Preface

Medicines have been delivered across the skin since ancient times. However, the first rigorous scientific studies involving transdermal delivery seeking to determine what caused skin to have barrier properties that prevent molecular permeation were not carried out until the 1920s. Rein proposed that a layer of cells joining the skin's stratum corneum (SC) to the epidermis posed the major resistance to transdermal transport. Blank modified this hypothesis after removing sequential layers of SC from the surface of skin and showing that the rate of water loss from skin increased dramatically once the SC was removed. Finally, Scheuplein and colleagues showed that transdermal permeation was limited by the SC by a passive process. Despite the significant barrier properties of skin, Michaels and coworkers measured apparent diffusion coefficients of model drugs in the SC and showed that some drugs had significant permeability. This led to the active development of transdermal patches in the 1970s, which yielded the first patch approved by the United States Food and Drug Administration in 1979. It was a 3-day patch that delivered scopolamine to treat motion sickness. In 1981, patches for nitroglycerin were approved. Understanding of the barrier properties of skin and how they can be chemically manipulated was greatly enhanced in the 1980s and early 1990s through the work of Maibach, Barry, Guy, Potts and Hadgraft. Today there are a number of transdermal patches marketed for delivery of drugs such as clonidine, fentanyl, lidocaine, nicotine, nitroglycerin, oestradiol, oxybutynin, scopolamine and testosterone. There are also combination patches for contraception, as well as hormone replacement.

Recently, the transdermal route has vied with oral treatment as the most successful innovative research area in drug delivery. In the United States (the most important pharmaceutical market), out of 129 API delivery products under clinical evaluation, 51 are transdermal or dermal systems; 30% of 77 candidate products in preclinical development represent such API delivery. The worldwide transdermal patch market approaches $20 billion, yet is based on only 20 drugs. This rather limited number of drug substances is attributed to the excellent barrier function of the skin, which is accomplished almost entirely by the outermost 10-15?µm (in the dry state) of tissue, the SC. Before being taken up by blood vessels in the upper dermis and prior to entering the systemic circulation, substances permeating the skin must cross the SC and the viable epidermis. There are three possible pathways leading to the capillary network: through hair follicles with associated sebaceous glands, via sweat ducts or across continuous SC between these appendages. As the fractional appendageal area available for transport is only about 0.1%, this route usually contributes negligibly to apparent steady state drug flux. The intact SC thus provides the main barrier to exogenous substances, including drugs. The corneocytes of hydrated keratin are analogous to 'bricks', embedded in a 'mortar' composed of highly organised, multiple lipid bilayers of ceramides, fatty acids, cholesterol and its esters. These bilayers form regions of semicrystalline gel and liquid crystal domains. Most molecules penetrate through skin via this intercellular microroute. Facilitation of drug penetration through the SC may involve bypass or reversible disruption of its elegant molecular architecture. The ideal properties of a molecule penetrating intact SC well are as follows:

• Molecular mass less than 600?Da
• Adequate solubility in both oil and water so that the membrane concentration gradient, which is the driving force for passive drug diffusion along a concentration gradient, may be high
• Partition coefficient such that the drug can diffuse out of the vehicle, partition into, and move across the SC, without becoming sequestered within it
• Low melting point, correlating with good solubility, as predicted by ideal solubility theory.

Clearly, many drug molecules do not meet these criteria. This is especially true for biopharmaceutical drugs, which are becoming increasingly important in therapeutics and diagnostics of a wide range of illnesses. Drugs that suffer poor oral bioavailability or susceptibility to first-pass metabolism, and are thus often ideal candidates for transdermal delivery, may fail to realise their clinical application because they do not meet one or more of the above conditions. Examples include peptides, proteins and vaccines which, due to their large molecular size and susceptibility to acid destruction in the stomach, cannot be given orally and, hence, must be dosed parenterally. Such agents are currently precluded from successful transdermal administration, not only by their large sizes but also by their extreme hydrophilicities. Several approaches have been used to enhance the transport of drugs through the SC. However, in many cases, only moderate success has been achieved and each approach is associated with significant problems. Chemical penetration enhancers allow only a modest improvement in penetration. Chemical modification to increase lipophilicity is not always possible and, in any case, necessitates additional studies for regulatory approval, due to generation of new chemical entities. Significant enhancement in delivery of a large number of drugs has been reported using iontophoresis. However, specialized devices are required and the agents delivered tend to accumulate in the skin appendages. The method is presently best-suited to acute applications. Electroporation and sonophoresis are known to increase transdermal delivery. However, they both cause pain and local skin reactions and sonophoresis can cause breakdown of the therapeutic entity. Techniques aimed at removing the SC barrier such as tape-stripping and suction/laser/thermal ablation are impractical, while needle-free injections have so far failed to replace conventional needle-based insulin delivery. Clearly, robust alternative strategies are required to enhance drug transport across the SC and thus widen the range of drug substances amenable to transdermal delivery.

Recently, nanoparticulate and super-saturated delivery systems have been extensively investigated. Nanoparticles of various designs and compositions have been studied and, while successful transdermal delivery is often claimed, therapeutically useful plasma concentrations are rarely achieved. This is understandable, given the size of solid nanoparticles. So called ultra-deformable particles may act more as penetration enhancers, due to their lipid content, while solid nanoparticles may find use in controlling the rate or extending the duration of topical delivery. Super-saturated delivery systems, such as 'spray-on' patches may prove useful in enhancing delivery efficiency and reducing lag times.

Amongst the more promising transdermal delivery systems to emerge in the past few decades are microneedle (MN) arrays. MN arrays are minimally invasive devices that can be used to bypass the SC barrier and thus achieve transdermal drug delivery. MNs (50-900?µm in height, up to 2000 MN cm-2) in various geometries and materials (silicon, metal, polymer) have been produced using recently-developed microfabrication techniques. Silicon MNs arrays are prepared by modification of the dry- or wet-etching processes employed in microchip manufacture. Metal MNs are produced by electrodeposition in defined polymeric moulds or photochemical etching of needle shapes into a flat metal sheet and then bending these down at right angles to the sheet. Polymeric MNs have been manufactured by micromoulding of molten/dissolved polymers. MNs are applied to the skin surface and pierce the epidermis (devoid of nociceptors), creating microscopic holes through which drugs diffuse to the dermal microcirculation. MNs are long enough to penetrate to the dermis but are short and narrow enough to avoid stimulation of dermal nerves. Solid MNs puncture skin prior to application of a drug-loaded patch or are pre-coated with drug prior to insertion. Hollow bore MNs allow diffusion or pressure-driven flow of drugs through a central lumen, while polymeric drug-containing MNs release their payload as they biodegrade in the viable skin layers. In vivo studies using solid MNs have demonstrated delivery of oligonucleotides, desmopressin and human growth hormone, reduction of blood glucose levels from insulin delivery, increase in skin transfection with DNA and enhanced elicitation of immune response from delivery of DNA and protein antigens. Hollow MNs have also been shown to deliver insulin and reduce blood glucose levels. MN arrays do not cause pain on application and no reports of development of skin infection currently exist. Recently, MNs have been considered for a range of other applications, in addition to transdermal and intradermal drug/vaccine delivery. These include minimally-invasive therapeutic drug monitoring, as a stimulus for collagen remodelling in anti-ageing strategies and for delivery of active cosmeceutical ingredients. MN technology is likely to find ever-increasing utility in the healthcare field as further advancements are made. However, some significant barriers will need to be overcome before we see the first MN-based drug delivery or monitoring device on the market. Regulators, for example, will need to be convinced that MN puncture of skin does not lead to skin infections or...