OIL SOLUBLE BIOACTIVE COMPLEX TO REDUCE SEBUM PRODUCTION IN OILY SKIN FM-097B TDS Unireduce R-35 en(04).doc Version: 04 / 19.05.2008 1/12
Contents 1. Introduction... 3 2. Concept of the Complex Unireduce R-35... 4 3. Mode of Action... 5 4. Evidence of Effectiveness Reduction of Forehead Sebum... 7 4.1 Vehicle and Active Ingredients... 7 4.2 In vivo study... 7 4.3 Measurement of Skin Surface Lipids... 8 4.4 Statistical Analysis... 8 4.5 Results... 8 4.6 Conclusions... 10 5. Characteristics... 11 6. References... 12 FM-097B TDS Unireduce R-35 en(04).doc Version: 04 / 19.05.2008 2/12
1. Introduction Oily skin, usually accompanied by mild to moderate acne, is a widespread problem for nearly all teenagers and for many adults. Studies report that 90% of teenage boys and 80% of teenage girls [1,2] and 40-50% of adults aged 20-40 [3] are affected. Excessive skin surface oil is cosmetically unappealing, but can also trigger acne by clogging pores and by providing a growth medium for inflammation-causing bacteria. Sebum, which contains more than 50% triglycerides, as well as free fatty acids, wax esters, squalene, cholesterol esters and cholesterol, is produced by sebaceous glands located within the pilosebaceous unit (sebaceous gland(s), hair and follicle). It normally takes 14-21 days for sebum producing cells to generate their lipids, release them and then for these lipids to reach the skin s surface. Normal amounts of sebum, upon reaching the skin s surface and mixing with skin surface lipids, may play an important role of lubricating skin and hair and providing a protective layer on the skin s surface. Sebum production is stimulated by androgens, stress hormones and, as more recently discovered, peroxisome proliferators-activated receptor (PPAR) ligands. [4], which appear to play a crucial role in lipid metabolism. While the exact mechanism of acne formation is still unknown, traditional theory centers on excess sebum, which mixes with hyperproliferated keratinocytes to block follicles to form microcomedones (blackheads and whiteheads). P. acnes and other bacteria lipases break down sebum triglycerides into irritating free fatty acids, which, combined with other sources of inflammation, can lead to more severe types of acne, including pustules and cysts. There are many pharmaceutical approaches to acne, many of which reduce sebum. These include topical and oral retinoids, topical and oral antimicrobials and keratolitic agents such as salicylic acid. However, they are commonly associated with irritation and other negative side effects that are especially significant to the growing numbers of adults seeking treatment. Most cosmetic approaches to sebum control rely upon absorption of surface oils with materials such as talc and microsponges. A few cosmetic ingredients help to inhibit the underlying causes of oily skin and acne. They include 5- alpha reductase inhibitors, which block the conversion of testosterone into DHT and thus block a primary trigger of sebum production, and anti-inflammatory and antibacterial agents. In most cases of oily skin and/or acne, a multi-pronged approach to treatment is advised. Recent studies have linked oily skin and acne to abnormalities in lipid metabolism within the pilosebaceous unit. In individuals with oily skin, hyperkeratosis of the follicular epithelium is often linked to abnormalities in lipid composition in the follicle cell membrane [1]. These abnormalities lead to barrier dysfunction of the follicle membrane with consequent release of digested lipids, which eventually increases the amount of superficial lipids. A dysfunctional lipid metabolism in the sebaceous gland is responsible for the lack of correct intra membrane lipid production, with accumulation of free fatty acids and breakdown products. [1,5,6]. FM-097B TDS Unireduce R-35 en(04).doc Version: 04 / 19.05.2008 3/12
It is possible that a local deficiency of certain lipid precursors is associated with this abnormal lipid metabolism in the sebaceous glands of oily skin individuals, with a decreased catabolism of free fatty acids and a slower anabolism and increased breakdown of lipids important for the integrity and functionality of the follicle membrane such as phospholipids, isoprenoids, cholesterol, ceramides, etc. Recent studies have shown in fact that the lack of cholesterol, certain fatty acids and ceramides were responsible for the membrane barrier disruption of the follicle cell [7]. This abnormal lipid metabolism in the pilosebaceous unit would lead to free fatty acid accumulation and to a non functional follicle membrane, resulting in membrane rupture, release of free fatty acids and overall superficial sebum increase. One study [8-9] links oily skin and acne to a deficiency of Coenzyme A (CoA), which the body uses in two very important metabolic pathways: the synthesis of sex hormones and in fatty acid metabolism. CoA carries acyl groups used to lengthen and degrade long chain fatty acids along the metabolic pathway. When forced by shortage to choose between the two uses of CoA, the body will choose the most important process, production of sex hormones. Without enough CoA to properly metabolize fatty acids, lipids accumulate in the sebaceous glands, sebum increases and acne forms. Oily skin, acne and pore size were significantly improved by internal and external administration of pantothenic acid, the only precursor of CoA not produced within the body. Based on these studies associating deficient lipid metabolism with excess sebum and acne, it is possible to treat oily skin with a cosmetic blend of lipid precursors (in particular of the isoprenoids and sterols synthesis) which act as bioactivators on the skin, helping to normalize lipid metabolism. 2. Concept of the Complex Unireduce R-35 Unireduce R-35 is a carefully balanced blend of the isoprenoids and sterols biosynthesis precursors panthenyl triacetate (PTA) and farnesyl acetate (FA) which are converted in the skin to their active forms, pantothenic acid and farnesyl phyrophosphate, respectively. Lipophilic forms of both ingredients help penetration into the pilosebaceous unit, increasing their availability at the target tissue. The ester forms of both components also lead to a slow transformation into their active forms, creating a reservoir for extended release. In addition, d-panthenol derivatives are known to heal minor wounds, moisturize skin and sooth irritation. Farnesol derivatives are also used in a variety of cosmetics for their anti-bacterial properties. FM-097B TDS Unireduce R-35 en(04).doc Version: 04 / 19.05.2008 4/12
3. Mode of Action Panthenyl Triacetate (PTA) and farnesyl acetate (FA) are converted respectively in Panthotenic acid and in Farnesyl Pyrophosphate after application to the skin. However, this conversion takes place considerably more slowly in the case of the PTA and FA contained in Unireduce R-35 than in the case of their non acetylated forms, i.e. it displays a sustained action or depot effect. Pantothenic acid is classed as part of the vitamin B complex [10] and is a characteristic natural component of human metabolism. Pantothenic acid is one of several precursor substances forming coenzyme A, which is an important cofactor for acetylation reactions in numerous biochemical processes in the body such as lipids biosynthesis [11]. Coenzyme A plays a decisive part in cholesterol synthesis, outlined below in Figure 1. Both PTA and FA act as precursors in the cholesterol synthesis. FM-097B TDS Unireduce R-35 en(04).doc Version: 04 / 19.05.2008 5/12
PTA Acetyl-CoA HMG-CoA Mevalonate Mevalonate PP Isopentenyl PP FA Geranyl PP Farnesyl PP Squalene Cholesterol Figure 1: Role of Coenzyme A in cholesterol synthesis. FM-097B TDS Unireduce R-35 en(04).doc Version: 04 / 19.05.2008 6/12
4. Evidence of Effectiveness Reduction of Forehead Sebum 4.1 Vehicle and Active Ingredients Unireduce R-35, consisting of d-panthenyl triacetate and farnesyl acetate, was incorporated at 3% in a freshly produced cosmetic emulsion with a low lipid phase and with no fragrance. Care was taken not to incorporate in the emulsion any potential skin irritating ingredients. 4.2 In vivo study Twenty-five subjects were selected from the Derma Consult Concept GmbH (Bonn, Germany) database. They were informed about the importance and meaning of the study. Written informed consent was obtained from all the subjects prior to entry into the trial. The following criteria were used for selection of subjects: For inclusion in study: Female (between 25 and 35 years of age) clinically healthy oily skin (sebum 200 µg/cm²) For exclusion from study: skin diseases pregnancy The 25 subjects of this study were between 25-35 years of age (average: 30,4) and had oily skin. They could withdraw from study at any time without giving any reason. Subjects were instructed not to use any topical preparations on the test areas starting from seven days prior to testing and until the end of the test. For cleansing, water or a mild syndet (Eubos flüssig blau; manufacturer: Dr. Hobein, D-53340 Meckenheim- Merl, Germany) was allowed only (whole study inclusive the run-in phase), excluding a period of 12 hours before measurement. FM-097B TDS Unireduce R-35 en(04).doc Version: 04 / 19.05.2008 7/12
Prior to the first application of the test product, measurements were taken at clearly defined sites on the forehead. One side (randomized) remained untreated and served as control through the study. Further measuring was performed after 14, 28, 42 days of application 8-12 hours following the last daily application (adaptation time: 30 min, room temperature: 21±1 C, relative humidity: 50± 5%) and 2 weeks (day 56) after the last product application. The subjects used the test product (approximately 2 mg/cm²) twice daily (in the morning and evening) in home application after a demonstration in the test institute in a manner corresponding as largely as possible to that to be practiced by the future consumer. 4.3 Measurement of Skin Surface Lipids Measurements of sebum were performed with the Sebumeter SM 810 (Courage & Khazaka, Cologne, Germany). The sebum measurement on the skin is based on the world-wide acknowledged SEBUMETER method. It is a direct measurement of the sebum secretion on skin. The measurement principle is the photometric method, the grease spot photometer. This method is independent of moisture. A mirror under the measuring section of the tape protruding approx. 1 mm from the measuring head is linked with the cassette by a 0.3 N spring. This makes sure that the tape is pressed onto the measuring area with constant pressure by the mirror. The measuring time of 30 seconds is controlled by a clock in the device. For the determination of the sebum, the measuring head of the cassette is inserted into the aperture of the device, where a photocell measures the transparency. The light transmission represents the sebum content on the surface of the measuring area. A microprocessor calculates the result, which is shown on the display in µg sebum/cm² of the skin. Each value was the average of three measurements. 4.4 Statistical Analysis Data were analysed using the Student s T Test. 4.5 Results Treatment with 3% Unireduce R-35 was found to decrease sebum content on the forehead of oily skin volunteers at all time points tested. Reduction was statistically significant (p < 0.01, Student s T test) after 28 and 42 days of application (-19.8% at day 42) and on day 56 (14 days after discontinuation of product use) demonstrating that the product had a lasting reduction effect. Figure 2 and Figure 3 summarize the results. FM-097B TDS Unireduce R-35 en(04).doc Version: 04 / 19.05.2008 8/12
300 Untreated Unireduce R-35 3% Forehead sebum (µg/cm2) 250 200 150 100 * * * 50 0 14 28 42 56 Days * p < 0.01 vs untreated control, Student s T test Figure 2: Treatment of oily skin volunteers with Unireduce R-35 at 3% effectively reduced forehead sebum when compared to untreated area. FM-097B TDS Unireduce R-35 en(04).doc Version: 04 / 19.05.2008 9/12
treatment after treatment 100 95 Sebum content (% of untreated control) 90 85 80 * -19.8% * * 75 70 14 28 42 56 Days * p < 0.01 vs untreated control, Student s T test Figure 3: Treatment of oily skin volunteers with Unireduce R-35 at 3% effectively reduced forehead sebum. The product demonstrated a long lasting effect after 14 days of discontinuation. Results are expressed as % of untreated controls. Finally, the product showed an excellent safety profile. Dermatological tests didn t evidence any sign of skin irritation and the product was well tolerated. 4.6 Conclusions Unireduce R-35 is an excellent product to fight oily skin conditions. It demonstrates high efficiency in reducing skin sebum level over time and possesses a long lasting effect. Moreover, unlike other aggressive treatments for oily skin associated with skin exfoliation or irritation, Unireduce R-35 is well tolerated by human skin. FM-097B TDS Unireduce R-35 en(04).doc Version: 04 / 19.05.2008 10/12
5. Characteristics Composition Appearance Analytical data Solubility Unireduce R-35 contains no solvents or excipients and has a total active content of 99%, consisting of farnesyl acetate and d-panthenyl triacetate with 1% tocopheryl acetate as a stabilizer Slightly viscous liquid See specifications. Readily soluble in ethanol (80-90%), isopropyl myristate, propylene glycol, polyethylene glycol, and vegetable oils. Insoluble in water. Safety See safety data sheet Dosage 1-5% Storage Storage conditions: see safety data sheet Shelf life: see specifications Identification INCI name CAS No. Farnesyl Acetate 29548-30-9 Panthenyl Triacetate 94089-18-6 Tocopheryl Acetate 7695-91-2 FM-097B TDS Unireduce R-35 en(04).doc Version: 04 / 19.05.2008 11/12
6. References 1. James W.D. Acne. Clinical practice, N. Engl. J. Med., 352 (14), 1463-72 (2005). 2. Cordain L., Lindeberg S., Hurtado M., Hill K., Eaton S.B., Brand-Miller J. Acne vulgaris. A disease of western civilization, Arch. Dermatol., 138, 1584-90 (2002). 3. Rai L. Acne: face it, Skin Inc, 13 (5), 68 (2001). 4. Rosenfield R.L., Deplewski D., Kentsis A., Ciletti N. Mechanisms of androgen induction of sebocyte differentiation, Dermatol., 196, 43-46 (1998). 5. Pierard G.E., Ries G., Cauwenbergh G. New insight into the topical management of excessive sebum flow at the skin surface, Dermatol., 196, 126-129 (1998). 6. Yamamoto A., Takenouchi K., Ito M. Impaired water barrier function in acne vulgaris, Arch. Dermatol. Res., 287, 214-218 (1995). 7. Harris I.R., Farrell A.M., Grunfeld C., Holleran W.M., Elias P.M., Feingold K.R. Permeability barrier disruption coordinately regulates mrna levels for key enzymes of cholesterol, fatty acid, and ceramide synthesis in the epidermis, J. Invest. Dermatol., 109, 783-787 (1997). 8. Leung L.H. Pantothenic acid deficiency as the pathogenesis of acne vulgaris, Med. Hypotheses, 44, 490-492 (1995). 9. Leung L.H. A stone that kills two birds: how pantothenic acid unveils the mysteries of acne vulgaris and obesity, J. Orthomolecular Med., 12, 99 (1997). 10. Lehninger A.L. The citric acid cycle In: Lehninger A.L., Nelson D.L., Cox M.M. (eds.), Principles of Biochemistry, 2 nd Edition, Worth Publishers, New York, pp. 448-449 (1993). 11. Lehninger A.L. Lipid biosynthesis. In: Lehninger A.L., Nelson D.L., Cox M.M. (eds.). Principles of Biochemistry, 2 nd Edition, Worth Publishers, New York, pp. 669-674 (1993). ** Our indications and recommendations have been worked out to the best of our knowledge and conscience, but without any obligation from our part. In particular, we do not take any responsibility concerning protection rights of a third party. FM-097B TDS Unireduce R-35 en(04).doc Version: 04 / 19.05.2008 12/12