Introduction

1Skin Structure, Pharmaceuticals, Cosmetics, and the Efficacy of Topically Applied Agents

Michael S. Roberts

School of Medicine, University of Queensland, Princess Alexandra Hospital,

Woolloongabba, Queensland, Australia

Kenneth A. Walters

An-eX Analytical Services Ltd., Cardiff, U.K.

INTRODUCTION

The structure of human skin is a formidable barrier to determining the efficacy of topically applied compounds. Much emphasis is placed on the efficacy of topically applied therapeutic agents and developing appropriate formulations (pharmaceuti- cals) to facilitate their delivery. Because the structure of the skin, especially the stra- tum corneum, in relation to its role in percutaneous absorption has been discussed in Chapter 1 in the companion volume (1), this aspect is not being considered here. The emphasis in this chapter is on introducing key concepts in dermatological and cosmetic development, which are dealt with in greater detail in the other chapters of this book.

STRUCTURE AND THE SKIN IN RELATION TO SKIN FUNCTION

Figure 1 shows an overview of the skin in terms of the functions it performs. Pro- tection, homeostatic, and sensing are both integrated and overlapping (2). Many products are applied to the skin to modify skin function. However, classifying them as a cosmetic or as a pharmaceutical is often difficult. Products applied to the skin to provide color or smell can be argued to not directly affect skin function. In con- trast, all moisturizing cosmetic products applied to the skin do affect skin function. Both stratum corneum hydration and the rate of its turnover by desquamation can be affected when an occlusive product is applied to the skin. Further, a number of localized events follow perturbation in stratum corneum function by interventions such as delipidization, stratum corneum stripping, and surfactant applications (2). These events are discussed in Chapter 5 of the companion volume (1).

COSMETICS, COSMECEUTICALS, AND PHARMACEUTICALS

In previous decades, skin conditions, such as male-pattern baldness, dandruff, skin aging, and wrinkles, were managed using cosmetics (3). In general, cosmetics are as- serted not to have any therapeutic effects and have been defined by the U.S. Fed- eral Food, Drug, and Cosmetic Act (FD&C) as “an article intended to be applied to the human body…for cleansing, beautifying, promoting attractiveness, or alter- ing the appearance without affecting the body’s structure or function.” In contrast, a drug is defined by FD&C (2) as “an article intended for use in the diagnosis, cure,

				Roberts and Walters
		Harmful external stimuli
		Chemicals, microbes, solvents,
	Desquamation	Radiation, electrical, thermal etc
			Sweat ducts	Hair
	and removal of solutes	Catabolic Barrier to
				protection
	absorbed to stratum	enzymes environment	Control of body
				Sebum
	corneum		temperature,
			removal of waste	lubrication
	Stratum
	corneum
		Maintain body
		composition
	Formation and	Body components
	maintenance of
	Stratum corneum	Water, electrolytes,	Melanocyte for
		Biochemicals etc
			skin
			pigmentation
	Stratum granulosum

Epidermis

Stratum spinosum

Stratum basale

Keratinocyte

Report to immune

system via Langerhan	Barrier function	Blood vessels
and other cells		Skin nutrition, removal of
	Metabolism of
		metabolic products,
	chemicals, filtering of
		immune function,
	UV radiation etc
		regulation of body
		temperature, blood
		pressure regulation

Dermis		Nerves
		Pressure, pain
		temperature
	Insulation and	Lymph
Subcutaneous	cushioning
tissue		remove waste,
		tissue pressure,

immune function

Figure 1  Skin components and functions performed. Source: Adapted from Ref. 2.

mitigation, treatment or prevention of disease, (or) intended to affect the structure or any function of the body.” Thus, the conundrum, if a topical product modifies the skin, is it a cosmetic or is it a drug? What is a side effect? Hence, a deodorant is a cosmetic, whereas an antiperspirant is a drug; a shampoo is a cosmetic, whereas an antidandruff shampoo is a drug and so on. Hence, it is the purpose of the product rather than what is in it that defines its category. At this time, as is evident for very effective ingredients, such as the antiseptic tea tree oil, it is not what the products or ingredients do to the skin but rather what is stated on the label to be the intended use of the product. In general, cosmetic products should contain generally regarded

Skin Structure, Pharmaceuticals, and Cosmetics
Table 1  The Continuum of Dermatological Knowledge
Dermatology	Cosmetic physician	Beauty therapist
Infections	Preventative antiseptics	Hygiene
Ichthyosis	Xerosis	Dry skin
Photodermatoses	Prevention of photoaging	Prevention
		of sunburn
Premature aging	Photoaging	Wrinkles
Pigmentary disorders	Melasma, actinic lentigines	Desire for
		bleaching
Acne	Hyperseborrhea	Oily skin
Scalp psoriasis	Seborrheic dermatitis	Dandruff
Hyperhidrosis	Hyperhidrosis	Sweating
Rosacea	Erythrosis	Red skin
Adipose tissue diseases	Adipose dystrophy	Cellulite
Alopecia	Male-pattern alopecia	Hair loss
Allergic dermatitis	Irritant dermatitis	Sensitive skin
Hypertrichosis	Idiopathic hirsutism	Socially excessive
		facial hair

Source: From Ref. 5.

as safe ingredients as defined by the U.S. Food Drug Administration (FDA) (i.e., not contain harmful substances). The European Commission’s Scientific Committee on Consumer Products (SCCP) follows directives that state “a cosmetic product shall mean any substance or preparation intended to be placed in contact with the vari- ous parts of the human body (epidermis, hair system, nails, lips and external genital organs) or with the teeth and the mucous membranes of the oral cavity with a view exclusively or mainly to cleaning them, perfuming them, changing their appearance and/or correcting body odours and/or protecting them or keeping them in good con- dition” (2) and that a cosmetic product “must not cause damage to human health when applied under normal or reasonably foreseeable conditions of use” (4).

Wallach (5) has pointed out that the definition of a skin disease is not straight- forward. Although a number of dermatoses, such as malignancies, autoimmune diseases, and severe adverse drug reactions, can be considered as diseases, there are a number that are not but may benefit from a cosmetic or other intervention. These include conditions such as greasy hair, oily skin, wrinkles, and sensitive skin. In reality, as shown in Table 1, there is a continuum of dermatological knowledge, and no clear demarcation exists between the categories requiring intervention by a der- matologist, cosmetic physician, and a beauty therapist. He points out that a drug or pharmaceutical is intended to prevent or treat a disease and that its efficacy must be proven by a double-blind, random, controlled trial. However, safety is a major con- sideration for such agents. In contrast, a cosmetic is intended to improve the appear- ance of the skin. Here, efficacy is whether it provides “beauty,” and this may include acting as a camouflage for a disfiguration. In contrast, safety considerations need to carefully evaluated, recognizing that, in the past, systemic toxicity has resulted from cosmetic use. An example is hexachlorophene-containing cosmetic products, which were responsible for the death of 36 babies in France in 1972 (6).

Cosmeceuticals were originally proposed for drugs with efficacy in topical conditions, such as topical minoxidil and retinoic acid (3). A 2007 Medline search of this term reveal only 14 articles using this term since 2005. Hence, topical prod- ucts are generally considered either cosmetics or pharmaceuticals. As Wallach (5) points out the key areas of overlap between these agents are in hygiene/prevention

Roberts and Walters

of infection, moisturizers, sunscreens, aging skin, acne, scaly scalp conditions, hy- perhidrosis, and rosacea. Chapters 2 and 3 emphasize traditional pharmaceutical approaches whereas Chapter 4 emphasizes application of cosmeceutic principles.

PHARMACEUTICALS

The formulation of cosmetics and pharmaceuticals is critical not only to their efficacy but also to patient acceptance. As discussed in the companion volume, formulation can be used to maximize penetration and efficacy (1). A number of the technologies used in cosmetic formulations have been summarized by Morganti et al. (7). They classify these as closed system, open system, and polymeric reservoir. The first two of these systems are summarized in Tables 2 and 3. A key strategy in each of these systems is to leave a residue that is undetectable to the eye and neither tacky nor greasy. A number of strategies that facilitate penetration by affecting the stratum corneum integrity may also be used, and these are summarized in Figure 2. The processes associated with each strategy and examples in practice are discussed more fully in Chapters 30–36. Cosmetic product stability is also important and should be on two levels: the product and its ingredient. Product stability normally entails an assessment of the physical characteristics (e.g., rheology, evaporation rate) of the system, whereas ingredient stability is usually concerned with minimal degradation during various storage conditions. Many cosmetic products now contain either solid lipid nanoparticles or nanostructured lipid carriers. The cosmetic benefits

Table 2  Closed Systems

	Liposomes	Cyclodextrins	Microcapsules	Submicrocapsules
Average size	40–300 nm	Variable; 3-D	50–500 nm	0.1–1.0 nm
		structure
Wall composition	Phospholipid,	Oligosaccharide	Gelatin,	Gelatin, alginate,
	POE, alkyl	matrix con-	polyvinyl al-	albumin, car-
	ethers, fatty ac-	sisting of 6, 7,	cohol, ethyl	rageenan
	ids, ceramides,	or 8 glucopy-	cellulose,
	or polyglycerol	ranose units	urethane
	ethers
Mode of action	Release occurs	Release occurs	Release oc-	Release occurs
	when the	when the	curs when	when the matrix
	vesicle wall is	complex is	the shell is	is disrupted by
	disrupted while	disrupted	disrupted	shear, abrasion,
	in contact with	while in	by shear,	or pressure or
	the SC	contact with	abrasion, or	by permeability
		the SC	pressure or
			by perme-
			ability
Other	May be unilamel-	Host complex	Composition	Matrix can be
	lar (single layer	can accom-	of shell can	coated or un-
	membrane) or	modate single	function as	coated; release
	multilamellar	molecule	membrane	or nonrelease
		of active	to control	can be designed
		component.	release
		Cds are also
		hygroscopic

Abbreviations: POE, polyoxyethylene; SC, stratum corneum; Cds, cyclodextrins. Source: From Ref. 7.

Skin Structure, Pharmaceuticals, and Cosmetics
Table 3  Open Systems
	Microsponge	Polymeric liquid reservoir
Average size	5–300 nm	Variable
Composition	Polymeric: usually cross-linked,	Polyester or polyurethane polymers:
	substituted acrylate	cross-linked or linear
Mode of action	Release occurs via several different	Diffusion of active into the epidermis
	“triggers”: applied physical pressure,	by partitioning mechanism: degree
	skin temperature, solvent for	of skin penetration is dependent
	entrapped active, perspiration, and	on geometry and molecular weight
	evaporation	of polymer
Other	Porous and weblike systems: function	Co-compatibility of the polymer with
	through sorption-desorption	actives and excipients is related to
	mechanism	the relative polarity of the polymer

Source: From Ref. 7.

of these lipid ingredients are reported to be enhanced chemical stability of active components, formation of a film, controlled occlusion, skin hydration, enhanced skin bioavailability, and physical stability (8). Other products include a water-dis- solvable cellulose film for a localized antiwrinkle effect (9). Packaging can be crucial, as evidenced by the better compliance when a “luxury jar” was used (10). Ultimately, more research is needed in this area—especially in relation to the “metamorphosis” of the vehicle after application to the skin (11). Here, the initial organization and composition of the product is altered with the evaporation of ingredients and fric- tion associated with the product application.

Powder	Aqueous		Oil in
in oil
	in oil		aqueous
			Matrix releas	Membrane	Adhesi
				control from	release
				solution	control
Powder	Oil	Aqueous	Powder
			in aqueous

	Conventional					Transdermal patches
	Physical
	Methods, e.g.,		Electrical/
	Stripping
			Magnetic, e.g.,			Physical barrier
	Dermal abrasion
			Iontophoresis
	Massage				Direct		N-0915 lipid
Ultrasound	Flexing		Electroporation
	Heat		Dermaportation Injection, e.g.,				stabilizer
	Laser ablation		+	-	Microneedles
					Gene gun
			N	S		Polymer barrier
	Force facilitated					Retardation
Effects on			On		Occlusion
lipid tails		desmosomes
						+	-
	On polar		Liposomes improve water			glucose	Reverse
	head groups			surface contact		Sweat	iontophoresis
						patch
	Chemical facilitated					Monitoring

Figure 2  Strategies for altering percutaneous absorption. Source: Updated from Ref. 2.

Roberts and Walters

EFFICACY

There are now many biophysical methods available to measure efficacy of products applied to treat local skin conditions. In assessing skin hydration, transepidermal water loss (TEWL) remains one of the most widely used because TEWL correlates directly with skin barrier dysfunction. Other measures, as discussed in Chapter 7, rely on measuring skin relief by using the electrical properties of the skin, such as conductance and capacitance. More advanced techniques include near infrared multispectral imaging, nuclear magnetic resonance spectroscopy, and optical coherence tomography. Laser Doppler flowmetry is used to measure local skin blood flow.

TESTING OF DERMATOLOGICS, COSMETICS, AND THEIR SAFETY EVALUATION

The United States distinguishes cosmetics and dermatologics through congressional legislature. In general, cosmetics beautify, cleanse, or promote attractiveness. When they go beyond this action, affecting the structure or function of the body, they become a drug. In relation to dermatologics, the FDA issued a white paper on critical paths on March 16, 2004 for the development of new medical products (12). A key focus in this white paper is updating the tools currently used to assess the safety and efficacy of new medical products. These tools need to be characterized by welldefined procedures, validation, standardized training, reproducibility, predictabil- ity, and clinical relevance. The FDA advocates a “maximal-use” study in the patient population of interest for topical products and an emphasis on systemic safety. This involves representing the largest anticipated usage/exposure that is consistent with the clinical trials and anticipated indication/labeling. Three categories of drugs are of interest: 505(b)(1)—classical new drug, 505(b)(2)—new formulation/form, and 505(j)—generic drug applications. In all cases, validation is the key to acceptance. In addition, as discussed in the accompanying volume (2), there is a range of safety tests required for topical products. Issues to be considered may include acute (singlepatch) and cumulative (repeated-patch) irritation, use of neat or diluted material, open or occlusive, risk-benefit, type of irritation, and the selection of negative and positive controls for appropriately sensitive individuals.

In the European setting, SCCP provides guidance for the testing of cosmetic ingredients and their safety evaluation. The sixth revision of their guidance notes was adopted by the SCCP during the 10th plenary meeting in December 19, 2006

(4). SCCP points out that although cosmetic products have used a variety of ingre- dients derived from plants, animals, and mineral sources for thousands of years, a number of synthetic and semisynthetic ingredients have been added in recent times. Further, cosmetic products are now widely and extensively used. Although there are rare associations with serious health hazards, there is a need for a longterm safety assessment and monitoring of cosmetic ingredient chemical structures, toxicity profiles, and exposure patterns. Accordingly, the safety requirements for cosmetic products are becoming more similar to those imposed on drugs being ap- plied for therapeutic purposes. The main difference in requirements between these two groups appears to be in relation to proof of efficacy.

Safety evaluation of cosmetic ingredients relies on data obtained from in vivo animal studies, in vitro test, quantitative structure-activity relationships, clinical studies, epidemiological studies, and reported adverse incidents. There is now an

Skin Structure, Pharmaceuticals, and Cosmetics

Table 4  SSCP Safety Evaluation of Cosmetic Requirements

Chemical and physical specifications of cosmetic ingredients

 Chemical identity

 Physical form molecular weight

 Characterization and purity of the chemical

 Characterization of the impurities or accompanying contaminants

 Solubility

 Partition coefficient (log Pow)

 Additional relevant physical and chemical specifications Relevant toxicity studies on cosmetic ingredients

 Acute toxicity

 Irritation and corrosivity

 Skin sensitization

 Dermal/percutaneous absorption

 Repeated dose toxicity

 Mutagenicity, genotoxicity, and carcinogenicity

 Reproductive toxicity

 Toxicokinetic studies

 Photoinduced toxicity

 Human data

Toxicological requirements for inclusion of a substance in one of the annexes to Dir. 76/768/EEC

 (which are evaluated by the SCCP)

   General toxicological requirements

   Annex II

   Annex III

   Annex IV

   Annex VI

   Annex VII

   Requirements for partial evaluations

Basic requirements for cosmetic ingredients (which are evaluated by individual safety assessors)

 General toxicological requirements

 Identification of mineral, animal, botanical, and biotechnological ingredients

 Fragrance materials

 Potential endocrine disruptors

 Animal-derived ingredients, including BSE issues

 CMR ingredients

 Nanoparticles

General principles for the calculation of the MoS and lifetime cancer risk for a cosmetic ingredient

 Introduction: definitions

 MoS

 Dermal absorption issues in the calculation of the SED

 MoS for children

 TTC

 Lifetime cancer risk

Abbreviations: BSE, bovine spongiform encephalopathy; CMR, carcinogenic, mutagenic, toxic to reproduction; MoS, margin of safety; SCCP, Scientific Committee on Consumer Products; SED, systemic exposure dosage; TTC, threshold of toxicological concern.

Source: From Ref. 4.

increasing emphasis on non-animal–based safety evaluations as per their Dir. 2003/15/EC2. SCCP relies on a risk assessment procedure consisting of the follow- ing (4): (i) hazard identification, (ii) dose-response assessment, (iii) exposure assess- ment, and (iv) risk characterization. In the case of a threshold effect, the margin of safety (MoS) is calculated according to the following formula: MoS = no observable effect level (NOAEL)/SED, where SED represents the systemic exposure dosage. For nonthreshold effects (e.g., nonthreshold carcinogenic effect), the lifetime risk usually

Roberts and Walters

Table 5  SCCP Safety Evaluation of Finished Cosmetic Products

Categories of cosmetic products and exposure levels in use

Guidelines for the safety evaluation of finished cosmetic products

Toxicological profile of the ingredients

 Stability and physical and chemical characteristics of the finished cosmetic product

 Evaluation of the safety of the finished product

Guidelines on microbiological quality of the finished cosmetic product

 Quantitative and qualitative limits

 Challenge testing

 Good manufacturing practice

Abbreviation: SCCP, Scientific Committee on Consumer Products.

Source: From Ref. 4.

is determined through the use of a dose descriptor. The SCCP also emphasizes the need to assess the safety profile of cosmetic ingredients (defined in Table 4) and their products (defined in Table 5).

In addition to experimental data, SCCP seeks (i) any report on epidemiologi- cal and/or observational experiences, (ii) description of all available ecological, and environmental effects of the respective substance/compound/preparation, (iii) all relevant published literature, (iv) a description of the bibliographical methods used, (v) any useful finding to the applicant’s best ability, and (vi) any “gray ma- terial” available elsewhere. Table 5 shows SCCP guidelines for cosmetic product evaluations.

In general, the MoS used to extrapolate from test animals to sensitive human subpopulations must be at least 100 and is defined as a factor 10 for the extrapolation from animal to man and another factor 10 taking into account the interindividual variations within the human population (Fig. 3). According to Organisation for Economic Co-operation and Development Guideline 428 (Skin Absorption: In Vitro Method), normally, 1–5 mg/cm2 for a solid and up to 10 μL/cm2 for liquids should be used in in vitro tests to have an application that mimics human exposure (4). Exposure values used for various products are shown in Table 6.

As a result of such deliberations, the SCCP provides opinions on various prod- ucts. One recent opinion, adopted in March 21, 2007, is on the UV filter homosalate (13). This opinion concluded, “Based on the information provided, the SCCP is of the opinion that the use of homosalate at a maximum concentration of 10%w/w in cosmetic sunscreen does not pose a risk to the health of the consumer. Use of homo-

NOAEL NOAEL from human data

from animal data

Species					Human
differences					variability
	10			10
Kinetics			Dynamics
					Kinetics			Dynamics
4.0			2.5
					3.2			3.2

Figure 3  Approach to assessment of safety margin using animal and human studies. Source: From Ref. 4.

Skin Structure, Pharmaceuticals, and Cosmetics
Table 6  Daily Consumer Exposure Values
		Amount of		Daily exposure
		substance	Retention	calculated
Product type		applied (g)	factor	(g/day)
Shampoo		10.46	0.01	0.11
Face cream		1.54	1.0	1.54
Body lotion		7.82	1.0	7.82
Deodorant
	Stick	1.51	1.0	1.51
	Spray	6.54	1.0	6.54
Lipstick, lip salve		0.057	1.0	0.057
Toothpaste (adult)		2.75	0.05	0.138

Source: From Ref. 4.

salate in other types of cosmetic products at concentrations up to 10.0% also does not pose a risk to the health of the consumer.”

IS IT A SUCCESSFUL PRODUCT?

There are a number of necessary prerequisites for a topical dermatological or cosmetic product, including meeting technical, user acceptance, health care provider acceptance, regulatory approval, and adequate financial return considerations. At the end of the day, user acceptance and an adequate financial return may be the main determinants for product success. However, without a product, these conditions are rather irrelevant.

CONCLUSION

The success of both cosmetic and pharmaceutical products depends on an appropri- ate integration of skin structure and function aspects with the nature of the formula- tion (pharmaceuticals), its efficacy as defined by the goal of the product (cosmetic or pharmaceutical), and its safety. The function of the skin and especially the morphol- ogy of the stratum corneum are dependent on whether the barrier has been modi- fied by hydration or by a perturbation, with consequences for the lipid assembly of the intercellular stratum corneum lipids (2). As Morganti et al. (7) point out, “To be really effective, each product should contain the right active principles in the right dose to be transported by the right carrier onto the selected skin area. These active principles have to be released by the carrier on the skin and remain there for the time needed to fulfil their function.” The question remains, will cosmetic products ever become more, that is, will any of these products be commonly referred to in the future as “cosmeceuticals”? Ultimately, however, the efficacy and toxicity of a topi- cally applied agent will depend on the intrinsic activity of any active ingredient, its interaction with the formulation, and how its ingredients affect the skin.

REFERENCES

1.Roberts MS, Walters KA. The relationship between structure and barrier function of skin. In: Roberts MS, Walters KA, eds. Dermal Absorption and Toxicity Assessment. Marcel Dekker, 1998; 91:1–42.

10	Roberts and Walters

2.Roberts MS, Walters KA. Human skin morphology and dermal absorption. In: Roberts MS, Walters KA, eds. Dermal Absorption and Toxicity Assessment, 2nd edition. New York: Informa Healthcare, 2008; 1–13.

3.Lavrijsen AP, Vermeer BJ. Cosmetics and drugs. Is there a need for a third group: cosmeceutics? Br J Dermatol 1991; 124:503–504.

4.The SCCP’s Notes of Guidance for the Testing of Cosmetic Ingredients and Their Safety Evaluation. 6th rev., European Commission, 2006. (http://ec.europa.eu/health/ph_risk/ committees/04_sccp/docs/sccp_o_03j.pdf).

5.Wallach D. The field of cosmetic dermatology: the need for a patient-centred approach. J Cosmet Dermatol 2002 Oct; 1(3):137–141.

6.Editorial. Hexachlorophene today. Lancet 1982; 1:87–88.

7.Morganti P, Ruocco E, Wolf R, Ruocco V. Percutaneous absorption and delivery systems. Clin Dermatol 2001 Jul–Aug; 19(4):489–501.

8.Muller RH, Petersen RD, Hommoss A, Pardeike J. Nanostructured lipid carriers (NLC) in cosmetic dermal products. Adv Drug Deliv Rev 2007; (59):522–530.

9.Legendre JY, Schnitzler I, Li QY, et al. Formulation, characterization, and efficacy of an adenosine-containing dissolvable film for a localized anti-wrinkle effect. J Cosmet Sci 2007 Mar–Apr; 58(2):147–155.

10.Lodén M, Buraczewska I, Halvarsson K. Facial anti-wrinkle cream: influence of product presentation on effectiveness: a randomized and controlled study. Skin Res Technol 2007 May; 13(2):189–194.

11.Zhang J, Smith EW, Surber C. Galenical principles in skin protection. Curr Probl Dermatol 2007; 34:11–18.

12.Innovation or Stagnation: Challenge and Opportunity on the Critical Path to New Medical Products. U.S. Food and Drug Administration, Rockville, MD, 2006. (www.fda

.gov/oc/initiatives/criticalpath/whitepaper.html). Accessed July 2007.

13.SCCP. Opinion on Homosalate. European Commission, 2006. (http://ec.europa.eu/health/ ph_risk/committees/04_sccp/docs/sccp_o_097.pdf). Accessed July 2007.