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

项目总结 这项提案的重点是表征最近批准的铁纳米药物--单铁 (麦芽糖亚铁)，以解决有关药物物质和药物产品的关键问题。 单铁被用来治疗缺铁性贫血(IDA)，这种疾病的病例在世界范围内不断增加。 很宽。单铁属于一类静脉注射(IV)铁纳米药物，由以下组成 具有碳水化合物外壳的中心铁氧羟基核心。单铁的明显优势 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 需给药的药物。这减轻了对多轮静脉注射铁剂的需要 病人。因此，MonoIron是仿制药开发的一种有吸引力的产品。然而， 关于MonoIron的药物物质和药物的组成存在不确定性 产品和需要新的分析方法来表征这些复杂的分子。 在这项建议中，我们的目标是通过表征单铁的复杂结构来确定其复杂结构。 药物物质和药物制品，重点是铁核、碳水化合物配体和 铁与配体的相互作用。一种多学科的方法，利用过多的高级和 包括LC-MS、LC-ICPMS、DLS、SAXS、XAS、穆斯堡尔、 XRPD、高场多核(~7Li、~(13)C、~(19)F和~(23)Na)核磁共振扩散和驰豫测量，以及低能谱 将采用野外核磁共振技术。将获得的数据将使监管科学家能够将 药物产品归因于安全、质量和性能数据，并有助于开发 仿制药。该方法将分为五个目标：(1)开发和验证方法 为了分析铁核结构，(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的相互作用，(3) 评估药物成分，(4)获得药物的完整的物理化学表征 药物产品和(5)分析莫尼铁的批内和批间变异。数据将被 所取得的成果将有助于开发新的仿制药。

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.