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P124: Not Just Icing: The Importance of Surface Characteristics of Iron-Carbohydrate Nanomedicines

Poster Presenter

Amy Barton

Science Lead, Nanomedicine
Vifor Pharma
United States

Objectives

When polynuclear iron oxyhydroxide complexes are formed with carbohydrates through controlled manufacturing processes, these complexes safely deliver iron to the body. The entire iron-carbohydrate complex, including the surface characteristics dictates its biodisposition and pharmacological activity

Method

For the six main iron-carbohydrate complexes the composition was evaluated. The types of interactions between the iron core and the carbohydrate were determined, and the physicochemical properties and surface characteristics were reviewed. The pharmacokinetic and -dynamic profiles were compared.

Results

All six of the iron-carbohydrate preparations evaluated were heterogenous and differed with regard to carbohydrate type, total carbohydrate content as well as bonding and structural features. Although all preparations have been documented to be stable in colloidal suspension, their factors enabling the stability differ. In these high-molecular-weight complexes, there are multiple bonds that may contribute to the overall stability, including coordination bonds, ionic–ionic interactions, ionic–dipole interactions, e.g., hydrogen bonds, and Van der Waals forces. For example, for iron sucrose, the ligand has a low molecular weight and therefore the ligand amount compared to the iron content as well as its molar concentration are quite high, and the pH is high (=10.5), enabling an increased formation of hydrogen bonds between deprotonated hydroxy groups of the ferric oxyhydroxide core and the hydroxy groups of the sucrose. In contrast, ferric carboxymaltose contains carboxymaltose, a ligand unifying the potential of multiple hydrogen bonds and a coordinative bond within the same molecule, the carboxylate forming a coordinative bond and a chelate with adjacent hydroxy groups. Absolute and relative amounts of the carbohydrate are lower than for iron sucrose. The complexity of the surface ligand characteristics together with the bonding to the polynuclear iron core produces complexes with very distinct physicochemical characteristics (PCC) (e.g. particle size, molecular weight and zeta potential). The differences in PCC among the iron-carbohydrate complexes is further underscored by vastly different pharmacokinetic and pharmacodynamic profiles among the six preprations. In pre-clinical models, tissue biodistribution has been shown to be highly variable in key pharmacologic tissues such as the liver and spleen. This has translated to differences in serum ferritin area-under-the-curve profiles for different iron complexes administered at the same doses of elemental iron.

Conclusion

Upon comprehensive review of surface chemistry of the six main intravenous iron preparations, it is clear that the entire iron–carbohydrate complex is necessary to adequately furnish pharmacological activity. There are substantial differences in the properties of the different preparations. There are many characterization parameters that have been defined as critical quality attributes (CQAs) for iron–carbohydrate complexes but there are also CQAs that have not yet been fully identified and measured for these widely used drug products. Importantly, analytical methods to measure these CQAs are much more complex than for small molecules, and for some CQAs, these methods may not be reproducible and fully validated. The precise mechanism by which the structural and surface attributes relevant for the interaction of these nanomedicines with the biological environment is not fully understood and requires further investigation.