Transdermal, from latin trans – through and dermis – skin, literally means “through skin”. It is well known that certain chemicals can easily penetrate skin even under regular conditions of fat, dirty or sweaty skin surface. For example, even a small drop of acetonitrile on bare skin can give one head rushes, though mostly it will not probably kill you, because the rate of toxin metabolism is around the same as the rate of absorption. Substances like nicotine or LSD, on the other hand can be extremely hazardous to life (or mental health) even in microscopic doses, if a concentrated solution comes into contact with the naked skin.
Skin, as a barrier that covers our muscles and internal organs and protects body from overheat and harmful external factors, like pathogens or mechanical influences, as well as presents a barrier for water contained within the body, is also an immune barrier (one of the many ones). It has a three-layer structure. First layer is created by the external packed coverage of dead epidermis corneocyte or keratinocytes, in a “brick and mortar structure” (Prausnitz, et al., 2008). Since the cells are dead, this is essentially a dry mixture of lipids from their outer walls, organized into bilayers, cross-linked with keratin. This first layer is titled stratum corneum and is 10 to 20 µm thick. Second layer is composed of the living epidermis cells, which measures 50 to 100 µm and does not contain any blood vessels. Third layer is the dermis itself, which is 1-2 mm thick, and contains a dense vascular network that is the basis for efficient delivery of target drugs into the bloodstream. Unfortunately, first two layers are to be passed before any external substance can reach the blood, and it is only essential that it is hard for most everyday macromolecular objects, like proteins or other macromolecules, or pathogens like viruses and bacteria to get around this barrier. Essentially, lipid-soluble or lipophilic small molecules penetrate stratum corneum easily., since it is itself a structure composed almost entirely of lipids. Water soluble, or hydrophilic substances can also travel through stratum corneum, by exploiting the hydrophilic properties of lipid heads. Thus, something similar to a double capillary, extremely tangled network exists within stratum corneum, with one half of these capillaries transporting lipid-soluble and the other – water-soluble substances (Prausnitz, et al., 2008). Of course, a great set of constraints exists – in molecule size that fits into the “capillary diameter”, their solubility requirements and, most frustratingly – diffusion speeds.
All transdermal delivery methods, or transdermal delivery systems (TDS) can be divided into three generations (Prausnitz, et al., 2008; Van Buskirk, et al., 2012). The first generation, usually termed as “passive” TDS, entirely rely on the natural process of diffusion/osmosis of the delivered drug from a patch that contacts the skin. Along with the drugs, the delivery system usually contains other substances “like oils, alcohols, glycerin, water, fatty acid esters, surfactants, and may also contain fillers or excipients such as lactose, …