CURRENT TOPICS IN NUTRACEUTICAL RESEARCH Vol. 20, No. 4, pp.

685–690, 2022
doi: https://doi.org/10.37290/ctnr2641-452X.20:685-690
ISSN 1540-7535 print, ISSN 2641-452X online, Copyright © 2022 by New Century Health Publishers, LLC
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Research Article All rights of reproduction in any form reserved

A Randomized Controlled Pilot Study to Compare

the Efficacy of Different Iron Formulations:
Sucrosomal Ferric Pyrophosphate, Micronized
Microencapsulated Ferric Pyrophosphate, and
Intravenous Ferric Gluconate
1,2
R. Mallaci Bocchio, 1,3M. Lo Monaco, 1G. Natoli, 1S. Scibetta, 1C. Argano and 1,2,3S. Corrao
1
Department of Clinical Medicine, Internal Medicine Unit with Rheumatology, Dermatology, Diabetology and Tertiary Diabetic Foot Healthcare, National Relevance and High
Specialization Hospital Trust ARNAS Civico, Di Cristina, Benfratelli, Palermo, 90127 Italy; 2Department of Health Promotion Sciences, Maternal and Infant Care, Internal
Medicine and Medical Specialties (PROMISE), PhD School of Molecular and Clinical Medicine, University of Palermo, Palermo, 90133 Italy and 3Department of Health
Promotion Sciences, Maternal and Infant Care, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, Palermo, 90133 Italy

Received June 23, 2022; Accepted August 7, 2022

Communicated By: Prof. Chandan Prasad

Despite their gastrointestinal side effects, oral iron supplements are the first-line therapy in iron deficiency anemia. This
study aims to compare different iron formulations in anemic outpatients. One-hundred and six outpatients with siderope-
nic microcytic hypochromic anemia (Hb < 12 g/dL for women, Hb < 13 g/dL for men) were enrolled and divided into two
groups (Hb > 10 g/dL and Hb < 10 g/dL). One group was randomized (1:1) to receive sucrosomal ferric pyrophosphate or
micronized microencapsulated ferric pyrophosphate, while the other group was randomized (1:1:1) to receive sucrosomal
ferric pyrophosphate, micronized microencapsulated ferric pyrophosphate or intravenous ferric gluconate. After 3 months
of follow-up, hemoglobin was significantly higher in the micronized microencapsulated ferric pyrophosphate group than in
the sucrosomal ferric pyrophosphate group (1.87 vs 1.10; P = 0.04). No significant difference in adverse events was regis-
tered between the two groups. In patients with Hb > 10 g/dL, the pyrophosphate or micronized microencapsulated ferric
pyrophosphate (30 mg/day) treatment in combination with folic acid (400 mcg), lactoferrin (10 mg), and vitamin C (180 mg)
we found out to bring in a significant increase in hemoglobin, without any significant side effects. The reason for this effec-
tiveness is probably due to its favorable bioavailability. Further comparative studies are needed with other forms of iron.

Keywords: Anemia, Iron deficiency, Iron formulations, Iron supplements, Outpatients, Randomized controlled trial

Abbreviations Used: Body mass index, BMI; Consolidated Reporting of Trials, CONSORT; Hemoglobin, Hb; Heart rate, HR; Iron
deficiency anemia, IDA; Mean corpuscular hemoglobin concentration, MCHC; Mean corpuscular volume, MCV; Micronized micro-
encapsulated ferric pyrophosphate, MMFP; Prospective randomized open blinded end-point, PROBE; Systolic blood pressure, SBP;
Peripheral oxygen saturation, SpO2

Corresponding Author: Marika Lo Monaco, PhD, Department of Health Promotion Sciences, Maternal and Infant Care, Internal
Medicine and Medical Specialties (PROMISE), University of Palermo, Palermo, 90133 Italy; Email: marika.lomonaco@unipa.it; marika.
lomonaco@hotmail.it

INTRODUCTION
The World Health Organization defines anemia as blood hemoglo-
bin levels less than 7.7 mmol/L (13 g/dL) in men and 7.4 mmol/L
(12 g/dL) in women (WHO, 2007). The prevalence of anemia is
more than 20% in individuals 85 years old or older. Common
causes are blood loss, iron deficiency, vitamin B12, or folate defi-
ciency (Patel, 2008). Globally, IDA is the most common cause of
anemia, and it is characterized by low levels of total body iron, a
decrease in the total amount of hemoglobin, or the number of red
blood cells and microcytic, hypochromic erythrocytes (Johnson-
Wimbley et al., 2011). Iron deficiency is usually due to poor dietary

Current Topics in Nutraceutical Research 685 November 2022 | Volume 20 | Article 15

R. Mallaci Bocchio et al.
iron intake, blood loss from the gastrointestinal tract, or monthly
blood loss through menstruation. Common symptoms are fatigue,
weakness, dizziness, and shortness of breath (Patel, 2008).
Once the cause of iron deficiency anemia is identified, its man-
agement options include oral or intravenous iron administration
to supply sufficient quantities of iron to normalize and preserve
target hemoglobin levels, stimulating correct erythropoiesis, and
reconstituting the iron reserves in the body (Jimenez et al., 2015).
Although the correction of IDA with intravenous iron administra-
tion is the gold standard (Hedenus et al., 2007), it may be asso-
ciated with adverse reactions (e.g., allergy and thrombophlebitis).
Furthermore, intravenous iron administration might be uncom-
fortable and also increase health care costs compared to oral treat-
ment. Therefore, oral iron supplementation may represent a better
alternative to intravenous therapy, although it is frequently associ-
ated with gastrointestinal adverse effects (i.e., nausea, vomiting, and
constipation) (Grzywacz et al., 2017; Tolkien et al., 2015; Cancelo-
Hidalgo et al., 2013). Moreover, oral therapy is not recommended in
case of inflammation or gastrointestinal malabsorption (Grzywacz
et al., 2017). Currently, several oral iron formulations are on the
market, including MMFP and sucrosomal ferric pyrophosphate.
MMFP is a preparation in which ferric pyrophosphate is trans-
ported inside a phospholipid membrane. It aims to increase gastro-
intestinal absorption and bioavailability to obtain a lower incidence
of side effects since iron never interacts with the mucous mem-
branes and is absorbed directly in the intestine, without causing
the classic discomfort associated with iron supplementation ionic
form (Gómez-Ramírez et al., 2018). The sucrosomal ferric pyro-
phosphate is a preparation of ferric pyrophosphate conveyed inside
a phospholipid membrane, resulting in its gastroprotective effects
(Briguglio et al., 2020). It is characterized by a gradual release in the
intestine that allows a high absorption without undesirable effects.
The system allows for high serum levels even after 8–10 h of intake.
In contrast, intravenous iron administration (ferric gluco-
nate) may be better indicated in patients who do not tolerate the
expected amounts of oral therapy or when oral preparations are
ineffective and cannot be used (Killip et al., 2007; Gozzard, 2011).
The drawback of intravenous administration is that it can be
administered only in authorized centers as it may be associated
with severe adverse reactions with an incidence ranging from 0.1%
to 0.6% of the subjects (Anker et al., 2009). The symptoms are vari-
able and include palpitations, paresthesia, pruritus, cough, urti-
caria, angioedema, and breathing problems due to laryngeal edema
or bronchospasm, sometimes accompanied with gastrointestinal
involvement (Qunibi, 2010).
The study aimed to evaluate the effects of iron therapy, compared
different iron formulations (sucrosomal ferric pyrophosphate,
MMFP, and ferric gluconate), and different ways of administration
(oral and intravenous) in outpatients with anemia.
MATERIALS AND METHODS
Study Design
A single-center PROBE trial was conducted in the Internal Medicine
Department at the National Relevance and High Specialization
Hospital Trust, ARNAS Civico-Di Cristina-Benfratelli, Palermo,
Italy, from November 2015 until May 2016. The reporting of the
Current Topics in Nutraceutical Research
A Study to Test the Efficacy of Different Iron Formulations
study followed the guidelines of the Consolidated Reporting of
Trials (CONSORT). The present study was developed in accor-
dance with the Declaration of Helsinki and had approval from the
Ethics Committee Palermo 2, in October 2015 with the number
CIVICO 326 2015. All patients gave their written informed con-
sent, and the trial was registered at ClinicalTrials.Gov (https://clin-
icaltrials.gov/), ID: NCT03771092.
Participant Selection, Randomization, and
Treatment
One hundred and forty-six outpatients with sideropenic micro-
cytic hypochromic anemia were enrolled in this study. The inclu-
sion criteria included diagnosis of IDA (Hb < 12 g/dL for women
and Hb < 13 g/dL for men), MCV < 80 fL, MCHC < 32 g/dL, and
age >18. Patients with celiac disease, clinically relevant cognitive
impairment, hemodynamic instability defined by the presence of
arterial hypotension, SBP < 100, HR > 100, and SpO2 ​​< 94% were
excluded.
After the first evaluation, participants were divided into two
groups according to their hemoglobin levels: group one (Hb > 10 g/
dL, Hb < 12 g/dL for women and Hb < 13 g/dL for men) and group
two (Hb < 10 g/dL). An external researcher blinded to randomiza-
tion evaluated the outcome according to the PROBE design. Group
one was randomized (1:1) to receive one pill made of 30 mg MMFP +
400 mcg of folic acid + 10 mg di lactoferrin + 180 mg of vitamin C
a day for 3 months or one pill made of 30 mg.
Outcome Measurements
The main objective of the study was to assess the efficacy and safety
of oral administration of 30 mg MMFP in comparison with 30 mg
Fe sucrosomal ferric pyrophosphate® and intravenous ferric gluco-
nate. At baseline and follow-up, each patient was evaluated for the
cause of anemia, presence of other diseases, drug therapy, eating
habits, BMI, waist circumference, Hb, MCV, MCH, MCHC, sider-
emia, ferritin, and transferrin.
Statistical Analyses
Data were reported as percentages for categorical variables and as
means (95% confidence interval) for quantitative ones. The exact
Fisher test for contingency tables and the z-test for proportions
were used for comparison between groups. A two-tailed P < 0.05
was considered statistically significant. Stata (StataCorp. 2016. Stata
Statistical Software: Release 14.1 College Station, TX: StataCorp
LP) was used for databasing management and analysis.
RESULTS
The data presented in Figure 1 show a CONSORT diagram (Moher
et al., 2001) of the 146 patients, 30 mg sucrosomal ferric pyrophos-
phate® + 70 mg Vit C a day for 3 months. Group two was random-
ized (1:1:1) to receive one pill made by 30 mg MMFP + 400 mcg
of folic acid + 10 mg di lactoferrin + 180 mg of vitamin C a day for
3 months or 30 mg sucrosomal ferric pyrophosphate® + 70 mg Vit C
a day for 3 months or intravenous ferric gluconate. According to
normal clinical practice, intravenous iron was administered up to
the target of 10 mg/dL of hemoglobin.
686 November 2022 | Volume 20 | Article 15
R. Mallaci Bocchio et al. A Study to Test the Efficacy of Different Iron Formulations

Assessed to eligibility
(n = 146)

Excluded (n = 40)
Not meeting inclusion criteria
(n = 14)
Declined to participate (n = 26)

Randomized
(n = 106)

Hb ≥ 10 mg/dL Hb < 10 mg/dL

(n = 40) (n = 68)
Allocation

SunActive® Lipofer® SunActive® Lipofer® Ferric gluconate

(n = 20) (n = 20) (n = 20) (n = 20) (n = 28)

Follow-up

Analysed Analysed Analysed Analysed Analysed

(n = 18) (n = 20) (n = 20) (n = 8) (n = 28)
Lost to follow-up Lost to follow-up Lost to follow-up Lost to follow-up Lost to follow-up
(n = 2) (n = 0) (n = 0) (n = 12) (n = 0)

FIGURE 1 | Flow diagram according to the Consort Statement (Moher, 2001) of the progress through the phases of the study groups (enrolment, intervention allocation,
follow-up, and data analysis). The number of patients (n) screened for eligibility, excluded, randomized and allocated to the study groups, is reported.

In the case of both oral formulations, the subjects received one TABLE 1 | Comparison of demographic and basal characteristic between patients
that were administered with micronized microencapsulated ferric pyrophosphate
pill a day on an empty stomach. Patients were reassessed at a quar-
(n = 20) and sucrosomal ferric pyrophosphate (n = 20) on hemoglobin value up to
terly follow-up for up to 9 months for increase in hemoglobin com- 10 mg/dL. *Data are reported as average with confidence interval of 95% in the
pared to the initial values, sideremia, ferritin and transferrin levels, parentheses.
adherence to therapy, tolerability by the patient, and any side effects
Micronized Sucrosomal P-values
were evaluated.
microencapsulated ferric
Among the 146 patients screened, 40 were excluded for not ferric pyrophosphate Pyrophosphate
providing the informed consent or meeting the inclusion crite-
Age* 45.9 (38.4 to 53.4) 55.9 (48.3 to 63.5) 0.1354
ria. The remaining 106 patients were included and randomized
into two arms (82.8% female and 17.2% male; mean age 50.4 BMI* 25.72 (24.04 to 27.41) 26.86 (24.58 to 29.14) 1.0000

years). The first group included 40 patients with hemoglobin Waist circumference* 94.5 (90.2 to 98.8) 97.4 (92.7 to 102.2) 0.4479
levels > 10 mg/dL. Of these 20 were randomized to MMFP, and HB (mg/dL)* 10.93 (10.74 to 11.13) 11.11 (10.81 to 11.41) 0.5904
the other 20 to sucrosomal ferric pyrophosphate. The second MCH pg* 24.56 (23.73 to 25.40) 27.13 (22.70 to 31.56) 0.9286
group included 68 patients with hemoglobin levels < 10 mg/dL. MCHC g/dL* 31.63 (30.61 to 32.66) 30.27 (29.93 to 30.62) 0.0182
Within this group, 20 patients were randomized to MMFP, Sideremìa ug/dL* 25.61 (22.37 to 28.85) 31.73 (27.90 to 35.56) 0.0162
20 to sucrosomal ferric pyrophosphate, and 28 were admin-
Ferritin mg/L* 11.99 (5.85 to 18.13) 10.23 (4.80 to 15.66) 0.4376
istered intravenous ferric gluconate. By the end of 3 months,
Transferrin mg/dL* 309.2 (295.9 to 322.6) 313.5 (294.7 to 332.3) 0.4203
all subjects remained in the study except those 12 patients in
the sucrosomal ferric pyrophosphate group dropped out at the
follow-up. no difference in the value of hemoglobin between the two treat-
A summary of the baseline demographic and clinical charac- ments. Table 2 summarizes the laboratory values after 3 months
teristics for the first group is shown in Table 1. Overall, subjects of follow-up. In patients who were on MMFP, the hemoglo-
with Hb > 10 g/dL had the median age of 45–55 years. There is bin increase was significantly higher (P = 0.04) compared

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R. Mallaci Bocchio et al. A Study to Test the Efficacy of Different Iron Formulations

TABLE 2 | A comparison of laboratory values between patients (with hemoglobin value up to 10 mg/dL) that were administered with micronized microencapsulated ferric
pyrophosphate (n = 18) and sucrosomal ferric pyrophosphate (n = 20) at 3 months. *Data are reported as average with confidence interval of 95% in the parentheses.

Micronized microencapsulated ferric Sucrosomal ferric P-values

pyrophosphate pyrophosphate

Hemoglobin (mg/dL) 12.74 (12.24 to 13.24) 12.22 (11.79 to 12.65) 0.1259

δ-Hemoglobin at T0 1.87 (1.31 to 2.43) 1.10 (0.65 to 1.54) 0.0399
MCV fL 84.83 (83.83 to 85.84) 78.95 (73.81 to 84.08) 0.0970
δ-MCV at T0 3.48 (0.92 to 6.04) 3.18 (−4.08 to 10.45) 0.7333
MCH pg 27.63 (27.15 to 28.11) 31.16 (24.14 to 38.17) 0.1463
δ-MCH at T0 2.48 (1.13 to 3.84) 2.99 (−6.20 to 12.19) 0.0870
MCHC g/dL 32.45 (31.87 to 33.02) 31.35 (30.69 to 32.01) 0.0428
δ-MCHC at T0 1.46 (0.48 to 2.44) 1.02 (0.45 to 1.58) 0.2531
Sideremìa µg/dL 49.77 (37.62 to 61.93) 55.07 (41.41 to 68.73) 0.8482
δ-Sideremìa at T0 24.11 (11.90 to 36.31) 22.92 (9.10 to 36.74) 0.8484
Ferritin mg/L 18.92 (10.47 to 27.36) 12.18 (9.87 to 14.49) 0.2529
δ-Ferritin at T0 6.71 (3.57 to 9.84) 4.75 (2.52 to 6.98) 0.3837
Transferrin mg/dL 270.1 (254.3 to 285.9) 315.9 (294.7 to 337.1) 0.0039
δ-Transferrin at T0 −5.15 (−29.10 to 18.79) −21.16 (−40.52 to −1.80) 0.4267
% Transferrin saturation 13.75 (9.27 to 18.22) 13.73 (8.36 to 19.10) 0.3865
δ-% Transferrin saturation at T0 7.64 (2.77 to 12.52) 6.13 (0.80 to 11.46) 0.3123

TABLE 3 | A comparison of adverse events between patients (with hemoglobin value to subjects who had used sucrosomal ferric pyrophosphate
up to 10 mg/dL) that were administered with micronized microencapsulated ferric
pyrophosphate (n = 18) and sucrosomal ferric pyrophosphate (n = 20) at 3 months.
(1.87 vs. 1.10). At 3 months follow-up, a comparison of adverse
events showed no significant differences between the two
Micronized Sucrosomal ferric P-values treatments (Table 3) in patients of the first group (hemoglobin
microencapsulated pyrophosphate
ferric pyrophosphate >10 mg/dL). The baseline characteristics of the second group
(Hb < 10 g/dL) are summarized in Table 4. At 3 months follow-up,
Diarrea (%) 0.0 15.4 0.0809
outcomes evaluation showed a significant difference in hemo-
Constipation (%) 11.1 7.7 0.6981
globin levels (Table 5). A cost comparison for 30 days therapy
Nausea (%) 11.1 15.4 0.6846
with 30 mg MMFP containing 400 mcg of folic acid, 10 mg lac-
Vomit (%) 0.0 7.7 0.2284
toferrin, and 180 mg of vitamin C was half (19.80 €) of therapy
Abdominal pain (%) 0.0 7.7 0.2284
using 30 mg sucrosomal ferric pyrophosphate containing 70 mg
Dark feces (%) 0.0 7.7 0.2284
Vit C (38.10 €).

TABLE 4 | A comparison of demographic and basal characteristic between patients (with hemoglobin value up to 10 mg/dL) that were administered with micronized
microencapsulated ferric pyrophosphate (n = 20), sucrosomal ferric pyrophosphate (n = 20), and intravenous ferric gluconate (n = 28). *Data are reported as average with
confidence interval of 95% in the parentheses.

Micronized Sucrosomal ferric Ferric gluconate P-values

microencapsulated pyrophosphate
ferric pyrophosphate

Age* 46.3 (41.6 to 50.9) 40.2 (33.0 to 47.4) 53.9 (46.3 to 61.4) 0.0577
BMI* 23.95 (20.67 to 27.23) 26.65 (17.42 to 35.88) 27.67 (25.54 to 29.80) 0.1987
Waist circumference* 92.4 (85.2 to 99.5) 98.0 (80.5 to 115.4) 99.5 (92.8 to 106.2) 0.3596
HB (mg/dL)* 8.93 (8.56 to 9.29) 9.05 (8.27 to 9.82) 8.50 (8.12 to 8.88) 0.1659
MCH pg* 21.09 (19.68 to 22.49) 21.10 (17.72 to 24.47) 20.28 (18.93 to 21.64) 0.6777
MCHC g/dL* 29.79 (29.14 to 30.43) 30.40 (28.69 to 32.10) 28.55 (27.89 to 29.21) 0.0066
Sideremìa µg/dL* 23.60 (19.20 to 27.99) 24.50 (18.90 to 30.09) 20.00 (17.10 to 22.89) 0.2090
Ferritin mg/L* 5.74 (2.43 to 9.05) 4.02 (2.10 to 5.94) 5.56 (4.24 to 6.88) 0.6915
Transferrin mg/dL* 342.9 (324.8 to 360.9) 417.5 (409.2 to 425.7) 337.5 (317.4 to 357.5) 0.0069

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R. Mallaci Bocchio et al. A Study to Test the Efficacy of Different Iron Formulations

TABLE 5 | A comparison of laboratory values between patients (with hemoglobin value up to 10 mg/dL at T0 ) that were administered with micronized microencapsulated
ferric pyrophosphate (n = 20), sucrosomal ferric pyrophosphate (n = 8), and intravenous ferric gluconate (n = 28) at 3 months. *Data are reported as average with confidence
interval of 95% in the parentheses.

Micronized microencapsulated Sucrosomal ferric Ferric P-values

ferric pyrophosphate pyrophosphate gluconate

Hemoglobin (mg/dL) 10.64 (9.96 to 11.31) 10.20 (9.27 to 11.12) 11.01 (10.43 to 11.59) 0.3305
δ-Hemoglobin at T0 1.71 (1.15 to 2.26) 1.15 (0.41 to 1.88) 2.50 (1.96 to 3.04) 0.0146
MCV fL 77.65 (73.41 to 81.88) 70.32 (63.00 to 77.64) 77.74 (74.50 to 80.98) 0.0927
δ-MCV at T0 6.55 (3.11 to 9.98) 1.00 (−2.51 to 4.51) 7.16 (5.46 to 8.86) 0.0270
MCH pg 23.63 (22.06 to 25.19) 22.00 (19.61 to 24.38) 23.65 (22.41 to 24.88) 0.4107
δ-MCH at T0 2.54 (1.14 to 3.93) 0.9 (−0.56 to 2.36) 3.36 (2.54 to 4.18) 0.0441
MCHC g/dL 30.73 (30.05 to 31.40) 31.37 (29.60 to 33.14) 30.23 (29.57 to 30.89) 0.2173
δ-MCHC at T0 0.94 (0.34 to 1.53) 0.97 (0.16 to 1.78) 1.63 (0.85 to 2.40) 0.3023
Sideremìa µg/dL 43.90 (26.80 to 60.99) 50.25 (14.72 to 85.77) 42.35 (35.68 to 49.03) 0.8003
δ-Sideremìa at T0 20.30 (2.23 to 38.36) 25.75 (−11.07 to 62.57) 22.35 (17.34 to 27.37) 0.9060
Ferritin mg/L 16.79 (10.22 to 23.35) 15.31 (4.69 to 25.92) 27.87 (15.01 to 40.73) 0.2288
δ-Ferritin at T0 11.04 (3.47 to 18.62) 11.28 (2.27 to 20.29) 22.11 (9.92 to 34.30) 0.2424
Transferrin mg/dL 325.3 (312.5 to 338.0) 307.5 (209.6 to 405.3) 292.4 (270.1 to 314.7) 0.1982
δ-Transferrin at T0 −17.6 (−42.4 to 7.2) −44.0 (−51.3 to 36.6) −45.4 (−72.2 to 18.6) 0.2764
% Transferrin saturation 9.77 (5.55 to 13.98) 21.53 (−3.71 to 46.78) 11.36 (8.10 to 14.61) 0.1184
δ-% Transferrin saturation at T0 4.82 (0.38 to 9.26) 2.00 (1.34 to 2.67) 6.95 (4.07 to 9.83) 0.4242

DISCUSSION hemoglobin levels more than sucrosomal ferric pyrophosphate.

This prospective randomized open blinded end-point trial
(Hansson et al., 1992) has assessed the efficacy and the safety of iron
therapy, comparing sucrosomal ferric pyrophosphate, MMFP, and
ferric gluconate and oral and intravenous administration in outpa-
tients with anemia. According to previous data from the REPOSI
registry anemia represented one of the most frequent comorbidi-
ties in the elderly population hospitalized in internal medicine and
geriatric Italian wards for anemia (Corrao, 2019; Argano, 2021;
Corrao, 2015). Moreover, women aged 20–40 years and men aged
20–60 years have the highest incidence of IDA. The prevalence of
IDA is growing with increasing age and is particularly evident in
the female population between ages 35 and 54, including women of
child-bearing age and in the premenopausal phase (Clark, 2008).
Furthermore, the REPOSI registry reveals that in Italy among
patients over 65 years hospitalized under ordinary conditions,
58.4% had lower hemoglobin values than normal ones. It is also
possible to observe how in the elderly population, the trend can be
overlapped in the two sexes (Riva, 2016).
Since MMFP is a relatively new pharmacological product with
limited data regarding its efficacy or the incidence of adverse
effects (Pappalardo, 2019; Kaundal, 2020), the aim of the pres-
ent study was to evaluate whether daily administration of low-
dose MMFP (30 mg) was efficacious in correcting IDA. While
oral supplementation with iron salts can be an effective strategy
to increase Hb levels in IDA (Muñoz, 2017), its effectiveness
in replenishing iron stores can be reduced by its low bioavail-
ability leading to reduced iron absorption in the gastrointesti-
nal tract and iron retention in the reticuloendothelial system
(Babitt, 2010). Our present data showed that MMFP increased
These results are consistent with a previous report showing that
orally administered microencapsulated iron pyrophosphate
increases hemoglobin levels as well as sideraemia and ferritinae-
mia (Pappalardo, 2019).
One possible explanation is that MMFP is water soluble and
has better bioavailability than nonmicronized iron pyrophosphate,
which has a larger particle size, and nonencapsulated iron pyro-
phosphate (LeFevre, 1980). Another mechanism explaining the
higher bioavailability of MMFP is that M cells preferentially bind
particles up to 10 mM in diameter and transport them to immu-
nocompetent cells in the underlying mucosal lymphoid tissue
(Ermak, 1995).
There were several limitations to this study, particularly the
small sample size and the number of dropouts in the second group.
It is possible that the cause of the dropout was the cost difference
between the different formulations. In addition, the results and
conclusions are based on a limited treatment period without any
additional information about long-term follow-up.
CONFLICT OF INTEREST DECLARATION
The authors state that there are no conflicts of interest to
disclose.
AUTHORS’ CONTRIBUTION
All authors have participated equally in all phases of data collec-
tion, analysis, and manuscript preparation.

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R. Mallaci Bocchio et al.
REFERENCES
Anker, S.D., Colet, J.C., Filippatos, G., Willenheimer, R., Dickstein, K., Drexler,
H., Lüscher, T.F., Mori, C., Von Eisenhart Rothe, B., Pocock, S., Poole-Wilson,
P.A. and Ponikowski, P. (2009). Rationale and design of Ferinject assessment
in patients with iron deficiency and chronic heart failure (FAIR-HF) study: a
randomized, placebo-controlled study of intravenous iron supplementation
in patients with and without anaemia. European Journal of Heart Failure 11:
1084–1091. doi: 10.1093/eurjhf/hfp140
Argano, C., Scichilone, N., Natoli, G., Nobili, A., Corazza, G.R., Mannucci, P.M.,
Perticone, F. and Corrao, S. (2021). Pattern of comorbidities and 1-year mortality
in elderly patients with COPD hospitalized in internal medicine wards: Data from
the RePoSI Registry. Internal and Emergency Medicine 16:389–400 doi: 10.1007/
s11739-020-02412-1
Babitt, J.L. and Lin, H.Y. (2010). Molecular mechanisms of hepcidin regulation:
Implications for the anemia of CKD. American Journal of Kidney Diseases 55:726–
741. doi: 10.1053/j.ajkd.2009.12.030
Briguglio, M., Hrelia, S., Malaguti, M., De Vecchi, E., Lombardi, G., Banfi, G., Riso,
P., Porrini, M., Romagnoli, S., Pino, F., Crespi, T. and Perazzo, P. (2020). Oral
Supplementation with Sucrosomial Ferric Pyrophosphate Plus L-Ascorbic Acid to
Ameliorate the Martial Status: A Randomized Controlled Trial. Nutrients 12:386.
doi: 10.3390/nu12020386
Cancelo-Hidalgo, M.J., Castelo-Branco, C., Palacios, S., Haya-Palazuelos, J., Ciria-
Recasens, M., Manasanch, J. and Pérez-Edo, L. (2013). Tolerability of different oral
iron supplements: A systematic review. Current Medical Research and Opinion
29:291–303. doi: 10.1185/03007995.2012.761599
Clark, S.F. (2008). Iron deficiency anemia. Nutrition in Clinical Practice 23:128–141.
doi: 10.1177/0884533608314536
Corrao, S., Argano, C., Nobili, A., Marcucci, M., Djade, C.D., Tettamanti, M., Pasina,
L., Franchi, C., Marengoni, A., Salerno, F., Violi, F., Mannucci, P.M. and Perticone,
F. (2015). Brain and kidney, victims of atrial microembolism in elderly hospital-
ized patients? Data from the REPOSI study. European Journal of Internal Medicine
26:243–249. doi: 10.1016/j.ejim.2015.02.018
Corrao, S., Argano, C., Natoli, G., Nobili, A., Corazza, G.R., Mannucci, P.M. and
Perticone, F. (2019). Sex-differences in the pattern of comorbidities, functional
independence, and mortality in elderly inpatients: Evidence from the RePoSI
Register. Journal of Clinical Medicine 8:81. doi: 10.3390/jcm8010081
Ermak, T.H., Dougherty, E.P., Bhagat, H.R., Kabok, Z. and Pappo, J. (1995). Uptake
and transport of copolymer biodegradable microspheres by rabbit Peyer’s patch
M cells. Cell and Tissue Research 279:433–436. doi: 10.1007/BF00318501
Gómez-Ramírez, S., Brilli, E., Tarantino, G. and Muñoz, M. (2018). Sucrosomial® iron:
A new generation iron for improving oral supplementation. Pharmaceuticals
(Basel) 11:97. doi: 10.3390/ph11040097
Gozzard, D. (2011). When is high-dose intravenous iron repletion needed? Assessing
new treatment options. Drug Design, Development and Therapy 5:51–60. doi:
10.2147/DDDT.S15817. PMID: 21340038; PMCID: PMC3038995.
Grzywacz, A., Lubas, A., Fiedor, P., Fiedor, M. and Niemczyk, S. (2017). Safety
and efficacy of intravenous administration of iron preparations. Acta Poloniae
Pharmaceutica 74:13–24. PMID: 29474757.
Hansson, L., Hedner, T. and Dahlöf, B. (1992). Prospective randomized open
blinded end-point (PROBE) study. A novel design for intervention trials.
Prospective Randomized Open Blinded End-Point. Blood Pressure 1:113–119.
doi: 10.3109/08037059209077502
Current Topics in Nutraceutical Research
A Study to Test the Efficacy of Different Iron Formulations
Hedenus, M., Birgegård, G., Näsman, P., Ahlberg, L., Karlsson, T., Lauri, B., Lundin,
J., Lärfars, G. and Osterborg, A. (2007). Addition of intravenous iron to epoe-
tin beta increases hemoglobin response and decreases epoetin dose requirement
in anemic patients with lymphoproliferative malignancies: a randomized multi-
center study. Leukemia 21:627–632. doi: 10.1038/sj.leu.2404562
Jimenez, K., Kulnigg-Dabsch, S. and Gasche, C. (2015). Management of iron defi-
ciency anemia. Gastroenterology and Hepatology 11:241–250. PMID: 27099596;
PMCID: PMC4836595.
Johnson-Wimbley, T.D. and Graham, D.Y. (2011). Diagnosis and management of iron
deficiency anemia in the 21st century. Therapeutic Advances in Gastroenterology
4:177–184. doi: 10.1177/1756283X11398736
Kaundal, R., Bhatia, P., Jain, A., Jain, A., Nampoothiri, R.V., Mishra, K., Jandial, A.,
Goni, D., Sandal, R., Jindal, N., Meshram, A., Sharma, R., Khaire, N., Singh, C.,
Khadwal, A., Prakash, G., Das, R., Varma, N., Varma, S., Malhotra, P. and Lad,
D.P. (2020). Randomized controlled trial of twice-daily versus alternate-day oral
iron therapy in the treatment of iron-deficiency anemia. Annals of Hematology
99:57–63. doi: 10.1007/s00277-019-03871-z
Killip, S., Bennett, J.M. and Chambers, M.D. (2008). Iron deficiency anemia.
American Family Physician 75:671–678. PMID: 17375513.
LeFevre, M.E., Hancock, D.C. and Joel, D.D. (1980). Intestinal barrier to large
particulates in mice. Journal of Toxicology and Environment Health 6:691–704
doi: 10.1080/15287398009529888
Moher, D., Schulz, K.F. and Altman, D.G. (2001). The CONSORT statement: Revised
recommendations for improving the quality of reports of parallel-group ran-
domised trials. Lancet 357:1191–1194. PMID: 11323066.
Muñoz, M., Gómez-Ramírez, S., Besser, M., Pavía, J., Gomollón, F., Liumbruno, G.M.,
Bhandari, S., Cladellas, M., Shander, A. and Auerbach, M. (2017). Current mis-
conceptions in diagnosis and management of iron deficiency. Blood Transfusion
15:422–437. doi: 10.2450/2017.0113-17
Pappalardo, A., Currenti, W., Ponzio, R., Mellini, G., Nicolosi, D., Longhitano, L.,
Tibullo, D., Castorina, S. and Palumbo, G. (2019). Effects of micronized micro-
encapsulated ferric pyrophosphate supplementation in patients with advanced
cancer and iron deficiency: a single-centre cohort pilot study. Blood Transfusion
17:196–199. doi: 10.2450/2019.0181-18
Patel, K.V. (2008). Epidemiology of anemia in older adults. Seminars in Hematology
45:210–217. doi: 10.1053/j.seminhematol.2008.06.006
Qunibi, W.Y. (2010). The efficacy and safety of current intravenous iron preparations
for the management of iron-deficiency anaemia: A review. Arzneimittelforschung
60:399–412. doi: 10.1055/s-0031-1296304
Riva, E., Colombo, R., Moreo, G., Mandelli, S., Franchi, C., Pasina, L., Tettamanti,
M., Lucca, U., Mannucci, P.M. and Nobili, A. (2017). Prognostic value of
degree and types of anaemia on clinical outcomes for hospitalized older
patients. Archives of Gerontology and Geriatrics 69:21–30. doi: 10.1016/j.
archger.2016.11.005
Tolkien, Z., Stecher, L., Mander, A.P., Pereira, D.I. and Powell, J.J. (2015). Ferrous
sulfate supplementation causes significant gastrointestinal side-effects in adults:
A systematic review and meta-analysis. PLoS One 10:e0117383. doi: 10.1371/jour-
nal.pone.0117383
World Health Organization. (2007). Assessing the iron status of populations: Report
of a joint World Health Organization/Centers for Disease Control and Prevention
technical consultation on the assessment of iron status at the population level. 2nd
ed., Geneva. Available at http://www.who.int/nutrition/publications/micronutri-
ents/anaemia_iron_deficiency/9789241596107.pdf (last access on 9 May 2022).
690 November 2022 | Volume 20 | Article 15