Sytenol® A
The First Natural Alternative to Retinol for Acne-prone Skin
Sytenol® A
Propionibacterium acnes (P. acnes) is a gram-positive normal skin commensal bacterium present in all individuals. Clinically relevant
inflammation in acne may be initiated by disruption of the follicular epithelium followed by the spread of bacteria, including
Propionibacterium acnes, to the dermis, leading to the development of papules, pustules, and nodulocystic lesions (Zouboulis, Clin Dermatol
22:360–366,2005). P. acnes induces the expression of pro-inflammatory cytokines in various cells involved in cutaneous innate immunity
(Ingham et al., J Invest Dermatol 98:895–901, 1992). Although P. acnes is a commensal bacterium of normal skin, it (together with the
sebaceous gland) is considered to have an important role in acne development. Several studies have indicated that specific strains of P.
acnes bacteria are more commonly associated with acne vulgaris. However, other bacteria (e.g. Staphylococcus and Corynebacterium) can
also reside in the follicle and on the surface of the skin.
Acne is a disease of pilosebaceous unit affecting about 80% of teenagers and young adults typically aged 12 to 24 years. Acne is not life
threatening; however, it does have a significant psychological impact. Embarrassment, low self-esteem, anxiety, anger, frustration, feelings of
depression and social withdrawal may be associated with acne (Baldwin et al., Cutis, 70:133-139, 2002).
Product Information
Trade Name Sytenol® A
INCI Name Bakuchiol
Chemical Name Phenol, 4-[(1E, 3S)-3-ethenyl-3, 7-dimethyl-1, 6-octadienyl]
CAS # 10309-37-2
Origin 100% Natural; Extracted and purified from edible seeds
Appearance Yellow to yellowish brown liquid
Purity 95 % min. (Typically, around 99%)
Solubility/Miscibility Miscible with a wide-range of hydrophobic emollients
Stability Photochemically & hydrolytically stable
Suggested use level 0.5 to 1%
Storage Store in original sealed container at +10 to +30 0C; Avoid exposure to light & heat
Regulatory Approved for use in all major countries – US, Australia, Europe, Canada, Japan, Korea and many others
Patents US 8,529,967; US 8,859,021; Multiple pending US & European patents
What are the Treatment Targets Available for Acne?
No single factor causes acne. Acne is a complex, chronic and common skin disorder. Increased sebum excretion from sebocytes via androgen
stimulation & integrity of sebum, bacterial over population, inflammatory cytokines and hyperkeratinization of keratinocytes are the major
factors involved in the pathophysiology of acne. Acne research continues to deliver new pieces to the puzzle, and helps us to understand
acne pathogenesis and assist the development of new treatment against acne. Therefore, a multi-tasking strategy is needed to improve the
conditions of acne-affected skin. Sytenol® A, certainly has some of these key attributes.
Factors Affecting Acne
Sebum Production Overpopulation
Inflammation Hyperkeratinization
& Its Integrity of Bacteria
2 www.sytheonltd.com
Clinically Proven to Mitigate Multiple Signs of Acne
Percent reduction in acne was determined by Global Acne Grading System (Burke et al., British J Dermatol, 111:83-92, 1984). This system takes
into account both non-inflammatory and inflammatory lesions. Based on the results, formulations containing 1% Sytenol® A + 2% Salicylic
acid showed a nearly 70% reduction in acne lesions and the next best results were with Sytenol® A alone, which reduced acne score by about
57% (Chaudhuri & Marchio, Cosm & Toil, 126:502-510, 2011).
Recently, Polakova et al., reported an 8-week 111 subject study with adapalene (0.1%) vs Bakuchiol + adapalene containing formulations
(Polakova et al., Clin Cosmet Investig Dermatol, 8:187–191,2015). Results show statistically significant improvement in all parameters and
Bakuchiol certainly improved the treatment outcome of adapalene 0.1% gel in acne subjects. Overall performance, safety and tolerance with
Bakuchiol containing formulation was much better than adapalene alone.
% Reduction in Acne: Global Acne Grading
Protocol: 0
• Subjects – 15 x 4 with mild (up to 10 comedones) & moderate (10 to 25)
• Duration of the study – 6 weeks
• Frequency of application – Twice a day
• Products – Sytenol® A (1% lotion), Salicylic acid (2% lotion), Sytenol® A +
Salicylic acid (1+2% lotion) and Placebo (no active)
• Assessment of Efficacy – -40
o Acne score at initial day
o Reduction in comedones after 2, 4 & 6 weeks of treatment
o Reduction in erythema and pruritus after 2, 4 & 6-weeks of treatment
• Results – Sytenol® A alone or in combination with Salicylic acid provide
-80
statistically significant improvement in acne-affected skin and is well
tolerated. n Sytenol® A n Salicylic Acid
n Sytenol® A + Salicylic Acid n Placebo
Treatment with 1% Sytenol® A Lotion
Subject - ID7, Front Subject - ID7, Left
Initial day After 6-weeks Initial day After 6-weeks
Subject - ID9, Front Subject - ID9, Left
Initial day After 6-weeks Initial day After 6-weeks
www.sytheonltd.com 3
Science Behind the Product - Controlling Sebum Production & Its Integrity
Sytenol® A helps maintain the integrity of skin lipids
Free fatty acids and squalene are major lipids that make up sebum. Squalene is one of the most common lipids produced by human
skin cells (Spanova and Daum, Eur J Lipid Sci Technol, DOI:10.1002/eljt.01100203, 2011). Squalene is a polyunsaturated lipid and is highly
susceptible to peroxidation and photodegradation. The byproducts, squalene peroxides, promote acne, roughening of skin, and wrinkling
(Chiba, J Toxicol Sci, 25:77-83, 200; Chiba et al., Exper Dermatol, 8:471-479, 1999). Squalene peroxides also diminish the important skin
antioxidant glutathione (Chiba et al., J Biochem Mol Toxicol, 15:150-158, 2001).
Squalene production is highly upregulated in acne. As expected, an increase in squalene sets the stage for significantly higher levels of
squalene peroxides and diminished vitamin E (Vit.E) in the sebum of acne subjects (Picardo et al., Dermatoendocrinol, 1:68-71, 2009). The
squalene peroxides confirmed to be highly comedogenic (Chiba et al., Toxicol Sci, 25:77-83, 2000), they have recently been reported to set
an inflammatory cascade in motion. Specifically, exposure of squalene peroxides to human keratinocyte cells stimulates production of
inflammatory cytokines and upregulates lipooxygenase (LOX) activity (Ottaviani et al., J Invest Dermatol, 126:2430-2437, 2006). This has
been implicated in promoting inflammation in acne even in the absence of P. acnes.
When keratinocytes are exposed to P. acnes surface proteins, there is an immediate generation of ROS, mainly superoxide. This explains
why superoxide dismutase (SOD) and glutathione peroxidase become exhausted due to the burden of oxidative stress, particularly in more
severe forms of acne. In papulopustular acne, antioxidant system is reported to be compromised (Basak et al., J Dermatol, 28(3):123-127,
2001). It would seem reasonable to assume that clinical interventions with topical agents designated to support the antioxidant defense
system and/or direct quenching of radicals generated on the skin surface would be helpful in improving acne-affected skin (Grange at al.,
PLoS Pathol, 5:e1000527, 2009; Whitney et al., J Drugs Dermatol, 11(6):742-746, 2012).
Sytenol® A is a broad-spectrum radical and non-radical quencher and has an excellent lipid peroxidation inhibitory activity (Chaudhuri & Bou, C&T,
130:63-75, 2015). It is also capable of stimulating antioxidant defense system (Chaudhuri, EuroCosmetics,11-12:20-24, 2015). This dual antioxidant
pathways of Sytenol® A can help maintain lipid homeostasis and hence relief to acne-affected skin.
Consequences of squalene peroxidation
UV, 02 Vit. E Squalene
Squalene Monohydroperoxide
SOD
Comedones Hyperkeratosis
IL-1α, IL-6, IL-8, IL-10 PPARs 5-LOX COX2 PGE2
Cytotoxicity
Inflammation MMPs
Immunosuppression
4 www.sytheonltd.com
Sytenol® A is a radical & non-radical quencher
Singlet Lipid
Unit1 Peroxyl Hydroxyl Superoxide Peroxynitrite Oxygen Peroxidation2
Sytenol® A 15,165 569 204 130 1,325 0.5
Natural Tocopherol 813 Not detected Not detected 1 1,110 30
1
µmole Trolox equivalent/g
2
Squalene was used as a substrate for lipid peroxidation inhibitory activity; data is expressed in IC50 in µg/ml; 60-fold more effective than Tocopherol
Sytenol® A up-regulates antioxidant defense genes
Fold Change: Sytenol® A vs. Retinol
5
Protocol:
DNA microarray test using full thickness Epiderm tissue (Mattek)
2.5
• Retinol and Sytenol® A were dissolved in DMSO, further diluted
in water and applied to full thickness Epiderm tissues
• Incubation for two days
0
• Selected gene expressions having >± 2-fold change
• Statistical significance: p = ≤0.05
n Sytenol® A n Retinol
Roles played by the antioxidant defense genes
• Glutathione peroxidase (GPX3): Reduces lipid hydroperoxides • NAD(P)H dehydrogenase (quinone)] gene (NQO1): Catalyzes
to their corresponding alcohols and to reduce free hydrogen metabolic detoxification of quinones and protects cells against
peroxide to water quinone-induced oxidative stress, cytotoxicity, and mutagenicity
• Glutathione S-transferases (GSST1 and GSTP1): Regulates the (Long etal., 60(21):5913-5915, 2000).
intracellular concentrations of the lipid peroxidation products
Science Behind the Product - Controlling Bacterial Overpopulation
The significance of the involvement of P. acnes in acne pathogenesis is still controversial, mainly due to the fact that it belongs to the
resident microbiota. Recently, metagenomic analysis demonstrated that while the relative abundance of P. acnes were similar in healthy and
acne-affected skin, the strain population structures were significantly different in the two cohorts. Certain strains were highly associated
with acne and other strains were enriched in healthy skin (Fitz-Gibbon et al., J Invest Dermatol, 133(9):2151-2160, 2013).
Overwhelming body of evidence, however, implicates propionibacteria, and P. acnes in particular, in inflammatory acne. P. acnes is neither
a primary pathogen nor a bystander. P acnes plays an active role in determining the nature and extent of the immune response (Mouser
at al., J Invest Dermatol, 121:1226-1228, 2003; Lodes et al., Microbiol, 151(12):3667-3681, 2006). Treatments that reduce P. acnes numbers
lead to clinical improvement of acne (Thiboutot et al, 15:97-109, 1997). Acne-affected skin has also been reported to have higher levels of
Staphylococcus and Candida (Nishijima et al., J Dermatol, 27(5):318-323, 2000; Slobododnikova et al., Phytother Res, 18(8):674-676, 2004).
Sytenol® A has broad-spectrum antibacterial and antifungal property (MIC values in µg/ml)
Microorganisms Sytenol® A Retinol Benzoyl Peroxide Salicylic acid
P. acnes 1.5 31 50 >100
Staphylococcus aureus 1 N/D 15.6 N/D
Staphylococcus epidermidis 2 N/D >100 N/D
Candida albicans 1.5 N/D N/D N/D
N/D = Not determined
www.sytheonltd.com 5
Science Behind the Product - Inhibiting Inflammation
Emerging data indicate that acne is a primary inflammatory disease, with histological, immunological and clinical evidence suggesting
that inflammation occurs at all stages of acne lesion development (Tenghetti, J Clin Aesthet Dermaol, 6(9):27-35, 2013). The immunochemical
pathways underlying the initiation and propagation of the inflammation in acne are complex and still being elucidated but shown to
involve P. acnes (Ottaviani et al., J Invest Dermatol., 127:2430-2437, 2006). However, inflammatory response can occur in the absence of P.
acnes, in both early and clinically inflammatory lesions, other pathways must exist.
It is well documented that inflammation is critical to all types of acne lesions and is multifactorial, Sytenol® A is expected to provide relief
to acne-affected skin (Chaudhuri & Marchio, Cosmet &Toilet, 126(7):502-510, 2011; Chaudhuri, Cosmeceuticals & Active Cosmetics, 3rd edition,
Maibach et al, eds, Chapter 1, pp-1-18, 2015) by inhibiting multiple inflammatory genes and enzymes.
Sytenol® A down-regulates pro-inflammatory genes
Protocol
DNA microarray test using full thickness Epiderm tissue (Mattek)
• Incubation for two days
• Retinol and Sytenol® A were dissolved in DMSO, further diluted • Selected gene expressions having >± 2-fold change
in water and applied to full thickness Epiderm tissues • Statistical significance: p = ≤0.05
Gene Gene Description Retinol Sytenol® A
COX1/PTGS1 Cyclooxygenase-1 (Prostaglandin G/H synthase precursor) -3.4 -3.6
PLAA Phospholipase A-2-activating protein No effect -7.7
PLA2G4A Cytosolic phopholipase A2 -3.1 -2.6
PTGER2 Prostaglandin E2 receptor EP2 subtype (PGE2) -2.2 -2.4
PTGER4 Prostaglandin E2 receptor EP4 subtype (PGE2) -3.0 -6.1
*HPGD/15PGDH Prostaglandin dehydrogenase 1 +4.1 +21.8
* HPGD is a catabolic enzyme controlling the biological activities of prostaglandins by converting them into inactive keto-metabolites
Diacyl glycerol or
Phospholipid
Sytenol® A inhibits pro-inflammatory enzymes
Sytenol® A has inhibitory activity against pro-inflammatory PLA
enzymes, such as phospholipase A2 (PLA2) and dose-
dependently reduce formation of LTB4 and TXB2 (Ferrandiz et
al., J Pharm Pharmacol, 48(9):975-980, 1996). Our study showed Arachidonic Acid
that Sytenol A is effective in inhibiting COX-1 IC50 14.7 µg/ml)
and COX-2 (IC50 514 µg/ml) activities. Interestingly, at higher
dose (50 µg/ml), Retinol boosts COX-2 activity while Sytenol® A Sytenol® A
LO
X
CO
reduced the activity by 40% (Chaudhuri & Marchio, Cosmet &Toilet,
126(7):502-510, 2011). Literarture also shows that Sytenol® A has
lipooxygenase (LOX) inhibitory activity (Ferrandiz et al., J Pharm
Pharmacol, 48(9):975-980, 1996).
Inflammatory Balance
Prostaglandins Leukotrienes
6 www.sytheonltd.com
Science Behind the Product - Correcting Hyperkeratinization
One of the most crucial initial events in the development of acne lesions is hyperkeratinization in the follicular infundibulum and sebaceous
duct resulting in microcomedones. Folicular keratinization seems to be triggered by relative deficiency of linoleic acid and peroxides in
sebum (Georgel et al., Infect Immune, 73:4512-4521, 2005). Increased 5-α-reductase (DHT) may act on infundibular keratinocytes leading
also to abnormal hyperkeratinization (Akamatsu et al., J Invest Dermatol, 99:509-511, 1992).
% Down-regulation of 5-α-reductase expression
Sytenol® A is an excellent down-regulator of
Type-1 5-α-reductase
Sytenol® A Retinoic acid
Protocol 0
• Cell – HaCat human keratinocytes
• Incubation time – 48 hrs.
• Quantification – Immunofluorescence technique; Determined
spectrophotometrically at 485/518 nm Ex/Em
• Result – At 10 µg/ml, Sytenol® A down regulates 5-α-reductase -50
by about 40% and compares well with retinoic acid n 5ug/ml n 10 ug/ml n 20 ug/ml
Formulation Guidelines
Sytenol® A is a lipophilic compound miscible in a wide variety of emollients, such as, caprylic/capric triglycerides, ethyl linoleate, C12-15
alkyl benzoates, squalane, jojoba oils, olive oils, etc. Sytenol® A can be easily formulated into creams, lotions, oils, serums, hydro-alcoholic
sprays, etc.
• Sytenol® A should be used at a level of 0.5 to 1.0% (w/w) of • Addition of a small amount of a chelating agent (0.05%) is helpful in
finished formulation overcoming coloration issue due to the presence of iron or copper
• Add Sytenol® A to the formulation after making emulsion with • The finished product must be acidic, preferably having pH below
a processing temperature of about 50 0C. Alternately, Sytenol® A 6 and must be protected from prolong exposure to heat and light
can be included in the oil phase for maintaining product integrity over time.
Suggested additives for improving effectiveness of Sytenol® A
Additives Rationale Use Level
Salicylic Acid Helps unclog pores to resolve and prevent lesions 2%
Provides potent anti-inflammatory activity without the risk of inducing
Niacinamide 2%
bacterial resistance (Int J Dermatol,34(6):434-437,1995): Multiple skin benefits
HydraSynol™ IDL Regulates follicular keratinization, maintains barrier functions,
2-4%
(Isosorbide dilinoleate) maintains stratum corneum acidity; Review also Synovea® EL brochure
Key References
1. RK Chaudhuri, Bakuchiol; A retinol-like functional compound modulating multiple retinol and non-retinol targets, In Cosmeceuticals and
Active Cosmetics, 3r Edition, Eds., RK Sivamani, J Jagdeo, P Elsner & HI Maibach, Francis & Taylor, Boca Raton, Chapter 1, 1-18, 2015
2. K Poláková, A Fauger, M Sayag, and E Jourdan, A dermocosmetic containing bakuchiol, Ginkgo biloba extract and mannitol improves the
efficacy of adapalene in patients with acne vulgaris: result from a controlled randomized trial, Clin Cosmet Investig Dermatol, 8: 187–191,2015
3. RK Chaudhuri, B Ou, Bakuchiol to stabilize retinol and polyunsaturated lipids, Cosm & Toil, 130:64-75, 2015
4. RK Chaudhuri & K Bojanowski, Bakuchiol: A retinol-like functional compound revealed by gene expression profiling and clinically
proven to have anti-aging effects, International J Cosmetic Science, 36(3):221-230, 2014
5. RK Chaudhuri & F Marchio, Bakuchiol in the management of acne-affected skin, Cosm & Toil, 126:502-510, 2011
www.sytheonltd.com 7
Sytheon Ltd.
315 Wootton Street, Boonton, NJ 07005
www.sytheonltd.com • [email protected]
Tel.: +1 973.988.1075
Sytheon SARL
112 rue de Paris, 92100 Boulogne Billancourt
www.sytheonltd.com • [email protected]
Tel.: +33 (0)1.4110.8182
Disclaimer
The information given and the recommendations made herein are based on our research and literature search and are believed to be accurate but no guarantee of their accuracy is made. This information is intended to be helpful, but no warranty
is expressed or implied as to the results obtained from use in the formulation, procedure or products suggested herein. Neither is any permission or recommendation to practice any invention covered by patent either expressed or implied.
