COSMECEUTICS

COSMECEUTICS

The term cosmeceutical was introduced for the first time, about 20 years ago, by the dermatologist Albert Kligman. Cosmeceuticals actually represent a category of cosmetic products, which claims the presence of biologically active ingredients, thus bearing the benefits typical of drugs. Many substances, whether chemically synthesized or extracted from plants or animals, can be used as functional ingredients. Cosmeceuticals can perform various functions: protective, whitening, tanning, anti-wrinkle, anti-aging or nail healing. However, they can also be the cause of unwanted events. The most common events are: skin irritability, contact dermatitis, photosensitization, blackhead formation, hair and nail damage, hyper- or hypo-pigmentation, infections, carcinogenesis and also systemic adverse reactions. Therefore, those who research and develop cosmeceuticals, especially if they contain different active ingredients, should declare the source from which they derive, their structure, their mechanism of action and, above all, the efficacy and safety against the skin (1). Furthermore, the interaction between the cosmeceutical and the skin could be influenced by various environmental factors, such as temperature, humidity, pollution, microorganisms and solar radiation. There are, however, skin conditions that can alter the interaction between the cosmeceutical and the skin and, consequently, the expected result. Today, there are many cosmetic products, containing biologically active ingredients, that are developed and marketed; although, there is a gap at the level of the various countries regarding their regulation and approval (1). The term cosmeceutical, used in the cosmetic industry and also on the academic level, is not universally accepted by regulatory authorities. Below is the opinion expressed by some regulatory agencies on the issue.
European Commission: As reported in a guidance document of the European Commission, the decision on the demarcation limit between the Cosmetics Directive 76/768/EEC and the Medicines Directive 2001/83/EEC (amended by Directive 2004/27/EEC) is crucial for the correct interpretation and application of the two Directives (2). The definition of cosmetic (product at the interface with a wide range of other product categories, such as medicines, biocides and medical devices) is based on two aspects: the site of application (external surfaces of the body/teeth/mucous membranes) and the designated function (cleansing, perfuming, changing appearance and/or correcting body odors and/or maintaining good condition) (3). The definition of medicinal product, as reported by Directive 2004/27/EEC (which amended Directive 2001/83/EEC) takes into account its “presentation” (a medicinal product is indicated for the treatment or prevention of diseases) and its “Function” (a medicine is capable of modifying physiological functions, exerting a pharmacological, immunological or metabolic action or for carrying out a medical diagnosis). A general rule is that no product can be regulated by both Directives at the same time (“principle of non-overlap”, principle of non-cumulation). It is, however, recognized that some products, known as borderline products, can satisfy both the definition of a cosmetic and a drug. In these cases the problem arises regarding which legislation they fall. Article 2 (2) of the Medicines Directive states that “in case of doubt, they apply to a product, which can fall within the definition of a medicinal product and that of a product governed by another Community legislation, taking into account of its characteristics, the provisions of the Medicines Directive “. Even if a product falls within the definition of cosmetic (article 1 of Directive 76/768), it must be treated as a “medicinal product” and therefore regulated by the relevant legislation, if it is indicated for the treatment and prevention of diseases or if administered for correct or modify physiological functions. This does not mean, however, that there is no obligation to perform a detailed assessment in order to determine whether the product belongs to one or the other category.
Food and Drug Administration (FDA): Under the FD&C Act, the FDA does not recognize any product category that goes under the term cosmeceutical. In fact, according to US law, a product can be a drug, a cosmetic or a combination of both. US law defines a drug as a product that treats, mitigates or prevents a disease or that acts on the structures and functions of the human body. In addition, in the United States, a drug is subject to approval by the FDA before it is placed on the market, while for a cosmetic there is no pre-sale approval (except for dyes). Therefore, the FDA believes that if a product has therapeutic properties it should be approved as a drug. The FDA also declares that a product can be defined as both a drug and a cosmetic. This can, in fact, happen when a product boasts two uses. For example, a shampoo is a cosmetic if its use is intended as a hair cleanser; it is, on the other hand, a drug if its use is intended as a treatment against dandruff (4).
Health Canada: In Canada, as defined by the Food and Drug Act, there are products that can have both characteristics of a cosmetic and a drug (products at the interface between cosmetic and drug) that are difficult to classify. Such products may include anti-acne treatments, anti-dandruff products, anti-caries products containing fluoride, skin medications, diaper redness products, sunscreen, skin and tooth whiteners. In the event that the classification of a product at the interface between cosmetic and drug is not immediately evident, Health Canada decides, on a case by case basis, whether to classify this product as a drug or cosmetic. In 2007, Health Canada expressed the need to establish a well-defined approach with which to classify these products, after consultation with stakeholders. This approach has been described in a guide document, in which the Department clarifies how it interprets and applies the definitions of cosmetic and drug (5). The distinction between cosmetic and drug is based on two main factors: the declared purposes and the composition of the product. In recent times, the intended purpose takes precedence in the decision making process. The drug must exhibit pharmacological activity, through interaction with a receptor site in order to achieve a biological response. Some ingredients are internationally recognized as drugs (eg glucocorticoids). To be such, a cosmetic must not be absorbed at a percutaneous level in order to exert its effect. Products administered by inhalation, ingestion and injection (intramuscular, subcutaneous, intravenous, etc.), with the sole exception of tattoos, are not considered cosmetic. However, it is generally recognized that cosmetics can exert a negligible organic effect. An example is given by a moisturizing product that carries out its action by adding water to the epidermis.
The situation regarding cosmetic products containing active ingredients is certainly very complex, not only due to the difficulty in classifying such products either as cosmetics or as drugs, but also because of the ambiguous advertising made on them. From a regulatory point of view, it is the Consumer Code (Legislative Decree 206/05) which governs the advertising of cosmetic products. It is considered deceptive if it misleads the consumer, influencing their choices with false or ambiguous statements, presentations and images of the product regarding the characteristics and effects (Article 23) (6). In this regard, we report as an example a work by Lodén M et al. in which it was highlighted how the great interest in maintaining a youthful appearance with minimal signs of skin aging has led to an ever-growing market of prestigious and expensive skincare products, which claim anti-aging effects (3 ). As reported in this work, the anti-aging effect can be obtained by physical methods (by applying colored products on the face e.g. foundation, or by adding pigments that have a reflective action to ordinary creams, which therefore reduces the shadow effect on the face skin) or by adding UV filters that block the sun’s UV radiation by reflection or absorption. However, many anti-aging cosmetics claim the presence of growth factors, substances of natural origin (eg. Phyto-estrogens), etc. Although Directive 76/768/EEC does not allow the use of estrogens in cosmetics, phyto-estrogens, such as Genistein (isoflavone present in soy), are intended for women with low hormonal activity (e.g. in menopause) and affected by signs of aging (7). Effects claimed by growth factors and plant extracts include increased collagen content and skin density (8). Therefore, if growth factors and plant substances exert a significant pharmacological, immunological or metabolic action, their formulations should be classified as medicinal products. Furthermore, it is relatively easy for consumers to evaluate the benefits deriving from a superficial and immediate physical action of anti-aging creams (eg. filling or coloring effect). However, the advertisements of many anti-wrinkle products give the impression that they have deeper effects, which become evident after weeks or months of treatment. Consumers therefore find it difficult to select an anti-wrinkle cream, due to the limited transparency of the scientific evidence associated with the product. For example, consumers may prefer the use of ordinary sunscreen rather than an expensive face cream, as the anti-aging effect is only given by the content of UV filters. To this day, no studies have been carried out on the effectiveness of anti-wrinkle products due to the long duration required by these studies and the complicated techniques for evaluating the effects associated with the use of these products (3). In fact, while many products cite clinical trials to prove their effectiveness, PubMed search doesn’t reveal as many studies indexed in Medline (9). According to Lodén M et al., in order to ensure adequate safety of use of the new active ingredients introduced on the market in cosmetics, health professionals and consumers should have access to scientific evidence regarding the claimed effects of these products. It is therefore essential for the cosmetic industry, and for all interested parties, an efficient post-marketing surveillance, which focuses attention on the evaluation procedures for the safety of use and on the possible undesirable effects associated with use of such products (3). We remind you that consumers who intend to report alleged cases of unfair commercial practices, misleading and hidden advertising can contact the Italian Competition and Market Authority (AGCM), which annually takes numerous measures also in the cosmetic sector (10).
Liberata Sportiello* and Lidia Sautebin (Department of Experimental Pharmacology and Interdepartmental Center for Research in Pharmacoeconomics and Pharmacotherapy, Faculty of Pharmacy, University of Naples Federico II).

thus bearing the benefits typical of drugs. Many substances, whether chemically synthesized or extracted from plants or animals, can be used as functional ingredients. Cosmeceuticals can perform various functions: protective, whitening, tanning, anti-wrinkle, anti-aging or nail healing. However, they can also be the cause of unwanted events. The most common events are: skin irritability, contact dermatitis, photosensitization, blackhead formation, hair and nail damage, hyper- or hypo-pigmentation, infections, carcinogenesis and also systemic adverse reactions. Therefore, those who research and develop cosmeceuticals, especially if they contain different active ingredients, should declare the source from which they derive, their structure, their mechanism of action and, above all, the efficacy and safety against the skin (1). Furthermore, the interaction between the cosmeceutical and the skin could be influenced by various environmental factors, such as temperature, humidity, pollution, microorganisms and solar radiation. There are, however, skin conditions that can alter the interaction between the cosmeceutical and the skin and, consequently, the expected result. Today, there are many cosmetic products, containing biologically active ingredients, that are developed and marketed; although, there is a gap at the level of the various countries regarding their regulation and approval (1). The term cosmeceutical, used in the cosmetic industry and also on the academic level, is not universally accepted by regulatory authorities. Below is the opinion expressed by some regulatory agencies on the issue.

European Commission: As reported in a guidance document of the European Commission, the decision on the demarcation limit between the Cosmetics Directive 76/768/EEC and the Medicines Directive 2001/83/EEC (amended by Directive 2004/27/EEC) is crucial for the correct interpretation and application of the two Directives (2). The definition of cosmetic (product at the interface with a wide range of other product categories, such as medicines, biocides and medical devices) is based on two aspects: the site of application (external surfaces of the body/teeth/mucous membranes) and the designated function (cleansing, perfuming, changing appearance and/or correcting body odors and/or maintaining good condition) (3). The definition of medicinal product, as reported by Directive 2004/27/EEC (which amended Directive 2001/83/EEC) takes into account its “presentation” (a medicinal product is indicated for the treatment or prevention of diseases) and its “Function” (a medicine is capable of modifying physiological functions, exerting a pharmacological, immunological or metabolic action or for carrying out a medical diagnosis). A general rule is that no product can be regulated by both Directives at the same time (“principle of non-overlap”, principle of non-cumulation). It is, however, recognized that some products, known as borderline products, can satisfy both the definition of a cosmetic and a drug. In these cases the problem arises regarding which legislation they fall. Article 2 (2) of the Medicines Directive states that “in case of doubt, they apply to a product, which can fall within the definition of a medicinal product and that of a product governed by another Community legislation, taking into account of its characteristics, the provisions of the Medicines Directive “. Even if a product falls within the definition of cosmetic (article 1 of Directive 76/768), it must be treated as a “medicinal product” and therefore regulated by the relevant legislation, if it is indicated for the treatment and prevention of diseases or if administered for correct or modify physiological functions. This does not mean, however, that there is no obligation to perform a detailed assessment in order to determine whether the product belongs to one or the other category.
Food and Drug Administration (FDA): Under the FD&C Act, the FDA does not recognize any product category that goes under the term cosmeceutical. In fact, according to US law, a product can be a drug, a cosmetic or a combination of both. US law defines a drug as a product that treats, mitigates or prevents a disease or that acts on the structures and functions of the human body. In addition, in the United States, a drug is subject to approval by the FDA before it is placed on the market, while for a cosmetic there is no pre-sale approval (except for dyes). Therefore, the FDA believes that if a product has therapeutic properties it should be approved as a drug. The FDA also declares that a product can be defined as both a drug and a cosmetic. This can, in fact, happen when a product boasts two uses. For example, a shampoo is a cosmetic if its use is intended as a hair cleanser; it is, on the other hand, a drug if its use is intended as a treatment against dandruff (4).
Health Canada: In Canada, as defined by the Food and Drug Act, there are products that can have both characteristics of a cosmetic and a drug (products at the interface between cosmetic and drug) that are difficult to classify. Such products may include anti-acne treatments, anti-dandruff products, anti-caries products containing fluoride, skin medications, diaper redness products, sunscreen, skin and tooth whiteners. In the event that the classification of a product at the interface between cosmetic and drug is not immediately evident, Health Canada decides, on a case by case basis, whether to classify this product as a drug or cosmetic. In 2007, Health Canada expressed the need to establish a well-defined approach with which to classify these products, after consultation with stakeholders. This approach has been described in a guide document, in which the Department clarifies how it interprets and applies the definitions of cosmetic and drug (5). The distinction between cosmetic and drug is based on two main factors: the declared purposes and the composition of the product. In recent times, the intended purpose takes precedence in the decision making process. The drug must exhibit pharmacological activity, through interaction with a receptor site in order to achieve a biological response. Some ingredients are internationally recognized as drugs (eg glucocorticoids). To be such, a cosmetic must not be absorbed at a percutaneous level in order to exert its effect. Products administered by inhalation, ingestion and injection (intramuscular, subcutaneous, intravenous, etc.), with the sole exception of tattoos, are not considered cosmetic. However, it is generally recognized that cosmetics can exert a negligible organic effect. An example is given by a moisturizing product that carries out its action by adding water to the epidermis.
The situation regarding cosmetic products containing active ingredients is certainly very complex, not only due to the difficulty in classifying such products either as cosmetics or as drugs, but also because of the ambiguous advertising made on them. From a regulatory point of view, it is the Consumer Code (Legislative Decree 206/05) which governs the advertising of cosmetic products. It is considered deceptive if it misleads the consumer, influencing their choices with false or ambiguous statements, presentations and images of the product regarding the characteristics and effects (Article 23) (6). In this regard, we report as an example a work by Lodén M et al. in which it was highlighted how the great interest in maintaining a youthful appearance with minimal signs of skin aging has led to an ever-growing market of prestigious and expensive skincare products, which claim anti-aging effects (3 ). As reported in this work, the anti-aging effect can be obtained by physical methods (by applying colored products on the face e.g. foundation, or by adding pigments that have a reflective action to ordinary creams, which therefore reduces the shadow effect on the face skin) or by adding UV filters that block the sun’s UV radiation by reflection or absorption. However, many anti-aging cosmetics claim the presence of growth factors, substances of natural origin (eg. Phyto-estrogens), etc. Although Directive 76/768/EEC does not allow the use of estrogens in cosmetics, phyto-estrogens, such as Genistein (isoflavone present in soy), are intended for women with low hormonal activity (e.g. in menopause) and affected by signs of aging (7). Effects claimed by growth factors and plant extracts include increased collagen content and skin density (8). Therefore, if growth factors and plant substances exert a significant pharmacological, immunological or metabolic action, their formulations should be classified as medicinal products. Furthermore, it is relatively easy for consumers to evaluate the benefits deriving from a superficial and immediate physical action of anti-aging creams (eg. filling or coloring effect). However, the advertisements of many anti-wrinkle products give the impression that they have deeper effects, which become evident after weeks or months of treatment. Consumers therefore find it difficult to select an anti-wrinkle cream, due to the limited transparency of the scientific evidence associated with the product. For example, consumers may prefer the use of ordinary sunscreen rather than an expensive face cream, as the anti-aging effect is only given by the content of UV filters. To this day, no studies have been carried out on the effectiveness of anti-wrinkle products due to the long duration required by these studies and the complicated techniques for evaluating the effects associated with the use of these products (3). In fact, while many products cite clinical trials to prove their effectiveness, PubMed search doesn’t reveal as many studies indexed in Medline (9). According to Lodén M et al., in order to ensure adequate safety of use of the new active ingredients introduced on the market in cosmetics, health professionals and consumers should have access to scientific evidence regarding the claimed effects of these products. It is therefore essential for the cosmetic industry, and for all interested parties, an efficient post-marketing surveillance, which focuses attention on the evaluation procedures for the safety of use and on the possible undesirable effects associated with use of such products (3). We remind you that consumers who intend to report alleged cases of unfair commercial practices, misleading and hidden advertising can contact the Italian Competition and Market Authority (AGCM), which annually takes numerous measures also in the cosmetic sector (10).
Liberata Sportiello* and Lidia Sautebin (Department of Experimental Pharmacology and Interdepartmental Center for Research in Pharmacoeconomics and Pharmacotherapy, Faculty of Pharmacy, University of Naples Federico II).

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