PROPOLIS M.E.D.

® AND BEEKEEPING DERIVATIVES

PURPOSE & MISSION

Leveraging 40 years of experience with bee products, B Natural is an Italian

company expert in the scientific valorization of brown propolis, through a patented
method of extraction of polyphenols developed to obtain a standardized extract of
propolis.

B Natural takes inspiration from the outstanding work of bees in transforming a

natural substance into a scientifically-supported solution. Today, B Natural
produces high-quality propolis extracts and other beehive derivatives, entering the
formulation of the leading propolis-based healthcare products, worldwide.
COMPANY PROFILE
First European propolis manufacturer
Leader in promoting scientifically supported bee compounds

FOUNDED 40 years ago SCIENTIFIC & QUALITY FIRST APPROACH

LOCATION Corbetta (Milano), Italy TEAM OF EXPERTS Including 3 PhDs and MSc
INDUSTRY Propolis & Beekeeping derivatives for NETWORK 6 scientific collaborations
pharmaceutical & nutraceutical industries INVESTMENTS 10% of annual turnover
ACTIVITY Scientifically supported ingredients PUBLICATIONS 20 in vivo and clinical studies
CSR Cross-services published

1980 1980 to 2000 2010 to 2020 2020 2021 - 2022

Dr Luciano Imbriani had B Natural became market Change in First human clinical Acquisition by ABFI under Fytexia
the intuition about the leader for propolis and governance and new trial published. Group, with the aim to build the
potential use of Propolis beekeeping derivatives in branding. European leader in polyphenols..
and developed a method Italy. Access to new international
to make it soluble in markets and acceleration of the
water. R&D pipeline.
TECHNOLOGY-DRIVEN ACTIVITY

MANUFACTURING ACTIVITY
300 MT PRODUCTION CAPACITY
3 DEDICATED PRODUCTION LINES

EXTRACTION LINE LIQUID LINE SPRAY DRYING LINE

Processing Processing Capacity to dry up to

capabilities up to capabilities from 300 kg/day of
200 kg/day of raw 500 to 1000 propolis mother
Propolis with an liters/day extract
evaporative capacity
of solvent up to 100
liters/hour

CERTIFICATIONS
HACCP / ISO 9001-2015 / GMP / ORGANIC / KOSHER / HALAL (upon request)
 BEEHIVE PRODUCTS PROPOLIS
THE HIVE “IMMUNE SYSTEM”
From the nectar of flowers A natural product used for hive defense
Honey

The word propolis is derived from Greek, in which

pro stands for “at the entrance to” and polis for
From the pollen of flowers “city”, alluding to the barrier function of the hive.
Bee pollen
Propolis is a building material used to:
▪ adapt the barrier function at the entrance of
the hive according to climatic conditions
▪ seal gaps, repair cracks and protects from rays
▪ embalm external invaders
Secreted by the bees
Propolis is a protective support, acting as:
Royal jelly ▪ a cleansing tool at the threshold of the hive.
▪ an antiseptic and a bacteriostatic to prevent
microbial infections of larvae, honey stores,
Secreted by the bees and the combs and fight against the
Beeswax development of mold or other pathogens in
the hive.

From the buds & exudates of plants

Propolis
PROPOLIS A COMPLEX COMPOSITION

Propolis
A bee-derived compound made from plants From bees, hive and plants
Worker bees :
Secreted by the bees
- harvest from buds and exudates of Beeswax
Impurities
specific plants a resinous, balsamic
Other
substance (organic
Wax and mineral
- add waxy and salivary secretions 30 – 40 % substances)

Raw Propolis
Propolis produced by Apis mellifera, after the Pollen
5%
removal from the hive by beekeepers without Resins and balsams
any other intervention Essential oils 50-55%
6-8%

POLYPHENOLS

Plant part used

buds & exudates of plants harvested by the bees
PROPOLIS CHALLENGE
A COMPLEX … AND A HIGH
COMPOSITION… VARIABILITY
Raw propolis, which is barely soluble in water, cannot be The bioactive composition of propolis is also highly
used as a raw material and it must be purified by extraction variable depending on geographical area, climatic
with solvents to : conditions, plants present, seasonality.
▪ remove the inert material (wax, impurities)
▪ extract the entire polyphenolic fraction from resin

In food supplements propolis is added in the form of extracts.

More than 300 polyphenols have been identified in propolis.

Major components with health properties: flavonoids & phenolic acids such as
caffeic, coumaric, ferulic acids, or caffeic acid phenethyl ester (CAPE).

REACHING A STABLE BIOACTIVE FINGERPRINT IS A CHALLENGE

B NATURAL developed the patented Multi Dynamic Extraction M.E.D.® process to:

1. EXTRACT WIDE POLYPHENOLIC

SPECTRUM
from the most hydrophilic to the most
2. OBTAIN A REPRODUCIBLE
FINGERPRINT OF POLYPHENOLIC
MARKERS
hydrophobic polyphenols
Propolis M.E.D.®
Patented process
 PROPOLIS M.E.D.® – PATENTED PROCESS

M.E.D.®
Multi Dynamic Extraction

WATER
PROPOLIS M.E.D.® MOTHER EXTRACT

RAW QA DEPURATION Propolis M.E.D.® GALANGIN

PROPOLIS INSPECTION ALCOHOL EXTRACTS QUERCETIN
PINOCEMBRIN
Six major polyphenols
identified PINOBANSKIN
PHENOLIC ACIDS FLAVONOIDS
APIGENIN
≥ 25% of the total CHRYSIN
polyphenols content in
HPLC-ESI-MS
Reference of the patent: N 0001425516 (Italy)

COMPLETE POLYPHENOL EXTRACTION

▪ Propolis M.E.D.® preserves intact, complete, the polyphenolic complex naturally present in raw propolis
▪ Propolis M.E.D.® contains an identified and characterized polyphenolic complex, a stable bioactive fingerprint
 GRADES & APPLICATIONS

ESIT® GREIT® EPE® POLE®

Powder microencapsulated Hydroglyceric extract Hydroalcoholic extract Oily extract
in Arabic gum

GRADE ESIT 12 GREIT 120 EPE 38 80 GA POLE G

>12% total polyphenols expressed 12mg/ml total polyphenols 38mg/ml total polyphenols 30 mg/ml total polyphenols
as Galangin HPLC-ESI-MS expressed as Galangin in sunflower oil
UV Folin Ciocalteu - HPLC-ESI-MS UV Folin Ciocalteu - HPLC-ESI-MS
CLINICALLY TESTED 100-200 mg 1-2 mL 0,31-0,62 mL 0,4-1,5 mL
DOSAGE EQUIVALENT

DELIVERY SYSTEM Tablets Sprays Tinctures Soft gels

Capsules Mouthwashes
Toothpastes

Samples obtained from propolis M.E.D. mother extract show similar HPLC- UV profile when formulated with different carriers.
▪ Complete characterization
▪ Guaranteed activity
▪ Suitable with any manufacturing process
QUALITY INSIDE

SUSTAINABILITY
B Natural guarantees the use of raw materials coming from strictly controlled origins,
enforcing quality controls all the process.

Each beekeeper who provides B Natural with its products signs a Technical Agreement listing
mandatory characteristics:

• Not an irradiated product,

• GMO-free,
• Not treated with pesticides or antibiotics,
• Products produced by bees living in unpolluted environments and not subjected to
genetic manipulation.

Protection of nature and sustainable beekeeping are the foundation of these specifications.

Quality seal “B Natural Quality Inside”

available under license
Clinically proven propolis extract
 PROMUNEL®
FROM A TRADITIONAL MATERIAL TO A CUTTING-EDGE INGREDIENT

PHENOLIC COMPOUNDS MECHANISM OF ACTION CLINICAL BENEFITS

CHARACTERIZATION
• Full polyphenolic spectrum • Direct virucidal effect • Improvement of URTIs
from raw propolis • Gut-microbiota modulation symptoms
• Standardization in 6 phenolic and SCFAs homeostasis • Decrease recovery time
compounds • Nrf2 modulation, the master
regulator of immune stress
during innate response

SUPPORTING STUDIES - Publications

Esposito et. Al. Phytomedicine, 2021 Galeotti et. Al. J. Med. Plants Res. 2019
Galeotti et. Al. Foods, 2018 Curti et. Al. Int. J. Mol. Sci. 2019
Zaccaria et. Al. Nutrients, 2017
Zaccaria et. Al. Materials, 2019
PROMUNEL® CHARACTERIZATION

Phenolic compounds Pic number

Galangins 12, 16

Quercetins 4,5,11,13

Pinocembrins 15

Pinobanksins 6,17,20,21

D Apigenin 7

Chrysin 14

D
Promunel® contains an intact, complete,
identified and characterized polyphenolic
complex, standardized with the six major
immunomodulator polyphenols
UPPER RESPIRATORY TRACT INFECTIONS (URTIs)
KEY FIGURES
7-10 DAYS Risks of complications are increased
Worldwide > 17 billion occurrence/y1
Average duration in elders & children < 5 y

US > 40 million work- and US - Societal cost Adults: 2-5 URTIs/year Obese4, allergic5, athletes6, asthmatic5,
school-day missed/y 2 > 22 billion USD/y 2 Young children: 6-8 URTIs/year3 smokers7 are more prone to contract URTIs.

90% of URTIs are caused by viral pathogens, rhinovirus and Propolis has been commonly used worldwide.
coronavirus being the most common

Symptoms include cough, sore throat, runny nose, nasal congestion,

headache, low-grade fever, facial pressure, sneezing, malaise and
myalgias2.

Treatment for URTIs aimed at relieve symptoms with anti-

inflammatory drugs or antibiotics.

1 Global Burden of Disease Study, 2019 5 Rantala et al., 2013

2 Thomas & Bomar, 2021 6 Spence et al., 2007
3 Murgia et al., 2020 7 Charlson et al., 2010
4 Maccioni et al., 2018
LOCAL AND SYSTEMIC ACTION

DIRECT VIRUCIDAL ACTIVITY

APIGENIN CHRYSIN PINOBANSKINS PINOCEMBRINS GALANGINS QUERCETINS

Small intestine Liver

Hydrolysis, Conjugation

Large intestine
Blood, Lungs IMMUNE STRESS
Other organs HOMEOSTASIS
Bacterial enzymatic reactions

SCFAs have immunomodulatory roles (1)

Short chain fatty acids SCFAs have shown to inhibit HDACs which upregulates B10 cell
SCFAs SCFAs
SCFAs differentiation and functions (2). Potential regulations of T
cells, innate lymphoid cells (3) by SCFAs present a therapeutic
opportunity to regulate immunity by increasing production of
SCFAs.
IMMUNOMODULATION

1: https://doi.org/10.1038/s41423-020-00625-0
Innate Lymphoid cells T cells Dendritic cells B cells 2:https://doi.org/10.1038/s41419-021-03880-9
3: https://doi.org/10.1038/s41423-020-00625-0
IN VITRO STUDY PROMUNEL® INACTIVATES URTIS-LINKED VIRAL PATHOGEN
Virucidal activity of Promunel®

% inactivation HCoV-OC43 % inactivation HCoV-229E

Posology from human clinical
investigation on URTIs: 100 100

250 mg to 500 mg of 90 90
Promunel® ESIT 12, 80 80 500 mg/cm2
3 times a day 70 70
50 mg/cm2
60 60
50 50 5 mg/cm2
40 40
0.5 mg/cm2
30 30
20 20
10 10
0 0
5 min 15 min 30 min 5 min 15 min 30 min

PUBLICATION PENDING STUDY

Study conducted in the Dipartimento Dose/time response virucidal activity of Promunel®
di Medicina Molecolare
D. M. M., University of Sapienza - Prof. Phenolic compounds in Promunel® demonstrate a direct virucidal activity in vitro with physiological
Guido Antonelli doses in a short kinetic on enveloped virus models involved in the etiology of URTIs.
EX VIVO STUDY PROMUNEL® IMPROVES GUT DYSBIOSIS AND RESTORES
Human gut microbiota
biofermentation of Promunel® SCFAS HOMEOSTASIS
Increase in butyrate producers
Bifidobacterium Dorea Faecalibacterium
PRIMARY OUTCOME:
Composition and functionality Healthy adult Healthy children Celiac children
of gut microbiota Healthy children Obese children
Allergic children
Obese children
0 1 2 3 4
Celiac children
INPUT 0 1 2 3 4
Allergic children
• Healthy adult
• Children (5-10 years old) 0 2 4 6
• Healthy children
• Obese children
• Celiac children Butyrate concentration (mM) SCFAs concentration (mM)
• Allergenic children 120 1500
100
80 1000
MEASURES 60
• 16S rRNA sequencing 40 500
20
• HPLC 0 0
Healthy Healthy Allergic Obese Celiac Healthy Healthy Allergic Obese Celiac
adults children children children children adults children children children children

Blank Promunel Blank Promunel

PUBLISHED STUDY
Garzarella et al. , 2022, Biomedecine &
Bifidobacterium, butyrate producer, increased in all the tested groups.
Pharmacotherapy Consequently, butyrate and total SCFAs increased in all the tested groups
Evaluating the effects of a standardized
polyphenol mixture extracted from Clinical studies administering Bifidobacterium containing probiotics has shown protective
poplar-type propolis on healthy and diseased effects in alleviating the severity of URT viral infections1,2,3
human gut microbiota
EX VIVO STUDY EPIGENETIC REGULATION
Human keratinocytes cell line
Most abundant cells in oral cavity

miRNA level miR-27a-3p miR-19a-3p miR-203a-3p

1 ** ** 0.8 2
*** Propolis phenolic
0.6 ** **
**
1.5 *** *** compounds modulate
0.5 0.4 1 immune stress-linked
0.2 0.5 miRNAs functionality.
0 0 0
0 0.78 1.56 3.125 0 0.78 1.56 3.125 0 0.78 1.56 3.125

mRNA level Nrf2 mRNA TNF-a mRNA

3.6 0 0.78 1.56 3.125 miRNAs targets immune stress-linked mRNAs to
3.4 0
degrade or prevent their translation.
3.2 -1
3 ** **
-2
2.8
2.6 -3
0 0.78 1.56 3.125 -4 *** *** ***

Protein level Nrf2 (ng/mL) TNF-a (pg/mL) Consequently, immune stress-linked protein
0.2 1 level is decreased
0.15
Polyphenol complex in Promunel® helps regulate
0.1 0.5
** ** * the anti inflammatory and antioxidant
0.05 * *
** homeostasis to bring together the optimal
0 0 conditions for the proper functioning of the
0 0.78 1.56 3.125 0 0.78 1.56 3.125
immune system.
CLINICAL TRIAL
Randomized, double-blind,
placebo-controlled study LOCATION
Benevento, Italy
Samnium Medical Cooperative

YEAR & DURATION

2020
5 days of supplementation & follow-up
T0 = baseline; T1=after 3 days; T2=after 5 days
Follow-up: T3=15 days after the end of supplementation
POPULATIONS
122 subjects
Age: 18-77 years old
Inclusion with mild URTI symptoms from viral or bacterial origin
PROTOCOLS
Clinical evaluation by medical doctor for URTI symptoms
PUBLISHED CLINICAL STUDY Throat swabs for bacterial collection
Esposito et al. , 2020, Phytomedicine Questionnaires
A standardized polyphenol mixture
extracted from poplar-type propolis for
remission of symptoms of
INTAKES
uncomplicated upper respiratory tract Propolis oral spray
infection (URTI): A monocentric, 2-4 sprays three times/day over 5 days
randomized, double-blind, placebo-
Equivalent to 12-24 mg of standardized polyphenols per day
controlled
clinical trial
CLINICAL TRIAL
% of subjects positive to symptom (T0-T1)

PRIMARY OUTCOME: Sore throat Hoarseness

Muffled dysphonia Swelling and redness
Remission of the symptoms
n=102 n=17
associated with URTIs 80 80 100 n=40
68% 71% 83%
60 60 80

MEASURES: 40 40
60

At baseline (T0) ***

16%
40 ***
20 20 * 18%
At T1=3 days of supplementation 10% 20 *p<0.05
At T2=5 days of supplementation 0 0 0 ***p<0.001
Placebo Promunel®
Propolis M.E.D Polacebo
Placebo Promunel®
Propolis M.E.D Placebo Promunel®
Propolis M.E.D

No adverse effect reported.

At least one symptom
n=122
After 3 days of treatment, 83% of the subjects treated with
Day 3 80
72% Propolis M.E.D.® in oral spray had remission of symptoms,
Placebo
60 against 28% in the placebo group.
N= 64 40
***
17% After 5 days, all the subjects had remissions of symptoms.
20
Resolution from mild uncomplicated URTIs took place 2
0 days earlier in the treated group.
Promunel Placebo Promunel®
Propolis M.E.D
N= 58

Recovered
Not recovered
KEY OUTCOMES APPLICATIONS

COMMERCIAL NAME
Characterized propolis extract
Promunel®

Consistent polyphenol fingerprint COMPOSITION

Propolis M.E.D.® extract
Guaranteed biological activity
ACTIVE COMPOUNDS
Proven biological activity Polyphenol complex standardized; main markers:
Galangin, Apigenin, Quercetin, Pinobanksin, Crysin,
Clinically studied: reduction of the symptoms of Pinocembrin.

URTIs
RECOMMENDED DOSAGE
Publications of studies available 12 to 24 mg polyphenol complex / day

APPLICATIONS
Tablet, capsule, sachet, soft gel, ovule, lozenge, spray,
syrup, mouthwash, toothpaste
OTHERS
No allergen, non-GMO, halal, kosher, gluten-free,
suitable for vegetarians
Available as organic
HEALTH BENEFITS

RESPIRATORY GASTROINTESTINAL ORAL INTIMATE COSMETIC

HEALTH HEALTH CARE CARE APPLICATIONS