Synactin AC Providing 5-in-1 Solutions for Mitigating Acne-affected Skin
Background Acne is a red, irritating skin rash affecting about 80% of teenagers and young adults aged 12 to 24 years, although it can occur at all ages. Typically, acne appears in the oil-producing areas of the body namely, the face, chest, and back. Acne can have a short-term, potentially lasting psychological effect. No one factor causes acne. Acne is a complex, chronic and common skin disorder of pilosebaceous units. Hyperkeratinization of keratinocytes, increased sebum excretion from sebocytes via androgen stimulation, bacterial over population, and inflammatory cytokines are the major factors involved in the pathophysiology of acne. If the inflammation is right near the surface, one gets a pustule; if it s deeper, a papule (pimple); still deeper, then it s a cyst. If the oil breaks through to the surface, the result is a whitehead. If the oil becomes oxidized, especially squalene, the oil changes from white to black, and the result is a blackhead. Post-inflammatory hyperpigmentation (PIH) is a significant source of problem in acne subjects, especially affecting phototypes IV and above, and can last longer than actual acne lesions. Most of the exfoliating agents have the potential to cause cutaneous irritation and can lead to additional PIH. The recommendation now is that acne treatments be combined to target as many pathogenic factors as possible. Dark skin is more prone to PIH. Even though a good treatment might solve the acne problem, it does not address PIH. Stages of the development of acne Product Information Trade Name Synactin AC INCI Name Caprylic/Capric Triglycerides and Ethyl Linoleate and Hexylresorcinol CAS # 65381-09-1; 544-35-4; 136-77-6 ELINCS 265-724-3; 208-868-4; 205-257-4 Appearance Yellow to yellowish brown liquid Solubility Miscible with a wide-range of hydrophobic emollients Suggested use level 2 to 4% Storage Store in original sealed container at +10 to +30 0C; Avoid exposure to light & heat Skin Tolerance All three ingredients have long history of human use; Human Repeat Insult Patch Test (HRIPT) at 10% in corn oil is found to be a non-primary irritant and non-primary sensitizer Regulatory Globally approved 2 www.sytheonltd.com
Key Strategic Targets We have come a long way since 1896, when it was first suggested that Propionibacterium acne (P. acne), found in acne lesion, was the cause of acne. Although several lines of evidence suggest the direct role of P. acnes in acne, the mechanism by which P. acnes contribute to the pathogenesis of acne is debated. Despite extensive research on acne pathogenesis, the exact sequence of events and their possible mechanisms leading to the development of a microcomedone and its transformation into an inflamed lesion has remained unclear. Recent studies, however, have shown that only a minimal percentage of sebaceous glands are having lesions in any acne patient, even in severe cases (Saurat et al., Dermatology, 231:105-111, 2015). Typically, the mean lifetime of each lesion is a few days for inflammatory and a few weeks for non-inflammatory ones. Two distinct, partially overlapping, processes need to be addressed during the treatment of acne. One is to accelerate the healing of the ongoing lesions and the other one is to prevent the huge number of sebaceous glands prone to enter the acne cycle. The key strategic target in acne care appears to be the pilosebaceous follicle that is not yet involved in the acne cycle and the second one is to adequately control the key switching factors of comedone formation for long term relief. Therefore, a multi-tasking strategy is needed to improve the conditions of acne-affected skin. Taking this into consideration, Synactin AC has been designed to address all four major targets governing acne therapy while preventing hyperpigmentation issue. Synactin AC: Providing 5-in-1 Solutions in Mitigating Acne-affected Skin Reduces post-inflammatory hyperpigmentation Regulates follicular keratinization and barrier functions Synactin AC Produces anti-inflammatory effect Decreases sebaceous gland activity Decreases follicular bacterial population www.sytheonltd.com 3
Clinically Proven to Mitigate All Major Targets of Acne-affected Skin Protocol: Subjects (10) Mild acne as graded by trained expert 5 and 20 total lesions (inflammatory and non-inflammatory lesions); 3 inflammatory lesions Age 21.30 ± 4.54 Fritzpatrick skin Type Skin type II (2), III (6) & IV (2) Race White (9); Hispanics (1) Gender Male (5); Female (5) Duration of the study 6 weeks Frequency of application Twice a day Product Synactin AC (3% lotion) Assessment of Efficacy Methodology º Tolerance evaluation Objective (Dryness; Erythema & Edema) & Subjective (Stinging; Tingling; Itching & Burning) Well tolerated; 50% of subjects showing reduction in erythema (p = 0.015) º Photography Clarity 2D Ti image analysis Acne lesions; Post-inflammatory hyper-pigmentation; Pores º Subjective questionnaire (1) Total acne lesions; (2) Inflammatory acne lesions (Whiteheads); (3) Non-inflammatory acne lesions (Blackheads); (4) Post inflammatory hyperpigmentation & (5) Overall texture / appearance of skin 120 % of Subjects Responded Favorably (Subjective Questionnaire) 100 % of Subjects Showing Improvement from Baseline (Clarity 2D Ti Image Analysis) n 3 weeks n 6 weeks NS - Not statistically significant n 3 weeks n 6 weeks NS NS NS 60 50 0 Results 1 2 3 4 5 0 Acne Lesions Post inflammatory Hyperpigmentation Average Pore Diameter Pore Count Subjective questionnaire (1 to 5) showed an overall positive response, indicating that the subjects felt the test product reduced appearance in acne lesions (inflammatory and non-inflammatory), PIH and improved the overall texture/appearance of skin. Also, subjects have seen, after six-week treatment, significant reduction in erythema with no incidence of worsening in any tolerance attributes when compared to baseline. Subject 09TAD Clarity Image Analysis further supported clinical grading findings indicating a statistically significant reduction (p < 0.05) in acne lesions after three and six weeks of product use. Additionally, image analysis revealed a significant improvement in PIH as well as reduction in average diameter (size) of pores and pore count after six weeks of product use. Subject 03MB Baseline Subject 01AMR After 6-week treatment Baseline After 6-week treatment Baseline After 6-week treatment 4 www.sytheonltd.com
Science Behind the Product Why Select Synovea HR (Hexylresorcinol)? Hexylresorcinol (HR) is the most studied and well-known alkylresorcinol, which has an 80+year history of human use in food and pharmaceuticals. HR has a GRAS status and is considered to be safe and effective product for human use for both oral and topical applications. HR is a new gold standard for making skin lightening/even toning/brightening products. In addition, HR has preventive and restorative anti-aging properties (Chaudhuri, Cosmeceuticals and Active Cosmetics, 3r Edition, Chapter 7, 73-83, 2015; Review Synovea HR/Asyntra SL brochure). Produces anti-inflammatory effect by reducing NF-κB P. acne causes an inflammatory acne that is characterized by massive neutrophilic infiltration. IL-8 plays an important role in the pathophysiology of P. acne. A recent study confirmed that NF-κB activation is involved in the IL-8 production of monocytic cells stimulated by P. acne (Chen et al., J Dermatol Sci, 29(2):97-103, 2002). Protocol: Concentrations used Synovea HR (50 µg/ml) and Synactin AC (100 µg/ml) Cells Human 293T cells (1X105/ml) per well plate Medium DMEM medium supplemented with 10% fetal bovine serum, L-glutamine, penicillin-streptomycin NF-κB generation TNF-α induced Quantification Whole cell proteins were extracted and levels of NF-κB was measured using a TransAM NF-κB ELISA Kit. NF-κB was calculated against a standard curve Results Our study clearly showed that Synovea HR is a very potent NF-kB inhibitor with 43% inhibition and this effect is still intact (10.5%) in Synactin AC. 200 100 0-50 NFκB Inhibitory Activity of Synactin AC Control Synovea HR Synactin AC Reference: Chen et al., Food Chemistry, 12(3):914-920, 2011 n NFkB yield in pg/ml n % Reduction Decreases follicular bacterial population P. acne constitutes a major part of the skin microbiome and contributes to human health. However, it has also been implicated as a pathogenic factor in several diseases, including acne. Broad antibacterial/antifungal activities are also desired for anti-acne treatments since affected skin has much higher levels of Staphylococcus and candida (Nishijima et al., J Dermatol, 5:318-323, 2000). Synovea HR is indeed a broad-spectrum antibacterial/ antifungal agent (Chaudhuri, Cosmeceuticals and Active Cosmetics, 3r Edition, Chapter 7, 73-83, 2015) and shows synergism when blended with Ethyl Linoleate which does not have any anti-bacterial/antifungal activity at the dose tested. Antibacterial/antifungal activity of Synovea HR Microorganisms MIC in µg/ml Propionibacterium acne 50/25 Staphylococcus aureus 2.2 Staphylococcus epidermidis 2.2 Candida albicans 1.7 Streptococcus 0.7 Aspergilus 0.1 Synactin AC is an effective anti-acne blend Product P. Acne (MIC in µg/ml) Synactin AC (Contains only ~25% Synovea HR) 50/25 Synovea HR 50/25 Ethyl linoleate > 100 Synactin AC containing products may require low levels of preservation. Reduces post-inflammatory hyperpigmentation (PIH) PIH results from the overproduction of melanin or an irregular dispersion of pigment after cutaneous inflammation. When PIH is confined to the epidermis, there is an increase in the production and transfer of melanin to surrounding keratinocytes. Although the exact mechanism is unknown, this rise in melanocyte activity has been shown to be stimulated by inflammatory mediators as well as reactive oxygen species that are released during the inflammatory process (Davis et al., J Clin Aesthet Dermatol, 3(7): 20 31, 2010). Our study shows that Synovea HR is an effective product in reducing hyperpigmented spots without affecting the surrounding areas and also stimulates endogenous antioxidant defense system, specifically glutathione (Chaudhuri, Cosmeceuticals and Active Cosmetics, 3r Edition, Chapter 7, 73-83, 2015). www.sytheonltd.com 5
Science Behind the Product Why Select Synovea EL (Ethyl Linoleate)? Ethyl Linoleate (EL) is a neutral, lipid-soluble form of Linoleic acid (LA) which is an essential fatty acid needed for skin nourishment. EL is easy to use and has a high stability against oxidation over LA. Decreased amount of LA is found in the skin surface lipids of acne subjects (Ottaviani et al, Mediators of Inflammation, Article ID 858176, 2010). EL is reported to accelerate healing of wounds (Jelenko et al, Ann Surg, 182(5):562-566, 1975). In addition, LA lightens UV-induced skin pigmentation (Ando et al., Arch Dermatol Res, 290:375-381, 1998) and works by accelerating post-translational degradation of tyrosinase (Ando et al., Biochem J, 394:43-50, 2006). EL is reported to be converted to LA in-vivo (Hungund et al., Alcohol Clin Exp Res, 19(2):374-377, 1995). Ethyl Linoleate is clinically proven to have anti-acne property Protocol: Subjects Treatment group 20; Placebo group 20 Mild to moderate facial acne as graded by trained expert Age: 16 to 45 yrs. Fritzpatrick skin Type: Skin type II to V Race: Treatment group: White (14); Asian (4); African-Caribbean (2) Placebo group: White (15); Asian (3); African-Caribbean (2) Gender: Treatment group - Male (7); Female (13) Placebo group Male (11) & Female (9) Duration of the study 12 weeks Frequency of application Twice a day Product Lotion containing EL and Triethyl citrate and placebo without the actives Assessment of Efficacy Methodology º Primary endpoints Changes in acne severity and sebum production after 12 weeks treatment based on Leeds revised grading system, Photometric measurement of the Sebutape and adverse events at any time º Secondary endpoints Total, inflammatory and noninflammatory lesions º Statistical analysis Statistical package SPSS 11 (SPSS, Chicago, IL, USA); Linear regression model Reference: Charakida et al., Brit J Dermatol, 157(3):569-574, 2007 Results 12-week treatment clearly showed that the treatment group substantially affected the reduction in acne severity (from 4 to 2) in 12 weeks whereas the placebo group worsens the severity of acne (from 4 to 5). Product is well tolerated with only one drop out from the treatment group and none with the placebo. 120 Assessment of Efficacy - Lesions & Sebum production 60 Improving Worsening 0 Active-Initial Active-12 weeks Placebo-Initial Placebo-12 weeks n Inflam lesions n Non-inflam lesions n Sebum production Regulates follicular keratinization and barrier function A major pathogenic factor of acne is the disturbed keratinization of the follicular infundibulum. It has been demonstrated that a relative decrease in linoleic acid in the sebum is responsible for this, at least partially (Letawe et al., Clin Exp Dermatol, 23(2):56-58, 1998). Alteration of skin surface lipids and linoleate deficiency also has impact in skin s sphingolipids in particular acylceramides. Lower levels of sphingolipids and ceramides in keratinocytes of acne subjects has been shown. These altered ceramides is dysfunctional, resulting in hyperkeratotic follicular epithelium with an incompetent water barrier and possibly other functional defects favorable to the formation of acne (Stewart et al., J Invest Dermatol, 87(6):733-6, 1986). In addition ceramides can trigger NF-kB generation (Schultz et al., Cell, 71(5):765-776, 1992). 6 www.sytheonltd.com
Decreases sebaceous gland activity The normal function of sebaceous glands is to produce and secrete sebum, a group of complex oils including triglycerides and fatty acid breakdown products, wax esters, squalene, cholesterol esters and cholesterol. Sebum lubricates the skin to protect against friction and makes it more impervious to moisture. Low levels of linoleic acid have been observed in skin surface lipids of acne patients. The biological function of sebocytes is regulated by several factors, linoleic acid is one of them (Makrantonaski et al., Dermatoendocrinol, 3(1): 41 49, 2011), lacking any one of these factors makes sebaceous gland dysfunctional with increasing severity of acne. Produces anti-inflammatory effect by inhibition of NF-kB Recent study showed that LA and other unsaturated fatty acids has anti-inflammatory activity (Zhao et al., Biochem Biophys Res Commun, 336(3):909-917, 2005). When cells were pre-incubated with LA for 2-h and then stimulated with lipopolysaccharide for 24-h in the presence of fatty acids, secretion of interleukin (IL)-6, IL-1ß, and tumor necrosis factor-alpha (TNFα) was significantly decreased after treatment with LA (p < 0.01l. These effects were comparable to those for 15-deoxy- 12, 14-prostaglandin J2 (15d-PGJ2) and were dose-dependent. In addition, LA decreased IL-6, IL-1ß, and TNFα gene expression (p < 0.05l) and NF-kB DNA-binding activity, whereas peroxisome proliferator-activated receptor-gamma (PPARγ) DNA-binding activity was increased. The results indicate that the anti-inflammatory effects of LA may be, in part, due to the inhibition of NF-kB activation via activation of PPARγ. Formulation Guidelines A unique stand-alone product with Synactin AC can easily be developed for mitigating acne-affected skin with the improvement in postinflammatory pigmentation. With appropriate selection of additional co-actives, effective multi-functional finished formulations can be developed. Following guidelines need to be followed in order to develop effective and aesthetically pleasant formulated products: Add Synactin AC to the oil phase directly or after making the lotion while cooling at around 40 0 C. For preparation of serum or transparent gel, use non-ionic solubilizers having high HLB values. Use PEG-40 hydrogenated castor oil, Laureth 23, Polysorbate 20 or 80 Addition of a chelant (0.1%) resolves the coloration problem, if any, due to the presence of iron or copper; Propyl gallate (0.15 to 0.2%) can be used to stabilize color, if needed The finished product must be acidic, preferably having ph below 5.5 Formulations containing Synactin AC may cause drop in viscosity. Acidic (such as Xanthan gum) or neutral thickeners (such as Cellulosics) are good for maintaining desired viscosity The finished product should be protected from prolong exposure to heat and light Suggested Co-actives for Improving Anti-acne Benefit Co-actives Rational/Skin Benefits Use Level Salicylic Acid Helps unclog pores to resolve and prevent lesions 2% Sytenol A (INCI: Bakuchiol) Niacinamide Required for inhibiting formation of squalene peroxide which promotes acne, roughening of skin, and wrinkling (Chiba et al., Exper Dermatol, 8:471 479, 1999); Sytenol A is an excellent lipid peroxidation inhibitor (IC 50 = 0.61; IC 100 = 1.46 µg/ml) (Chaudhuri & Ou, 130:64-75, 2015) and has a very effective anti-acne property (Chaudhuri & Marchio, 126:502-510, 2011) Provides potent anti-inflammatory activity without the risk of inducing bacterial resistance (Shalita et al., Int J Dermatol, 34(6):434-437, 1995): Multiple skin benefits 0.25% 2% www.sytheonltd.com 7
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