A1 (en) | 2016-11-30 | 2017-11-30 | Fracture targeted bone regeneration through parathyroid hormone receptor stimulation |
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| EP3790574A4 (en) | 2018-05-30 | 2022-07-13 | Purdue Research Foundation | TARGETING ANABOLIC DRUGS TO ACCELERATE FRACTURE REPAIR |
| CN110551201B (zh) * | 2019-08-26 | 2020-04-28 | 杭州彗搏科技有限公司 | 一种新型骨形成蛋白2来源的环肽、制备方法及其应用 |
| EP4027899A4 (en) * | 2019-09-12 | 2023-08-16 | Radius Health, Inc. | METHODS OF ENHANCING SPINE FUSION USING ABALOPARATIDE |
| CN112646042A (zh) * | 2019-10-10 | 2021-04-13 | 陕西麦科奥特科技有限公司 | 活性多肽化合物 |
| CN116848146A (zh) * | 2020-09-03 | 2023-10-03 | I·S·Y·陈 | 可溶性碱性磷酸酶构建体和包含编码可溶性碱性磷酸酶构建体的多核苷酸的表达载体 |
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| US20230390363A1 (en) * | 2020-10-26 | 2023-12-07 | Purdue Research Foundation | Compounds, Compositions and Methods of Use to Treat Spinal Fusions |
| WO2022149066A1 (en) * | 2021-01-05 | 2022-07-14 | Radius Health, Inc. | Treatment of long bone fractures with abaloparatide |
| US20250295725A1 (en) * | 2022-01-14 | 2025-09-25 | Purdue Research Foundation | Bone targeted treatment in osteogenesis imperfecta |
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| US20150246957A1 (en) * | 2012-08-28 | 2015-09-03 | The Governors Of The University Of Alberta | Parathyroid hormone, insulin, and related peptides conjugated to bone targeting moieties and methods and making and using thereof |
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|---|---|---|---|---|
| CA2098283A1 (en) * | 1990-12-21 | 1992-06-22 | Richard P. Bozzato | Oxidation resistant variants of parathyroid hormone |
| WO1995002610A1 (en) * | 1993-07-13 | 1995-01-26 | Syntex (U.S.A.) Inc. | Analogs of parathyroid hormone and parathyroid hormone related peptide: synthesis and use for the treatment of osteoporosis |
| AU757658B2 (en) * | 1998-03-09 | 2003-02-27 | Zealand Pharma A/S | Pharmacologically active peptide conjugates having a reduced tendency towards enzymatic hydrolysis |
| US7057012B1 (en) * | 1998-12-31 | 2006-06-06 | The General Hospital Corporation | PTH functional domain conjugate peptides, derivatives thereof and novel tethered ligand-receptor molecules |
| JP2000327583A (ja) * | 1999-05-17 | 2000-11-28 | Medei Sci Puraningu:Kk | 骨指向性ホルモン誘導体 |
| WO2004062588A2 (en) * | 2003-01-06 | 2004-07-29 | University Of Utah | Water-soluble polymeric bone-targeting drug delivery system |
| PL2348114T3 (pl) * | 2004-04-21 | 2019-08-30 | Alexion Pharmaceuticals, Inc. | Koniugaty do dostarczania do kości i sposób ich wykorzystania do nakierowywania białek na kość |
| US7863238B2 (en) * | 2004-06-10 | 2011-01-04 | Saint Louis University | Proteins with an attached short peptide of acidic amino acids |
| US20110046059A1 (en) * | 2005-09-06 | 2011-02-24 | Zelos Therapeutics, Inc. | Pharmaceutically acceptable formulations/compositions for peptidyl drugs |
| US7803770B2 (en) * | 2006-10-03 | 2010-09-28 | Radius Health, Inc. | Method of treating osteoporosis comprising administration of PTHrP analog |
| CA2664734C (en) * | 2006-10-03 | 2023-08-01 | Radius Health, Inc. | Method of drug delivery for bone anabolic protein |
| ES2675174T3 (es) * | 2007-04-09 | 2018-07-09 | The Board Of Trustees Of The University Of Arkansas | Proteínas de fusión de un dominio de enlazamiento a colágeno y hormona paratiroidea |
| RS53302B (sr) * | 2007-05-11 | 2014-08-29 | Alexion Pharma Holding | Alkalna fosfataza koja je usmerena na kosti, pribor i postupci upotrebe |
| EP2303288A4 (en) * | 2008-05-22 | 2015-04-22 | Univ Ramot | CONJUGATES OF A POLYMER, A BISPHOSPHONATE AND AN ANTI-ANGIOGENESE MEDIUM AND ITS USE IN THE TREATMENT AND CONTROL OF ILLNESSES RELATED TO BONE |
| WO2012111852A1 (ja) * | 2011-02-17 | 2012-08-23 | 帝人ファーマ株式会社 | 椎体骨折治療剤及びその評価方法 |
| SG194570A1 (en) * | 2011-04-22 | 2013-12-30 | Radius Health Inc | Method of drug delivery for pth, pthrp and related peptides |
| CN102824647B (zh) * | 2011-06-13 | 2014-07-23 | 香港中文大学 | 基于小核酸药物成骨治疗的骨靶向递送系统及其制备方法 |
| EP3016674A4 (en) * | 2013-06-23 | 2017-03-15 | Wisconsin Alumni Research Foundation | Alpha-/beta-polypeptide analogs of parathyroid hormone (pth) and method of using same |
| WO2016141250A1 (en) * | 2015-03-03 | 2016-09-09 | Radius Health, Inc. | USES OF PTHrP ANALOGUE IN REDUCING FRACTURE RISK |
| US10279044B2 (en) * | 2015-05-29 | 2019-05-07 | Purdue Research Foundation | Bone fracture repair by targeting of agents that promote bone healing |
| CN106039316B (zh) * | 2016-05-03 | 2019-04-02 | 同济大学 | 一种基于多肽构建的成骨细胞靶向载体及其制备与应用 |
| BR112019011070A2 (pt) * | 2016-11-30 | 2019-10-01 | Purdue Research Foundation | regeneração óssea direcionada à fratura através da estimulação do receptor de hormônio da paratireoide |
| MX2023004796A (es) * | 2020-10-26 | 2023-07-18 | Purdue Research Foundation | Compuestos, composiciones y metodos de uso para tratar fracturas oseas. |
-
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- 2017-11-30 WO PCT/US2017/064081 patent/WO2018102616A1/en not_active Ceased
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20150246957A1 (en) * | 2012-08-28 | 2015-09-03 | The Governors Of The University Of Alberta | Parathyroid hormone, insulin, and related peptides conjugated to bone targeting moieties and methods and making and using thereof |
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| US20200316174A1 (en) | 2020-10-08 |
| US20200317745A1 (en) | 2020-10-08 |
| AU2017367699A1 (en) | 2019-07-11 |
| JP2023029957A (ja) | 2023-03-07 |
| EP3548012A4 (en) | 2020-07-22 |
| JP7649624B2 (ja) | 2025-03-21 |
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| MX2019006189A (es) | 2019-11-18 |
| JP2020500871A (ja) | 2020-01-16 |
| RU2019119701A3 (OSRAM) | 2021-02-16 |
| US20210283227A1 (en) | 2021-09-16 |
| EP3548012A1 (en) | 2019-10-09 |
| IL266977A (en) | 2019-07-31 |
| AU2017367699B2 (en) | 2023-12-07 |
| CA3045458A1 (en) | 2018-06-07 |
| WO2018102616A1 (en) | 2018-06-07 |
| BR112019011070A2 (pt) | 2019-10-01 |
| CN110114065A (zh) | 2019-08-09 |
| RU2019119701A (ru) | 2021-01-14 |
| US10960054B2 (en) | 2021-03-30 |
| IL266977B1 (en) | 2023-09-01 |
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