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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| WO2019232280A1 (en) | 2018-05-30 | 2019-12-05 | Purdue Research Foundation | Targeting anabolic drugs for accelerated 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 |
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| 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 |
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| CN118973605A (zh) * | 2022-01-14 | 2024-11-15 | 普渡研究基金会 | 成骨不全症的骨靶向治疗 |
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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 |
| CA2321026A1 (en) * | 1998-03-09 | 1999-09-16 | Zealand Pharmaceuticals 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 |
| ES2887039T3 (es) | 2004-04-21 | 2021-12-21 | Alexion Pharma Inc | Conjugados para administración ósea y procedimiento de uso de estos para dirigir proteínas al hueso |
| 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 |
| DK2957278T3 (en) | 2006-10-03 | 2017-07-31 | Radius Health Inc | STABLE COMPOSITION COMPREHENSIVE PTHRP AND APPLICATIONS THEREOF |
| CA2930681C (en) * | 2007-04-09 | 2019-10-15 | The Board Of Trustees Of The University Of Arkansas | Fusion protein of collagen-binding domain and parathyroid hormone |
| AU2008250945B2 (en) | 2007-05-11 | 2013-12-12 | Alexion Pharmaceuticals, Inc. | Bone targeted alkaline phosphatase, kits and methods of use thereof |
| EP2303288A4 (en) * | 2008-05-22 | 2015-04-22 | Univ Ramot | CONJUGATES OF A POLYMER, BISPHOSPHONATE AND ANTI-ANGIOGENESIS AGENT AND USES THEREOF IN THE TREATMENT AND MONITORING OF DISEASES RELATING TO BONES |
| 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 |
| US20130006217A1 (en) * | 2011-04-22 | 2013-01-03 | Gary Hattersley | 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 |
| EP3265115B1 (en) * | 2015-03-03 | 2022-06-22 | Radius Health, Inc. | Abaloparatide combined with alendronate for reducing non-vertebral bone fractures |
| WO2016196400A1 (en) * | 2015-05-29 | 2016-12-08 | 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 |
| WO2018102616A1 (en) * | 2016-11-30 | 2018-06-07 | Purdue Research Foundation | Fracture targeted bone regeneration through parathyroid hormone receptor stimulation |
| MX2023004796A (es) * | 2020-10-26 | 2023-07-18 | Purdue Research Foundation | Compuestos, composiciones y metodos de uso para tratar fracturas oseas. |
-
2017
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- 2017-11-30 CN CN201780073942.4A patent/CN110114065A/zh active Pending
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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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| US10960054B2 (en) | 2021-03-30 |
| JP7649624B2 (ja) | 2025-03-21 |
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| US20210283227A1 (en) | 2021-09-16 |
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| AU2017367699A1 (en) | 2019-07-11 |
| US20200317745A1 (en) | 2020-10-08 |
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| US20200316174A1 (en) | 2020-10-08 |
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| EP3548012A4 (en) | 2020-07-22 |
| CA3045458A1 (en) | 2018-06-07 |
| AU2017367699A8 (en) | 2019-07-25 |
| IL266977B1 (en) | 2023-09-01 |
| AU2017367699B2 (en) | 2023-12-07 |
| BR112019011070A2 (pt) | 2019-10-01 |
| EP3548012A1 (en) | 2019-10-09 |
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