Physicochemical Characterization of Iron Carbohydrate Colloid Drug Products.

Iron carbohydrate colloid drug products are intravenously administered to patients with chronic kidney disease for the treatment of iron deficiency anemia. Physicochemical characterization of iron colloids is critical to establish pharmaceutical equivalence between an innovator iron colloid product and generic version. The purpose of this review is to summarize literature-reported techniques for physicochemical characterization of iron carbohydrate colloid drug products. The mechanisms, reported testing results, and common technical pitfalls for individual characterization test are discussed. A better understanding of the physicochemical characterization techniques will facilitate generic iron carbohydrate colloid product development, accelerate products to market, and ensure iron carbohydrate colloid product quality.

Evaluation of the safety of iron dextran with parenteral nutrition in the paediatric inpatient setting.

AIM: Practitioners often avoid administering iron dextran in parenteral nutrition (PN) for hospitalised children because of the concern for anaphylaxis. The primary aim of the present study was to determine the risk of anaphylaxis associated with exposure to PN containing iron dextran in the inpatient setting. METHODS: Charts were reviewed for all children admitted to The Children's Hospital of Philadelphia from January 1, 2011 to December 30, 2013 who received PN containing low molecular weight (LMW) iron dextran. Subject characteristics, primary diagnoses and PN orders were evaluated. The pharmacy adverse events database was queried for adverse drug reactions. RESULTS: Over three years, 89 subjects received PN containing a maintenance dose of LMW iron dextran with a total of 2774 days of exposure. Subjects ranged from two months to 21 years of age and received between 1 and 196 days of PN containing iron dextran. The mean dose of iron dextran in children decreased as the weight category increased from <5 kg (0.21 ± 0.05 mg/kg/day) to ≥40 kg (1.9 ± 0.5 mg/day; P-value for trend <0.005). No anaphylactic reactions occurred in any subjects. CONCLUSIONS: PN containing a maintenance dose of LMW iron dextran can be safely administered to hospitalised children, and further studies are need to evaluate the potential to prevent iron deficiency anaemia and the need for additional IV iron infusions.

Photoinduced Iron-Based Water-Induced Phase Separable Catalysis (WPSC) ICAR ATRP of Poly(ethylene glycol) Methyl Ether Methacrylate.

Iron-mediated atom transfer radical polymerization (ATRP) has gained extensive attention because of the superiority of iron catalysts, such as low toxicity, abundant reserves, and good biocompatibility. Herein, a practical iron catalyst recycling system, photoinduced iron-based water-induced phase separable catalysis ATRP with initiators for continuous activator regeneration, at room temperature is developed for the first time. In this polymerization system, the polymerization is conducted in homogenous solvents consisting of p-xylene and ethanol, using commercially available 5,10,15,20-tetraphenyl-21H,23H-porphine iron(III) chloride as the iron catalyst, ethyl 2-bromophenylacetate as the ATRP initiator, 2,4,6-trimethylbenzoyl diphenylphosphine oxide as the photoinitiator, and poly(ethylene glycol) methyl ether methacrylate as the model hydrophilic monomer. After polymerization, a certain amount of water is added to induce the phase separation so that the catalyst can be separated and recycled in p-xylene phase with very low residual metal complexes (<12 ppm) in the resultant polymers even after six times recycle experiments.

Ferrous iron content of intravenous iron formulations.

The observed biological differences in safety and efficacy of intravenous (IV) iron formulations are attributable to physicochemical differences. In addition to differences in carbohydrate shell, polarographic signatures due to ferric iron [Fe(III)] and ferrous iron [Fe(II)] differ among IV iron formulations. Intravenous iron contains Fe(II) and releases labile iron in the circulation. Fe(II) generates toxic free radicals and reactive oxygen species and binds to bacterial siderophores and other in vivo sequestering agents. To evaluate whether differences in Fe(II) content may account for some observed biological differences between IV iron formulations, samples from multiple lots of various IV iron formulations were dissolved in 12 M concentrated HCl to dissociate and release all iron and then diluted with water to achieve 0.1 M HCl concentration. Fe(II) was then directly measured using ferrozine reagent and ultraviolet spectroscopy at 562 nm. Total iron content was measured by adding an excess of ascorbic acid to reduce Fe(III) to Fe(II), and Fe(II) was then measured by ferrozine assay. The Fe(II) concentration as a proportion of total iron content [Fe(III) + Fe(II)] in different lots of IV iron formulations was as follows: iron gluconate, 1.4 and 1.8 %; ferumoxytol, 0.26 %; ferric carboxymaltose, 1.4 %; iron dextran, 0.8 %; and iron sucrose, 10.2, 15.5, and 11.0 % (average, 12.2 %). The average Fe(II) content in iron sucrose was, therefore, ≥7.5-fold higher than in the other IV iron formulations. Further studies are needed to investigate the relationship between Fe(II) content and increased risk of oxidative stress and infections with iron sucrose.

Core size determination and structural characterization of intravenous iron complexes by cryogenic transmission electron microscopy.

Understanding physicochemical properties of intravenous (IV) iron drug products is essential to ensure the manufacturing process is consistent and streamlined. The history of physicochemical characterization of IV iron complex formulations stretches over several decades, with disparities in iron core size and particle morphology as the major source of debate. One of the main reasons for this controversy is room temperature sample preparation artifacts, which affect accurate determination of size, shape and agglomeration/aggregation of nanoscale iron particles. The present study is first to report the ultra-fine iron core structures of four IV iron complex formulations, sodium ferric gluconate, iron sucrose, low molecular weight iron dextran and ferumoxytol, using a cryogenic transmission electron microscopy (cryo-TEM) preservation technique, as opposed to the conventional room temperature (RT-TEM) technique. Our results show that room temperature preparation causes nanoparticle aggregation and deformation, while cryo-TEM preserves IV iron colloidal suspension in their native frozen-hydrated and undiluted state. In contrast to the current consensus in literature, all four IV iron colloids exhibit a similar morphology of their iron oxide cores with a spherical shape, narrow size distribution and an average size of 2nm. Moreover, out of the four tested formulations, ferumoxytol exhibits a cluster-like community of several iron carbohydrate particles which likely accounts for its large hydrodynamic size of 25nm, measured with dynamic light scattering. Our findings outline a suitable method for identifying colloidal nanoparticle core size in the native state, which is increasingly important for manufacturing and design control of complex drug formulations, such as IV iron drug products.

Electrochemical sensing of iron (III) by using rhodamine dimer as an electroactive material.

The voltammetric and potentiometric sensors based on a novel electroactive rhodamine dimer (RD) have been developed for the determination of Fe (III) ions. The RD exhibits two anodic peaks at 0.5 V and 0.7 V vs. Ag/Ag(+) within the potential range of 0.2-1.2V, which on addition of Fe (III) ions get converted to single anodic peak with a shift toward more positive potential of 0.9 V vs. Ag/Ag(+) due to the formation of Fe (III)-RD complex. The voltammetric sensor has been found to work well in the concentration range of 1.5 × 10(-5)-3.5 × 10(-4)M with the detection limit of 3.3 × 10(-6)M. Further, the potentiometric response of proposed PVC based solid contact coated graphite electrode (CGE-1) was linear for Fe (III) ions in the concentration range of 1.0 × 10(-1)-1.0 × 10(-7)M. The electrode showed a slope of 18.8 mV/decade with a detection limit of 4.68 × 10(-8)M for Fe (III) ions. Both of the sensors revealed good selectivity towards Fe (III) ions in comparison to various diverse metal ions. The analytical utility of the proposed sensors has been confirmed by the estimation of the Fe (III) content in different sample matrices.

Lower molecular weight intravenous iron dextran for restless legs syndrome.

BACKGROUND: Various techniques used to assess brain iron concentrations have demonstrated the presence of low iron stores in patients with restless legs syndrome (RLS). Previous open-label and randomized studies generally support the value of iron treatment for RLS symptoms. Only one of these studies assessed iron therapy response to changes in brain iron status. The current study was designed to assess the effect of iron therapy on RLS symptoms and on CSF measures of brain iron status. METHODS: Idiopathic RLS patients drawn from the Korean population received four weekly intravenous (IV) doses of 250 mg low-molecular weight iron dextran for a total dose of 1g. One week after the last dose, any subject on RLS medication tapered off the RLS medications. Blood and CSF samples were taken to measure iron parameters at baseline and again, three weeks after the last dose. We have been following their response to the drug for two years after treatment. RESULTS: Twenty-five patients (age 55.2 ± 9.3, 18 female) enrolled in this study without serious adverse reactions. Seventeen of the 25 patients (68%) showed moderate or complete improvement of all RLS symptoms after treatment based on the Korean-translated versions of the International RLS Severity scale (K-IRLS). Changes in the K-IRLS did not correlate significantly with changes in CSF ferritin. The response to IV iron could not be predicted by patients' demographics, or by blood or CSF iron baseline characteristics. RLS symptom improvement started between one and six weeks after treatment and the treatment benefits lasted from one month to 22 months. Fourteen patients, (56%) completely stopped all medications, for a mean duration of 31.3 ± 33.1 weeks. These results are comparable to those from a prior study with high molecular weight dextran. CONCLUSIONS: Intravenous low-molecular weight iron dextran produced significant improvement of RLS symptoms in a majority of patients without any significant adverse effects. Serious anaphylaxis occurs with high molecular weight, but rarely, if ever, with this low molecular weight dextran. Given apparent comparable efficacy the low molecular weight and not the high molecular weight iron dextran, should be considered for RLS treatment. Although changes in CSF ferritin were seen following therapy, these changes were not related to clinical improvements.

Comparative study of the iron cores in human liver ferritin, its pharmaceutical models and ferritin in chicken liver and spleen tissues using Mössbauer spectroscopy with a high velocity resolution.

Application of Mössbauer spectroscopy with a high velocity resolution (4096 channels) for comparative analysis of iron cores in a human liver ferritin and its pharmaceutically important models Imferon, Maltofer(®) and Ferrum Lek as well as in iron storage proteins in chicken liver and spleen tissues allowed to reveal small variations in the (57)Fe hyperfine parameters related to differences in the iron core structure. Moreover, it was shown that the best fit of Mössbauer spectra of these samples required different number of components. The latter may indicate that the real iron core structure is more complex than that following from a simple core-shell model. The effect of different living conditions and age on the iron core in chicken liver was also considered.

Different effect of hydrogelation on antifouling and circulation properties of dextran-iron oxide nanoparticles.

Premature recognition and clearance of nanoparticulate imaging and therapeutic agents by macrophages in the tissues can dramatically reduce both the nanoparticle half-life and delivery to the diseased tissue. Grafting nanoparticles with hydrogels prevents nanoparticulate recognition by liver and spleen macrophages and greatly prolongs circulation times in vivo. Understanding the mechanisms by which hydrogels achieve this "stealth" effect has implications for the design of long-circulating nanoparticles. Thus, the role of plasma protein absorption in the hydrogel effect is not yet understood. Short-circulating dextran-coated iron oxide nanoparticles could be converted into stealth hydrogel nanoparticles by cross-linking with 1-chloro-2,3-epoxypropane. We show that hydrogelation did not affect the size, shape and zeta potential, but completely prevented the recognition and clearance by liver macrophages in vivo. Hydrogelation decreased the number of hydroxyl groups on the nanoparticle surface and reduced the binding of the anti-dextran antibody. At the same time, hydrogelation did not reduce the absorption of cationic proteins on the nanoparticle surface. Specifically, there was no effect on the binding of kininogen, histidine-rich glycoprotein, and protamine sulfate to the anionic nanoparticle surface. In addition, hydrogelation did not prevent activation of plasma kallikrein on the metal oxide surface. These data suggest that (a) a stealth hydrogel coating does not mask charge interactions with iron oxide surface and (b) the total blockade of plasma protein absorption is not required for maintaining iron oxide nanoparticles' long-circulating stealth properties. These data illustrate a novel, clinically promising property of long-circulating stealth nanoparticles.

Mössbauer spectroscopy with a high velocity resolution in the study of iron-containing proteins and model compounds.

Mössbauer spectroscopy with a high velocity resolution was used for comparative studies of human adult, rabbit and pig oxyhemoglobins, human liver ferritin and its pharmaceutically important models Imferon and Maltofer(®) as well as liver and spleen tissues from normal and lymphoid leukemia chicken. These studies revealed small variations of Mössbauer hyperfine parameters which were related to small variations of iron electronic structure and stereochemistry in these samples.

Physical and chemical stability of iron sucrose in parenteral nutrition.

INTRODUCTION: Current literature supports iron dextran as the only iron preparation compatible with parenteral nutrition (PN). Iron sucrose has been used for iron replacement therapy because of its lower rate of adverse events. The purpose of this study is to determine the physical and chemical stability of iron sucrose in PN. METHODS: Physical and chemical stability of iron sucrose in nonlipid PN solutions (PN 1 for neonates and PN 2 for patients weighing >20 kg) is tested over time in triplicate. Physical stability is determined by visually inspecting each PN solution for particulate matter and by filtering and analyzing each aliquot quantitatively for crystal precipitates. Chemical stability is confirmed if the iron concentrations by mass spectrometry remain within United States Pharmacopeia (USP) standards. RESULTS: Visual clarity is maintained in all PN solutions at hours 0 through 4. PN solution 1 remains clear for hours 8 through 24, whereas PN solution 2 shows an increase in particulate matter by 8 hours. All PN solutions 2 are considered visually incompatible by hour 24. Physical stability of iron sucrose for PN solutions 1 and 2 from hours 0 to 4 is within the USP guidelines for crystalline particulate matter. At hour 24, only solution 1 remains within USP guidelines. Chemical stability data indicate that iron concentrations are maintained throughout the 24-hour time period. CONCLUSION: The physical stability of iron sucrose in PN is time and concentration dependent. Concentrations >0.25 mg/dL showed increasing particulate and should not be added to PN. However, iron sucrose is chemically stable in PN solutions.

[Nanoparticles: the industrial viewpoint. Applications in diagnostic imaging]. / Nanoparticules : le point de vue d'un industriel. Applications en imagerie diagnostique.

Iron oxide particles can be divided into two categories: small superparamagnetic iron oxide (SPIO) and ultrasmall superparamagnetic iron oxide (USPIO). Both describe nanoparticles most often formulated with dextran or dextran derivatives. For magnetic resonance imaging, these agents are of major importance because of their superparamagnetic effect, that is the magnetic field generated locally by their presence. Clinical applications have been well differentiated: 1) SPIO (larger than 50nm) are mainly used via intravenous infusion to detect and characterize small focal lesions in the liver. SPIO can also be given orally to visualize the digestive tract; 2) USPIO (smaller than 50nm) have a longer plasmatic half-life (>36hours) and exhibit slower uptake by liver and spleen after intravenous administration. This allows the product to access macrophages in normal (lymph nodes) or diseased tissue (multiple sclerosis, graft rejection, atheroma plaques, stroke, rhumatoid arthritis). They can also be used as biomarkers to evaluate the efficacy of treatments. In addition to routine clinical applications, these agents are also under investigation to improve diagnoses in oncological, inflammatory and degenerative as well as cardiovascular diseases (risk of atheroma plaques).

The molecular formula and proposed structure of the iron-dextran complex, imferon.

The first iron-dextran complex was discovered in 1953, when we attempted to synthesize an analog of ferritin, by substituting polysaccharide for its protein shell. This new complex soon became the most widely used parental therapy for hypochromic anemia in humans. No molecular formula has been proposed, but Cox has attributed an outline structure to it. The present article proposes a structure greatly different from the Cox model, by having a polynuclear beta-ferric oxyhydroxide core, closely similar or identical to Akaganeite, chelated firmly by an encircling framework of dextran gluconic acid chains and surrounded by a removable outer sheath of colloidal dextran gluconic acid. The molecular weight of the iron-dextran core molecule, including its chelated framework, has been determined by gel filtration and analysis and its molecular formula (1.3) calculated. Also, these new data and existing electron photomicrographic, X-ray diffraction and crystallographic studies, have enabled a molecular weight, formula, and model structure to be proposed for its complex (2), which includes the outer sheath. The 480 iron atoms in both the core molecule and its sheathed complex are close to the number calculated from the core's unit cell dimensions and volume.

Mössbauer spectroscopy in biomedical research.

This work discusses the main directions and results of the application of Mössbauer spectroscopy of iron containing species in biomedical research. These studies demonstrate the wide possibilities of Mössbauer spectroscopy to obtain physical parameters and information about the iron electronic structure in normal and pathological biomolecules, model compounds and pharmaceutical samples as well as about qualitative and quantitative changes of iron containing biomolecules during pathological processes or the effect of environmental factors. The results obtained may be useful for further understanding of the molecular nature of diseases and pathological processes.

Labile iron in parenteral iron formulations: a quantitative and comparative study.

BACKGROUND: Evidence of iron-mediated oxidative stress, neutrophil dysfunction and enhanced bacterial growth after intravenous (IV) iron administration has been ascribed to a labile or bioactive iron fraction present in all IV iron agents. METHODS: To quantify and compare the size of the labile fraction in several classes of IV iron agents, we examined iron donation to transferrin (Tf) in vitro. We added dilutions of ferric gluconate, iron sucrose and each of two iron dextran preparations to serum in vitro, passed the resulting samples through alumina columns to remove iron agent and free organic iron, and measured Tf-bound iron in the resulting eluates. Comparing results to serum samples without added iron, we calculated delta Tf-bound iron for each agent at each concentration. Finally, we compared delta Tf-bound iron to the concentration of added agent and calculated the percent iron donation to Tf. RESULTS: We found that Tf-bound iron increased with added iron concentration for each agent: delta Tf-bound iron was directly related to the concentration and type of iron agent (P<0.001). Mean percent iron donation to Tf ranged from 2.5 to 5.8% with the following progression: iron dextran-Dexferrum

Determination of iron sucrose (Venofer) or iron dextran (DexFerrum) removal by hemodialysis: an in-vitro study.

BACKGROUND: Intravenous iron is typically administered during the hemodialysis (HD) procedure. HD patients may be prescribed high-flux (HF) or high-efficiency (HE) dialysis membranes. The extent of iron sucrose and iron dextran removal by HD using HF or HE membranes and by ultrafiltration rate (UFR) is unknown. METHODS: Two in vitro HD systems were designed and constructed to determine the dialyzabiltiy of iron from a simulated blood system (SBS) containing 100 mg iron sucrose or iron dextran (system A) or 1000 mg iron sucrose (system B). Both in vitro systems utilized a 6-L closed-loop SBS system that was subject to 4 different HD conditions conducted over 4 hours: HE membrane + 0 ml/hr UFR; HE membrane + 500 ml/hr UFR; HF membrane + 0 ml/hr UFR; HF membrane + 500 ml/hr UFR. Blood flow and dialysate flow rates were 500 ml/min and 800 ml/min, respectively. The dialysate compartment was a 192-L open system for system A and a 6-L closed-loop system for system B. Samples from the SBS and dialysate compartments were taken at various time points and iron elimination rate and HD clearance was determined. Iron removal from the SBS > 15% was considered clinically significant. RESULTS: The greatest percentage removal from the SBS was 13.5% and -0.03% utilizing system A and B, respectively. Iron sucrose and iron dextran dialysate concentration was below the lower limits of assay (< 2 ppm) for system A. Dialysate recovery of iron was negligible: 0-5.4 mg system A and 5.47-23.59 mg for system B. Dialyzer type or UFR did not affect iron removal. CONCLUSION: HF or HE dialysis membranes do not remove clinically significant amounts of iron sucrose or dextran formulations over a 4-hour HD session. This effect remained constant even controlling for UFR up to 500 ml/hour. Therefore, iron sucrose and iron dextran are not dialyzed by HE or HF dialysis membranes irrespective of UFR.