Formulated under dermatological control

and tested by paediatrician

The expert on baby’s skin From birth

Mustela®. The skincare expert for babies and mothers-to-be for over 60 years.

Major new discoveries on infant skin from the first days of life

P u b l i s h e d i n

the Journal of

D e r m a t o l o g y

S C I E N T I F I C D O S S I E R

Dear Colleagues,

Researchers at the Innovation, Research and Development (IRD) Division of Laboratoires

Expanscience, the baby skin experts for more than three generations, are proud to present you the

EV.E.I.L.S (EValution of Early Infant Life: Skin) research programme.

After reviewing the current state of children’s skincare, Laboratoires Expanscience decided to

deepen their understanding of the physiology of newborn skin, from the very first days of life. For

this purpose, the Innovation, Research and Development Division has brought together researchers

of international recognition.

This research programme, ongoing for the past ten years and the only one of its kind in the world, is

centered on innovative and non-invasive technologies. It has resulted in major discoveries about the

skin barrier and skin hydration as well as epidermal stem cells in infants from the earliest moments

of life.

Acting upon these new findings and in an endeavour to provide baby's skin with what it requires

specifically to protect it and promote its development, the R&D centre has developed an exclusive,

natural and biomimetic active ingredient, derived from the avocado: Avocado Perseose®.

Avocado Perseose® has proven its activity in vitro from the surface of the skin right down to the

epidermal stem cells. It strengthens the skin barrier, helps maintain the level of epidermal hydration

and preserves the irreplaceable lifetime supply of epidermal stem cells.

Mustela® is now able to offer a new generation of clinically-tested skincare products, which act in

perfect harmony with a baby's skin, providing both maximum tolerance and targeted efficacy.

Best regards

Philippe Msika Director of Innovation

Research and Developmentat Laboratoires Expanscience

C O N T E N T S

Introduction to the skin page 6

Published knowledge about baby’s skin page 11

EV.E.I.L.S (Evaluation of the Early Infant life: the Skin): an internationally unprecedented fundamental research programme page 15

A. Innovative and ethical new investigative technologies a. Scanning Electron Microscopy b. Raman spectroscopy c. In vitro epidermal skin models and genomic analysis

B. Three major discoveries about the skin of infants from birth to 2 years a. On the organisation of the Stratum corneum b. On the distribution of moisturising factors in the Stratum granulosum c. On the stem cells of the Stratum germinativum

A new generation active ingredient: Avocado Perseose® page 29

A. Its actions extend from the Stratum corneum through to the Stratum germinativum B. Unique, patented extraction processes C. An ethical and responsible supply chain

The formulation: a new technological challenge page 41

A. To incorporate Avocado Perseose® in all formulas B. To maximise the safety, innocuity and tolerance of the products C. To ensure a high sensory quality D. To be consistent with a strategy of environmental responsibility

Conclusion page 47

References page 50

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The skin is a vital organ that covers and protects the body.Its principal functions include protection against environmental aggression (chemical, mechanical, thermal, microbial infections and UV radiation) and control of water loss.This protective "barrier function" is provided by the epidermis and more particularly by the cornified layer known as the Stratum corneum.

Introduction to the skin

76

The epidermis is a stratified epithelium, composed of 4 main layers:

• Stratum corneum: the most superficial layer arranged in a “brick-and-mortar” structure. Composed of corneocytes without

nuclei (representing the bricks) and lipids (forming the mortar), the Stratum corneum fulfills principally the barrier function.

• Stratum granulosum

and

• Stratum spinosum: in these two layers, the keratinocytes produce lamellar granules and keratohyalin granules, necessary

for producing lipid cement and for skin hydration, respectively. The lamellar granules provide, among other functions, the constituents of the lipid cement of the Stratum

corneum. The keratohyalin granules give rise to NMF (Natural Moisturising Factors).

• Stratum germinativum: this is the deepest layer of the epidermis, composed of a single layer of proliferating keratinocytes and

basal stem cells responsible for the integrity of the epidermis throughout and individual's lifetime.

98

FOCUS ON THE STRATUM CORNEUM WHICH FULFILS THE BARRIER FUNCTION

Representative schema of the Stratum corneum

It is organised according to a model conventionally called "brick and mortar" and composed of:

• Corneocytes, anucleate cells of which the cornified envelope is a structure formed by a protein envelope and a lipid envelope.

• Lipid cement, equimolar mixture of ceramides (40 to 50% of total weight), cholesterol (20-25%) and free fatty acids (10-20%), playing a role in holding cells together. It has now been clearly established that the structure of the corneocytes and the organisation of the lipid bilayer constitute a dynamic barrier more complex than a simple brick wall.

• Corneodesmosomes which also play a primordial role in the cohesion of the Stratum corneum. The corneodes-mosomes are intercellular junctions, specific to the Stratum corneum, the role of which is to link corneocytes to one another.

Corneodesmosomes are composed mainly of proteins, such as desmoglein-1, desmocollin-1 and corneodesmosin.

FOCUS ON THE STRATUM GRANULOSUM AND STRATUM SPINOSUM WHICH PLAY AN ESSENTIAL ROLE IN HYDRATION

The keratinocytes of this layer contain keratohyalin and lamellar granules.

Lamellar granules are rich in lipids and contribute to the production of the intercellular cement.

The keratohyalin granules are hydrolysed into filaggrin, which participates in the consolidation of the network of keratin formation, a component of corneocytes.

The filaggrin is proteolysed into free polar amino acids, making up the natural moisturising factors (or NMF), some of which are water-trapping molecules.

The NMF (Natural Moisturising Factors) thus play a fundamental role in skin hydration.

Corneocytes

CorneodesmosomesLipid matrix (ceramides)

Cornified envelope (involucrin, transglutaminase) NMF

98

FOCUS ON THE STRATUM GERMINATIVUM, STOREHOUSE OF EPIDERMAL STEM CELLS

The different layers of the epidermis

The Stratum germinativum is the deepest layer of the epidermis: this is where the epidermal cells are created.

So-called adult stem cells are undifferentiated yet specialised cells which may be defined by

two main and distinct properties: • their ability to renew themselves and remain in place for long periods of time, • their ability to generate different types of cells.

The skin, an organ subject to rapid and continuous renewal, belongs to the group of tissues containing a significant number of stem cells. Accordingly, each compartment of the skin has stem cells that can develop into melanocytes, adipocytes, nerve cells, endothelial cells, mesenchymal cells or epidermal cells.

Epidermal stem cells are found in the region of the hair follicle bulb (follicle stem cells), in sebaceous glands (sebaceous stem cells) and in the Stratum germinativum (interfollicular epidermal stem cells or basal stem cells).

The basal stem cells (or epidermal stem cells) constitute the main supply of epidermal stem cells and ensure keratinocyte renewal.

Thus, they contribute to maintaining the skin’s homeostasis as well as to the repair and regeneration of the epidermis, thereby ensuring its integrity throughout life.

Granular layer(Stratum granulosum)

Spinous layer(Stratum spinosum)

Basal layer(Stratum basale)

Basal stem cell

Transit amplifying cell

Cornified layer(Stratum corneum)

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Published knowledge about baby's skin

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1312

Current knowledge indicates a difference in skin functions between babies and adults.

Birth and the early months of life are decisive for adaptation from intra-uterine life to a gaseous and relatively dry environment. The events responsible for these adjustments are characterised by changes in physiological functions demonstrated by certain biophysical parameters.

1) The pH on the surface of the skin The pH of the cornified layer plays an essential role in the equilibrium of the skin barrier, through its action on the formation of the Stratum corneum and on the constitution of the antimicrobial barrier. The elevated (alkaline) pH levels present at birth, drop to values found in adults between the first and fourth weeks after birth.

2) Barrier function expressed as IWL (insensible water loss) In full-term new-borns, a slight increase in insensible water loss (measured in g/m²/h) is observed during the first hours after birth. IWL values then stabilise quickly, to levels comparable with those observed in adults.

3) Hydration of the Stratum corneumSkin hydration is one of the key factors in skin resistance against mechanical aggressions. Minimal at birth, hydration of the Stratum corneum increases during the first six months of life. It then stabilises at a level comparable to that of an adult.

4) Sebum secretion At birth, the sebaceous glands are present but functionally immature. It has been shown that sebum secretion increases after birth to attain a level observed in adults during the first months of postnatal life. At six months of age, the values are lower than in adults and remain identical until puberty.

5) Sweat gland secretion Sweat gland secretion (sweating or perspiration) triggered by emotions or temperature is present in full-term new-borns. Birth accelerates the development of sweat gland secretion in response to temperature rather than to emotions.This represents a major distinction between new-borns and older children.

Published knowledge about baby's skin

1

1312

6) Skin vascularisation Immediately after birth, skin microvascularisation consists in a dense horizontal plexus with a disorganised capil-lary network.A looped capillary network can be observed within all skin sites only at the age of 14-17 weeks.

VARIABLESFunctional parameters Gestational age Postnatal age Sex Anatomical

siteAmbient

temperatureAmbient humidity

IWL + + 0 + + +

SC hydration + + 0 + + +

Surface pH 0 + +/- + ? ?

Sebum secretion ? + 0 + ? ?

Sweat gland secretion (perspiration)

+ + ? + + +

Skin vascularisation +/- + ? + + ?

Variables influencing functional parameters of the skin

« + » : influence present - « 0 » : no influence - « ? » : no data - « +/- » : conflicting data IWL : insensible water loss SC - SC : Stratum corneum

The literature tells us that, at birth, the skin’s development is incomplete, which makes it highly vulnerable to aggression.However, there are no published data about the evolution of the epidermis between birth and 2 years with regard to: • the organisation of the Stratum corneum • the analysis of the biochemical composition of the Stratum corneum and the Stratum granulosum • changes in gene markers, in particular those of the Stratum germinativumThere thus remain many unanswered questions, especially about how the maturation of the epidermis is organised between birth and 2 years, from the Stratum corneum to the epidermal stem cells. This is why Laboratoires Expanscience decided to conduct a programme of fundamental research, which began in 2003 and for which the initial findings are presented in the following chapters.

T O S U M U P

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The EV.E.I.L.S research programmeEValuation of the Early Infant Life: the Skin

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The EV.E.I.L.S research programme (Evaluation of the Early Infant Life: the Skin) is a series of studies, unprecedented in the world, conducted over the past ten years with the support of international researchers,J. FLUHR, assistant professor, Department of Dermato-surgery, Berlin,J.P. HACHEM, professor of dermatology, University of Brussels.

The aim of this research programme is to gain a better understanding of and analyse the maturation of healthy infant skin from birth and over the course of the first years of life. Using innovative and non-invasive technology, the IRD centre of Laboratoires Expanscience has carried out unprecedented fundamental research on the physiology of baby’s skin from the surface down to the stem cell layer of the epidermis, starting in the earliest days of life.

In vivo study conducted in 66 subjects, divided into 6 age groups.

In vivo study conducted in 30 subjects, divided into 5 age groups.

In vivo study conducted in 108 subjects, divided into 6 age groups.

In vivo study, reconstructed epidermis of babies models.1 month, 4 months, 6 months, 1 year, 2 years, 3 years, 7 years, 12 years, Adult

e

d

c

ba

From the surface of the skin

to the epidermal stem cells

SCANNING ELECTRON MICROSCOPYViewing of the cutaneous barrier from skin cell samples (D-Squame®)

RAMAN SPECTROSCOPYEvaluation of the dynamic change in skin hydration

EPIDERMAL SKIN MODELS AND GENOMIC ANALYSISGenomic study using real-time quantitative PCR of reconstructed epidermis of babies models

The initial results, which at the time of writing have been the subject of 9 patent applications and 18 international publications - including the British Journal of Dermatology -, are presented to you in this scientific dossier.

PROTOCOLS AND TECHNOLOGIES OF THE EV.E.I.L.S STUDY

The EV.E.I.L.S research programmeEValuation of the Early Infant Life: the Skin

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A. Innovative and ethical new investigative technologies

3 unprecedented studies have been conducted using technologies that are innovative and non-invasive.

a. Scanning Electron Microscopy

Scanning Electron Microscopy is an electron microscope technique capable of producing high resolution images of the surface of a skin sample.

The technique involves a beam of electrons that sweeps over the surface of the skin which, in response, emits certain particles. These particles are analysed by different detectors, thereby enabling the reconstruction of a three-dimensional image.

Scientists at Laboratoires Expanscience have analysed, for the first time in the world, skin cell samples taken from new-borns using non-invasive D-Squame® sampling discs.

These samples were collected from the forearm then observed with Scanning Electron Microscopy, enabling changes in the cornified layer to be visualised, at the cellular level.

This in vivo study, divided into 2 phases has enabled researchers to observe and analyse the organisation of the skin barrier.

A first "preliminary" phase was conducted in 66 subjects, divided into 6 age groups: • full-term new-borns (1-15 days) • 5 weeks (+/- 1 week) • 6 months (+/- 1 month) • 1-2 years • 4-5 years • adult (20-35 years)

A second "validation" phase was conducted in 30 subjects, divided into 5 age groups: • 5 weeks (+/- 1 week) • 6 months (+/- 1 month) • 1-2 years • 4-5 years • adult (20-35 years)

This innovative approach has enabled the development of the first skin barrier maturity score.

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b. Raman spectroscopy

This technology, uses a probe placed on the skin, and the emission of a laser beam, to measure the distribution of water in the different layers of the epidermis and the identification and quantification of NMF (Natural Moisturising Factors). (Max. depth: 50µm - measurement pitch: 5µm)

Due to the use of this non-invasive technology, scientists at Laboratoires Expanscience have been able to measure the distribution of water and Natural Moisturising Factors in the various layers of the Stratum corneum in the skin of babies from the first days of life.

This study was conducted in vivo in 108 subjects, divided into 6 age groups: • full-term new-borns (1-15 days) • 5 weeks (+/- 1 week) • 6 months (+/- 1 month) • 1-2 years • 4-5 years • adult (20-35 years)

Conventional measurements such as insensible water loss (indicating the permeability of the skin barrier), skin capacitance (measure of hydration of the superficial layers of the epidermis) and the pH of the surface of the skin were also carried out.

This study has allowed an evaluation of the dynamic changes in hydration not only on the surface of the skin but also in the deeper layers of the Stratum corneum.The results have been published in the British Journal of Dermatology.

1918

The scientists at Laboratoires Expans-cience have, for the first time in the world, used keratinocytes

to create models and analyse the epidermis of babies of varying ages and obtained specific models for each age group:

• 1 month / 4 month / 6 month / 1 year / 2 years / 3 years / 7 years / 12 years / Adult

To create these epidermal skin models, an innovative approach has been developed. Using samples of skin of different ages, the keratinocytes of the epidermal cells were isolated and put into suspension. It was then possible to reconstruct, using cell engineering techniques, the epidermis of infants and children of different ages. A histo-logical examination then enabled the quality of the reconstructed epidermis to be confirmed.

This study has enabled the analysis of gene expression, from the skin surface to the stem cells, in reconstructed epidermal models from babies of different ages.

To get to the core of the cell and gain a better understanding of the changes it

undergoes, Laboratoires Expanscience decided to analyse thousands of genes.

The expression profiles of marker genes were analysed using real-time quantitative PCR (Polymerase Chain Reaction) assay, which enables the selected genes to be detected easily and precisely quantified.

c. In vitro epidermal skin models and genomic analysis

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B. Three major discoveries about the skin of infants from birth to 2 years

e

d

c

ba

From the surface of the skin

to the epidermal stem cells

Cutaneous barrier organisationDevelopment of a maturity score for the cutaneous barrier (E.M.I. Score)

Subject of research

Quantification of water distribution in epidermis’ depthQuantification of NaturalMoisturising Factors (NMF)

Analysis of the profile of stem cells gene / biomarker expression

Major discoveries

0-2 years: the skin surface is immature at birth and reaches a first stage of maturity from the second year of life

0-2 years: period of vulnerability during which hydration regulation mechanisms are perturbed

0-2 years: Maximum stem cells resources at birth which decrease significantly between 0 and 2 years under the effect of outside aggression

These different studies on the skin of babies of varying ages, starting at birth, from the surface of the epidermis to the stem cells, has enabled us to make 3 major discoveries.

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a. On the organisation of the Stratum corneum

First discovery and determination of the 1st skin barrier maturation score: an immature barrier function that evolves over the course of the first years of life.

• The existence of changes in the organisation of the Stratum corneum with age has been demonstrated through the observation and description of 300 images obtained by Scanning Electron Microscopy, in the course of the "preliminary" study phase.

The images (X 500 magnification) obtained by Scanning Electron Microscopy show that the Stratum corneum:

is heterogeneous (disorganised) in the newborn, then organised networks start to appear around the age of 2 years finally, in adulthood, the organisation is homogeneous.

1-2 years

x 500

4-5 years Adults

Newborns 5-6 weeks 6 months

Skin surface heterogeneous and disorganised in infants during the first months of life: anisotropic organisation

Appearance of organised, non oriented, homogeneous networks: isotropic organisation

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• Due to the analysis of these images, for the first time in the world, researchers at Laboratoires Expanscience have developed a maturity score for the Stratum corneum: the E.M.I (Electron Microscopy Isotropy) score, based on 4 criteria:

Cell density, Cell clustering, Cohesion between cells, The shapes of the cells and ability to distinguish between them.

IMAGES OBTAINED BY SEM(X30 MAGNIFICATION)

IMAGES OBTAINED BY SEM(X500 MAGNIFICATION)

Cell density Cell clusters Cell adhesion/shape Ability to distinguish between cells

0 Cells separated Irregular clusters Asymmetric cellsIrregular shapes Cells not distinguishable

1 Cells grouped/scattered Mixture of regular and irregular clusters

Cells partially symmetricalShapes partially irregular

Cells partially distinguishable

2 Cells evenly scattered Mostly regular clustersCells mostly symmetricalShapes mostly irregular

Cells mostly distinguishable

3 Cells linked Regular clusters

Symmetrical cellsRegular shapesidentical in all geometric directions to an octogon with regular surface

Cells easily distinguishable

Basic criteria of the EMI score

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ISOTROPY SCORE MATURITY

Anisotropy 0-4 Immature

Intermediate isotropy 5-7 Intermediate

Complete isotropy 8-12 Mature

The 3 stages of maturity derived from the EMI score

This study has confirmed that surface of the skin undergoes significant change, and has enabled us to establish the existence of a first stage of maturity from the second year of life.Between birth and 2 years, the skin barrier does not fully accomplish its protective role. It is therefore necessary to support it during its development.

It has been established thereby that the Stratum corneum is: immature in newborns at an intermediate stage after 5-6 weeks in a first stage of maturity from the age of 1-2 years

The EMI score, developed and patented by Laboratoires Expanscience, constitutes an effective tool for analysing the topography of the surface of baby’s skin throughout the years.

Using the EMI score, the IRD centre has defined three stages of maturity of Stratum corneum organisation:

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b. On the distribution of moisturising factors in the Stratum granulosum

Second discovery: skin dehydrated at birth and mechanisms regulating water balance disturbed.

Measurements taken with Raman spectroscopy (NMF + water content) have provided evidence for three phenomena never before demonstrated and which have been reported in an article published in the British Journal of Dermatology.

• In newborns, a dual phenomenon has been discovered:

water content is low, in correlation with low hydration of the surface measured by corneometry.

the NMF concentration is high (contrary to expectations).

This phenomenon may be explained by the "stress" caused at birth by the change from a liquid to a gaseous environment.

This stress in the newborn triggers compensatory mechanisms (release of high levels of NMF), a phenomenon that helps to regulate the pH and water content (too high and too low, respectively) and thereby enable the skin to adapt to its new environment.

• Between 0 and 6 months, an abrupt drop in NMF to regulate pH and hydration is observed

• Between 6 months and 2 years: Gradual return to an NMF level comparable with that of an adult.

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86420

NB(1 to 15 d)

5 weeks

6 months

1-2 years

4-5 years

Adults (20-25 years)

Hydration (corneometry)

Water content (RAMAN)

NMF (RAMAN)

pH (pH meter)

Return to hydration level comparable with adults

Hydration

WaterpH

NMF

2524

Changes in NMF concentration with age.Values calculated from area under the curve of Raman profiles for each age group at depths between 0 and 25 µm (mean +/- SE)

20

15

10

5

01-15 days 5-6 weeks 1-2 years 4-5 years 20-35 years6 +/- 1 months

NMF

Prof

ile (b

ulk)

AUC

(a.u

.)

17.2 12.0 12.211.7

6.4 9.7

Research at Laboratoires Expanscience has revealed for the first time the molecular composition of the skin in relation to its dynamic functional adaptation during the first months of life.We have shown that the mechanisms of water balance regulation are disturbed between birth and 2 years, which corresponds to a period of vulnerability.This is why it is important to moisturise the skin of infants daily, from birth and during the first two years of life.

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c. On the stem cells of the Stratum germinativum

Recent advances in stem cell research are extre-mely relevant to our study.

The latest scientific advances have taught us that these stem cells reside in a specialised microenvironment, called

a "niche", made up of an extracellular matrix, rich in proteins, which helps to maintain the stem phenotype of these cells.

This microenvironment contributes to maintaining the stem cells in good condition, influences cell division and differentiation on one hand and ensures to a certain extent the protection of stem cells against outside aggression on the other.

Basal stem cells contribute to the maintenance of skin homeostasis. Their protection is therefore essential for limiting the harmful effects of outside aggression.

Third discovery: stem cells, an essential and vulnerable supply.

For the first time in the world, we have analysed the expression of stem cells genes in recons-tructed epidermis, from babies of varying ages, both under normal conditions and under aggression.

To help identify stem cells, we chose to ana-lyse the expression of the most commonly cited gene markers in the scientific literature:

• Keratin 19: marker of stem cell proliferation

• Integrin a6, integrin β4, integrin β1: cell receptors implicated in intercellular commu-nication, in the adhesion of cells in the extra-cellular matrix, in the regulation of stem cell proliferation and differentiation

• Notch Homolog 1: gene that regulates the correct functioning of stem cell activity

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100 % 100 %

20% Integrin alpha-6

(green)

20% Integrin beta-1 (pink)

Stress conditions Stress conditions

Stem cells, the skin’s guarantee of survival, called into action for the construction of the epidermis throughout an individual’s lifetime, must be conserved and protected against environmental aggression regardless of age.

This has revealed 2 major discoveries:

• Under normal conditions, the expression of stem cell marker genes are highest at birth, diminishing spontaneously in the first few months of life.

• En conditions normales, l’expression des marqueurs des gènes des cellules souches est plus fortement exprimée dès la naissance puis, diminue spontanément dès les premiers mois de vie.

• Under the effect of outside aggression, the expression of certain basal stem cell marker genes decrease significantly.

We attached immunofluorescent labels to alpha 6 and beta 1 integrins in the epidermal stem cells of the basal layer of a skin explant before and after irradiation with UVA (10J/cm² )+ UVB (200J/cm²)

We observed a very marked decrease in the expression of these stem cell genes, confirming the very high vulnerability of stem cells to environmental aggression.

12 ansAdulte

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100

80

60

40

20

0

Stem cells genes change1 month4 months6 months1 year2 years3 years

Norm

aliz

ed re

lativ

e ex

pres

sion

(%

to th

e co

ntro

l)

KRT19 ITGB1 NID1

7 years12 yearsAdults

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Laboratoires Expanscience have carried out a programme of research on children’s skin, from birth to 2 years of age, from the surface to the stem cells of the epidermis, and have established that the period between 0 and 2 years is critical for children’s skin.

From 0 to 2 years:

the Stratum corneum, which guarantees the barrier function of the skin, is under-going a process of maturation,

the skin is dehydrated and water balance is disturbed,

the supply of stem cells is extremely vulnerable to outside aggression.

This is why it is essential to protect and moisturise the skin daily between the ages of 0 and 2 years.

DISCOVERIES OF THE EV.E.I.L.S PROGRAMME

TO SUM UP

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A new generation active ingredient: Avocado Perseose®

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A new generation active ingredient: Avocado Perseose®

3

e

d

c

ba

From the skin surface

to the epidermal stem cells

AVOCADO PERSEOSE® REINFORCES THE SKIN BARRIER

AVOCADO PERSEOSE® MAINTAINS THE HYDRATION LEVEL OF THE EPIDERMIS

AVOCADO PERSEOSE® PROTECTS THE SKIN'S STEM CELL SUPPLY

Having become aware of the need to support the development of the skin and protect the fragile skin cell supply of infants between 0 and 2 years, Laboratoires Expanscience have pursued their research programme.

Due to its dual know-how in plant extraction and cell biology, the IRD centre has developed an exclusive, natural and patented active ingredient: Avocado Perseose®.Avocado Perseose® is a unique patented active ingredient composed of mannoheptulose and perseitol, sugars with seven carbon atoms, rare in the plant kingdom and present in very few species.

Avocado Perseose® belongs to the new generation of biomimetic active ingredients: active ingredients of natural origin, which are able to act in perfect affinity with baby’s skin while combining targeted efficacy and maximum tolerance.

The researchers at the IRD centre present to you, in this section, the biological activities targeted by Avocado Perseose® while respecting the skin’s integrity, the unique, patented extraction process for Avocado Perseose®, as well as the Laboratoires Expanscience pharmaceutical supply chain from which the avocado is sourced.

A. Its actions extend from the Stratum corneum through to the Stratum germinativum

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a. Action on the skin barrier• Avocado Perseose® acts on the cohesion of the Stratum corneum Protocol: A thin layer chromatography analysis enabled the isolation of ceramides from other major

lipids in the extracellular matrix and precise quantification after treatment with a 0.005% solution of Avocado Perseose® over 72 hours.

Result: Avocado Perseose® increased the synthesis of ceramides in reconstructed epidermis by 32%.

• Avocado Perseose® acts on the consolidation of the microarchitecture of the Stratum corneum Protocol: The ELISA technique was used to measure the quantity of involucrin (constituent of the

cornified envelope around cells) and desmoglein-1 (constituent of corneodesmosomes, structures linking cells together) produced by keratinocytes after treatment with a 0.005% solution of Avocado Perseose® over 48 hours.

Result: Avocado Perseose® significantly stimulated the expression of involucrin and desmoglein-1 in keratinocytes: + 49% (p < 0.001) and + 41% (p < 0.001) respectively.

Production of involucrin and desmoglein-1 in keratinocytes

Neosynthesis of ceramides in reconstructed epidermis

QUANTITY OF CERAMIDESRelative intensity (mean) % of control

Control epidermis 14.2 100 Differentiated epidermis 19.7 138Avocado Perseose 0.005% 18.0 132

10

8

6

4

2

0

Untreated cells

Avocado Perseose®

Rela

tive

quan

tity

of d

esm

ogle

in-1

/ nu

mbe

r of c

ells

***+ 41 %4

3.53

2.52

1.51

0,50

Untreated cells

Avocado Perseose®

Rela

tive

quan

tity

of in

volu

crin

/ nu

mbe

r of c

ells

***+ 49 %

*** p<0.001, Dunnett test*** p<0.001, Dunnett test

Avocado Perseose® reinforces the skin barrier.

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b. Action on skin hydration

• Avocado Perseose® acts on the retention of water in the epidermis

Protocol: The ELISA technique was used to measure the quantity of hyaluronic acid produced by keratinocytes after treatment with a 0.005% solution of Avocado Perseose® over 24 hours.

Result: Avocado Perseose® significantly increased the quantity of hyaluronic acid produced by keratinocytes: + 47% (p<0.05).

Production of hyaluronic acid by keratinocytes

• Avocado Perseose® acts on the semi-permeability of the Stratum corneum

1st step: detection by immunolabelling

Protocol: Immunolabelling enabled the detection of transglutaminase, an enzyme that promotes the adhesion of the cornified envelope around cells to maintain water within, produced by keratinocytes after delipidation of the skin (explant mimicking dry skin) and treatment with Avocado Perseose® for 3 hours.

Result: Topical treatment with Avocado Perseose® of delipidated skin explants stimulated transgluta-minase expression.

700

600

500

400

300

200

100

0

Untreated cells

Retinoic acid (ref)

Avocado Perseose®

Rela

tive

quan

tity

of h

yalu

roni

c ac

id/

num

ber o

f cel

ls

***

*

+ 119 %

+ 47 %

* p<0.05, *** p<0.001, Dunnett test

versus untreated cells

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Expression of transglutaminase in delipidated skin explantsImmunofluorescent labelling: green = transglutaminase (FITC) - red = cell nuclei (propidium iodide)

2nd step: activity assay

Protocol: The activity of the transglutaminase produced by keratinocytes was assayed using the Transglutaminase Colorimetric MicroAssay kit after treatment with a 0.005% solution of Avocado Perseose® for 72 hours.

Result: Avocado Perseose® significantly stimulated the activity of the enzyme transglutaminase in keratinocytes: + 175% (p<0.05).

Transglutaminase activity in keratinocytes

Dry skin (delipidated) control Dry skin (delipidated) + Avocado Perseose®

0.00005

0.00004

0.00003

0.00002

0.00001

0.00000

Untreated cells

Reference (Ca) Avocado Perseose®

Tran

sglu

tam

inas

e ac

tivity

(D

0)/t

otal

pro

tein

s

**+ 146 %

+ 175 %* p<0.05, Dunnett test

versus untreated cells

Avocado Perseose® maintains the level of hydration in the epidermis

3

3736

c. Action on stem cells

The effect of Avocado Perseose® on basal stem cell markers was studied both under baseline conditions (without aggression) and in conditions of serious aggression such as UV irradiation.

• Under normal physiological conditions, Avocado Perseose® has a completely neutral effect on stem cells.

Protocol: Skin samples were taken from donors aged 1 month, 3 months, 3 years, 6 years and 11 years, as well as from adults. From these skin samples, keratinocytes were extracted and cultured for 24 hours with and without (control) a 0.005% solution of Avocado Perseose®.

The expression of stem cells marker genes (KRT19, ITGB1, ITGA6, NOTCH1) was evaluated using the real-time quantitative PCR (Polymerase Chain Reaction) assay method.

The genomic analysis demonstrated that the expression of basal stem cells genes was high at birth and decreased with age.

Result: This expression profile is maintained in the presence of Avocado Perseose®, indicating that the latter is well tolerated by cells and that it maintains the balance of basal stem cells and the epidermis.

Changes in basal stem cell genes/markers by age in the presence of Avocado Perseose®

120

100

80

60

40

20

0KRT19 ITGB1 ITGA6 NOTCH1

1 month3 months3 years6 years11 yearsAdult

Rela

tive

quan

tity

expr

esse

d in

%

3736

• In the face of serious environmental aggression (UVA and UVB), Avocado Perseose® guarantees the protection of basal epidermal stem cells

Protocol: Skin explants were irradiated with UV (UVA: 10 J/cm2 and UVB: 200 mJ/cm2) and treated with or without Avocado Perseose®, 24 hours before and 24 hours after irradiation. Protein immunolabelling enabled the measurement of expression of alpha-6 and beta-1 integrins, basal stem cell markers, under different conditions.

Result: In the face of serious environmental aggression (UVA and UVB) and in the presence of Avocado Perseose®, 80% of stem cell markers were conserved (compared with 20%)

Immunolabelling of basal stem cell markers. Effect of Avocado Perseose® in presence of UV irradiation

INTEGRIN alpha-6 INTEGRIN beta-1

20% 20%

80% 80%

Stress conditions

Stress conditions

+ PERSEOSE + PERSEOSE

INTEGRIN alpha-6(green)

INTEGRIN beta-1(pink)

Avocado Perseose® helps protect the potential of basal stem cells in the face of serious aggression such as UV exposure.Avocado Perseose® hence has a positive effect on the protection of basal stem cell potency and contributes to the maintenance of the integrity and balance of the epidermis.

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B. Unique, patented extraction processes

Avocado Perseose® is a natural active ingredient from Laboratoires Expanscience produced by its subsidiaries in South Africa and Peru.

On the strength of knowledge and know-how regarding the chemistry of the avocado developed over the course of the last thirty years, our R&D centre, in its Lipid Chemistry and Plant Extraction Laboratory, has used a unique and patented process to extract the desired active ingredient from the plant.

Working with a C7 sugar concentration of less than 1% in raw avocado, it proved a real technological challenge to purify, conserve and concentrate the molecular rarity of Avocado Perseose® from raw avocado, while taking into consideration the volume restrictions.

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Selection of raw avocado

Slicing and drying under patented and optimised conditions to preserve molecular integrity

Extraction by pressing to obtain oil and press cake

Pharmaceutical grade oil used in

certain Laboratoires Expanscience

products

Selective extraction of sugars using extraction media that respect the environment and mankind

Purification and Concentration by specific filtration systems and stabilisation of the active principle

by lyophilisation

Press cake: mixture of sugars and proteins

Mannoheptulose and Perseitol

Avocado

Perseose

To achieve this, the selected avocado must undergo a process comprising over 8 steps and calling on specific technological means.

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C. An ethical and responsible supply chain

Avocado Perseose® is the product of a controlled pharmaceutical process, governed by our guidelines for corporate social responsibility, and subject to evaluation by the UEBT (Union for Ethical Bio Trade).

An organisation inspired by a United Nations initiative, the UEBT is an international not-for-profit association, which promotes ethical practices for the supply of ingredients sourced from biodiversity.

Joining the UEBT is a pioneering initiative, especially in the pharmaceutical sector.

Since December 2011, Laboratoires Expanscience is the first French pharmaceutical company to become an official member of the Union for Ethical Bio Trade (UEBT) and through its membership affirms its commitment to promoting biodiversity.

In addition, Laboratoires Expanscience has willingly adopted a strategy of Corporate Social Responsibility

This commitment is demonstrated in particular by the incorporation of eco-design principles during the development of pharmaceutical and cosmetic active ingredients.

Specialists in the use of products of natural origin, and due to the extensive knowledge and know-how regarding the chemistry of the avocado, which has been developed over the course of the last thirty years, Laboratoires Expanscience is now able to use every part of the fruit to produce a dozen raw materials or cosmetic active ingredients, including Avocado Perseose®

We present to you here the avocado processing cycle.

ACOCADO SUGARS

(C7)

4140

SLICING + DRYING

GrindingExfoliating

avocado power

Refined avocadooil

Unrefined oilMeal

Avocadooil concentrate

Avocadooil unsaponifiables

5a Avocuta®

Enz. hydrolysisAvocado peptides

Extraction

Refining

Esterification

Mol. distillation (MD)

MD + extraction

ACOCADO SUGARS

(C7)

Free fatty acids

100% of the avocado recovered

EXTRACTION FROM AVOCADO TREE

The R&D centre has developed, due to its dual know-how in plant extraction and cell biology, an exclusive, natural and patented active ingredient: Avocado Perseose®.

Avocado Perseose® belongs to the new generation of biomimetic active ingredients, active ingredients of natu-ral origin which are able to act in perfect affinity with skin while combining targeted efficacy and maximum tolerance, from birth.

The Avocado Perseose® fits the specific needs of the baby skin from 0 to 2 years, and it : • reinforces the skin barrier • maintains hydration and regulating water balance • and protects the skin’s supply of cells

T O S U M U P

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Pressure

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The formulation:a new technological challenge

4

4

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The formulation: a new technological challenge

4

Following this programme of unprecedented research, these exciting discoveries and the development of Avocado Perseose®, Laboratoires Expanscience has completely reviewed the Mustela® Bébé skincare products.

The global reformulation of Mustela® Bébé line was a fantastic technological challenge, revolved around 4 objectives:

A. To incorporate Avocado Perseose® in all formulas

The formulation of new products incorporating Avocado Perseose® had to conform to a highly ambitious internal charter reflecting our very strict safety requirements and criteria, while maintaining the galenic properties that satisfy the demands of our consumers in terms of texture and fragrance, efficacy and high degree of naturalness.

The challenge was to maintain the stability of the formulas, as the addition of Avocado Perseose® upset the equilibrium of the existing formulas particularly during the incorporation - in certain lipophilic formulas - of a hydrophilic active ingredient.

To guarantee the beneficial effects of Avocado Perseose® in the products, the efficacy of all the new Mustela® Bébé products have been tested on babies and children - via in vivo studies in observational clinical tests under real conditions of use and under dermatological and paediatric supervision, and in vitro, on reconstructed baby epidermis.

B. To maximise the safety and tolerance of the products while guaranteeing a high degree of naturalness and excluding questionable ingredients in all product formulas

D. To be consistent with a volunteer strategy of social and environmental responsibility

A. To incorporate Avocado Perseose® in all formulas and guarantee all its beneficial effects in the finished products

C. To ensure a high sensory quality in the products for unequalled pleasure of use

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B. To maximise the safety, innocuity and tolerance of the products

In addition to the stringent regulatory framework of the ISO 22716 standard and adherence to good manufactu-ring practices, Laboratoires Expanscience maintains a high level of surveillance for all the ingredients selected, at every stage of development and before releasing the product on the market.

SAFETY – INNOCUITY

• Rigorous selection of raw materials

An in-depth file is assembled and submitted to an independent expert toxicologist. The documents included a review of published data for each raw material, an analytical study of the raw material as well as information from suppliers on the source, stability and safety of the raw materials.

Concerning fragrances or our fragrance compositions, we ensure their safety is subject to a toxicology assess-ment. We choose them pursuant to specifications that meet the prevailing cosmetics and perfumery regulations (Cosmetics Directive 76/768/EC/Regulation (EC) No 1223/2009 of the European Parliament and of the Council on cosmetic products, and current IFRA regulations), and also require the removal from label-ling of the 26 allergenic substances (identified as entailing a potential allergen in Cosmetics Directive 76/768/EC - 2003 revision).

• Priority given to ingredients of natural origin and substitution of a maximum of synthetic raw materials

Today, Mustela® Bébé products contain on average 92% ingredients of natural origin. Priority is given to natural ingredients or ingredients of natural origin, as long as they meet our demands in terms of safety, efficacy and pleasure of use.

However, when there is no natural alternative, we authorise the recourse to synthetic ingredients. The selection is then made uniquely from ingredients permitted by European regulations, and which meet all our safety and efficacy requirements.

We limit the use of certain synthetic ingredients, such as synthetic waxes and mineral oils, silicones, synthetic colouring agents,...

• Acute assessment of the safety and innocuity of the finished product

A rigorous procedure enables us to evaluate the safety of the finished product throughout its life cycle. Every Mustela® formula undergoes numerous tests to establish that it is perfectly safe: tolerance is tested in vitro and

in vivo under maximising conditions, tests of hypoallergenicity and/or phototoxicity are conducted. To evaluate product safety in an even more reliable and comprehensive manner, our researchers have pioneered

the reconstruction of baby’s and children’s epidermis from birth (Expanscience Laboratories exclusivity).

O N A V E R A G E

EN MOYENNE

Paraben / Phenoxyethanol / Phtalate / Chlorphenesin / Alcohol / SLS / EDTA...

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TOLERANCE

All Mustela® products are developed to minimise the risks of allergy.They all possess a level of high tolerance, which have been tested under worst-case conditions in vitro and in vivo, with procedures that are unique and exclusive to Expanscience, including testing on reconstructed baby skin epidermis.

Product tolerance is also evaluated in observational clinical tests, under real use conditions and under dermatological and paediatric supervision on groups of babies of whom 25% are aged less than 1 month.

in vitroon reconstructed epidermal

models of baby’s skin in vitro

These epidermal models of 1-month-old baby skin constitute a tolerance evaluation model (histological measurements and cell viability) for products designed for skincare and hygiene in babies. These models are now systematically used in evaluation procedures for all Laboratoires Expanscience cosmetic products for babies.

in vivospecific Mustela stinging test conducted under worst-case

conditions

The aim of this test is to measure non-visible objective signs, generally not detected in other tolerance tests.We conduct the test under “worst case” conditions by changing parameters such as ambient temperature, humidity level, and using kinetic measurement techniques.

WORLD EXCLUSIVITY

4746

C. To ensure a high sensory quality

The formulation challenge was successfully met by the Cosmetic Development Division of the R&D Centre of Laboratoires Expanscience.With a high sensory quality, and an unequalled comfort and pleasure of use, the new patented formulas of Mustela® Bébé line contribute to the well-being and sensory awakening of newborns and babies due to the t extures adapted to each of the products without changing the emblematic Mustela® Bébé fragrance.

D. To be consistent with a strategy of environmental responsibility

• From ethical and responsible sourcing

A voluntary and transparent approach taken by Laboratoires Expanscience on the selection of ingredients details the company’s position on this important issue.

Information on raw materials (The life cycle of Mustela® products) can be found on the Mustela® website: http://www.mustela.com as well as on the website: www.expanscience.com/en/sustainable-development

• To eco-designed products

As for packaging, an eco-design strategy called 3R (reduce, replace, recycle) is followed. The reduction in weight of certain bottles and the partial incorporation of recycled plastic in tubes, bottle and lids of certain items have led to a 9-tonne decrease in the annual consumption of plastic and an additional reduction of 4.4 tonnes in the amount of virgin plastic used

Use of recycled plastic in tubes Use of cardboard sourced from sustainably-managed forests Use of plant-based inks on boxes No superfluous over-packaging, no paper package inserts

• To the end of the product’s life cycle, in order to reduce the environnemental impact

All our liquid cleansing formulas are biodegradable, in accordance with the guidelines (OCDE 302B) And Mustela® bottles are 100% recyclable according to French criteria of recyclability (excluding samples).

4

4948

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Conclusion

5

5

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Conclusion5

This research programme, ongoing for the past ten years and unique in the world, is founded on ethical and innovative investigative technology.

It has enabled us to deepen our understanding of the physiology of baby’s skin from the Stratum corneum to the epidermal stem cells, from the very first days of life.

Major discoveries about the skin barrier, hydration and epidermal stem cells have enabled us to establish the existence of a critical period for children’s skin between birth and 2 years.

To provide baby's skin with what it requires specifically during this period of vulnerability between 0 to 2 years, the Expanscience Laboratories R&D centre has rethought all the Mustela® Bébé formulas and enriched them with an exclusive, natural and biomimetic active ingredient, derived from the avocado: Avocado Perseose®.

Mustela® offers a new generation of skincare products, clinically tested, which act in perfect harmony with a baby’s skin and combine targeted efficacy, a high level of safety and maximum tolerance, with no less than 92% ingredients of natural origin on average.

Expanscience Laboratories R&D centre, Epernon, France.

5150

New Mustela® Bébé line developed thanks to Expanscience Laboratories expertises and manufactured on the industrial site located in Epernon - France. 5

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References

6

6

5554

• Direction Innovation, Research and Development (IRD) - Biologie Cellulaire - Laboratoires Expanscience. Dossier technique: perséose d’avocat et fonction barrière. July 2013.

• Fluhr JW, Darlenski R, Lachmann N et al. Infant epidermal skin physiology: adaptation after birth. British Journal of Dermatology 2012; 166(3):483-90.

• R & D Center Laboratoires Expanscience. Fluhr JW, Darlenski R, Hachem JP et al. Skin adaptation from birth to childhood: practical considerations.

• Innovation, R & D Laboratoires Expanscience. Belilovsky (de) C, Fluhr JW, Baudouin C et al. E.V.E.I.L.S PROGRAMME: inside infants’ skin: new spectroscopic, microscopic, genomic data leading to cutting edge and patented genera-tion of baby skin research and care.

• Innovation, R & D Laboratoires Expanscience. Fluhr JW, Msika Ph, Baudouin C et al. Surface isotropy as a marker for epidermal maturation in infancy: development and validation of the patented Electron Microscopy Isotropy (E.M.I) score.

• R & D Center Laboratoires Expanscience. Fluhr JW, Lachmann N, Baudouin C et al. Comparison of the skin physiology of neonates and young children with that of adults: a randomised clinical trial.

• Innovation, R & D Laboratoires Expanscience. Baudouin C, Brédif S, Pedretti N et al. Modeling and genomic signature of age-specific infants and children epidermis: new data and innovative discoveries.

References 6

5554

• Direction Innovation, Research and Development (IRD) - Biologie Cellulaire - Laboratoires Expanscience. Dossier technique: perséose d’avocat et cellules souches. July 2013.

• Direction Innovation, Research and Development (IRD) - Laboratoires Expanscience. Baudouin C. Point sur les cellules souches épidermiques. January 2013.

• Innovation, R & D Laboratoires Expanscience. Leclère-Bienfait S, Brédif S, Rocheteau J et al. Avocado Perseose®, a biomimetic patented active ingredient targeted to the needs of infant’s skin.

• R & D Center Laboratoires Expanscience.Cochet P, Menu F, Msika Ph. Safety evaluation and formulation of cosmetic products designed for children under age of 3 years.

• Innovation, R & D Center Laboratoires Expanscience. Baudouin C, Belivovsky (de) C, Lachmann N et al. Tolerance assessment of cosmetic products dedicated to baby’s skin: innovative approaches using stinging test and infant epidermis model.

• Fluhr JW, Darlenski R, Taieb A, Hachem JP, Baudouin C, Msika P, Belilovsky (de) C, Berardesca E. Functional skin adaptation in infancy - almost complete but not fully competent. Experimental dermatology 2010; 19(6): 483-92.

• Mustela® website: www.mustela.fr

6

- 840

8796

- P

hoto

thèq

ue :

Foto

lia :

© K

urha

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Une gamme complète pour les peaux sèches et les peaux à tendance atopique

(1) Explants de peau dans solutions mimant l’environnement inflammatoire de la dermatite atopique (molécule Th2), application topique de Stelatopia et du placebo. Immunomarquage pour visualiser le niveau d’expression des marqueurs d’intérêts.

(2) Étude clinique auprès de 86 enfants répartis en 5 groupes, âgés de 4 mois à 4 ans et souffrant d’une dermatite atopique d’intensité faible à modérée avec des lésions aigües sous contrôle pédiatrique pendant 3 semaines. Tous les patients ont été traités pendant 21 jours par dermocorticoïdes à différents dosages sur les zones eczémateuses associés ou non aux soins émollients STELATOPIA®.

(3) Étude multicentrique auprès de 80 enfants âgés de 4 mois à 4 ans ayant une dermatite atopique légère à modérée sous contrôle dermatologique en milieu pédiatrique : Groupe A (40 enfants) : traitement par dermocorticoïde fort seul (crème à 0.1% de butyro-propionate d’hydrocortisone), appliqué sur les lésions matin et soir. Groupe B (40 enfants) : traitement par STELATOPIA® Crème émolliente seule, appliquée sur les lésions et l’ensemble du corps matin et soir.

Suivi clinique effectué à J0, J7 et J21.

AU QUOTIDIEN POUSSÉES INFLAMMATOIRES

Tube 200 ml /Flacon pompe

400 ml

Tube 200 mlFlacon 200 ml Flacon 200 mlFlacon pompe200ml & 400 ml

Quoi de neuf dans la dermatite atopique?

Défaut de la barrière Des anomalies immunologiques une altération de la balance Lymphocytes Th1/Th2 en faveur des lymphocytes Th2

ce qui entraîne une réponse de type allergique alternant phases aigües et chroniques.

barrière lipidique

barrière protéique

≥ inflammation

≥ prurit

filaggrine

≥ protéases

pH ≥

PPAR directement impliqués dans la dermatite atopique :

Les sujets atteints de dermatite atopique expriment moins de PPAR que les sujets sains.

Rôle du PPAR ( Peroxisome Proliferator Activated Receptors)

Inflam-mation

≥Fonctionbarrière

≥Synthèselipidique

Réponse immunitaire altérée

Défaut de la barrièreOutside

Inside

L'Oléodistillat de Tournesol : Un activateur naturel des PPAR

Mécanisme d'action de l'Oléodistillat de Tournesol au niveau cellulaire

L' Oléodistillat de Tournesol active spécifiquement les récepteurs PPAR

Composition :- 90 % d'acides gras essentiels- 10 % d' insaponifiables

Véhicule ODT 0.2ppm Acide fénofibrique 1.59ppm

Vecteur contrôle

PPAR Vecteurs d’expression

16141210

86420

x 7.8

x 3.2

MODÈLE DE TRANSACTIVATION IN VITRO

DIMINUTION DEL'INFLAMMATION

VIA NF KAPPA B

RESTAURATION DE LA BARRIÈRE

Activation des constituants lipidiques et protéiques

INFLAMMATION

ODT

ÉLÉMENTS CLÉS DE LA BARRIÈRE

Activation PPAR-α

L’ODT, en restaurant la barrière et réduisant l’inflammation, améliore les symptômes de la DA : xérose, lésions eczémateuses, prurit.

RelipidationActive®

Stelatopia® : des soins émollients concentrés à 2% en Oléodistillat de Tournesol

Des résultats équivalents en comparaison des dermocorticoïdes

L'Oléodistillat de Tournesol stimule l'expression de la filaggrine (1)

L’Oléodistillat de Tournesol limite l'expression de la kallikreine (1)

Marquage DAPI (bleu) : noyau des cellules. Marquage anti-filaggrine-FITC (vert): Filaggrine.

Marquage DAPI (bleu) : noyau des cellules. Marquage anti-kallikreine-TRITC (rouge): Kallikreine.

ÉPARGNE DE 75% DES DERMOCORTICOÏDES.(2)

AMÉLIORATION DE 75% DU SCORAD, SIMILAIRE À UN DERMOCORTICOÏDE.(3)

RAPPEL DE GAMME

T O I L E T T E B A I NS O I N

Tube 200 ml Flacon 400 mlTube 200 ml Flacon 200 ml Flacon pompe200 ml & 400 ml

SOIN

NOUVEAUSTELATOPIA® Baume Relipidant :

Le soin d’attaque Pour le Prurit, la sécheresse extrême et les poussées d’eczéma atopique fréquentes des nourrissons, bébés et enfants

Visage et corps

STELATOPIA® Crème émolliente :

Le soin rééquilibrant des peaux sèches et peaux atopiques Pour la Xérose et le traitement de fond de l’eczéma des nourrissons, bébés et enfants.

Visage et corps

TOILETTE

STELATOPIA® Eau nettoyante sans rinçage

Toilette quotidienne sans rinçage

Visage, corps et siège

BAIN

STELATOPIA® Crème lavante

Hygiène quotidienne

Corps et cheveux

STELATOPIA®Huile de bain lactée

Hygiène en période de poussées irritatives

C’est dans ces moments-là que la peau a besoin de Mustela®.

Comment prendre en charge cette affection cutanée

en fonction de son intensité ?

Formulé sous contrôle dermatologique et testé en milieu pédiatrique

STELATOPIA®

EN MOYENNE, 1 ENFANT SUR 5 SOUFFRE D’ECZÉMA ATOPIQUE(1)

* St

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DES RÉSULTATS ÉQUIVALENTS EN COMPARAISON DES DERMOCORTICOÏDESEtude multicentrique auprès de 80 enfants âgés de 4 mois à 4 ans ayant une dermatite atopique légère à modérée sous contrôle dermatologique en milieu pédiatrique :

• Groupe A (40 enfants) : traitement par dermocorticoïde fort seul (crème à 0.1% de butyro-propionate d’hydrocortisone), appliqué sur les lésions matin et soir.

• Groupe B (40 enfants) : traitement par STELATOPIA® Crème émolliente seule, appliquée sur les lésions et l’ensemble du corps matin et soir.

• Suivi clinique effectué à J0, J7 et J21.

% d'

amél

iora

tion

0

20

40

60

80

48 %*

49 %*

75 %*

70 %*

Groupe A = DCT

DCT : DermocorticoïdeSE : STELATOPIA® Emollient* p < 0,01 - Test de Wilcoxon** NS - A versus B Test de Mann et Whitney

Groupe B = SE

A = B**

A = B**

J0 J7 J21

SCORAD

Étude clinique auprès de 86 enfants répartis en 5 groupes, âgés de 4 mois à 4 ans et souffrant d’une dermatite atopique d’intensité faible à modérée avec des lésions aigües sous contrôle pédiatrique pendant 3 semaines.Tous les patients ont été traités pendant 21 jours par dermocorticoïdes à différents dosages sur les zones eczémateuses associés ou non aux soins émollients STELATOPIA®.

% d'

amél

iora

tion

0

20

40

60

80

58%**63%**

75%**72%**72%**

Groupe A = DCT

Groupe C = DCT

Groupe B - SE + DCT

Groupe D - SE + DCT

Groupe E - SE + DCT

J0 J7 J21

** p < 0,01 par rapport à J0

Pourcentage d’amélioration du SCORAD entre J0 et J21 dans les 5 groupes de traitement

Sans soin STELATOPIA®

Avec soin STELATOPIA®

SE : Soin STELATOPIA® DCT : Dermocorticoïde

Permet de limiter le recours aux dermocorticoïdes jusqu’à 100%

UNE EFFICACITÉ PROUVÉE EN ASSOCIATION AVEC LES DERMOCORTICOÏDES

En association avec un dermocorticoïde : réduction du SCORAD –75%

Amélioration du SCORAD : 75% versus 70%

Groupes de traitement A B C D E

matin DCT DCT DCT DCT DCT 1J½ + SE

soir DCT DCT + SE – SE SE

NOUVEAU

DES RÉSULTATS D’ÉTUDES IMPACTANTS

8407429_ADV_Stelatopia_baume_FR.indd 1-3 13/12/11 22:10

RAPPEL DE GAMME

T O I L E T T E B A I NS O I N

Tube 200 ml Flacon 400 mlTube 200 ml Flacon 200 ml Flacon pompe200 ml & 400 ml

SOIN

NOUVEAUSTELATOPIA® Baume Relipidant :

Le soin d’attaque Pour le Prurit, la sécheresse extrême et les poussées d’eczéma atopique fréquentes des nourrissons, bébés et enfants

Visage et corps

STELATOPIA® Crème émolliente :

Le soin rééquilibrant des peaux sèches et peaux atopiques Pour la Xérose et le traitement de fond de l’eczéma des nourrissons, bébés et enfants.

Visage et corps

TOILETTE

STELATOPIA® Eau nettoyante sans rinçage

Toilette quotidienne sans rinçage

Visage, corps et siège

BAIN

STELATOPIA® Crème lavante

Hygiène quotidienne

Corps et cheveux

STELATOPIA®Huile de bain lactée

Hygiène en période de poussées irritatives

C’est dans ces moments-là que la peau a besoin de Mustela®.

Comment prendre en charge cette affection cutanée

en fonction de son intensité ?

Formulé sous contrôle dermatologique et testé en milieu pédiatrique

STELATOPIA®

EN MOYENNE, 1 ENFANT SUR 5 SOUFFRE D’ECZÉMA ATOPIQUE(1)

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9

DES RÉSULTATS ÉQUIVALENTS EN COMPARAISON DES DERMOCORTICOÏDESEtude multicentrique auprès de 80 enfants âgés de 4 mois à 4 ans ayant une dermatite atopique légère à modérée sous contrôle dermatologique en milieu pédiatrique :

• Groupe A (40 enfants) : traitement par dermocorticoïde fort seul (crème à 0.1% de butyro-propionate d’hydrocortisone), appliqué sur les lésions matin et soir.

• Groupe B (40 enfants) : traitement par STELATOPIA® Crème émolliente seule, appliquée sur les lésions et l’ensemble du corps matin et soir.

• Suivi clinique effectué à J0, J7 et J21.

% d'

amél

iora

tion

0

20

40

60

80

48 %*

49 %*

75 %*

70 %*

Groupe A = DCT

DCT : DermocorticoïdeSE : STELATOPIA® Emollient* p < 0,01 - Test de Wilcoxon** NS - A versus B Test de Mann et Whitney

Groupe B = SE

A = B**

A = B**

J0 J7 J21

SCORAD

Étude clinique auprès de 86 enfants répartis en 5 groupes, âgés de 4 mois à 4 ans et souffrant d’une dermatite atopique d’intensité faible à modérée avec des lésions aigües sous contrôle pédiatrique pendant 3 semaines.Tous les patients ont été traités pendant 21 jours par dermocorticoïdes à différents dosages sur les zones eczémateuses associés ou non aux soins émollients STELATOPIA®.

% d'

amél

iora

tion

0

20

40

60

80

58%**63%**

75%**72%**72%**

Groupe A = DCT

Groupe C = DCT

Groupe B - SE + DCT

Groupe D - SE + DCT

Groupe E - SE + DCT

J0 J7 J21

** p < 0,01 par rapport à J0

Pourcentage d’amélioration du SCORAD entre J0 et J21 dans les 5 groupes de traitement

Sans soin STELATOPIA®

Avec soin STELATOPIA®

SE : Soin STELATOPIA® DCT : Dermocorticoïde

Permet de limiter le recours aux dermocorticoïdes jusqu’à 100%

UNE EFFICACITÉ PROUVÉE EN ASSOCIATION AVEC LES DERMOCORTICOÏDES

En association avec un dermocorticoïde : réduction du SCORAD –75%

Amélioration du SCORAD : 75% versus 70%

Groupes de traitement A B C D E

matin DCT DCT DCT DCT DCT 1J½ + SE

soir DCT DCT + SE – SE SE

NOUVEAU

DES RÉSULTATS D’ÉTUDES IMPACTANTS

8407429_ADV_Stelatopia_baume_FR.indd 1-3 13/12/11 22:10

L’ Oléodistillat de Tournesol : une action démontrée

Stelatopia® : une efficacité prouvée

Filaggrine : marqueur de la barrière

Kallikreine : marqueur de purit

Peau atopique

Avec STELATOPIA Avec PLACEBO

Peau atopique

Avec STELATOPIA Avec PLACEBO

3 pôles de Recherche et Développement en dermatologie

• Pôle innovation principe actif : Lipochimie et extraction végétale, biologie cellulaire

• Pôle développement Pharmaceutique et cosmétique

• Pôle sécurité, qualité et efficacité (Chimie analytique, AQ R&D, études cliniques et veille technologique)

Une expertise indéniable en biologie végétale et cutanée

• Une parfaite maîtrise de la physiologie de la peau et de ses mécanismes de développement dès la naissance

• Un savoir-faire unique en technologies végétales innovantes

• Des filières végétales maîtrisées et responsables (ISO 26000)

Une reconnaissance internationale• Communications scientifiques internationnales :

398 posters scientifiques, 48 publications.

• 638 brevets déposés dans le monde depuis 1997

Situé sur le site d’Épernon en Eure-et-Loir, le Centre de Recherche et Développement (R&D) abrite le noyau scientifique et technique des Laboratoires Expanscience. Près de soixante experts y collaborent pour mettre au point des actifs d’origine naturelle innovants et des formules sûres et efficaces.

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Un centre de R&D à la pointe de l'innovation

Formulé sous contrôle dermatologique et testé

en milieu pédiatrique

C’est maintenant que se joue l’avenir de sa peau

L’expert de la peau du bébédès la naissance

Mustela®, l’expert de la peau des bébés et des futures mamans depuis plus de 60 ans.

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A brand with a cutting-edge Research & Development center

The Research and Development Center (R&D), located on the Epernon site in Eure-et-Loir, is home to the scientific and technical core of Expanscience Laboratories. Over sixty experts work together to develop new and innovative active ingredients of natural origin and safe and effective formulas.

3 DERMATOLOGY RESEARCH AND DEVELOPMENT DEPARTMENTS

• An active ingredient innovation department working in Lipid chemistry and cell biology

• A Pharmaceutical and Cosmetic development department

• A safety, quality and effectiveness department (Analytical chemistry, research and development, quality control, clinical trials and technology watch)

UNDENIABLE EXPERTISE IN PLANT BIOLOGY AND UNDERSTANDING OF THE SKIN

• Complete mastery of the skin’s physiology and development mechanisms from birth

• Unique expertise in innovative plant technologies• Controlled and responsible plant supply chains

(ISO 26000)

INTERNATIONAL RECOGNITION• International scientific communication:

398 scientific positions, 46 publications• 638 patents filed worldwide since 1997

Laboratoires Expanscience10, avenue de l’Arche, 92419 Courbevoie Cedex - France Tél. : +33 (0)1 43 34 60 00 - Fax : +33 (0)1 43 34 61 00

www.expanscience.com