Issue 38 — February 2005

Issue 38
Categorie		Title		Authors
Market Report		Impure skin: Natural actives in the treatment of acne-prone skin		Annette Mehling, Sybille Buchwald-Werner

Abstract

Over 90 percent of the population will at sometime during their lives be affected by impure skin. Approximately 80 percent of the teenagers develop impure skin, with the most common type of disease being acne vulgaris. About 20 percent of patients suffering from acne need clinical treatment. The oily skin and the lesions typical of acne (blackheads, pimples, pustules) can not only cause disfiguring scarring and hyperpigmentation but also cause severe emotional damage and social handicaps. There is a large demand for cosmetic products for impure skin because the affected people tend to wait as long as possible before they consult a dermatologist. Not only to help support dermatological therapies but also to avoid major skin damage due to self medication, market products should have a proven effect.

The etiology of the most common form of acne, acne vulgaris, is multifactorial but 4 main factors play a pathophysiological role: 1) increased sebum secretion; 2) abnormal keratinization of the follicle; 3) increased proliferation of the skin microflora (e.g. Propionibacterium acnes), and 4) inflammatory responses. The following are examples of natural actives that could find their application in cosmeceutical products: Licorice root extracts (seboregulating), centella asiatica extracts (anti-scarring), green tea extracts (anti-microbial), aloe vera extracts (anti-inflammatory), etc. Whitening properties of the extracts can also be used to combat hyperpigmentation (licorice root extract).

Introduction

There are probably very few of us that can look back to the days of their teens and that do not have those awful memories of staring into a mirror and being mortified by seeing a big pimple smack in the middle of our face, knowing that that huge zit is unquestionably going to draw stares, condescending sniggers, if not worse. Let your memories wander back to the days when you had moderate acne all over your face and the depreciative looks or the quiet commiseration it prompted. Who can’t remember the embarrassment and the emotional stress and suffering it caused and words like blemishes, zits, pimples, spots, pizza face made you cringe and want to hide. It is estimated that more than 40 percent of teenagers consider people with acne less desirable; one-third of all teenagers think that people with acne are definitely less popular and cool to hang out with. Impure skin affects many people during the course of their lives. In general impure skin refers to skin having one or more of the following attributes: Shiny, greasy or oily appearance, enlarged pores, tendency to develop comedones, pimples and pustules. This is why impure skin is usually used as a synonym for acne-prone skin.

Although people afflicted with impure skin suffer, many tend to wait as long as possible before they consult a dermatologist. This results in a large demand for cosmetic products to help alleviate some of the symptoms of impure skin. These products should therefore have a proven effect to help support dermatological therapies but also to avoid major skin damage due to self medication. Market analyses show that products for impure skin are represented in mass market products as well as in high price level products. The following article describes the etiology of impure skin and gives a short overview on the current market situation. Botanical actives for use in combinatorial or holistic approaches in cosmetics for impure skin are presented.

Etiology of impure skin

Genetics, hormones, and environment all influence impure skin. Impurities can result from adverse reactions resulting from allergies, from incompatibilities with skin care products, excessive use of steroids, etc. Acne itself is a disorder of the pilosebaceous follicle with various subtypes occurring. Approximately 80 percent of the teenagers develop impure skin, with the most common type of disorder being acne vulgaris. Not only men but an increasing amount of women experience a type of impure skin termed acne tarda far into adulthood and which often persists beyond the age of 40. Some forms -acne neonatorum and acne infantum - even affect newborns and infants.

Acne vulgaris has an estimated lifetime prevalence of appr. 80 percent. Because of this high prevalence, the main emphasis in this article will be placed on this form of impure skin. The most common anatomic sites of acne lesions are the face, neck, chest, back, shoulders, but the scalp, upper arms and legs can also be affected. The clinical presentation of acne spans the range from the mild comedonal (blackheads/whiteheads) to the massive inflamed lesional (papulopustular; nodular; cystic) forms. The inflammatory and non-inflammatory lesions typical of acne can not only cause disfiguring scarring and hyperpigmentation but also cause severe emotional damage and social handicaps. It is estimated that appr. 30 percent of adolescents and 5 percent of adults need clinical intervention to control acne.

The etiology of acne vulgaris is multifactorial but four main factors play a pathophysiological role:

1. Increased sebum secretion: The increase in androgens during puberty and adolescence result in a rise in testosterone levels. In the skin, this hormone is converted by the enzyme type 1 5-alpha-reductase to the more potent dihydrotestosterone, which in turn, triggers an enlargement of the sebaceous glands and a concomitant increase in sebum production.

2. Abnormal keratinization of the follicle: The increased proliferation of keratinizing cells lining the sebaceous follicle, the defective desquamation of the corneocytes, along with the excessive sebum buildup result in blockage and the formation of an adherent plug known as a comedone (the non-inflammatory lesions presenting clinically as whiteheads and blackheads).

3. Increased proliferation of the skin microflora (e.g. Propionibacterium acnes): The lipid rich sebum provides the Gram-positive bacteria with sufficient substrate for growth. This along with the microanaerobic milieu generated by the comedone, makes this an ideal environment for the proliferation of Propionibacterium acnes.

4. Inflammatory responses: Propionibacteria produce lipases which degrade diacylglycerols and triacylglycerols to glycerol and free fatty acids. These factors and other proinflammatory/chemotactic substances that are produced provoke inflammatory responses. In particular, the proinflammatory cytokine IL-1 alpha plays a major role in the processes governing inflammatory acne. The secretion of this interleukin seems to be only in part due to Propionibacteria and many comedones contain such high amounts that unspecific reactions can be initiated. Reactive oxygen species (ROS) also seem to play a role in the inflammatory processes associated with acne.

Market overview

The main target in public promotion and advertisements is the young problematic skin. Approximately 30 percent of the face care market are cleansing products and approximately 20 percent of these products are claimed for special cleansing applications, e.g. for impure skin (1). Various application forms can be found including creams, foams as well as wipes and masks. Follow-up skin care products for impure skin are unfortunately not as well presented. Main brands in Germany are Clearasil, Bebe clean & clear, Jade Hautklar and Normaderm. As pendant to a good cleansing product, a face care formulation which smoothes and moisturizes the skin, prevents shine, protects against UV and has a protecting function due to anti-oxidants is recommended. Traditional top actives for impure skin are salicylic acid, triclosan, zinc oxide, witch hazel and chamomile extract as well as alpha-hydroxy-acids (AHAs). In current trend products micro-sponges, vitamins A, B, and C, green tea extract and dipotassium glycyrrhizate are also often used.

Natural actives

So where does this put us with respect to acne? As salicylic acid (found in willow bark extracts) is well known and described in many papers, the main focus in this article is on other botanicals that have a beneficial role in combating the four major causative factors of acne. The list of botanicals described is only meant to provide some insight into their modes of function and is by no means exhaustive (Table 1).

1. Increased androgen/sebum secretion:
Cutaneous androgen metabolism can be modulated by plant extracts. A higher level of activity of type 1 5-alpha-reductases is found in the sebaceous glands compared to whole skin or non-acne prone areas of facial skin (2). Extracts of Serenoa repens (saw palmetto) extracts are well-known inhibitors of both type 1 and type 2 5-alpha-reductases. Phytoestrogens, green tea catechins, epicatechin-3-gallate and epigallocatechin-3-gallate, can also modulate the production and biological actions of androgens and other hormones (3, 4). Vitex agnus castus has been reported to possibly help reduce acne associated with the menstrual cycle in women (5). Witch hazel can be used as a natural astringent and cleanser. It refreshes the skin and can reduce excess of oil and tighten pores.

Table 1: Natural actives for impure skin

Sebum regulation :— Licorice: 18 b Glycyrhetinic acid (Zn Combination) — Green tea extract

Anti-scarring, decrease of abnormal keratinization: — Centella asiatica extract — Willow extract — Birch extract

Anti-microbial against “Propionibacterium acnes”: — Green tea extract — Tea tree oil — Olive leaf extract

Anti-inflammatory efficacy: — Aloe vera extract — Calendula extract — Passionflower extract — Witch hazel extract — Camomile extract — Tea tree oil

Hyperpigmentation: — Licorice extract — Green tea extract — Bearberry extract

Glycyrrhiza glabra	Centella asiatica
Camellia sinensis	Aloe vera
Passionflower	Olive

2. Abnormal keratinization of the follicle:
Salicylic acid is a well known keratolytic agent and is one of the most widely used ingredients in anti-acne formulations. Alpha-hydroxy acids (AHA) such as glycolic acid, an AHA that is derived e.g. from sugar cane, are often used as adjunctive therapies in the management of acne. They are often used as peeling agents and have been shown in clinical studies to improve acne as well as the hyperpigmentation and scarring associated with acne (6, 7).

3. Increased proliferation of the skin microflora:
Plants produce a plethora of anti-microbial substances, some of which can be used in the management of impure skin. Anti-microbial plant extracts are also becoming more attractive to the market due to awareness that many pathogens are becoming resistant to known antibiotics, the high degree of resistance actually encountered when using antibiotics and the regulatory issues associated with the use of the often used antimicrobial - triclosan. Natural alternatives are: Tea tree oil (Melaleuca alternafolia) has a long tradition as anti-microbial active (8). Terpinen-4-ol, alpha-terpineol and alpha-pinene are among the known active constituents in tea tree oil and were found to be active against Propionibacterium acnes, Staphylococcus aureus, and Staphylococcus epidermidis (8). Furthermore, it may help to reduce Propionibacterium acnes, with less stinging, itching and dryness than when benzoyl peroxide is used (9). Green tea extract (Camelia sinensis) has multifactorial benefits – it has anti-microbial activity (Figure 1), reduces inflammation, decrease hormone activity (5-alpha-reductase) and is a powerful antioxidant that scavenges damaging free radicals to protect and restore skin’s natural attributes. Extracts from licorice also have remarkable antibacterial activity against Propionibacterium acnes, with the benefit of negligible induction of resistance when compared to erythromycin (10).

4. Anti-inflammatory responses:
A wide variety of plant actives have anti-inflammatory and/or soothing effects (11, 12). Probably the most well known plants in this respect are chamomile and aloe vera. Both ale and chamomile are often used in bath additives or creams when skin inflammation or other disorders arise including use in diapers to protect against diaper rash. Aloe contains various substance, e.g. aloesin, that have reported to inhibit cyclooxygenase (Cox)-2 and thromboxane (Tx) A 2 synthase thus explaining its anti-inflammatory effects and beneficial role in wound healing. Anti-inflammatory effects have also been attributed to licorice root extract as these contain anti-inflammatory agents such as glabridin; an active reported to inhibit of superoxide anion production and cyclooxygenase activities (13). Marigold, arnica, shea butter and extracts thereof are also used in cosmetic formulations for impure skin. Passionflower is traditionally used to soothe the skin and convincing evidence for the anti-inflammatory efficacy of Passiflora incarnata extracts standardized on 6 percent flavonoids is presented in Figure 2. The described Passiflora incarnata extract dose-dependently reduces the UVB-indicated release of inflammatory mediators. A significant activity for the extract was determined at 0,1 percent and is suitable for claim substantiation. As plants are also a major source of antioxidants, their use in counteracting the adverse actions of reactive oxygen species (ROS) is indicated.

Figure 1: Antimicrobial efficacy of green tea extracts In vitro tests were carried out to determine the minimal inhibition concentration of green tea extract (contains 90% polyphenols, including 50% catechins) for typical skin microorganisms. The results show a significant antimicrobial efficacy against potential skin pathogens involved in processes related to impure skin with an optimal dosage of 0.5%. One should take in mind that the optimal dosage could be lower or higher depending on the formulation used. Enlarged version

Hyperpigmentation and scarring:
Hyperpigmentation and scarring are often a consequence of impure skin. Plants are also a source of actives that may help in reducing these effects which are particularly pronounced in the Asian population. Once again, extracts from licorice root have beneficial effects and can be used to reduce hyperpigmentation. Licorice root extracts contain substances such as glabrene and isoliquiritigenin (2',4',4-trihydroxychalcone) which can inhibit both mono- and diphenolase tyrosinase activities, both enzymes involved in melanin biosynthesis (14). Extracts from the Centella asiatica plant, in particular the terpenoids asiatic acid, madecassic acid, and asiaticoside have been reported to aid wound-healing and may be indicated in scar management (15).

Figure 2: Cytoprotection of human keratinocytes from UVB stress Cultures of human keratinocytes were incubated with 0.03% and 0.1% Passiflora incarnata extract and irritated by UVB. Aspirin and indomethacin were used as reference substance for anti-inflammatory products. This proceeding gives information about the anti-inflammatory efficacy related to the inhibition of the release of inflammation mediators called prostaglandins (PGE2). The analyses were performed with in vitro human cells at Laboratoires Sérobiologiques/Cognis France. The described Passiflora incarnata extract reduces the UVB-indicated release of inflammation mediators dose-dependently. Addition of 0.1% extract shows a significant activity and is suitable for claim substantiation. Enlarged version Enlarged version Enlarged version

Conclusion

Although it must be emphasized that people afflicted with acne should consult a dermatologist, many people do not. It is therefore exceedingly important that supportive therapies or over-the counter-products really work. Plants are valuable sources for biologically active substances and virtually all cultures rely on medicinal plants or plant extracts to a relatively high extent in primary health care. In addition, compliance is often higher when plant based therapeutics are used, as the consumer perceives them as being natural and therefore healthier. A basic skin care system for impure skin should consist of a mild cleansing formulation and a gentle gel cream. Because of the complexity of acne pathogenesis, combinatorial and holistic approaches should be considered. Plants represent a cornucopia of actives that can have beneficial effects and these have been well documented. Yet plant extracts can be of varying quality and the use of low quality material seldom leads to the desired effects. Therefore, high-quality plant extracts with a natural content of active ingredients which reproducibly provide the desired efficacy as well as the proper formulation are therefore a must.

This article entitled “Natural actives for impure skin” was previously published in SÖWF-Journal 130, 3-2004, pp. 2-6.

References

1) Nielssen, 2000.

2) Thiboutot D, Harris G, Iles V, Cimis G, Gilliland K, Hagari S. Activity of the type 1 5 alpha-reductase exhibits regional differences in isolated sebaceous glands and whole skin. J Invest Dermatol. 1995; 105:209-14.

3) Kawai, N., Phytoestrogens: Applications of soy isoflavones in skin care. Cosmetics & Toiletries; 2003; 118:73-80.

4 ) Liao S. The medicinal action of androgens and green tea epigallocatechin gallate. Hong Kong Med J. 2001; 7:369-74.

5) Schellenberg R. Treatment for the premenstrual syndrome with agnus castus fruit extract: prospective, randomized, placebo controlled study. BMJ 2001; 20:134-7.

6) Atzori L, Brundu MA, Orru A, Biggio P. Glycolic acid peeling in the treatment of acne. J Eur Acad Dermatol Venereol. 1999; 12:119-22.

7) Wang CM, Huang CL, Hu CT, Chan HL. The effect of glycolic acid on the treatment of acne in Asian skin. Dermatol Surg. 1997;23: 23-9.

8) Raman A, Weir U, Bloomfield SF. Antimicrobial effects of tea-tree oil and its major components on Staphylococcus aureus, Staph. epidermidis and Propionibacterium Acnes. Lett Appl Microbiol. 1995; 21:242-5.

9) Bassett IB, Pannowitz DL, Barnetson RS. A comparative study of tea-tree oil versus benzoylperoxide in the treatment of acne; Med J Aust. 1990;153:455-8.

10) Nam C, Kim S, Sim Y, Chang I. Anti-Acne effects of oriental herb extracts: a novel screening method to select anti-Acne agents. Skin Pharmacol Appl Skin Physiol. 2003; 16:84-90.

11) Vazquez B, Avila G, Segura D, Escalante B. Antiinflammatory activity of extracts from Aloe vera gel. J Ethnopharmacol. 1996;55:69-75.

12) Yagi A, Kabash A, Okamura N, Haraguchi H, Moustafa SM, Khalifa TI. Antioxidant, free radical scavenging and anti-inflammatory effects of aloesin derivatives in Aloe vera; Planta Med. 2002;68:957-60.

13) Yokota T, Nishio H, Kubota Y, Mizoguchi M. The inhibitory effect of glabridin from licorice extracts on melanogenesis and inflammation. Pigment Cell Res. 1998;11:355-61.

14) Nerya O, Vaya J, Musa R, Izrael S, Ben-Arie R, Tamir S. Glabrene and isoliquiritigenin as tyrosinase inhibitors from licorice roots. J Agric Food Chem. 2003 Feb 26;51(5):1201-7.

15) Widgerow AD, Chait, LA, Stals R, Stals PJ. New innovations in scar management. Aesthetic Plast Surg. 2000; 24:227-34.

Author



Dr. Annette Mehling has been working for Cognis Deutschland GmbH & Co. KG since 2001. She is part of the product safety and regulations department and is responsible for dermatological compatibility and efficacy testing. Dr. Mehling is a trained molecular biologist and obtained her PhD in microbiology at the University of Wuppertal. During her 4-year postdoctoral training at the Department of Dermatology, University of Münster, Germany, she was involved in research in the field of cutaneous immunology.