European Journal of Pharmaceutics and Biopharmaceutics
Research paperA comparative study of the physicochemical properties of iron isomaltoside 1000 (Monofer®), a new intravenous iron preparation and its clinical implications
Graphical abstract
Transmission electron microscopic image of iron isomaltoside 1000.
Introduction
Parenteral iron therapy is today widely used for the treatment of iron deficiency anemia. Patients with chronic kidney disease (CKD) also frequently need treatment with parenteral iron preparations in addition to erythropoietin stimulating agents [1]. For renal failure patients on dialysis, the average iron requirements due to blood loss are equivalent to 1–3 g of elemental iron per year [2]. This can easily be accomplished by frequent low dose IV iron administrations, during the regular dialysis sessions.
From initial, generalized use in nephrology parenteral iron therapy has spread in recent years to other disease areas; gastroenterology [3], cardiology [4], [5], oncology [6], pre/post operatively [7], obstetrics’, and gynecology [8]. However, care providers in these segments have less frequent patient contact, resulting in an increased demand for convenient administration of large IV iron doses in one clinical session.
Historically, the first parenteral iron preparations were toxic, being administered as an iron oxyhydroxide complex. This problem was circumvented with the introduction of compounds containing iron in a core surrounded by a carbohydrate shell [9]. The currently marketed parenteral iron preparations are considered equally efficacious but vary in molecular size, pharmacokinetics, and adverse reaction profiles. The intravenous iron agents currently available include high molecular weight iron dextran (Dexferrum®), low molecular weight iron dextran (Cosmofer®, Infed®), sodium ferric gluconate (Ferrlecit®), iron sucrose (Venofer®), iron carboxymaltose (Ferinject®/Injectafer®), and ferumoxytol (Feraheme®). High molecular weight iron dextran has been linked to an increased risk of anaphylaxis and anaphylactoid reactions, and it is not available in Europe [10], [11], [12], [13]. Although this problem is very much reduced with low molecular weight iron dextran [10], [11], [12], [13], there is still a test dose requirement and the infusion of larger doses is hampered by a 4–6 h infusion time. Sodium ferric gluconate and iron sucrose can only be used in moderate iron doses due to the relative weakness of the iron complex [14]. Two new parenteral iron compounds, iron carboxymaltose, and ferumoxytol were recently introduced in the EU and the US markets, respectively. The FDA failed to approve iron carboxymaltose for distribution in the USA due to unexplained hypophosphatemia, an increased number of adverse cardiac events and an imbalance in death rates in the treatment arm compared to the control arm in different RCTs [15].
Although more stable than sodium ferric gluconate and iron sucrose, the administration of iron carboxymaltose and ferumoxytol is still limited to a maximum total dose of 1000 mg and 510 mg, respectively.
The newest IV iron agent Iron isomaltoside 1000 (Monofer®) (e.g., iron oligo isomaltoside (1000) as generic name) is developed and manufactured by Pharmacosmos in Denmark and was introduced in Europe in 2010. The carbohydrate isomaltoside 1000 is a pure linear chemical structure of repeating α1-6 linked glucose units, with an average size of 5.2 glucose units and an average molecular weight of 1000 Da, respectively. It is a nonbranched, nonanaphylactic carbohydrate [16], [17], structurally different from branched polysaccharides used in iron dextran (Cosmofer).
The production method and the short nonionic isomaltoside 1000 allows for the construction of a special matrix-like structure with interchanging iron molecules and linear isomaltoside 1000 oligomers. The resulting matrix contains about 10 iron molecules per one isomaltoside pentamer in a strongly bound structure that enables a controlled and slow release of bioavailable iron to iron-binding proteins with little risk of free iron toxicity [18], [19]. This allows iron isomaltoside 1000 to be administered safely as a rapid high dose intravenous infusion or bolus injection offering considerable dose flexibility, including the possibility of providing full iron repletion in a single infusion, the so-called one-dose iron repletion.
This article introduces and compares physicochemical properties of iron isomaltoside 1000 (Monofer®) with currently marketed iron formulations. In addition, this comparative study of polynuclear iron formulations currently used in the treatment of anemic disorders includes perspectives on the relevance of these properties with respect to safety, efficacy, and convenience of administration.
Section snippets
Materials
Sodium ferric gluconate (Ferrlecit®, 12.5 mg Fe/mL in 3.2 mL ampoules; Sanofi-Aventis, Frankfurt, Germany), iron sucrose (Venofer®, 20 mg Fe/mL in 5 mL ampoules; Vifor, München, Germany), low molecular weight iron dextran (CosmoFer®, 50 mg Fe/mL in 2 mL ampoules; Teva, Mörfelden-Walldorf, Germany), iron isomaltoside 1000 (Monofer®, 100 mg Fe/mL in vials; Pharmacosmos, Holbaek, Denmark), iron carboxymaltose (Ferinject®, 50 mg Fe/mL in 2 mL vials; Vifor, München, Germany), and ferumoxytol (Feraheme®, 30 mg
Gel permeation chromatography
The distributions calculated from the GPC chromatograms of the iron preparations show homogenous distributions with the exception of ferumoxytol and iron carboxymaltose which show additional smaller and larger diameter peaks (Fig. 1). The hydrodynamic diameters dh rise in the order iron sucrose < sodium ferric gluconate < iron isomaltoside 1000 < LMW iron dextran < iron carboxymaltose < ferumoxytol (Table 1). Ferumoxytol was eluted near the exclusion volume, indicating that both its diameter and
Structure
Iron isomaltoside 1000 contains isomaltoside 1000, a pure linear chemical structure of repeating α1-6 linked glucopyranose residues. It is an unbranched, nonanaphylactic carbohydrate with an average size of 5.2 glucose units and an average molecular weight of 1000 Da, respectively, structurally different from the branched dextran polysaccharides present in iron dextran. Low molecular weight dextran has a molecular weight around 5000 and on average one α-1-3 branch point per 32 glucose residues.
Conclusions
The analyzed polynuclear iron formulations are all characterized by a nanosized structure resembling Lepidocrocite, Akaganeite, Ferrihydrite, Magnetite or Maghemite, or mixture of these depending on the product. The homogenicity of the products varied a lot with iron isomaltoside 1000 displaying very well defined spherically shaped particles. With the exception of iron carboxymaltose and ferumoxytol, all parenteral iron preparations followed a monomodal size distribution.
13C NMR and molecular
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