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Physico-chemical properties of the new generation IV iron preparations ferumoxytol, iron isomaltoside 1000 and ferric carboxymaltose

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Abstract

The advantage of the new generation IV iron preparations ferric carboxymaltose (FCM), ferumoxytol (FMX), and iron isomaltoside 1000 (IIM) is that they can be administered in relatively high doses in a short period of time. We investigated the physico-chemical properties of these preparations and compared them with those of the older preparations iron sucrose (IS), sodium ferric gluconate (SFG), and low molecular weight iron dextran (LMWID). Mössbauer spectroscopy, X-ray diffraction, and Fe K-edge X-ray absorption near edge structure spectroscopy indicated akaganeite structures (β-FeOOH) for the cores of FCM, IIM and IS, and a maghemite (γ-Fe2O3) structure for that of FMX. Nuclear magnetic resonance studies confirmed the structure of the carbohydrate of FMX as a reduced, carboxymethylated, low molecular weight dextran, and that of IIM as a reduced Dextran 1000. Polarography yielded significantly different fingerprints of the investigated compounds. Reductive degradation kinetics of FMX was faster than that of FCM and IIM, which is in contrast to the high stability of FMX towards acid degradation. The labile iron content, i.e. the amount of iron that is only weakly bound in the polynuclear iron core, was assessed by a qualitative test that confirmed decreasing labile iron contents in the order SFG ≈ IS > LMWID ≥ FMX ≈ IIM ≈ FCM. The presented data are a step forward in the characterization of these non-biological complex drugs, which is a prerequisite to understand their cellular uptake mechanisms and the relationship between the structure and physiological safety as well as efficacy of these complexes.

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Abbreviations

DQF-COSY:

Double quantum filtered correlation spectroscopy

EDTA:

Ethylenediaminetetraacetic acid

FCM:

Ferric carboxymaltose

FDA:

U.S. Food and Drug Administration

FMX:

Ferumoxytol

GFC:

Gel-filtration chromatography

Glc:

Glucose

GOF:

Goodness of fit

HMBC:

Heteronuclear multiple-bond correlation

HMWID:

High molecular weight iron dextran

HSQC:

Heteronuclear single quantum correlation

IIM:

Iron isomaltoside 1000

IS:

Iron sucrose

ISS:

Iron sucrose similar

IV:

Intravenous

LMWID:

Low molecular weight iron dextran

M n :

Number average molecular weight

M w :

Weight average molecular weight

M z :

z-average molecular weight

NBCD:

Non-biological complex drugs

NMR:

Nuclear magnetic resonance

NTBI:

Non-transferrin bound iron

P:

Polydispersity

PSC:

Polyglucose sorbitol carboxymethylether

QS:

Quadrupole splitting

s:

Standard deviation

SAED:

Selected area electron diffraction

SDCM :

Carboxymethylation substitution degree

SFG:

Sodium ferric gluconate

SHE:

Standard hydrogen electrode

TEM:

Transmission electron microscopy

TOCSY:

Total correlation spectroscopy

TRIS:

Tris(hydroxymethyl)aminomethane

USP:

United States Pharmacopeia

XANES:

X-ray absorption near edge structure

XRD:

X-ray diffraction

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Acknowledgments

We thank Werner Agster, Zorica Nikolic, Roland Riederer, and Maja Thum (all Vifor (International) Ltd.) for technical assistance. We are also grateful to Ralf Weigel from ANKA–Synchrotron Radiation Facility, Karlsruhe Institute for Technology (KIT), for constructing the cell for liquid samples used in Fe K-edge XANES spectroscopy. Dr. Peter Geisser, Vifor (International) Ltd., is thanked for valuable discussions.

Conflict of interest

S. Neiser, M. Wilhelm, M. Braitsch, F. Funk, E. Philipp, and S. Burckhardt are employees of Vifor (International) Ltd. D. Rentsch investigated the structure of the carbohydrate components by NMR, U. Dippon and A. Kappler examined the core structures by Mössbauer spectroscopy, P. Weidler investigated the core structures by XRD, and J. Göttlicher and R. Steininger examined the core structures by Fe K-edge XANES. The measurements for these studies were paid for by Vifor (International) Ltd.

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Authors and Affiliations

  1. Chemical and Preclinical Research and Development, Vifor (International) Ltd., St. Gallen, Switzerland

    Susann Neiser, Maria Wilhelm, Michaela Braitsch, Felix Funk, Erik Philipp & Susanna Burckhardt

  2. Swiss Federal Laboratories for Materials Science and Technology (Empa), Dübendorf, Switzerland

    Daniel Rentsch

  3. Geomicrobiology, Center for Applied Geosciences, University of Tübingen, Tübingen, Germany

    Urs Dippon & Andreas Kappler

  4. Institute of Functional Interfaces, Karlsruhe Institute of Technology (KIT), Eggenstein-Leopoldshafen, Germany

    Peter G. Weidler

  5. ANKA–Synchrotron Radiation Facility, Karlsruhe Institute for Technology (KIT), Eggenstein-Leopoldshafen, Germany

    Jörg Göttlicher & Ralph Steininger

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  1. Susann Neiser
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Neiser, S., Rentsch, D., Dippon, U. et al. Physico-chemical properties of the new generation IV iron preparations ferumoxytol, iron isomaltoside 1000 and ferric carboxymaltose. Biometals 28, 615–635 (2015). https://doi.org/10.1007/s10534-015-9845-9

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