'Cosmeceuticals' Spur Research But Worry FDA

Photo: John Wang ETHNOBOTANY: This Ava puhi Mohi plant will provide an ingredient for a Nu Skin cosmeticeutical to be launched in March. America's fascination with youth and physical beauty has prompted a rise in the development over recent years of "high-performance" cosmetics containing bioactive ingredients for skin damaged by the effects of sun and aging. Companies that produce personal-care products now are seeking new bioactive ingredients and new delivery system technologies. This demand is providing jobs for researchers in biopharmaceutical companies, but it also is causing headaches for government agencies faced with keeping track of products that often fall outside the control of safety and efficacy regulations. "Cosmeceuticals" is the term used to describe cosmetics containing ingredients that are bioactive, exerting effects on people. The regulatory question is whether or not such ingredients make a product a drug rather than a cosmetic. Under the Food, Drug, and Cosmetic Act of 1933, drugs treat a condition or affect the structure and function of the body, whereas cosmetics merely claim to improve appearance. Products classified as cosmetics have no efficacy requirement beyond the normal advertising stricture against false and misleading statements. Moreover, responsibility for ensuring the safety of cosmetics is left entirely with the manufacturers. This means companies may release cosmetics on the market without notifying the Food and Drug Administration (FDA). "A product can actually be a cosmetic and a drug at the same time, but there is no provision for cosmeceuticals," says John Bailey, director of FDA's office of cosmetics and colors. He demurs to Congress in determining whether or not any changes should be made in federal law to establish new regulations to cover the growing tendency for cosmetics to contain bioactive ingredients. "I think, though, that the cosmetics provisions of the statute work very well for traditional cosmetics," he says. "I don't think they work very well for the so-called cosmeceuticals, because there are hard questions that need to be asked and are not asked in this setting." Amendments to the federal act in 1960 established a review process for the safety and efficacy of over-the-counter (OTC) drugs. Their test requirements are generally less stringent and more clearly defined than the broader criteria that must be met for prescription drug approval. Many products fall into the OTC drug category, including aspirin, sunscreens, antidandruff shampoos, acne creams, mouthwashes, and preparations for hair growth. "Label claims are really the linchpin of this," Bailey observes. For example, he says, a product advertised as an antiperspirant would be an OTC drug because it claims to close skin pores, whereas a deodorant is a cosmetic. "We've seen a fairly significant change in the direction of industry, and this change is driven largely by an increase in the understanding of the structure and function of skin," he notes. "The AHAs [alpha hydroxy acids] have ushered this in, and we've been heavily engaged in the question of whether they really are cosmetics." "Drug Discovery and Development Approaches to Cosmeceuticals" is the title of an international industry conference to be held February 11 to 13 in the Hilton at Short Hills in Short Hills, N.J. Organized by Worcester, Mass.-based IBC USA Conferences Inc., the conference will feature 16 speakers from government, industry, and academia in the United States, the United Kingdom, Germany, France, Japan, and Monaco. Topics will include new dermatological drug targets, molecules, ingredients, new products, absorption methodologies, and comparisons of global regulatory differences in cosmetics versus drugs. For more information, call (508) 481-6400. Fax: (508) 481-7011. E-mail: inq@ibcusa.com. Derived from fruit and dairy products, alpha hydroxy acids are widely included in cosmetics as exfoliants. The most commonly used are glycolic acid and lactic acid, both of which seem to exert slight but significant effects in reducing skin discolorations and roughness when applied in a cream. However, adequate trials documenting the efficacy of alpha hydroxy acids remain to be performed (S.S. Helander, Drugs and Aging, 8:12-6, 1996). Bailey says clinical trials are now being prepared on the safety and efficacy of AHAs by the National Toxicology Program, a consortium of government agencies headed by the National Institute of Environmental Health Sciences (NIEHS) in Research Triangle Park, N.C. Beta hydroxy acids likewise have become popular cosmeceutical ingredients. One example is salicylic acid, also used in treating keratolysis, a skin disease marked by peeling of the outer layer of the epidermis. Hydroxy acids might enhance the risk of sun damage to the skin or the development of precancerous conditions and eventually melanomas, says Bailey. He charges that cosmetics companies rushed into the marketplace with hydroxy acid-containing products before adequately considering such safety issues. Some cosmetics also include antioxidants, vitamin derivatives believed to act as scavengers of free radicals that, in turn, are thought to damage skin tissue and cause wrinkling. Bailey says there is no clinical evidence concerning whether or not topically applied antioxidants exert any effect on free radicals. Photodamage, the deterioration of skin due to sun exposure and aging, is the biggest market segment for cosmeceuticals. The United States market for antiwrinkling products is estimated at $1.2 billion, and photodamage is responsible for about 90 percent of unwanted age-associated changes in the skin's appearance, according to the American Academy of Dermatology in Schaumburg, Ill. Photodamage occurs when ultraviolet radiation from the sun induces enzymes to break down the skin's collagen and elastin. The resultant wrinkles that are associated with aging seem to come from tangles of disrupted collagen and abnormal elastin in the dermis, together with a loss of normal collagen and elastin. The latter losses are much slower in sun-shielded skin, and the abnormal collagen and elastin are absent. Therefore, the effects of aging on skin are primarily environmental and can be separated from internal biological components (D.E. Brash, B.A. Gilchrest, Nature, 379:301-2, 1996). BEFORE AND AFTER: These images from Ortho Dermatological indicate the capability of tretinoin to reverse some effects of photoaging. Among topical treatments, the most potent active ingredient currently in use is retinoic acid, or tretinoin, derived from retinol, or vitamin A. There is evidence that tretinoin reduces the solar scars and wrinkling of photodamage (G.J. Fisher et al., Nature, 379:335-9, 1996). It increases the rate of cell turnover on the top layer of skin, allowing new cells to mature in place of sun-damaged cells. For years, a prescription drug for acne that contains tretinoin, called Retin-A, has been marketed by Ortho Dermatological of Raritan, N.J., a subsidiary of New Brunswick, N.J.-based Johnson & Johnson. After young women began noticing the beneficial effects of Retin-A on certain effects of photodamage, physicians began prescribing it for that purpose. Two controlled, multicenter trials involving a total of 619 patients subsequently showed that tretinoin applied topically will achieve a moderate but significant reduction in the appearance of fine wrinkles, age spots, or hyperpigmentation and surface roughness associated with chronic solar exposure (G.W. Weinstein et al., Archives of Dermatology, 127:659-65, 1991; E.A. Olsen et al., Journal of the American Academy of Dermatology, 26:215-24, 1992). Among tretinoin's side effects when applied topically are temporary peeling, redness, and blistering. Emerging from these trials was a tretinoin-containing Ortho product called Renova. The first prescription medication available specifically to treat photoaging, Renova was approved by FDA in December 1995. The concentrations of tretinoin contained in Renova and Retin-A are similar, although the latest formulation of the antiacne drug Retin-A Micro includes a controlled delivery system purchased from Advance Polymer Systems Inc., a Redwood City, Calif.-based biotech company. This delivery system entraps the tretinoin in polymer spheres that release the active ingredient over time, resulting in reduced irritation. Although the tretinoin-containing products are drugs rather than cosmeceuticals, Johnson & Johnson's worldwide director of dermatology, research, and drug discovery, Stan Shapiro, reports that Ortho is researching new cosmeceuticals. Johnson & Johnson, which employs more than 300 skin researchers worldwide, counts among its subsidiaries Neutrogena Corp., a Los Angeles-based skin-care company. Shapiro says of cosmeceuticals, "I think they're going to grow, because companies are going to be looking at active ingredients in skin-care products. We've passed the stage of beautification by cover-up and are on to active treatment." Biopharmaceutical companies that specialize in discovery of active ingredients and development of delivery technologies are beginning to list cosmetics companies among their clients, according to Pamela Bassett, a privately practicing New York City-based dentist and biopharmaceutical analyst with a special interest in drug delivery systems. She authored a recent 400-page report, Delivery Systems for Cosmetic Ingredients: Technologies, Trends and Market Opportunities, (P. Bassett, Southborough, Mass., Drug & Market Development, 1997), for which she examined more than 100 drug-delivery companies. Among delivery technologies they develop are lipid systems, nanoparticles, microcapsules, polymers, and films. These technologies are loaded into such vehicles as creams, liquids, gels, and patches. Bassett was surprised to discover that only "a handful" of drug delivery technology companies have made the leap from exclusively pharmaceutical clients to embracing the cosmetics industry as well. "It's a completely new business for these companies, so they obviously have made a number of strategic decisions," she explains. For example, cosmetics have relatively short shelf lives compared to pharmaceuticals, and they often contain many more ingredients than drugs. TOP RESEARCH: Cellegy founder Carl Thornfeldt believes his company is now a leading world authority on the stratum corneum layer of the skin. Foster City, Calif.-based Cellegy Pharmaceuticals Inc. is a publicly held biopharmaceutical company that develops prescription drugs, cosmeceuticals, and transdermal drug delivery technologies. The Cellegy stock prospectus estimates the total cosmeceutical market in the United States was $2.5 billion in sales for 1996, a figure the company expects will rise as the population continues to age. Glaxo Wellcome of the United Kingdom and Neutrogena are among companies that have made significant financial agreements with Cellegy, whose lead cosmeceutical is an antiwrinkling product designed to mitigate the visible effects of photodamage. Human trials are under way, and commercial sales are expected to begin this year. Oregon-based dermatologist Carl Thornfeldt founded Cellegy in 1989 and is its chief medical officer. Under his guidance, the company has gained significant expertise in the structure and function of the outer layer of skin, the stratum corneum. Thornfeldt and his colleagues discovered that an equimolar mixture of three lipids that are arranged between the stratum corneum cells in layers-ceramide, cholesterol, and linoleic acid-would optimize the repair of damaged outer skin of hairless mice (M. Mao-Qiang et al., Journal of Investigative Dermatology, 106:1096-101, 1996). This work led to the company's identification and isolation of a series of molecules that, when applied topically, have been shown in preclinical studies to reduce inflammation and allergic reactions caused by various drugs and cosmetics that come into contact with the skin. Cellegy's antiwrinkling products will incorporate this anti-irritant technology. "All our technology was predicated on manipulating the metabolic effects of the epidermis," Thornfeldt comments. "I think we are among the world leaders in understanding the stratum corneum barrier of the epidermis." He adds, "Cellegy's plan will be to market these compounds to people involved in skin care, such as dermatologists, plasticians, and estheticians." Although he believes Cellegy's main focus will remain on topical drug delivery systems, he adds, "I'm absolutely convinced of cosmeceuticals' importance." Cellegy Pharmaceuticals Inc. 1065 E. Hillsdale Blvd., Suite 418 Foster City, Calif. 94404 (415) 524-1600 Fax: (415) 524-1616 http://www.wco.com Nu Skin International Inc. One Nu Skin Plaza 75 W. Center St. Provo, Utah 84601 (801) 345-1000 Fax: (801) 345-2850 http://www.nuskin.com Penederm Inc. 320 Lakeside Dr., Suite A Foster City, Calif. 94404 (650) 358-0100 Fax: (650) 358-0101 http://www.penederm.com Another drug delivery technology company that has cosmetics company clients is Penederm Inc., also based in Foster City, Calif. This publicly held firm produces liquid polymers that blend into creams, ointments, or gels to enhance the delivery and effects of active agents in drugs and cosmetics. At least six major cosmetics companies use this technology. Last year, Penederm launched two topical prescription products, a retinoic acid-containing antiacne preparation (Avita) and an antifungal skin cream (Mentax). John Quigley, Jr., senior vice president of research and development, says Penederm sells its liquid polymers off the shelf to cosmetics companies, rather than loading them into specific cosmetic formulations. Now that bioactive ingredients are proliferating in nonprescription products, Quigley supports the idea of special cosmeceutical regulations, "but with careful steps, not across the board. Some compounds are not likely to be safe enough unless you know how to use them, and some are likely to be misused." He says much of the responsibility for making safety decisions about "high-performance" cosmetics currently lies with researchers. "The innovator has to make sure not to build unintended effects into the molecule." The active ingredients in Penederm's delivery systems are agents that either have gone out of patent or for which arrangements have been made with the patent holders. "It's a very effective short-term way to do things, but sooner or later, you'll run out of compounds and new delivery systems, so you'll always need a new string of active ingredients." Quigley foresees the emergence of cosmeceuticals containing active antifungal agents, other retinoids aside from tretinoin, and various analogs of vitamins A, D, and E. NO BIG TESTS: Nu Skin does not run clinical drug trials on active ingredients in its cosmetics, says Dale Kern. Nu Skin International Inc., a cosmetics company headquartered in Provo, Utah, sometimes uses biotech companies to test ingredients for its Epoch line of personal-care products that include natural ingredients collected by contracted ethnobotanists. However, Dale Kern, Nu Skin's director of technology, investigation, and development, says clinical drug trials would not be considered. "Many of these ingredients have been used for centuries without ill effects," he says. The company tries to "stay away from animal testing," although safety measures for botanical ingredients might include cytotoxicity trials in vitro or repeat insult patch tests for eye irritation. Kern declares that a novel synthetic compound emerging from a biotech lab would never be included in the company's cosmetics. Instead, he gives the example of mullein (Verbascum thapsus), a figwort indigenous to the Southwest used as by many Native Americans in poultices to treat abrasions. Mullein is contained in several Nu Skin shaving products. "It turns out there are a number of terpenoids in there that are anti-inflammatory," Kern comments. "The transition into cosmeceuticals can only grow. I know cosmetics companies are looking more and more to have active ingredients, and I think that will concern regulators, certainly," he declares. "We have to be very careful to market our products as cosmetics." He predicts the Epoch line will expand but adds, "We're staying tuned to ingredients that are efficacious and safe. We see a lot of things that are truly terrific, but we can't use them in cosmetics, because they simply don't have the track record."

'Cosmeceuticals' Spur Research But Worry FDA

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