Quercetin, made better.

These statements may not comply with your country’s laws and regulations or with Reg. EC n.
1924/2006 and have not been evaluated by the Food and Drug Administration. The products are notintended to diagnose, treat, cure or prevent any disease. Marketers of finished products containing
this ingredient are responsible for ensuring compliance with the applicable legal framework.

2

Index4

Flavonoids: a natural treasurefor human wellbeing

7

Quercetin, the queenof flavonoids

9

Quercefit®: the mostbioavailable quercetin

11

Main applications

1.

Flavonoids:a natural treasurefor human wellbeing1
Flavonoids are an important class of natural products; particularly, they
belong to a class of plant secondary metabolites having a polyphenolicstructure. Flavonoids are found in fruits, vegetables, grains, bark, roots,stems, flowers, tea and wine: all products whose beneficial effects on
health are well known. They are also abundantly found in foods andbeverages of plant origin, such as fruits, vegetables, tea, cocoa and wine;
hence they are termed as dietary flavonoids.

Flavonoids act in plants as
antioxidants, antimicrobials,
photoreceptors, visual attractors,
feeding repellents, and forlight screening.
41A. N. Panche, A. D. Diwan, S. R.
Chandra, Flavonoids: an overview,
Journal of Nutritional Science. 2016;
5: e47. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5465813/.

Basic skeleton

7681OA

C

5

4

3’

2’

6’

5’

3OH
OH

Apigenin

O

OH4’

B

2 1’Flavones
HO

Basic skeleton structure of ﬂavonoids
and their classes(from A. N. Panche, A. D. Diwan, S. R.
Chandra, Flavonoids: an overview, Journalof Nutritional Science. 2016; 5: e47)

O

OH

OH

OH

O

Isoflavones
Genistein

Daidzein
HOO

O

Phloretin

O

O

OH

OH

Flavonols

OH

Narigenin

O

HO

OH

OH

Chalconaringenin

HOO

O

O

Chalcones
OH

O

OH

OH

OH

OH

Kaempferol
HO

O

HO

O
OH

Quercetin
HO

O

HO

Flavonols OH

OH

Luteolin

HO

OH

OH

HO

OCH3

Hesperetin
O

HO

OH
OH

OH

O

O

Anthocyanins
HO

Dephinidin

OH
O+

HO

OH

OH
O+

HO

OH
OH

HO

CyanidinOH
OH

Many studies have suggested that flavonoids exhibit biological activities,
including anti-allergenic, antiviral, anti-inflammatory and vasodilatingactions. However, most interest has been devoted to the antioxidant
activity of flavonoids which is due to their ability to reduce free radical
formation and to scavenge free radicals.

Hence, flavonoids are associatedwith a broad spectrum of positiveeffects on human health,thanks to their antioxidative,
anti-inflammatory, anti-mutagenic
and anti-carcinogenic properties
coupled with their capacity
to modulate key cellularenzyme functions.

2Havsteen B (2002)
The biochemistry and medicalsignificance of the flavonoids. Pharmacol Ther 96, 67–202.

Dewick PM (2001) The shikimate
pathway: aromatic amino acids
and phenylpropanoids In Medicinal
Natural Products: a Biosynthetic Approach, 2nd ed., pp. 137–186 [DewickPM, editor]. Chichester: John Wiley.
3Flavonoids are used by vegetables for their growth and defence against
plaques.2 They belong to a class of low-molecular-weight phenolic
compounds that are widely distributed in the plant kingdom and constituteone of the most characteristic classesof compounds in higher plants.
Many flavonoids are easily recognized as flower pigments in mostangiosperm families. However, their occurrence is not restricted toflowers but are found in all parts of plants.3
Flavonoids have several subgroups, which include chalcones, flavones,flavonols and isoflavones. These subgroups have unique major sources.
For example, onions and tea are major dietary sources of flavonols andflavones.

6000

6

Currently there are 6000 flavonoids that
contribute to the colorful pigments of fruits,
herbs, vegetables and medicinal plants.

2.

Quercetin,the queen of flavonoids4
Quercetin is categorized as a flavonol, one of the six subclasses offlavonoid compounds. In Western populations, estimated daily intake offlavonols is in the range ofn20-50 mg/day. Of this, about 13.82 mg/day is in
the form of quercetin-type flavonols.5
The variety of dietary flavonols is created by the differential placementof phenolic-OH groups and attached sugars. All flavonols, including
quercetin, have in common a 3-hydroxyflavone backbone. The
determination of whether a flavonol is considered to be of the quercetin
type as opposed to a kaempferol or myricetin type, for example, is basedon the location of phenolic-OH groups.

Figure 1 shows the possible
attachment positions forhydroxyl and glycosylgroups76851O

44
Gregory S. Kelly, ND, Quercetin,
Alternative Medicine Review, Volume16, Number 2, 2011.

5Cao J, Zhang Y, Chen W, Zhao X. The
relationship between fasting plasma
concentrations of selected flavonoids
and their ordinary dietary intake. Br J
14. Nutr 2010;103:249-255.

2’2 1’

3’

6’

4’
5’3 OH
7

The International Union of Pure and Applied Chemistry (IUPAC)
nomenclature for quercetin is 3,3’,4’,5,7-pentahydroxyflavanone (or its
synonym 3,3’,4’,5,7-pentahydroxy-2-phenylchro-men-4-one).
This means that quercetin has an OH group attached at positions 3, 5, 7,3’, and 4’.

By definition quercetin is an aglycone,lacking an attached sugar. It is abrilliant citron yellow color and isentirely insoluble in cold water, poorly
soluble in hot water, but quite soluble
in alcohol and lipids.
Quercetin-type flavonols (primarily as quercetin glycosides),the most abundant of the flavonoid molecules, are widely distributed in
the plant kingdom. They are found in a variety of foods including apples,berries, Brassica vegetables, capers, grapes, onions, shallots, tea, andtomatoes, as well as many seeds, nuts, flowers, barks, and leaves.

6
Mitchell AE, Hong YJ, Koh E,
et al. Ten-year comparisonof the influence of organic and conventional crop management practices
on the content offlavonoids in tomatoes. J Agric Food
Chem 2007;55:6154-6159.

7
Chondrogianni N, Kapeta S,
Chinou I, Vassilatou K,
Papassideri I, Gonos ES. (2010)
Anti-ageing and rejuvenating efectsof quercetin.
Exp Gerontol. 45(10):763–71.

8Chopra M, Fitzsimons PE, StrainJJ, Thurnham DI, Howard AN. (2000)
Nonalcoholic red wine extract andquercetin inhibit LDL oxidation
without affecting plasma antioxidant
vitaminand carotenoid concentrations.
Clin Chem. 46(8 Pt 1):1162–70.

9Erlund I, Kosonen T, Alfthan G,
Mäenpää J, Perttunen K,Kenraali J, et al. (2000)
Pharmacokinetics of quercetin fromquercetin aglycone and rutin in healthy volunteers. Eur J Clin Pharmacol.
56(8):545–53.

Wang W, Sun C, Mao L, Ma P, Liu F,
Yang J, et al. (2016)
The biological activities,
chemical stability, metabolism anddelivery systems ofquercetin: a review. Trends Food Sci
Technol. 56:21–38.

10Growing conditions might significantly influence the amount of quercetinin food, with evidence indicating that organically grown tomatoes havesignificantly higher quercetin aglycone content than conventionallyproduced tomatoes.6
As suggested by scientific publications, quercetin has antioxidant,
antiaging, anti-aggregation and vasodilation properties.7-9 Scientific
literature highlights its potential use for maintaining well-being in1
D’Andrea G. (2015) Quercetin:a favonol with multifaceted
therapeutic applications?
Fitoterapia. 106:256–71.

situations of fatigue or stress.10-11OH

Quercetin chemicalcompositionOHO

HOOHOH
8O

3.

Quercefit®:
the most bioavailable
quercetin
Like many botanical extracts and natural compounds, quercetin, while being
potentially very effective for maintaining healthy conditions, on the other
hand is provided with poor water solubility. As a consequence, it is barely
bio-absorbable, and that decreases its potential effectiveness. For optimalbioabsorption, natural products must havea good balance between hydrophilicity
for dissolving into the gastro-intestinal
fluids and lipophilicity to cross cell’s lipidic
biomembranes. To face such a challenge,
Indena has adopted since years a “biomimetic approach”.
Biomimetics is the science that studies Nature and natural phenomena tounderstand the principles of underlying mechanisms, to obtain ideas fromnature, imitating its design, plans and processes and to apply concepts that
may beneﬁt Science, engineering, and medicine, to solve human problems.
The term “biomimetics” originates from the Greek
words “bios” (life) and “mimesis” (to imitate),
yet its definition is not as simple as just those
two words. More specifically, biomimetics
is a creative form of technology that uses orimitates nature to keep healthy levels in human
lives. In biomimetics, Nature is the measure and thestandard for judging appropriateness, sustainability andalso the formal, strategic and ethical correctness of technologicalproducts and process innovations. The central idea is that nature, bynecessity, has already solved many of the problems we are dealing with.
NATURE AS MEASURETM represents the very notionof biomimetics in literature and its philosophical origins. The search
for a bio-mimetic approach to optimize actives bioabsorption of naturalcompounds in the full respect of their natural proﬁle, has been pioneered
by Indena with the development of Phytosome® delivery system.
9

Indena has developed some of the most innovative products andtechnologies on the market to optimize the bioabsorption of selectedbotanicals. Phytosome®, Indena’s proprietary 100% food-grade biomimetic
delivery system, is the result of a wide experience and deep knowledge inproduct and process research.
In its innovative and genuine inspiration by Nature, Phytosome® allows
to maintain the original chaos of natural products according to thebiomimetic principle of Nature as MeasureTM, without involving new
chemical derivatives or new chemical entities, pharmaceutical excipientsor structural modification of the ingredients, rather maintaining theirtolerability over time and safety. In a continuous evolution and innovationof R&D value chain, every Phytosome® is specifically designed to optimize
the bioabsorption of the selected botanical.
Phytosome® represents a natural approach to obtain a solid dispersionof poorly oral bioavailable compounds that can promote phytochemicals
solubility and bioabsorption through improved wetting, reduced
agglomeration and changes in the physical state of the active ingredients(such as modifications in the crystalline status or production of either
partially or totally amorphous stable forms).

Quercefit®: specifications
Quercefit® is the Indena's unique Phytosome® formulation of quercetin
deriving from flower buds of the natural plant Sophora japonica L. Indeed,
the most bioavailable quercetin on the market.

34-42% quercetin by HPLC
suggested dose: 250 mg once or twice a day
yellow powder for use in nutritional supplementscompliant with main worldwide markets
food regulations (BELFRIT, US, EU)
high tolerability in individuals assuming antiplatelet
agents, anticoagulants or living with diabetes

10

4.

Main applications
New recent studies suggest positive
results in terms of bioavailability,
efficacy in sports, discomforts andhigh tolerability for Quercefit®.

Riva A. et al. Improved Oral
Absorption of Quercetin fromQuercetin Phytosome®, a New
Delivery System Based on Food
Grade Lecithin. Eur J Drug Metab
Pharmacokinet. 2018 Oct 16.
doi: 10.1007/s13318-018-0517-3.

12

Five human studies have been focused on Quercefit®, standardizedin ≥36.0% and ≤42.0% of quercetin.
According to a published human pharmacokinetic study comparing
the Indena formulation to unformulated quercetin, it proved tobe up to 20-fold more bioavailable and able to be used at lower
dosages, preserving its proﬁle of natural ingredient.12
Twelve healthy volunteers of both sexes, aged 18-50 years, wereadministered orally with a dose of quercetin (500 mg) and two
different doses of Quercefit® (250 and 500 mg). Pharmacokinetic
samples were collected at twelve time intervals (0h to 24h) afteradministration, and quercetin levels in plasma were measured by
HPLC/MS/MS.

AUC IMPROVEMENT

200

Mean ng/ml

180
160

Querceﬁt® 500mg

20x

140

Querceﬁt® 250mg

10x1x120

Quercetin 500mg

100
80
60
40
20
00200

400

600

800

Time (min)

1000

1200

1400

Riva, A., Ronchi, M.,
Petrangolini, G. et al. «Improved
Oral Absorption of Quercetin fromQuercetin Phytosome®,a New Delivery System Basedon Food Grade Lecithin”.
Eur J Drug Metab Pharmacokinet(2018). https://doi.org/10.1007/
s13318-018-0517-3

11

Sports performance/recovery

Quercefit® demonstrated a significant oral absorption of quercetin,both in terms of AUC, Tmax and with a maximum concentration of
223.10 ± 16.32 ng/ml at the highest dose, significantly improved
compared to unformulated quercetin(10.93 ± 2.22 ng/ml , p <0.0001) and the lowest dose
(126.35 ± 14.79 ng/ml, p <0.005), thus also suggestinga dose-related absorption profile.
Most importantly, Quercefit® allows to reach optimized quercetin
plasma levels in line with a diet rich in vegetables and fruits (suchas onions and apples).

Riva A. et al. Quercetin
Phytosome® in triathlon athletes: apilot registry study Minerva
Medica 2018 August;109(4):285-9.
13

http://www.salute.gov.it/portale/
salute/p1_5.jsp?lingua=italiano&id=158&area=Malattie_del_sistema_immunitario
14

Furthermore, the effectiveness of 250 mg (twice a day) of theingredient emerged in a controlled human study on amateur
healthy athletes practicing triathlon according to "Sprint"
format (100 minutes for swimming 750 m + cycling 20 km+ running 5 km).13Quercefit® has statistically maintained (P <0.05) the physicalresistance, measured as time to complete the race,
the performance and optimized recovery, minimizing stresses
such as muscle discomfort and post-training cramps.
The oxidative stress measured was also statistically lower(p <0.05 compared to the control group).
No undesirable effects were observed, showing excellent
tolerability to repeated supplementation.
This study suggests that oral supplementation with Quercefit® canoptimize sports performance and physical recovery.

This study suggests that oralsupplementation with Quercefit™
can optimize sports performanceand physical recovery.

Did you know?
know
Allergy is the most common immune disease, characterized by an inflammatory reaction
towards harmless agents which are present in the external environment: components ofinspired air (pollen, mold, dust of the domestic or working environment), components offood or drugs, poison of stinging insects. These substances are called "allergens" due totheir common characteristic of inducing allergies.
Allergic inflammatory pathologies have an important impact on people’s quality of life andrelevant health costs: recent epidemiological studies conducted in Italy indicate that 25%of the population aged between 18 and 44 suffer from allergic rhinitis and 5% suffer fromasthma.14
12

The spread of allergic diseases is increasingin Europe and, also due to climate change,
is no longer limited to specific seasons orenvironments.
Respiratory allergies are the most common form of allergies in Europe and the world.
Respiratory allergies are mainly characterized by lacrimation, sneezing, sometimes
coughing and asthma: symptoms that affect breath functionality, which can be objectively
measured testing the PEF – Peak Expiratory Flow, the maximal rate that a person canexhale during a short maximal expiratory effort after a full inspiration.
Science makes different remedies available to manage symptoms of allergies and solve
allergic discomforts, from drugs to nutritional supplements.

60%

Allergic rhinitis affects 60%of the European population.
From 15% to 20% of these patients 15-20%
suffer from a severe form of the disease.

It is estimated that allergic asthma affects

5-12% 5%-12% of the European population.15

Global Asthma Newtork Centres

EOI Centres

Registered Centres

March 201615

http://www.salute.gov.it/portale/salute/p1_5.jsp

13

Allergic discomforts

The optimized bioavailability of quercetin formulated with Indena’s Phytosome®
delivery system has recently allowed Quercefit® to achieve very interesting
results also for the maintenance of well-being by sensitive or intolerant
subjects, as demonstrated by two human studies.16,17

17

Manuscript submitted

Riva A, Corti A, Belcaro G,Cesarone MR, Dugall M, Vinciguerra G, Feragalli B, ZuccariniM, Eggenhoffner R, Giacomelli L.
(2019) Interaction study between
antiplatelet agents, anticoagulants, diabetic therapy and a novel
delivery form of quercetin. Minerva
Cardioangiol. 67(1):79-83.
18

A recent human study on supplementary management of discomforts
during allergy seasons, evaluated the benefits of Quercefit® in synergy withthe standard management (SM) in otherwise healthy subjects experiencing
discomforts during allergy seasons and taking only the standard management(SM).16After 30 days of supplementation, using either 1 or 2 tabs/day of Quercefit®,thesubjects wellbeing and their seasonal discomforts were evaluated according
to the GINA (Global INitiative for Asthma) classification system also considering
the need of additional support.
In such subjects Quercefit® demonstrated a reduction of day (up to 50%)
and night (up to 70%) intermittent discomfort frequency, and a significant
improvement of the breath function (Peak Expiratory Flow) in mild persistent
discomforts.
The supplementary use of Quercefit® synergistically improved the use of thebest available remedy, while optimizing additional discomfort conditions andkeeping a low oxidative stress with a very good safety profile.
In a second human study focussing on local skin discomforts, Quercefit® hasbeen administrated for just 3 days, followed by a histamin local skin stimulus.
Compared to the control, only the healthy volounteers administered withQuercefit® shown a statistically significant dose-dependent control of all main
local conditions and a skin conditions amelioration with capillary filtration
reduction.17

These recent human studies show apotential beneficial effect of Quercefit®
in controlling the most common
discomforts linked to allergy era andindividual intolerances.
Lastly, to further confirm the positive safety profile of Quercefit®, a preliminary
human study was conducted in order to investigate any interaction of thiscomplementary and natural approach with common standard synthetic drugs,
preventing any possible harmful effect.18
The preliminary results suggest that Quercefit® might not alter the activityof the most common antiplatelet agents (acetylsalicylic acid, ticlopidine orclopidogrel, after 10 days of supplementation), has no impact in stable patientstreated with warfarin or dabigatran after 20 days of supplementation and might
not influence the metabolic control of diabetic patients taking metformin. 19
1416Cesarone, M. R., et al. Minerva
medica (2019)19Riva A et al, Interaction study
between antiplatelet agents,anticoagulants, diabetic therapy
and a novel delivery form ofquercetin. Minerva Cardioangiol.
2018 Sep 13. doi: 10.23736/S00264725.18.04795-3.

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DPR0301 - 01/2020*08/2020, trademarks of Indena S.p.A. © 2020, Indena S.p.A.

® TM