Skin-deep: overcoming barriers for effective transdermal drug delivery
/
By Roger Smith
Ancient art, modern science
One shared medicinal practice amongst disparate ancient societies was the application of primitive ointments to the skin to treat almost all and any ailments. A vast plethora of poultices and plasters have been described, including in Babylonian and Greek medicine texts1 amongst others, suggesting that the magical health-restoring powers of ointments were well-recognised to traverse the skin. Thus, it was no coincidence that the skin was the preferred therapeutic route over surgical (and oral) intervention since the former method was likely to result in reduced mortality rates compared to the latter; undoubtedly an important consideration, given that the top ancient physicians were likely charged with the health of the royal courts.
Although the art of transdermal delivery of medicines dates back millennia, it is only in more recent times that the science of transdermal drug delivery in man has advanced significantly2. The choice of modern drugs for topical applications is, however, relatively limited compared to the seemingly infinite choice available for oral delivery. This is perhaps not surprising since the gut is an organ that has evolved with the main purpose of absorbing food (chemicals when it comes to it) whereas the skin, despite being the largest organ, has evolved primarily as a protective layer to prevent desiccation of underlying tissues and to keep out harmful environmental chemicals. As this includes medicinal drugs, the pursuit of transdermal administration would appear, at first sight, to be an illogical choice. However, there are several compelling reasons why transdermal delivery routes are an important alternative to pills, injections or inhalation routes:
It avoids poor absorption after oral ingestion—especially in animals, the absorption of a drug can vary between the omnivore (e.g., human) and herbivore (e.g., horse) stomach.
It avoids first-pass effect where the blood circulation from the gut passes through the liver to remove absorbed drugs.
It can reduce systemic drug levels to minimise adverse effects.
The design of sustained release formulations overcomes the frequent dosing necessitated by oral and injectables to achieve constant drug levels.
It enables ease and efficacy of drug withdrawal.
Transdermal drug delivery is painless and non-invasive, thereby potentially allowing longer treatment when daily injection is unacceptable or impractical.
It has the potential to target local administration such as for the treatment of flexor tendon disease because the tendons are subcutaneous.
Challenges for transdermal drug applications
The skin is made up of three key layers: the epidermis, dermis and hypodermis (figure 1) and the water-attracting (hydrophilic) or water-repelling (hydrophobic) properties within each raise unique challenges for topical or transdermal drug applications.
Figure 1 – Anatomy of the skin with expanded illustration showing the cells of the stratum corneum (‘bricks’) embedded in lipid matrix (‘mortar’).
Topical applications, such as insect repellents and sunscreen creams, target the surface of the skin or deliver a drug locally such as for the control of inflammation (insect bite or reaction to an allergen). In contrast the aim of transdermal, or subcutaneous, applications are to deliver the drug deeper to either an adjacent organ, or, more commonly, to the blood circulation as an alternative to oral or needle routes to reach distant organs. The main barrier to local or transdermal delivery is the outermost layer of the skin, called the stratum corneum in the epidermis (figure 1). This consists of dead skin cells, the corneocytes, that combine with lipid bilayers into a tightly packed “bricks-and-mortar” layer that form alternating hydrophilic (the water rich corneocytes) and hydrophobic (lipid bilayer) regions (figure 1). The stratum corneum therefore not only forms a mechanically robust layer but also presents a challenge in designing drugs with chemical properties that can negotiate their way into and through these contrasting hydrophobic and hydrophilic environments to reach the lower region of the epidermis. The epidermis consists of living skin cells but has no blood vessels for the drug to diffuse into, so instead the drug must penetrate further to the dermis where it can finally enter the bloodstream or the subcutaneous layers.
Routes for drugs through the skin
Most transdermal drugs are designed so that they diffuse through the skin in a passive fashion. The routes for drug can be through the skin cells (transcellular), around them (intercellular) or using the skin components hair follicles, sweat glands and sebaceous glands (produce lipids) to bypass the stratum corneum (so-called ‘appendageal’ routes).
Transcellular route: Drugs pass through the corneocytes of the stratum corneum rather than the lipid ‘mortar’ that surrounds them (figure 2). However, the drug has to exit the cell to enter the next corneocyte and therefore through the skin. It means that it has to encounter the external hydrophobic environment between the cells multiple times as it moves through the alternating cell and lipid layers of the epidermis. Drugs therefore have to have balanced hydrophilic and hydrophobic properties to enable this to happen.
Figure 2 – Path of molecules through (A) the stratum corneum for the transcellular route (Note: the drug has to enter and exit the aqueous environment of the cells into the surrounding lipid matrix requiring an ability to be soluble in both); (B) Intercellular route (Note: the tortuous path for molecules passing through the stratum corneum via this route which delays diffusion.
Intercellular route: The drug predominantly diffuses through the lipid rich ‘mortar’ around the corneocytes of the epidermis. This lipid matrix can form a continuous route through the epidermis (avoiding entering the cells), but this route has been suggested to be less efficient because it increases the distance 50-fold3 compared to the direct route through the stratum corneum due to the interdigitating brick and mortar arrangement (figure 2). Again, the chemical formulation used to carry the drug is important and drugs that more readily dissolve in lipids benefit from this route.
Appendageal route: The hair, sweat glands and sebaceous glands provide a direct channel to the deep layers of the skin circumventing the hazardous barriers of the epidermis and dermis. The main challenge for this relatively easy route is that the amount of drug that can be taken up is limited by the density of hair follicles and sweat glands, although in haired animals, such as the horse, the density can be as high as 1-5% of the skin surface area. Furthermore, sweat from an active sweat gland would be travelling against the direction of drug flow, washing out the drug and its carrier and severely limit drug uptake. It is likely that all skin applications use this appendageal route as it’s unavoidable but probably more efficient for drugs that are large molecules.