Novel Delivery Systems for Transdermal and Intradermal Drug Delivery

Ryan F. Donnelly, Thakur Raghu Raj Singh, Ryan F. Donnelly, Thakur Raghu Raj Singh

• Publisher: Wiley
• Year: 2015
• Print ISBN:
  9781118734513
• eBook ISBN:
  9781118734490
• Edition: 1
• Topic: Physical Sciences
• Subtopic: Organic Chemistry

Novel Delivery Systems for Transdermal and Intradermal Drug Delivery

This research book covers the major aspects relating to the use of novel delivery systems in enhancing both transdermal and intradermal drug delivery. It provides a review of transdermal and intradermal drug delivery, including the history of the field and the various methods employed to produce delivery systems from different materials such as device design, construction and evaluation, so as to provide a sound background to the use of novel systems in enhanced delivery applications.

Furthermore, it presents in-depth analyses of recent developments in this exponentially growing field, with a focus on microneedle arrays, needle-free injections, nanoparticulate systems and peptide-carrier-type systems. It also covers conventional physical enhancement strategies, such as tape-stripping, sonophoresis, iontophoresis, electroporation and thermal/suction/laser ablation Discussions about the penetration of the stratum corneum by the various novel strategies highlight the importance of the application method. Comprehensive and critical reviews of transdermal and intradermal delivery research using such systems focus on the outcomes of in vivo animal and human studies. The book includes laboratory, clinical and commercial case studies featuring safety and patient acceptability studies carried out to date, and depicts a growing area for use of these novel systems is in intradermal vaccine delivery. The final chapters review recent patents in this field and describe the work ongoing in industry.

1
Introduction

Gary P.J. Moss

School of Pharmacy, Keele University, Keele, UK

The skin is the most physiologically complex and diverse organ of the human body. It has many roles, including the regulation of temperature, mechanical and protective functions. This latter function includes the regulation of water ingress and egress, as well as the prevention of entry into the body of exogenous chemical and biological entities.

The skin is the largest organ of the body, accounting on average for approximately 10% of body mass. It receives approximately one-third of the blood circulating throughout the body and has a surface area of approximately 2–3 m² [1]. It provides a robust, flexible and self-repairing barrier to the external environment and protects internal body organs and fluids from external influences, harmful molecules and micro-organisms. Its permeability limits excessive water loss and exercises temperature regulation over the body. The skin forms an extensive sensory surface, transmitting sensations such as heat, cold, touch, pressure and pain to the central nervous system. The skin is a multi-layered organ consisting of three main histological layers: the epidermis, the dermis and the subcutis. Mammalian skin is a stratified epithelium, and each layer will be considered individually, below, progressing from the innermost tissues to the outermost.

1.1 The Subcutis (Subcutaneous Fat Layer)

Immediately beneath the epidermis and dermis lies the subcutaneous fatty tissue layer (or subcutis or hypodermis). This layer provides support and cushioning for the overlying skin, as well as attachment to deeper tissues. It acts as a depository for fat and contains blood vessels that supply the skin. It also acts as a heat insulator and a shock absorber. The subcutis is variable in thickness, ranging from a few centimetres thick in some regions, such as the abdominal wall, to areas where there is little or no fat, and the subcutis may be difficult to distinguish, such as the eyelid or scrotum. It is often difficult to distinguish the subcutis from the dermis, as both are irregular connective tissues, but the subcutis is generally looser and contains a higher proportion of adipose cells. The deeper layers of the subcutis are fully continuous, with layers of deep fascia surrounding muscles and periosteum.

1.2 The Dermis

The dermis, or corium, lies immediately below the dermo-epidermal junction. It is 10–20 times thicker than the epidermis and ranges from 0.1 to 0.5 cm in thickness, depending on its location in the body. It is a robust and durable tissue that provides flexibility and tensile strength. It protects the body from injury and infection and provides nutrition for the epidermis and acts as a water storage organ. The main feature of the dermis is a matrix of mechanically strong fibrous proteins, consisting mainly of collagen, but with elastin embedded in a gel-like mix of mucopolysaccharides [2]. Embedded within this matrix are various structures, including nerve tissues, vascular and lymphatic systems and the base of various skin appendages. The upper section of the dermis consists of loose connective tissue and a superficial, finely structured papillary layer which progresses upwards into the epidermis. The lower dermis is a coarse, fibrous layer which is the main supporting structural layer of the skin. The transition between epidermal and dermal structures occurs at the dermo-epidermal junction. Both the epidermis and dermis vary greatly in structure, with the former being mostly cellular in construction, whereas the latter contains few cells, other than mast cells. The dermis is the locus of the blood vessels in the skin, extending to within 0.2 mm of the skin surface and derived from the arterial and venous systems in the subcutaneous tissue. The blood vessels supply the hair follicles, glandular skin appendages and subcutaneous fat, as well as the dermis itself [1].

The vasculature of the skin is responsible for regulating the skin temperature, supplying nutrients and oxygen to the skin, removing toxins and waste products and for assisting in wound repair. Clearly, the vasculature also plays an important role in the removal of locally absorbed chemicals, carrying them into the systemic circulation. The blood supply to the skin can sit relatively close to the skin surface, meaning that exogenous penetrants are removed into the circulation from around the dermo-epidermal junction. Thus, for percutaneous absorption into the systemic circulation, including transdermal drug delivery, the blood supply to the skin facilitates the maintenance of a concentration gradient between the material applied to the external skin surface and the vasculature, across the skin barrier. Such clearance may also be facilitated by the lymphatic system, which is similarly located at a comparable distance from the exterior of the skin to the blood supply [3, 4].

1.3 Skin Appendages

Associated with the skin are several types of appendages, including hair follicles and their associated sebaceous glands (Figure 1.1) and eccrine and apocrine sweat glands.

Figure 1.1 Schematic diagram of the skin.

Reproduced with permission from Ref. [5].

On average, human skin contains 40–70 hair follicles and 200–250 sweat ducts/cm² of skin. The skin appendages occupy approximately 0.1% of the total human skin surface [4, 6], although this varies from region to region. Hairs are formed from compacted plates of keratinocytes and reside in hair follicles formed as an epidermal invagination. The associated sebaceous glands (Figure 1.1) are formed as outgrowths of the follicle and secrete an oily material – sebum – onto the skin surface. Sebum is a combination of various lipids and acts as a plasticiser for the stratum corneum, maintaining an acidic mantle of approximately pH 5 [6]. The eccrine glands are principally concerned with temperature control and are responsible for secretion and evaporation of sweat when stimulated by an increase in external temperature or emotional factors. These glands commonly occupy only 10⁻⁴ of the total skin area, and extend well into the dermis. Whereas eccrine glands are found throughout the body, apocrine glands are located in specific regions, such as the axillae and anogenital regions. Similar to eccrine glands, they descend into the dermis.

1.4 The Subcutaneous Sensory Mechanism

The extensive size of the skin lends itself to act as a major source of sensory input for the sensory nervous system. It provides information about the environment from both direct contact and from more remote sources, such as the effect of radiation on skin temperature. Cutaneous fibres within the dermis form a plexus lying parallel to the surface of the skin. This plexus is composed of unmyelinated and myelinated fibres, organised in the same manner as the parent nerve trunks. The dermal networks send ...

Table of contents

• Cover
• Title Page
• Table of Contents
• About the Editors
• Contributors
• Advances in Pharmaceutical Technology: Series Preface
• Preface
• 1 Introduction
• 2 Application of Spectroscopic Techniques to Interrogate Skin
• 3 Analysis of the Native Structure of the Skin Barrier by Cryo-TEM Combined with EM-Simulation
• 4 Intradermal Vaccination
• 5 Film-Forming and Heated Systems
• 6 Nanotechnology-Based Applications for Transdermal Delivery of Therapeutics
• 7 Magnetophoresis and Electret-Mediated Transdermal Delivery of Drugs
• 8 Microporation for Enhanced Transdermal Drug Delivery
• 9 Microneedle Technology
• 10 Intradermal Delivery of Active Cosmeceutical Ingredients
• 11 Commercial and Regulatory Considerations in Transdermal and Dermal Medicines Development
• Index
• End User License Agreement