Development of Advanced Analytical Methods for the Characterization of Iron Carbohydrate Complex - Ferric Derisomaltose

开发表征碳水化合物铁复合物 - 麦芽糖铁的先进分析方法

• 批准号: 10491846
• 负责人: SARAH L MICHEL
• 金额: $ 30万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-20 至 2024-09-19
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10491846
• 关键词: Development; Advanced; Analytical; Methods; Characterization

PROJECT SUMMARY This proposal focuses on characterizing the recently approved iron nanoparticle drug, Monoferric (ferric dersiomaltose) to address key questions regarding the drug substance and drug product. Monoferric is utilized to treat iron deficiency anemia (IDA) for which cases are increasing world- wide. Monoferric belongs to a class of intravenous (IV) iron nanomedicines that are composed of a central iron oxy-hydroxy core with a carbohydrate shell. A clear advantage of Monoferric over earlier approved IV iron products is its slow iron release rate which allows for higher doses of the drug to be administered. This mitigates the need for multiple rounds of IV iron administration to patients. As such, Monoferric, is an appealing product for generic drug development. However, there are uncertainties regarding the composition of Monoferric’s drug substance and drug product and there is a need for novel analytical methods to characterize these complex molecules. In this proposal, we aim to determine the complex structure of Monoferric by characterizing the drug substance and the drug product with a focus on the iron core, the carbohydrate ligands, and the iron-ligand interactions. A multidisciplinary approach that utilizes a plethora of advanced and orthogonal analytical methods including LC-MS, LC-ICP-MS, DLS, SAXS, XAS, Mossbauer, XRPD, high-field multinuclei (7Li, 13C, 19F and 23Na) NMR diffusometry and relaxometry, and low- field wNMR will be taken. The data to be obtained will allow for regulatory scientists to connect the drug product attributes to safety, quality and performance data and aid in the development of generic products. The approach will be divided into five aims: (1) Develop and validate methods to analyze the iron core structure, (2) Develop and validate methods to characterize the ligands, including the carbohydrate structure and the interactions of the ligands with the iron core, (3) Assess the drug substance composition, (4) Obtain a full physico-chemical characterization of the drug product and (5) Analyze intrabatch and interbatch variabilities of Moniferric. The data to be obtained will contribute to the development of new generic products.

项目摘要 这项提案的重点是表征最近批准的铁纳米颗粒药物， （赤麦芽糖铁），以解决有关原料药和制剂的关键问题。 一价铁用于治疗缺铁性贫血（IDA），其病例在世界范围内不断增加。 宽单铁属于一类静脉内（IV）铁纳米药物，由以下组成： 一个带有碳水化合物外壳的中心铁氧-羟基核。一元铁的明显优势超过 早期批准的IV铁产品是其缓慢的铁释放速率，允许更高剂量的 要给药的药物。这减轻了多轮IV铁剂给药的需要， 患者因此，单铁，是一个有吸引力的产品仿制药开发。但是，在这方面， 关于Monoferric原料药和药物的组成存在不确定性， 因此需要新的分析方法来表征这些复杂分子。 在这个提议中，我们的目标是通过表征单铁的络合物结构来确定单铁的络合物结构。 原料药和制剂，重点关注铁核心、碳水化合物配体，以及 铁与配体的相互作用一种多学科的方法，利用大量的先进和 正交分析方法包括LC-MS，LC-ICP-MS，DLS，SAXS，XAS，Mossbauer， XRPD、高场多核（7 Li、13 C、19 F和23 Na）NMR扩散测定法和弛豫测定法，以及低场多核（7 Li、13 C、19 F和23 Na）NMR扩散测定法和弛豫测定法。 将进行现场wNMR。获得的数据将使监管科学家能够连接 制剂的安全性、质量和性能数据，并有助于开发 通用产品。该方法将分为五个目标：（1）开发和验证方法 分析铁芯结构，（2）开发和验证表征配体的方法， 包括碳水化合物结构和配体与铁核心的相互作用，（3） 评估原料药组成，（4）获得原料药的完整理化表征。 分析Moniferric的批内和批间变异性。的数据 这将有助于开发新的仿制药。