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BioMetals

, Volume 28, Issue 4, pp 615–635 | Cite as

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

  • Susann Neiser
  • Daniel Rentsch
  • Urs Dippon
  • Andreas Kappler
  • Peter G. Weidler
  • Jörg Göttlicher
  • Ralph Steininger
  • Maria Wilhelm
  • Michaela Braitsch
  • Felix Funk
  • Erik Philipp
  • Susanna Burckhardt
Article

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.

Keywords

Intravenous iron Iron sucrose Ferric carboxymaltose Iron isomaltoside 1000 Ferumoxytol Low molecular weight iron dextran 

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

Mn

Number average molecular weight

Mw

Weight average molecular weight

Mz

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

Notes

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.

Supplementary material

10534_2015_9845_MOESM1_ESM.doc (288 kb)
Supplementary material 1 (DOC 288 kb)

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Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Susann Neiser
    • 1
  • Daniel Rentsch
    • 2
  • Urs Dippon
    • 3
  • Andreas Kappler
    • 3
  • Peter G. Weidler
    • 4
  • Jörg Göttlicher
    • 5
  • Ralph Steininger
    • 5
  • Maria Wilhelm
    • 1
  • Michaela Braitsch
    • 1
  • Felix Funk
    • 1
  • Erik Philipp
    • 1
  • Susanna Burckhardt
    • 1
  1. 1.Chemical and Preclinical Research and DevelopmentVifor (International) Ltd.St. GallenSwitzerland
  2. 2.Swiss Federal Laboratories for Materials Science and Technology (Empa)DübendorfSwitzerland
  3. 3.Geomicrobiology, Center for Applied GeosciencesUniversity of TübingenTübingenGermany
  4. 4.Institute of Functional Interfaces, Karlsruhe Institute of Technology (KIT)Eggenstein-LeopoldshafenGermany
  5. 5.ANKA–Synchrotron Radiation FacilityKarlsruhe Institute for Technology (KIT)Eggenstein-LeopoldshafenGermany

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