Structure-Function Relationships in Polysaccharide-Iron Complexes: Molecular Characterization, Acid-Stress Release Stability, and Gastrointestinal Tolerability.

Background

Polysaccharide-iron complexes (PICs) are widely used oral iron supplements, but their gastrointestinal tolerability varies and remains incompletely understood. As typical non-biological complex drugs (NBCDs), PICs exhibit structural heterogeneity, and their functional performance may be linked to higher-order structural attributes.

Methods

In this study, two commercial PIC preparations (test samples A and B) were comparatively investigated to explore their structure-function relationship using a multi-dimensional approach. Structural properties were characterized by gel permeation chromatography (GPC), mass spectrometry (MS), Fourier-transform infrared spectroscopy (FTIR) and nuclear magnetic resonance (NMR) spectroscopy, along with monosaccharide composition analysis. Functional behaviors and physiological relevance were further evaluated through in vitro acid-stress release studies and in vivo rat gastrointestinal tolerability assessments.

Results

The results revealed that test sample A exhibited a glucose-only detectable monosaccharide profile but a higher and broader apparent molecular-weight distribution, indicating monosaccharide compositional uniformity together with macromolecular heterogeneity. In contrast, test sample B showed detectable glucose and mannose, a lower and narrower apparent molecular-weight distribution, higher measured free iron, and greater iron release under the tested acidic conditions. An exploratory 7-day rat gastrointestinal tolerability study (n = 4 per group) indicated that these distinct profiles may impact mucosal tolerability. Structurally stable test sample A allowed intestinal iron accumulation while maintaining mucosal integrity. Conversely, the rapid dissociation of test sample B induced observable mucosal injury, despite lower local iron retention.

Conclusions

These findings suggest that the gastrointestinal tolerability of PICs may be associated with their structural attributes and release behavior, rather than total iron content alone. Overall, this exploratory study highlights a potential relationship between multi-dimensional PIC structure and functional performance, emphasizing the need for broader, structure-informed frameworks in the quality evaluation of complex iron therapies.