This document summarizes the key information about Revinage, a plant-based alternative to retinoids for treating skin aging. Revinage is a standardized extract of Picão Preto (Bidens pilosa) that interacts with retinoic acid receptors and has gene and protein expression profiles similar to retinoids. Clinical studies showed Revinage improved skin elasticity, density, dark spots, roughness and wrinkles comparable to retinol palmitate. Revinage also increased antioxidant enzymes, collagen and decreased MMP-1 like retinoids. It penetrated the skin faster than a placebo and was more stable than retinol against photodegradation and oxidation.

1. REVINAGE
The real bio-retinol

2. Aging of the world
United Nations 2015 Report

3. Aging
Who wants
to get old?

4. o Family of compounds related to vitamin A and its
derivatives
o They interact with specific nuclear receptors – RAR
(retinoic acid receptors) and RXR (retinoid X receptors)
o Retinoic acid is the most active and reactive form (with
side effects). Retinol and its esters are converted into
retinoic acid to provide biological function.
Retinoids

5. Retinoids
o Highly efficient for the treatment of aging, photo-
aging, acne, psoriasis and others
o The most prescribed active ingredient
o Diverse side effects include: skin irritation,
photosensibility, telangiectasia, teratogenicity and
embriotoxicity
o Instability in contact with light and oxygen

6. Revinage®
• Retinol-like activity
• Vegetal alternative to retinoids in the treatment of aging and
photoaged skin.
• Supercritical apolar extract of Picão Preto (Bidens pilosa)
standardized in phytol
INCI: Bidens Pilosa Extract (and) Elaeis Guineensis (Palm) Oil (and) Gossypium Herbaceum
(Cotton) Seed Oil (and) Linum Usitatissimum (Linseed) Seed Oil.

7. Revinage®
Retinoids Receptors
In silico evaluation of RXR and phytanic acid
Hydrogen bounds (yellow traces) between the
oxygen atoms of phytanic acid (in red) and
arginine R316 (in RXR receptor)
RXR (retinoid X receptors)

8. Revinage®
Retinoids Receptors
Human fibroblasts culture – 48hs – gene expression of RAR and
RXR receptors
0
0.5
1
1.5
2
2.5
RAR RXR
Gene
expression
(mRNA)
Control Retinoic Acid (30 µM)
Retinol (0,15%) Revinage (0,15%)
62,3%
-26% -20%
34%
90%
119%
RAR (retinoic acid receptors) and RXR (retinoid X receptors)

9. Revinage®
Retinoids Receptors
Ex vivo – 48hs – protein expression of RAR and RXR
RAR RXR
RAR (retinoic acid receptors) and RXR (retinoid X receptors)
Control Retinoic Acid 30µM
Control Retinoic Acid 30µM

10. Revinage®
Cellular proliferation, differentiation and
extracellular matrix (ECM)
Human fibroblasts culture – 48hs – gene expression
0
0.5
1
1.5
2
2.5
3
EGFr Pro-collagen
Gene
expression
(mRNA)
Controle Retinoic Acid (30 µM)
Retinol (0,15%) Revinage (0,15%)
134%
108% 121%
67%
159%
120%
EGFr – epidermal growth factor receptor

11. Revinage®
Cellular proliferation, differentiation and
extracellular matrix (ECM)
Human fibroblasts culture – 48hs – protein expression
0
20
40
60
80
100
120
collagen elastin
Protein
level
(mg/mL)
Control Retinoic Acid (30 µM)
Retinol (0,15%) Revinage (0,15%)
65%
* 46%
* 24%
*
67%
* 17%
*
26%
*
* p<0,05 in relation to the control

12. Revinage®
Cellular proliferation, differentiation and
extracellular matrix (ECM)
Skin fragments – 24hs – protein expression

13. Revinage®
Cellular proliferation, differentiation and
extracellular matrix (ECM)
Human fibroblasts culture – 48hs – protein expression
-34
-22
-33
-40
-30
-20
-10
0
MMP-1
production
(%
in
relation
to
the
control)
Retinoic Acid (30 µM) Retinol (0,15%) Revinage (0,15%)
MMP-1 – metalloproteinase type I

14. Revinage®
Cellular proliferation, differentiation and
extracellular matrix (ECM)
Skin fragments – 24hs – protein expression
10000
13000
16000
19000
22000
25000
28000
MMP-1
(pg/mL)
Placebo Retinol palmitate (2%)
Basal UV
-15%
*
-14%
*
-22%
*
-7%
*
UV radiation (3J/cm2) * p<0,05 in relation to the control
MMP-1 – metalloproteinase type I

15. Revinage®
Cellular proliferation, differentiation and
extracellular matrix (ECM)
Human fibroblasts culture – 48hs – protein expression
0
400
800
1200
1600
2000
FGF-

(pg/mL)
Control Retinoic Acid (30 µM)
Retinol (0,15%) Revinage (0,15%)
101%
*
71%
*
138%
*
* p<0,05 in relation to the control FGF-  - fibroblast growth factor 

16. Revinage®
Cellular proliferation, differentiation and
extracellular matrix (ECM)
Human fibroblasts culture – 48hs – protein expression
0
40000
80000
120000
160000
200000
TGF-

(pg/mL)
Control Retinoic Acid (30 µM)
Retinol (0,15%) Revinage (0,15%)
101%
*
26%
*
41%
*
* p<0,05 in relation to the control TGF-  - tissue growth factor 

17. Revinage®
Antioxidant and regulation of senescence
Human fibroblasts culture – 48hs – enzymatic activity
0
0.2
0.4
0.6
0.8
1
SOD
activity
(U/mL)
Control
Retinoic Acid (30 µM)
Retinol (0,15%)
445%
*
247%
*
99%
*
219%
*
* p<0,05 in relation to the control SOD – superoxide dismutase

18. Revinage®
Antioxidant and regulation of senescence
Human fibroblasts culture – 48hs – enzymatic activity
0
2
4
6
8
10
CAT
Activity
(U/mL)
Control Retinoic Acid (30 µM)
Retinol (0,15%) Revinage (0,15%)
Alfa-tocopherol (0,15%)
56%
*
67%
* 47%
*
60%
*
* p<0,05 in relation to the control CAT – catalase

19. Revinage®
Antioxidant and regulation of senescence
Mouse fibroblasts culture – 48hs – free radicals quantification
0
500
1000
1500
2000
2500
3000
Control Revinage
(0,15%)
Free
radicals
quantification
(relative
to
light
units
RUL/min)
54%

20. Revinage®
Antioxidant and regulation of senescence
Human fibroblasts culture – 48hs – MDA quantification
0
1
2
3
4
5
6
MDA
(mM)
Control Retinoic Acid (30 µM)
Retinol (0,15%) Revinage (0,15%)
Alfa-tocopherol (0,15%)
-68%
*
-41%
*
-30%
*
-90%
*
* p<0,05 in relation to the control MDA – malonaldelhyde

21. Revinage®
Antioxidant and regulation of senescence
Human fibroblasts culture – 48hs – gene expression
0
0.5
1
1.5
2
SIRT6
gene
expression
(mRNA)
Control Retinoic Acid (30 µM)
Retinol (0,15%) Revinage (0,15%)
70%
70% 72%
SIRT6 – sirtuin 6

22. Revinage®
Soothing effect
Human fibroblasts culture – 48hs – enzymatic activity
-11
-48
-34
-60
-50
-40
-30
-20
-10
0
AP-1
activity
(%
in
relation
to
the
control)
Retinoic Acid (30 µM) Retinol (0,15%) Revinage (0,15%)
AP-1 – activator protein-1 (transcriptional factor)

23. Revinage®
Soothing effect
Human keratinocytes culture – 48hs – protein expression
0
0.5
1
1.5
2
2.5
COX-2
(ng/mL)
Control
Retinoic Acid (30 µM)
Retinol (0,15%)
Revinage (0,15%)
8,5%
-33%
#
-69%
*
0
300
600
900
1200
1500
PGE2
(pg/mL)
Control
Retinoic Acid (30 µM)
Retinol (0,15%)
Revinage (0,15%)
19%
#
-5%
#
-26%
*
*p<0,01 and # p<0,05 in relation to the control
COX-2 - Ciclo-oxigenase-2
PGE2 – Prostaglandin 2

24. Revinage®
Soothing effect
Human keratinocytes culture – 48hs – protein expression
0
20
40
60
80
100
120
LTB4
(pg/mL)
Control Retinoic Acid (30 µM)
Retinol (0,15%) Revinage (0,15%)
-6,5% -16% -28%
#
# p<0,05 in relation to the control LTB4 – Leukotriene B4

25. Revinage®
Oiliness Control
Human keratinocytes culture – 48hs – protein expression
0
30
60
90
120
DHT
(pg/mL)
Control Sebonormine (0,05%)
Saw Palmeto (0,05%) Revinage (0,15%)
-39%
#
-63%
*
-64%
#
*p<0,01 and # p<0,05 in relation to the control DHT - di-hydro testosterone

26. Revinage®
Whitening Effect
Human melanocyte and keratinocyte culture – 48hs
0 20 40 60 80 100 120
Melanin Level (mg/mL)
Control alfa- arbutin 0,005%
kojic acid 0,05% Revinage (0,15%)
#
-50%
*
-80%
#
-56% 0.000
0.050
0.100
alfa-MSH
(mg/mL)
Control alfa- arbutin 0,005%
kojic acid 0,05% Revinage (0,15%)
-26%
# -23%
#
-72%
*
*p<0,01 and # p<0,05 in relation to the control Alfa-MSH - α-Melanocyte-stimulating hormone

27. Revinage®
Clinical Study
Panel
40 volunteers
(phototype II, III e IV)
2x a day for 56 days
on the face (hemi-face)
and forearm
Facial cream with
2% Revinage or
0.3% Retinol palmitate

28. Clinical Study– Elasticity (R2)
• Revinage® 2%
• Retinol Palmitate 0.3%
• 2X a day for 56 days
• Face (hemi-face)
40 volunteers
Revinage®
0%
10%
13%
17%
6%
18% 17%
20%
0%
5%
10%
15%
20%
25%
D14 D28 D42 D56
%
of
improvement
on
elasticity
(R2)
Revinage® Retinol Palmitate
Cutometer

29. Clinical Study– Re-densification
Revinage®
23%
14%
25%
16%
30%
14%
25%
12%
0%
5%
10%
15%
20%
25%
30%
35%
D42 D56 D42 D56
%
of
improvement
on
cutaneous
density
(arbitrary
units
of
ultrasound)
Revinage® Retinol plamitate
forearm face
Ultrasound DUB - USB
• Revinage® 2%
• Retinol Palmitate 0.3%
• 2X a day for 56 days
• Face (hemi-face) and forearm
40 volunteers

30. Clinical Study – Whitening (VISIA)
Revinage®
VISIA
-32%
-48%
-37%
-67%
-21%
-36%
-53%
-86%
-100%
-80%
-60%
-40%
-20%
0%
D14 D28 D42 D56
%
of
dark
spots
compared
to
the
basal
(VISIA)
Revinage® Retinol Palmitate
• Revinage® 2%
• Retinol Palmitate 0.3%
• 2X a day for 56 days
• Face (hemi-face)
40 volunteers

31. Revinage®
Clinical Study – Roughness and texture (Sa – PRIMOS)
PRIMOS
-37%
-29%
-32%
-35% -36%
-23%
-36%
-11%
-16% -16%
-27%
-24% -23% -23%
-26% -26%
-40%
-35%
-30%
-25%
-20%
-15%
-10%
-5%
0%
D14 D28 D42 D56 D14 D28 D42 D56
%
roughness
(PRIMOS
-
Sa)
Revinage® Retinol Palmitate
forearm face
• Revinage® 2%
• Retinol Palmitate 0.3%
• 2X a day for 56 days
• Face (hemi-face) and forearm
40 volunteers

32. Revinage®
Clinical Study– Wrinkles (Smax – PRIMOS)
PRIMOS
-16%
-26%
-28%
-18%
-18%
-10%
-8%
-15%
-30%
-25%
-20%
-15%
-10%
-5%
0%
D42 D56 D42 D56
%
wrinkles
(PRIMOS
-
Smax)
Revinage® Retinol Palmitate
forearm face
• Revinage® 2%
• Retinol Palmitate 0.3%
• 2X a day for 56 days
• Face (hemi-face) and forearm
40 volunteers

33. Revinage®
Clinical Study– Wrinkles (Smax – PRIMOS)
PRIMOS
Results after
28 days
D0
D28

34. Revinage®
Clinical Study – Wrinkles (OMNIA)
OMNIA
D zero D28

35. Revinage®
Clinical Study– NMF and Lipids (Raman)
5 volunteers
• Revinage® 1% at
lipstick
• 1 single application
Raman Spectroscopy
Description 2hs 4hs
NMF 92.78% -
Ceramide-3 33% 55.86%
Cholesterol - 12.25%

36. Revinage®
Clinical Study– Permeation (Raman)
2 volunteers
• Revinage® 3%
• Placebo
• 1 single application
Raman Spectroscopy
Samples
% of permeation of the active ingredient at 1-60µm
(related to the phytol concentration)
30min 1h 2h 4h 18h 24h
Placebo 0% 0% 0% 0% 0% 0%
Cream with Revinage® 8.12% 29.3% 62.17% 65.15% 9.13% 2.21%

37. Revinage®
Other Tests – Degradation and Stability
HPLC -High performance liquid chromatography
-54%
-3%
-100%
-8%
-120%
-100%
-80%
-60%
-40%
-20%
0%
%
degradation
Retinol Revinage®
photodegradation Oxidative degradation
• photodegradation (6 hs. under UV radiation in a sun simulator chamber)
• oxidation (peroxide at 3% for 15 hs. at 30C)

38. Revinage®
Benefits
• Provides "retinol-like" activity resulting in effective anti-
aging and anti-photoaging action
• Reaches the deepest layers of the skin in 4 hours
• High stability to photodegradation and oxidation

39. Revinage®
Benefits
• increases by 17% the elasticity of the facial skin of
volunteers after 56 days
• increases by 25% the re-densification of the dermis in the
face after 42 days
• reduce in 67% the hyperpigmented regions in the face
after 56 days
• reduces the roughness of the facial skin in 36% after
after 42 days
• reduces in 28% the deep wrinkles of the facial skin after
42 days

40. Revinage®
Application
• Cream, lotion, non-transparent gel, gel-cream, serum and oil
for the treatment of aged and photo aged skin. . Not
applicable to hydro alcoholic formulation.
Stability and compatibility
• Add at the oil phase up to 85ºC
• pH: 5.5 – 7.0
Suggested Concentration
• 1-2%

41. THANKYOU!