Sucrosomial® iron absorption studied by in vitro and ex-vivo models
Graphical Abstract
Introduction
Iron deficiency is one of the most widespread nutritional deficiencies (Kassebaum et al., 2014). Oral therapy of iron deficiency is mainly based on immediate release formulations of ferrous iron (Cook, 2005). Although supplementation can replete iron stores and increase hemoglobin levels, iron supplements often cause gastric irritation, nausea, epigastric discomfort, and constipation, which may lower compliance and long-term efficacy (Smith et al., 2014). The absorption of iron supplements in subjects with low iron stores ranges from 2% to 13% and 5% to 28% when consumed with and without food, respectively (Cook and Reddy, 1995). Thus, the major part of the iron is unabsorbed and this could be responsible for the alteration of the microbiota leading to intestinal inflammation (Zimmermann et al., 2010, Armah et al., 2015). It should also be considered that iron administration causes an increase of hepcidin blood levels, which appears to be related to a lower bioavailability of the administered iron (Moretti et al., 2015). Concerning Fe3 + bioavailability, it is known that at pH values higher than 3 the Fe3 + ion forms practically insoluble species. In fact, the Fe3 + bioavailability is very poor just because of its poor solubility at the physiologic pH of the intestine. For this reason, mammals have developed an efficient transport system based on the DMT-1 carrier (Srai et al., 2002). The first barrier iron encounters in its course through the gastro-intestine is the apical membrane of the duodenal enterocyte, that is a specialized absorbent cell of the intestinal epithelium involved in iron transport. Iron is initially solubilised through enzymatic reduction of Fe3 + to Fe2 +. This is then carried to the cell interior by a transport process mediated by the carrier DMT-1. Subsequently iron is transferred to the basolateral side of the enterocyte, where it may either be stored via binding to ferritin or cross the membrane and reach the systemic circulation. However, as have recently reported, a number of alternative routes of iron absorption can co-exist, for one, that based on adsorptive endocytosis for particle sizes below 500 nm (Jahn et al., 2012). For the above reasons altogether, to enhance the bioavailability of the administered iron, at the same time ruling out side effects it could be very useful to develop an oral pharmaceutical formulation which would directly carry the ferric ion as far as the intestine, then, after crossing the intestinal epithelium, into the bloodstream (Pereira et al., 2013). Therefore, to evaluate the ability of the carrier to transport Fe3 + across the epithelium, an ex vivo model based on excised rat intestine could be as predictive as required.
The present work compares the innovative oral iron formulation based on Sucrosomial® Iron (Sideral® RM), with different iron formulations in order to study the apparent intestinal permeability, using two different approaches: the Caco-2 cell monolayer, and the excised rat intestine model (Di Colo et al., 2008). Within the limitations of the in-vitro and ex-vivo models used, the study could provide us with further insight into the mechanism of iron absorption.
Section snippets
Materials
Pepsin, pancreatin, Chelex-100 resin, Caco-2 human cell line, bathophenanthrolinedisuphfonic acid disodium salt (BPDS) all were from Sigma-Aldrich, while polyester membrane filters (pore size 0.4 μm, area 1.12 cm2) were from Celbio, Milano, Italy. The carbon dioxide/oxygen (95/5 v/v) mixture (Oxycarb) was from Sol, Pisa, Italy. The samples tested, purchased from Pharmanutra®, are listed in Table 1. The formulation Sideral® RM - Sucrosomial® Iron (SRM) is now present on the market (Table 1).
Fe3 + Release Studies
The formulation of choice is supposed to carry the orally administered iron dose across the stomach and attain the small intestine, where iron absorption should occur. Therefore, the ability of the formulations under study to retain Fe3 + in gastric environment was studied. Fig. 1 shows the Fe3 + release profile from the formulations under study in SGF for 2 h. The figure represents no data for the reference SP, as this is readily soluble at acidic pH. The data show that the formulations can
Conclusions
The in vitro and ex vivo absorption data presented in this work indicate that SRM formulation, is able to retain the ferric iron in SGF conditions and is the most suitable to be taken up by Caco-2 cells, to protect the ferric iron from intestinal enzymes reduction and, finally, to promote the Fe3 + absorption across the intestinal epithelium even without the mediation of the DMT-1 carrier. Furthermore, our results demonstrate that an appropriate balance of sucrester-lecithin in the formulation
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2022, Pharmacological ResearchCitation Excerpt :We did not include this trial in our systematic review, since it is not a randomized study. Oral sucrosomial iron consists of ferric pyrophosphate, [23,24] which increased intestinal absorption with fewer gastrointestinal side effects [25,26]. After 3 months, patients assuming oral sucrosomial iron (28 mg daily) significantly improved 6MWT and KCCQ scores compared with the control group (all p < 0.01).