RESUMEN
Iron deficiency is an important subclinical disease affecting over one billion people worldwide. A growing body of clinical records supports the use of intravenous iron-carbohydrate complexes for patients where iron replenishment is necessary and oral iron supplements are either ineffective or cannot be tolerated by the gastrointestinal tract. A critical characteristic of iron-carbohydrate drugs is the complexity of their core-shell structure, which has led to differences in the efficacy and safety of various iron formulations. This review describes parameters influencing the safety and effectiveness of iron-carbohydrate complexes during production, storage, handling, and clinical application. We summarized the physicochemical and biological assessments of commercially available iron carbohydrate nanomedicines to provide an overview of publicly available data. Further, we reviewed studies that described how subtle differences in the manufacturing process of iron-carbohydrate complexes can impact on the physicochemical, biological, and clinical outcomes of original product versus their intended copies or so-called iron "similar" products.
Asunto(s)
Anemia Ferropénica/tratamiento farmacológico , Compuestos de Hierro/uso terapéutico , Hierro/uso terapéutico , Nanopartículas/uso terapéutico , Administración Intravenosa , Anemia Ferropénica/patología , Carbohidratos/química , Carbohidratos/uso terapéutico , Humanos , Hierro/metabolismo , Compuestos de Hierro/química , Nanomedicina/tendencias , Nanopartículas/química , Tamaño de la PartículaRESUMEN
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 (ß-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.
Asunto(s)
Disacáridos/química , Compuestos Férricos/química , Óxido Ferrosoférrico/química , Compuestos de Hierro/química , Maltosa/análogos & derivados , Química Física , Disacáridos/síntesis química , Compuestos Férricos/síntesis química , Óxido Ferrosoférrico/síntesis química , Compuestos de Hierro/síntesis química , Maltosa/síntesis química , Maltosa/química , Difracción de Rayos XRESUMEN
Intravenous (IV) iron-carbohydrate complexes are widely used nanoparticles (NPs) to treat iron deficiency anaemia, often associated with medical conditions such as chronic kidney disease, heart failure and various inflammatory conditions. Even though a plethora of physicochemical characterisation data and clinical studies are available for these products, evidence-based correlation between physicochemical properties of iron-carbohydrate complexes and clinical outcome has not fully been elucidated yet. Studies on other metal oxide NPs suggest that early interactions between NPs and blood upon IV injection are key to understanding how differences in physicochemical characteristics of iron-carbohydrate complexes cause variance in clinical outcomes. We therefore investigated the core-ligand structure of two clinically relevant iron-carbohydrate complexes, iron sucrose (IS) and ferric carboxymaltose (FCM), and their interactions with two structurally different human plasma proteins, human serum albumin (HSA) and fibrinogen, using a combination of cryo-scanning transmission electron microscopy (cryo-STEM), x-ray diffraction (XRD), small-angle x-ray scattering (SAXS) and small-angle neutron scattering (SANS). Using this orthogonal approach, we defined the nano-structure, individual building blocks and surface morphology for IS and FCM. Importantly, we revealed significant differences in the surface morphology of the iron-carbohydrate complexes. FCM shows a localised carbohydrate shell around its core, in contrast to IS, which is characterised by a diffuse and dynamic layer of carbohydrate ligand surrounding its core. We hypothesised that such differences in carbohydrate morphology determine the interaction between iron-carbohydrate complexes and proteins and therefore investigated the NPs in the presence of HSA and fibrinogen. Intriguingly, IS showed significant interaction with HSA and fibrinogen, forming NP-protein clusters, while FCM only showed significant interaction with fibrinogen. We postulate that these differences could influence bio-response of the two formulations and their clinical outcome. In conclusion, our study provides orthogonal characterisation of two clinically relevant iron-carbohydrate complexes and first hints at their interaction behaviour with proteins in the human bloodstream, setting a prerequisite towards complete understanding of the correlation between physicochemical properties and clinical outcome.
Asunto(s)
Anemia Ferropénica , Maltosa/análogos & derivados , Nanopartículas del Metal , Humanos , Hierro/química , Dispersión del Ángulo Pequeño , Ligandos , Difracción de Rayos X , Compuestos Férricos , Sacarato de Óxido Férrico/uso terapéutico , Anemia Ferropénica/tratamiento farmacológico , Nanopartículas del Metal/química , FibrinógenoRESUMEN
Intravenously administered iron-carbohydrate nanoparticle complexes are widely used to treat iron deficiency. This class includes several structurally heterogeneous nanoparticle complexes, which exhibit varying sensitivity to the conditions required for the methodologies available to physicochemically characterize these agents. Currently, the critical quality attributes of iron-carbohydrate complexes have not been fully established. Dynamic light scattering (DLS) has emerged as a fundamental method to determine intact particle size and distribution. However, challenges still remain regarding the standardization of methodologies across laboratories, specific modifications required for individual iron-carbohydrate products, and how the size distribution can be best described. Importantly, the diluent and serial dilutions used must be standardized. The wide variance in approaches for sample preparation and data reporting limit the use of DLS for the comparison of iron-carbohydrate agents. Herein, we detail a robust and easily reproducible protocol to measure the size and size distribution of the iron-carbohydrate complex, iron sucrose, using the Z-average and polydispersity index.
Asunto(s)
Nanopartículas , Dispersión Dinámica de Luz , Tamaño de la Partícula , Sacarato de Óxido Férrico , Nanopartículas/química , HierroRESUMEN
The aggregation and organization of membrane proteins and transmembrane peptides is related to the interacting molecular species itself and strongly depends on the lipid environment. Because of the complexity and dynamics of these interactions, they are often hardly traceable and nearly impossible to predict. For this reason, peptide model systems are a valuable tool in studying membrane associated processes since they are synthetically accessible and can be readily modified. To control and study the aggregation of peptide transmembrane domains (TMDs) the interacting interfaces of the TMDs themselves can be altered. A second less extensively studied approach targets the TMD assembly by using interaction and recognition of domains at the membrane outside as frequently found in the membrane protein interplay and protein assembly. In the present study, double helical transmembrane domains were designed and synthesized on the basis of a recently reported d,l-alternating peptide pore motif derived from gramicidin A. The highly hydrophobic and aromatic transmembrane peptide was covalently functionalized with a short peptide nucleic acid (PNA) used as specific outer-membrane recognition unit. The PNA sequences were chosen with high polarity to ensure localization within the aqueous phase. To estimate the impact of the membrane adjacent recognition on the TMD assembly by Förster resonance energy transfer (FRET), fluorescence probes were covalently attached to the side chains of the membrane spanning peptide helices. Dimerization of the TMD-peptide/PNA conjugates within unilamellar lipid vesicles was observed. The dimer/monomer ratio of TMDs can be controlled by temperature variation.
Asunto(s)
Emparejamiento Base , Membrana Celular/metabolismo , Fragmentos de Péptidos/química , Fragmentos de Péptidos/metabolismo , Agua , Secuencia de Aminoácidos , Membrana Celular/química , Transferencia Resonante de Energía de Fluorescencia , Secuencias Invertidas Repetidas , Membranas Artificiales , Modelos Moleculares , Datos de Secuencia Molecular , Ácidos Nucleicos de Péptidos/química , Ácidos Nucleicos de Péptidos/genética , Ácidos Nucleicos de Péptidos/metabolismo , Estructura Secundaria de Proteína , Estructura Terciaria de Proteína , TemperaturaRESUMEN
Oral iron therapy can efficaciously treat both iron deficiency and iron deficiency anemia. To overcome the recurrent side effects of iron(II) salts, medicines containing iron(III) such as iron polymaltose complex (IPC) have been introduced in several markets. Despite the claimed improved safety versus iron(II) preparations, divergent evidences are currently available on IPC efficacy. Indeed, the use of either an originator drug or a follow-on version ("similar") of this medicine might result in different clinical performances. The aim of this work was the pioneer evaluation of physicochemical properties of IPC vs. iron polymaltose complex similars (IPCSs) as nanomedicines. This, to assess the presence of deviations for commercially available products supposedly containing the same active pharmaceutical ingredient and currently considered as generics. Significant differences with respect to size, size distribution, stability and degradation kinetics of the products are reported here. Therapeutic equivalence of IPC and IPCSs is not proven, and new guidelines are needed to determine whether these nanomedicines can be regarded as interchangeable.
Asunto(s)
Compuestos Férricos/química , Estabilidad de Medicamentos , Concentración de Iones de Hidrógeno , Hierro/análisis , Peso Molecular , Nanomedicina , Tamaño de la PartículaRESUMEN
Iron sucrose (IS) is a complex nanocolloidal intravenous suspension used in the treatment of iron-deficiency anemia. Follow-on IS products (iron sucrose similars (ISSs)) have obtained marketing authorization by the generic pathway, implying that identical copies of IS may be manufactured. However, recent prospective and retrospective clinical studies showed discrepancies in clinical outcomes, which might be related to differences in physicochemical properties. The aim of this work is to measure and compare the physicochemical properties of IS and three ISSs available in the market using innovative analytical procedures. The comprehensive elucidation of size, size distribution, morphology, and stability of these complex drugs revealed very significant differences between the products. This study serves to provide the basis to define critical quality attributes that may be linked to differences in clinical outcome and thus may contribute to an adequate regulatory approach for IS and its follow-on products.
Asunto(s)
Biosimilares Farmacéuticos/química , Química Farmacéutica/métodos , Compuestos Férricos/química , Ácido Glucárico/química , Tecnología Farmacéutica/métodos , Anemia Ferropénica/tratamiento farmacológico , Biosimilares Farmacéuticos/farmacocinética , Biosimilares Farmacéuticos/uso terapéutico , Fenómenos Químicos , Aprobación de Drogas , Compuestos Férricos/farmacocinética , Compuestos Férricos/uso terapéutico , Sacarato de Óxido Férrico , Ácido Glucárico/farmacocinética , Ácido Glucárico/uso terapéutico , Humanos , Tamaño de la Partícula , Equivalencia TerapéuticaRESUMEN
OBJECTIVES: This study was designed to assess the physicochemical stability of colloidal ferric carboxymaltose solution (Ferinject) when diluted and stored in polypropylene (PP) bottles and bags for infusion. METHODS: Two batches of ferric carboxymaltose solution (Ferinject) were diluted (500 mg, 200 mg and 100â mg iron in 100â mL saline) in PP bottles or bags under aseptic conditions. The diluted solutions were stored at 30°C and 75%±5% relative humidity (rH) for 72â h, and samples were withdrawn aseptically at preparation and after 24 h, 48 h and 72â h. Multiple parameters were used to test stability-related measures (pH, total iron and iron (II) content, molecular weight range determination, microbial contamination and particles count ≥10â µm). RESULTS: Overall, Ferinject diluted in 0.9% (w/v) NaCl solution and stored in PP bottles and bags was stable within the specifications for the complex and the acceptability limits set for all assays. In both containers, total iron content remained stable, within 10% of the theoretical iron content, and levels of iron (II) remained far below the threshold of acceptability. All preparations were free from sediments, particle numbers were acceptable and there was no microbial contamination. The molecular weight distribution and polydispersity index were also acceptable. CONCLUSIONS: Under the tested experimental conditions, colloidal ferric carboxymaltose solution (Ferinject) diluted in saline in PP infusion bottles or bags demonstrated physical and chemical stability for up to 72â h at 30°C and 75% rH. Because of the lack of additional clinical data, when using ferric carboxymaltose, physicians/pharmacists should refer to the dilution and storing recommendations given in the product's summary of product characteristics.