Topical and Transdermal Drug Delivery

Principles and Practice

Heather A. E. Benson, Adam C. Watkinson, Heather A. E. Benson, Adam C. Watkinson

• Publisher: Wiley
• Year: 2012
• Print ISBN:
  9780470450291
• eBook ISBN:
  9781118140499
• Edition: 1
• Topic: Medicine
• Subtopic: Pharmacology

Practical drug development approaches presented by leading experts

Designed to support the development of new, effective therapeutics, Topical and Transdermal Drug Delivery: Principles and Practice explains the principles underlying the field and then demonstrates how these principles are put into practice in the design and development of new drug products. Drawing together and reviewing the latest research findings, the book focuses on practical, tested, and proven approaches that are backed by industry case studies and the authors' firsthand experience. Moreover, the book emphasizes the mechanistic information that is essential for successful drug product development.

Topical and Transdermal Drug Delivery: Principles and Practice is divided into two parts:

• Part One, Current Science, Skin Permeation, and Enhancement Approaches, offers readers a fundamental understanding of the underlying science in the field. It describes the principles and techniques needed to successfully perform experimental approaches, covering such issues as skin permeation, enhancement, and assessment.

• Part Two, Topical and Transdermal Product Development, guides readers through the complete product development process from concept to approval, offering practical tips and cautions from experts in the field. This part also discusses regulations that are specific to the development of dermal drug products. The final chapter explores current and future trends, forecasting new development techniques and therapeutics.

Throughout the book, the authors clearly set forth the basic science and experimental procedures, making it possible for researchers to design their own experimental approaches and accurately interpret their results.

With contributions from experienced drug researchers, this text is highly recommended for all researchers involved in topical and transdermal product development who need to know both the state of the science and the standards of practice.

Part One: Current Science, Skin Permeation, and Enhancement Approaches

Chapter 1

Skin Structure, Function, and Permeation

Heather A.E. Benson

INTRODUCTION

The skin is the largest organ of the body, covering about 1.7 m² and comprising approximately 10% of the total body mass of an average person. The primary function of the skin is to provide a barrier between the body and the external environment. This barrier protects against the permeation of ultraviolet (UV) radiation, chemicals, allergens and microorganisms, and the loss of moisture and body nutrients. In addition, the skin has a role in homeostasis, regulating body temperature and blood pressure. The skin also functions as an important sensory organ in touch with the environment, sensing stimulation in the form of temperature, pressure, and pain.

While the skin provides an ideal site for administration of therapeutic compounds for local and systemic effects, it presents a formidable barrier to the permeation of most compounds. The mechanisms by which compounds permeate the skin are discussed later in this chapter, and methods to enhance permeation are described in Chapters 2–4. An understanding of the structure and function of human skin is fundamental to the design of optimal topical and transdermal dosage forms. The structure and function of healthy human skin is the main focus of this chapter. Physiological factors that can compromise the skin barrier function, including age-related changes and skin disease, are also reviewed. Chapter 19 describes the current and future trends in the treatment of these and other skin diseases.

HEALTHY HUMAN SKIN: STRUCTURE AND FUNCTION

Human skin is composed of four main regions: the stratum corneum, the viable epidermis, dermis, and subcutaneous tissues (Fig. 1.1). A number of appendages are associated with the skin: hair follicles and eccrine and apocrine sweat glands. From a skin permeation viewpoint, the stratum corneum provides the main barrier and therefore the structure of this layer will be discussed in most detail. The other layers and appendages contribute important functions and are important target sites for drug delivery.

Figure 1.1 Diagrammatic cross-section of human skin.⁹⁶

Epidermis

The epidermis is a multilayered region that varies in thickness from about 0.06 mm on the eyelids to about 0.8 mm on the palms of the hands and soles of the feet. There are no blood vessels in the epidermis, therefore epidermal cells must source nutrients and remove waste by diffusion across the epidermal–dermal layer to the cutaneous circulation in the dermis. Consequently, cells loose viability with increasing distance from the basal layer of the epidermis. The term “viable epidermis” is often used for the epidermal layers below the stratum corneum, but this terminology is questionable, particularly for cells in the outer layers. The epidermis is in a constant state of renewal, with the formation of a new cell layer of keratinocytes at the stratum basale, and the loss of their nucleus and other organelles to form desiccated, proteinaceous corneocytes on their journey toward desquamation, which in normal skin occurs from the skin surface at the same rate as formation. Thus the structure of the epidermal cells changes from the stratum basale, through the stratum spinosum, stratum granulosum, and stratum lucidum to the outermost stratum corneum (Fig. 1.2). The skin possesses many enzymes capable of metabolizing topically applied compounds. These are involved in the keratinocyte maturation and desquamation process,¹ formation of natural moisturizing factor (NMF) and general homeostasis.²

Figure 1.2 Human epidermis.⁹⁷

While the stratum corneum provides an efficient physical barrier, when damaged, environmental contaminants can access the epidermis to initiate an immunological response. This includes (1) epithelial defense as characterized by antimicrobial peptides (AMP) produced by keratinocytes—both constitutively expressed (e.g., human beta defensin 1 [hBD1], RNAse 7, and psoriasin) and inducible (e.g., hBD 2-4 and LL-37); (2) innate-inflammatory immunity, involving expression of pro-inflammatory cytokines and interferons; and (3) adaptive immunity based on antigen presenting cells, such as epidermal Langerhans and dendritic cells, mediating a T cell response.³ An understanding of these systems is important as they can be involved in skin disease and may also be therapeutic targets for the management of skin disease. The importance of these systems as therapeutic targets is highlighted in Chapter 19.

Stratum Basale

The stratum basale is also referred to as the stratum germinativum or basal layer. This layer contains Langerhans cells, melanocytes, Merkel cells, and the only cells within the epidermis that undergo cell division, namely keratinocytes. The keratinocytes of the basal lamina are attached to the basement membrane by hemidesmosomes, which are proteinaceous anchors.^4,5 The absence of this effective adhesion results in rare chronic blistering diseases such as pemphigus and epidermolysis bullosa. Within the epidermis, desmosomes act as molecular rivets, interconnecting the keratin of adjacent cells, thereby ensuring the structural integrity of the skin.

Langerhans cells are dendritic cells and the major antigen presenting cells in the skin. They are generated in the bone marrow, and migrate to and localize in the stratum basale region of the epidermis. When activated by the binding of antigen to the cell surface, they migrate from the epidermis to the dermis and on to the regional lymph nodes, where they sensitize T cells to generate an immune response. Langerhans cells are implicated in allergic dermatitis and are also a target for the mediation of enhanced immune responses in skin-applied vaccine delivery.

Melanocytes produce melanins, high molecular weight polymers that provide the pigmentation of the skin, hair, and eyes. The main function of melanin is to protect the skin by absorbing potentially harmful UV radiation, thus minimizing the liberation of free-radicals in the basal layer. Melanin is present in two forms: eumelanins are brown-black, whereas pheomelanins are yellow-red. Melanin is synthesized from tyrosine in the melanosomes, which are membrane-bound organelles that are associated with the keratinocytes and widely distributed to ensure an even distribution of pigmentation. Regulation of melanogenesis involves over 80 genes, many of which have now been characterized and cloned.⁶ Mutations in these genes can result in conditions such as albinism and vitiligo, production of melanin with reduced photoprotective effects, and they may offer immune targets for the management of malignant melanoma.

Merkel cells are associated with the nerve endings and are concentrated in the touch-sensitive sites of the body such as the fingertips and lips.^7,8 Their location suggests that their primary function is in cutaneous sensation.

Stratum Spinosum

The stratum spinosum or prickle cell layer consists of the two to six rows of keratinocytes immediately above the basal layer (Fig. 1.3). Their morphology changes from columnar to polygonal, and they have an enlarged cytoplasm containing many organelles and filaments. The cells contain keratin tonofilaments and are interconnected by desmosomes.

Figure 1.3 Multiphoton microscopy and fluorescence lifetime imaging (MPM-FLIM) images of human epidermis. (A) Stratum granulosum; (B) stratum spinosum; (C) stratum basale.⁹⁸

Stratum Granulosum

Keratinocytes in the stratum granulosum or granular layer continue to differentiate. Present are intracellular keratohyalin granules and membrane-coating granules containing lamellar subunits arranged in parallel stacks, which are believed to be the precursors of the intercellular lipid lamellae of the stratum corneum.⁹ The lamellar granules also contain hydrolytic enzymes including stratum corneum chymotryptic enzyme (SCCE), a serine protease that has been associated with the desquamation process.^10,11 Overexpression of SCCE has been implicated in psoriasis¹² and dermatitis.¹³ As the cells approach the upper layers of the stratum granulosum, the lamellar granules are extruded into the intercellular spaces.

Stratum Lucidum

Within the stratum lucidum the cell nuclei and other organelles disintegrate, keratinization increases, and the cells are flattened and compacted. This layer takes on the typical structure common also to the stratum corneum of intracellular protein matrix and intercellular lipid lamellae, which is fundamentally important to the permeability barrier characteristics of the skin.

Stratum Corneum

The outermost layer, the stratum corneum (or horny layer), consists of 10–20 µm of high density (1.4 g/cm³ in the dry state) and low hydration (10%–20% compared with about 70% in other body tissues) cell layers. Although this layer is only 10–15 cells in depth, it serves as the primary barrier of the skin, regulating water loss from the body and preventing permeation of potentially harmful substances and microorganisms from the skin surface. The stratum corneum has been described as a brick wall-like structure of corneocytes as “bricks” in a matrix (or “mortar”) of intercellular lipids, with desmosomes acting as molecular rivets between the corneocytes.^14,15 While this is a useful analogy, it is important to recognize that the corneocytes are elongated and flattened, often up to 50 µm in length while only 1.5 µm thick and is more like a brick wall built by an amateur. The corneocytes lack a nucleus and are composed of about 70%–80% keratin and 20% lipid within a cornified cell envelope (∼10 nm thick). The cornified cell envelope is a protein/lipid polymer structure formed just below the cytoplasmic membrane that subsequently resides on the exterior of the corneocytes.¹⁶ It consists of two parts: a protein envelope and a lipid envelope. The protein envelope is thought to...

Table of contents

• Cover
• Title page
• Copyright page
• Dedication
• Preface
• About the Editors
• Contributors
• Part One: Current Science, Skin Permeation, and Enhancement Approaches
• Part Two: Topical and Transdermal Product Development
• Index