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What's New in Cosmetic RD?



Nature-based ingredients, in combination with innovative delivery systems and consumer-desirable benefits, are expected to lead new cosmetics research.



Published November 14, 2005
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What


Body, mind and soul. West meets the world. These two consumer themes may continue to drive cosmetics research in the foreseeable future. Consumers are in- creasingly asking, “Is it good for my body?” and “Am I pleased with the results?” To provide affirmative answers to such questions, marketers are searching for new ingredients and new technologies from around the world. Many economically disadvantaged nations continue to provide rich resources for innovative new ingredients. This has led to a new direction: major marketers are now developing new delivery systems in-house, while they search for new ingredients on a worldwide basis via eco-managed cooperative joint ventures, and assistance to local farmers and cottage industry manufacturers. This symbiotic relationship of “West meets the World” is fueling economic growth for the native populace without imparting any harmful effects on the local flora and fauna. The eco-sensitive, nature-based ingredients, in combination with innovative delivery systems, and consumer-desirable combination benefits are expected to highlight new cosmetics research.

The body aspect of modern consumerism continues to fuel anti-aging cosmetics research via a combination of new ingredients, delivery systems, and performance attributes. Next to aging concerns, maintenance of lean body shape is of prime consumer concern. America is fat and getting fatter.1 While the weight management category is exploding for nutraceuticals marketers, modern cosmetic science appears to have ignored this vast, unprecedented opportunity for topical body shape management and enhancement products. Anti-aging products still remain of ageless pursuit!

The mind portion of consumerism is demanding product satisfaction via the delivery of intended performance attributes and desired benefits. Brainwashing via flashy advertisements may attract initial purchase and trial of a new product. The longevity in the marketplace will depend increasingly on the consumer-perceived overall satisfaction with that new product.

The soul segment of consumerism is harder to pinpoint. Consumers now have a greater conscience for nature-based ingredients. New soul-pleasing, intellect-targeted concepts can fill this great current void in cosmetics research. Aromatherapy, chromatherapy, phytotherapy and similar coy concepts are still popular. Aromatherapy, a branch of herbology, is one of the fastest growing therapies in the world today. Historically, essential oils are best used in the form of massage or bath oils or inhalations. Aromatherapy leaves one feeling uplifted, stimulated, invigorated or rejuvenated, depending on the oil used. When inhaled, the various aromas penetrate the bloodstream via the lungs causing physiologic changes. In turn, the limbic system, which controls our emotions and memories, is affected.

Some consider aromatherapy mystical or magical; others, however, are attempting to validate empirically this ancient therapy as medicinally soul-pleasing. The use of complementary and alternative medicine is increasing, vis-a-vis Western medicine. In a survey conducted in Japan, users had a better “feeling” with natural medicine. This trend is also notable with cosmetics based on natural ingredients: such cosmetics seem more soul-healing. A placebo-controlled trial to determine the value of aromatherapy with essential oil of Melissa officinalis (lemon balm) for agitation in people with severe dementia showed that aromatherapy with essential balm oil is a safe and effective treatment for clinically significant agitation in people with severe dementia, with additional benefits for key quality of life.2

New Ingredients in Vogue
The performance-driven research continues to introduce new ingredients, both natural and synthetic, that provide formulators with innovative building blocks for their creativity. Products that provide multiple benefits via a selective combination of ingredients and delivery systems are driving new product innovations. The skin whitening products, popular in non-white skin nations and discussed in Happi,3 are being positioned for the white-skinned consumers in skin brightening, luminosity enhancing, anti-aging and age-spot lightening products. New skin whitening ingredients include Ecklonia cava extract with excellent tyrosinase inhibitory activity, which shows high stability and superior whitening effect in skin whitening cosmetics, and niacinamide which significantly decreased hyperpigmentation and increased skin lightness compared with vehicle alone after a four week clinical trial.4

An extract of olive fruits effectively inhibits melamine production and is superior to that observed for arbutin, a known skin whitening agent. The olive extract is effective at about 0.5 to 5 times that observed for arbutin.5 Hydroxytetronic acid, tetronic acid, and tetronic acid derivatives have been claimed as skin whitening agents.6 A beta-1, 3-glucan derivative, obtained from a liquid culture of Schizophyllum commune, has been shown to possess a surprising skin whitening property that is unpredicted from its chemical structure.7 Extracts of Spondias mombin, Maprounea guianensis, Walteria indica, Gouania blanchetiana, Cordia schomburgkii, Randia armata and Hibiscus furcellatus have been found to impart skin whitening effect with anti-aging effects.8

Estée Lauder’s Perfectionist is one of the newest products to help fight wrinkles.

Anti-aging Items Lead the Way
Several companies have recently launched innovative new products. Estée Lauder’s Perfectionist is an anti-wrinkle serum that boosts laminin production in the dermis and promotes integrin activity for a high-performance anti-wrinkle formula. Lauder’s WhiteLight is a skin brightening treatment line (based on green tea extract, highly-concentrated licorice extract and a vitamin C derivative) and Advanced Night Repair is an anti-aging, anti-wrinkle treatment line.

From Shiseido comes Bio-Performance, an anti-aging product line that is based on gambir extract (from Asian medicinal plant, Uncaria gambir) and vitamin A acetate, Future Solution, a youth-maintaining product based on marjorum and Chai Hu extracts, and Basala, a comprehensive 13-product men’s line. At the same time, Vitamin C Absolutes, an eight-product line from Revlon, touts the benefits of ascorbic acid.

Meanwhile, L’Oréal last year sponsored a conference to discuss progress in research on skin aging , and with 493 patent applications filed in 2001, it continues to lead cosmetics R&D worldwide.

All major marketers have entered the anti-aging cosmetics arena offering a mind-boggling arsenal of products, most of which are based on antioxidants. Unfortunately, consumers are starting to yawn at these launches: “You also have an anti-aging product, so what?” There is much thunder and lightning in now a limited horizon. Researchers are focusing on the biochemical mechanisms of the aging process in the hope of trailblazing new innovations to lead heightened consumer enthusiasm and market segmentation in this “never too old” market.

Skin aging is a complex process determined by the genetic endowment of the individual as well as by environmental factors. The appearance of old skin and the clinical consequences of skin aging have been well known for centuries, but only in the past 50 years have mechanisms and mediators been systematically pursued. Still, within this relatively short time there has been tremendous progress, a progress greatly enhanced by basic gerontologic research employing immunologic, biochemical, and particularly molecular biologic approaches. Human skin, like all other organs, undergoes chronological aging. In addition, unlike other organs, skin is in direct contact with the environment and therefore undergoes aging as a consequence of environmental damage. The primary environmental factor that causes human skin aging is UV.

During the past decade, substantial progress has been made in understanding cellular and molecular mechanisms that bring about chronological aging and photoaging. This emerging information reveals that chronological aging and photoaging share fundamental molecular pathways. These new insights regarding convergence of the molecular basis of chronological aging and photoaging provide exciting new opportunities for the development of new anti-aging therapies, which have been reviewed.9 The pro-inflammatory action of reactive oxygen and nitrogen species, including those that are a byproduct of normal energy metabolism in mitochondria, have a direct link to the aging process. The biochemical and molecular bases of such inflammatory process in the aging process have been reviewed to delineate the molecular inflammation hypothesis of aging.10
The recent use of growth hormones for anti-aging benefits has sparked controversy. Dehydroepiandro- sterone (DHEA) and its sulfate ester are major secretory products of the human adrenal. Serum DHEA concentrations decline with advancing age and DHEA supplementation in elderly people has been advertised as anti-aging medication. However, such claims are based on experiments in rodents with a fundamentally different DHEA physiology.

In humans, DHEA is a crucial precursor of sex steroid biosynthesis and exerts indirect endocrine and intra-crine actions following conversion to androgens and estrogens. In addition, it acts as a neurosteroid via effects on neurotransmitter receptors in the brain. DHEA has considerable effects on mood, well-being and sexuality in patients with adrenal insufficiency, and also in those with mood disorders. However, subjects with a physiological, age-related decline in DHEA secretions show little benefit from DHEA administration. However, in another study the beneficial effects of DHEA as an anti-aging steroid based on both in vitro and in vivo experiments, such as the stimulatory effect of immune system, anti-diabetes mellitus, anti-atherosclerosis, anti-dementia (neurosteroid), anti-obesity and anti-osteoporosis has been reported. 11

Deprenyl, a monoamine oxidase B inhibitor is known to upregulate activities of antioxidant enzymes such as superoxide dismutase and catalase in brain’s dopaminergic regions. The drug has also been shown to increase life spans of several animal species including rats, mice, hamsters and dogs. Further, the drug was recently found to enhance antioxidant enzyme activities in brain’s dopaminergic regions and also in extra-brain tissues such as the heart, kidneys, adrenal glands and the spleen. The use of monoamine oxidase B inhibitors that have biochemical mechanisms similar to Deprenyl may provide new topical anti-aging strategies.12 The nitrone-based free radical traps have significant potential in the treatment of neurodegenerative diseases as well as in the prolongation of life span. The most widely used compound in this series, alpha-phenyl-tert-butyl-nitrone (PBN), has been shown to extend life span in three published studies (two mouse models and one rat model). It is not known exactly why the nitrones possess anti-aging activity. As more rigorous research examining the anti-aging activity of the nitrones is conducted, new ingredients for topical anti-aging benefits may become available in a not too distant future.13 The chemical modification of superoxide dismutase enzyme leads to fusion enzymes that can penetrate into dermal layers of skin from topical applications. These results suggest that such fusion proteins can be used in anti-aging cosmetics.14

Among simpler solutions to anti-aging products, an extract of Fucus vesiculosus (a seaweed), is reported to promote the contraction of fibroblast-populated collagen cells through increased expression of integrin molecules. A gel formulation that included 1% of the extract was applied topically to human cheek skin twice daily for five weeks. A significant decrease in skin thickness and an improvement in skin elasticity were both noted. In cheek skin, the thickness normally increases and the elasticity usually decreases with age. These results suggest that the Fucus vesiculosus extract could be useful for anti-aging cosmetics.15

Moisture Defense Antioxidant eye cream from MD Formulations, reduces puffiness and rebuilds the protective barrier.

The Asian Influences
In the “East meets West” category, Asia, Korea, China and Japan have adopted the traditional Oriental (Chinese) medical system along with the Western system. Herbal therapy used in traditional Oriental medicine appears to be quite different from its counterpart Western drug therapy. The polypharmacy type of herbal therapy generally exhibits holistic effectiveness by exerting activities to multitarget organs (organ systems) according to the principles of traditional Oriental medicine. The Traditional Oriental Medicine Database (TradiMed 2000 DB) is a unique database of traditional Oriental herbal therapy containing a variety of information such as formulae, chemical information on ingredients, botanical information on herbal materials and a dictionary of disease classification. This database may be useful for the development of new anti-aging (and other) cosmetic ingredients in the “West meets the World” category.16

The inner shell of the chestnut (Castanea crenata) has been used as an anti-wrinkle/skin firming agent in East Asia, and a 70% ethanol extract from this plant material prevented cell detachment of skin fibroblasts from culture plates. The molecular mechanisms underlying this phenomenon, and its effects on skin adhesion molecules such as fibronectin and vitronectin, were investigated using the mouse skin fibroblast cells. The findings suggest that the enhanced expression of the adhesion molecules may be preventing cell detachment and may also be responsible for its anti-wrinkle/skin firming effect.17

Horse chestnut (Aesculus hippocastanum) extracts have long been used as anti-inflammatory agents for vascular insufficiency problems, including spider veins and leg edema. In a screening of 65 different plant extracts using the neotetrazolium method for detecting superoxide anion-scavenging effects, Aesculus hippocastanum and Hamamelis virginia extracts were found to have unexpectedly strong active-oxygen scavenging activity of and protective activity against cell damage induced by active oxygen. Both Aesculus hippocastanum and Hamamelis virginiana are proposed as anti-aging or anti-wrinkle ingredients for the skin. This would also suggest the evaluation of other non-antioxidant anti-inflammatory ingredients for anti-aging applications.18

Tanacetum parthenium, a plant commonly known as feverfew, has been recognized since the Middle Ages as having significant medicinal properties. As its name would suggest, feverfew acts as a febrifuge when taken orally. Recently, topical applications of this extract have shown strong anti-inflammatory action. Since the chemical constituents of whole feverfew extract include apigenin-7-glucoside, apigenin-7-glucuronide, 1-beta-hydroxyarbusculin, 6-hydroxykaempferol-3, 7-4’-trimethylether (Tanetin), and 6-hydroxykaempferol-3, 7-dimethyl ether, all of which possess antioxidant activity, the use of this extract in anti-aging applications deserves a look.19

Anti-aging medicine is a popular topic in the lay press, the semi-scientific literature and the internet. In nearly all instances, claims of drugs, health supplements and other types of intervention are not based on any evidence supported by sound scientific knowledge. Specifically, the aging process itself, in contrast to age-related diseases, is neither fully understood, nor significantly influenced in higher species, notably humans. In addition to the ill-defined effects, claims of anti-aging medicine pose an economic burden on the usually poorly-informed older segment of the population. A recent report by the United States General Accounting Office (GAO) has reviewed the questionable and even harmful effects of anti-aging health products for seniors. Are anti-aging cosmetics not on the same agenda? 20

Anti-aging cosmetics or medicines alone are not expected to provide significant anti-aging benefits. For a dietary anti-aging concept that “gives life to years and adds years to life” a low-fat, carbohydrate and fiber-rich diet containing plenty of fruits and vegetables and moderate amounts of protein (in particular of vegetable origin) has been recommended. Prolonging the fasting state is also of benefit. Five servings of fruits and vegetables (preferentially red, yellow and green) daily and whole-grain products provide sufficient amounts of vitamins C, E and beta-carotene, as well as secondary phytochemicals. Also to be included are low-fat dairy products, fish once or twice a week, little meat and eggs, and a maximum of 4-8 oz. (1/8 to 1/4 liter) of red wine per day.21

Enhanced Performance
The chemical bonding of cosmetic and drug ingredients to human skin cells provides one of the most exciting recent discovery for delivering sustained topical benefits. The concept is deceptively simple. The surface skin cells contain free amino, hydroxy, sufhydryl, carboxy, imino, and similar chemically reactive moieties in their protein and nucleic acid components that can be chemically attached, via a covalent chemical bond, to a cosmetic or drug molecule using an appropriate bonding agent attached to the drug or cosmetic ingredient (see figure). In practical applications, sunscreen and antioxidant ingredients can be attached directly to skin to provide extended term benefits since such chemically bonded ingredients are not removed by washing or rubbing actions, and they generally will last until the skin is shed.22 In order to achieve chemical bonding, chemically reactive forms of bonding components, such as alkylating agents, diazonium salts, anhydrides and acylating agents are used. This new technology may have to await additional work, as the safety and toxicology of chemically reactive agents themselves (several alkylating agents, diazonium compounds and acylating agents are known to have carcinogenic, mutagenic, skin sensitizing and allergenic properties), and the FDA status of chemically modified drug active ingredients (such as sunscreen active ingredients) after such ingredients have been attached to human skin.

An alternative to direct bonding of active ingredients to skin cells, that of chemically bonding a light refracting or polarizing ingredient to a particulate surface to form optically activated particles, has been disclosed. The optically-activated particles include a plurality of substrate particles selected from the group consisting of nylons, acrylics, polyesters, other plastic polymers, natural materials, regenerated cellulose, metals and minerals; an optical brightener chemically bonded to such substrate particles to form optically-activated particles for diffusing light to reduce the visual perception of skin imperfections, including cellulite, shadows, skin discolorations and wrinkles.23 The surface modification of particulates to achieve water solubility has also been achieved by electron plasma technology.24 Color-reflecting materials that can provide at least two discrete color ranges to a cosmetic composition have been prepared to provide the concealer cosmetics with a desired color effect.25

Avon’s Cellu-Sculpt is said to actively treat the entire condition of cellulite by targeting firmness, dimpling and texture.

In a recent article in Happi, additional new innovations in topical delivery systems have been highlighted.26 Nanoparticles (particle sizes in the range of 50-500nm) and their utilization in nanodispersions and micro- emulsions is an active area of current research. The most interesting properties of nanodispersions of active organic compounds include the impressive increase in solubility and the improvement in biological efficacy of organic compounds that are poorly soluble in water. In addition, the modification of optical, electrooptical and other physical properties is also possible. The production of organic nanoparticles as alternatives to the established mechanical milling processes urgently requires the development of new processes, as nanostructured materials are finding applications in a number of areas including medical implants, pharmacy and cosmetics. In a practical application, the use of nanoparticles of a crystalline lipid in a sunscreen containing benzophenone-3 showed that the amount of molecular sunscreen can be decreased by up to 50% while maintaining the UV protection efficacy.27

Nanoscale particle technology can be used for other common water insoluble materials, such as zinc omadine (anti-dandruff) and triclocarban (antibacterial) for the enhancement of the efficacy of such ingredients.28 A simplified preparation of nanodispersions has recently been reported.29

Winning the Battle of the Bulge
Cosmetics formulators may soon reap the rewards of developing cosmetic products for body shape management and body tone enhancement, a field dominated by nutraceutical companies. The U.S. sports nutrition and weight loss market totaled nearly $10 billion in 2001. Of various categories, the weight loss segment of the nutraceuticals market posted a whopping 20% growth from 2000 to 2001. The practical concepts of nutraceuticals formulation for topical applications have been described in Happi.30 It is worthy of note that several new, clinically-proven weight-loss and muscle-tone enhancement ingredients have become available to nutraceutical product marketers in recent years. Nature-based, “non-fiber” ingredients currently available for this application includes purified forskolin (from Coleus forskohlii), hydroxycitric acid (from Garcinia cambogia), phaseolamin (from Phaseolus vulgaris, kidney bean), fenugreek extract, chromium complexes, diglycerides (from Enova oil), carnitine, conjugated linoleic acid (CLA), soy and a host of antioxidants with cyclic AMP inhibition property.31

The cosmetics industry must awaken and recognize that topical compositions offering localized management of body slimming, firmness and tone will attract consumer enthusiasm. As the mechanisms of their biological action become clearer, the combinations of such ingredients to provide synergistic benefits will draw formulator’s attention. This author has technologies on the horizon to provide “bundled” benefits, such as wrinkle reduction with tone enhancement of face and chin (firming of “double-chin”), skin brightening with muscle-tightening of arms, skin smoothing with firming of arms and abdomen and similar consumer-desirable combination claims.32 Bundling of sun-protection and slimming benefits has also been reported.33

New Light on Sun Protection
Sun protection is receiving ever-increasing consumer attention due to direct relationship of UV with skin aging. Modern sunscreen formulations are still inadequate. New methods to protect skin from photodamage from sun exposure are necessary to conquer skin cancer and photoaging. Sun-screens are useful, but their protection is not ideal because of inadequate use, incomplete spectral protection and toxicity.

A review of what is known about how photodamage occurs; why sunscreens—the current gold standard of photoprotection—are inadequate; and how topical antioxidants help protect against skin cancer and photoaging changes concludes that topical use of vitamin C, vitamin E, selenium, zinc, silymarin, soy isoflavones and tea polyphenols may favorably supplement sunscreen protection and provide additional anticarcinogenic protection.34 The testing methodologies of sunscreen products for their SPF determination have been evaluated. In an Australian study using 30+ SPF products, it was determined that Sun Protection Factors (SPF) are often overestimated. In a U.S. evaluation, both the 1978 proposed monograph SPF test method and the 1993 TFM SPF test method can provide accurate and reproducible results for high SPF formulations. Further, these results can be achieved with panels of 20-25 subjects with an acceptable level of variability.35

Recent discoveries indicate that certain sunscreen and sunblock active ingredients can cause significant formation of reactive oxygen species (hydroxyl and peroxy radicals, and singlet oxygen) that can be harmful to skin. For example, it has been established that once the UV light has been absorbed by titanium dioxide and zinc oxide, two common sunblock ingredients, the de-excitation of that absorbed UV energy leads to the formation of hydroxyl free radicals in the presence of water on skin surface, which can cause significant damage to DNA. Similarly, certain organic UV absorbers, such as 2-ethylhexyl-4-dimethylaminobenzoate, and 2-ethylhexyl-p-methoxycinnamate, produce singlet oxygen under UV excitation. In addition, photoallergic contact dermatitis problems have also been recorded. Absorption into bloodstream may be another concern. Benzophe-none-3 is a common chemical UV-absorber. It has been used for many years to protect against UV radiation.

Previous studies have shown that Benzophenone-3 penetrates the skin, and it can be found in urine, feces and blood. Eleven human volunteers applied the recommended amount of a commercially available sunscreen and urine samples were collected during a 48-hour period after application. The average total amount excreted was 11 mg, median 9.8 mg, which is approximately 0.4% of the applied amount of benzophenone-3. Some of the volunteers still excreted it 48 hours after application. It is evident that benzophenone-3 undergoes conjugation in the body to make it water-soluble. However, it is not known at what age the ability to conjugate is fully developed, and therefore for children physical filters such as titanium dioxide and/or zinc oxide might still be considered a more appropriate sunscreen component. Even for adults, people with hepatic disorders may have similar metabolic issues.36

The search for formulations to circumvent such potential product safety issues has thus ensued. The free radicals generated by popular sunscreen Avobenzone, when exposed to simulated sunlight, are effectively scavenged by complexation of the sunscreen agent with hydroxypropyl-beta-cyclodextrin. Topical application of silymarin (Silybum marianum) results in a significant decrease in peroxide and nitric oxide formation. This suggests the evaluation of silymarin to sunscreen and skin care formulations as an antioxidant chemopreventive agent. Once again, it’s nanoparticles to the rescue: poly-D, L-lactide-coglycolide-based nanoparticles loaded with ethylhexyl methoxycinnamate resulted in enhanced photostability of this popular sunscreen ingredient.37 Recent additional findings in this area have already fueled the development of safer, more efficacious sunscreen formulations. It is clearly evident that this trend shall continue to provide renewed growth of sun-protection category via the development of new ingredients and new delivery systems.

References:
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2. D.V. Thomas, Aromatherapy: mythical, magical, or medicinal?, Holist Nurs Pract, 16, 8-16(2002); J. Buckle, Clinical aromatherapy. Therapeutic uses for essential oils, Adv Nurse Pract 2002, 10, 67-8, 88 (2002); L.L.Halcon, Aromatherapy: therapeutic applications of plant essential oils, Minn Med., 85, 42-6 (2002); H. Yamashita et al., Popularity of complementary and alternative medicine in Japan: a telephone survey, Complement Ther Med, 10, 84-93 (2002); C.G. Ballard et al., Aromatherapy as a safe and effective treatment for the management of agitation in severe dementia: the results of a double-blind, placebo-controlled trial with Melissa, J Clin Psychiatry, 63, 553-8 (2002).

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4. B.H. Lee et al., Whitening cosmetics containing extracts from Ecklonia cava, U.S. Pat. Appl. 20020044915 (2002); T. Hakazoki et al., The effect of niacinamide on reducing cutaneous pigmentation and suppression of melanosome transfer, Br J Dermatol, 47, 20-31(2002).

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12. K. Kitani et al., Why (--)deprenyl prolongs survivals of experimental animals: increase of antioxidant enzymes in brain and other body tissues as well as mobilization of various humoral factors may lead to systemic anti-aging effects, Mech Aging Dev, 123, 1087-100 (2002).

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22. H. Bekele, Topical composition comprising a functionally alkylating cosmetic bonding agent, U.S. Pat. Appl. 20030003119 (2003); H. Bekele, Topical composition comprising a diazonium salt-based cosmetic bonding agent, U.S. Pat. Appl. 20020172698 (2002), and additional patent applications.

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32. S. Gupta, Topical Nutraceutical Compositions with Selective Body Slimming and Tone Firming Anti-aging Benefits, Patents pending (for contract manufacturing and licensing inquiries, please contact Paul Dembow, Arizona Natural Resources, email paul@aznat.com, phone 602-569-6900, or Shyam Gupta, Bioderm Research, email shyam@bioderminc.com, phone 602-996-9700).

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36. G.H. Gustavsson et al., Percutaneous absorption of benzophenone-3, a common component of topical sunscreens., Clin Exp Dermatol, 27, 691-4 (2002); G. Wakefield, “Improved UV Absorbers: Eliminating The Free Radical Problem,” HBA 2002 Product Development Presentations, Session PD3, New York, NY, October 14-16, (2002); see online www.hbaexpo.com.

37. S. Scalia et al., Influence of hydroxypropyl-beta-cyclodextrin on photo-induced free radical production by the sunscreen agent, butyl-methoxydibenzoylmethane, J Pharm Pharmacol, 54, 1553-8 (2002); S.K. Katiyar, Treatment of silymarin, a plant flavonoid, prevents ultraviolet light-induced immune suppression and oxidative stress in mouse skin, Int J Oncol, 21, 1213-22 (2002); P.Perugini et al., Effect of nanoparticle encapsulation on the photostability of the sunscreen agent, 2-ethylhexyl-p-methoxy- cinnamate, Int J Pharm, 246, 37-45 (2002).

38. S. Gupta, et al., Natural Sunscreens & SPF Boosters, Happi, 96 (December 2002); D. Moyal et al., Prevention of solar-induced immunosuppression by a new highly protective broadspectrum sunscreen, Eur J Dermatol.,12, XII-XIV (2002); I. Duteil et al., High protective effect of a broad-spectrum sunscreen against tetracycline phototoxicity, Eur J Dermatol., 12, X-XI (2002); R. J. Mankovitz, Plant-based non-toxic sunscreen products, U.S. Pat. Appl. 20020187114 (2002).



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