Applying a xenobiotic to the skin to treat a systemic medical condition is not new. Ointments and other salves have been applied topically for thousands of years for the treatment of local and systemic diseases. During World War I, dynamite workers used nitroglycerin applied to their hatbands to prevent angina when they were away from work and no longer exposed to organic nitrates.³⁶ Mustard seed plaster for chest congestion, releasing allyl isothiocyanate, and topical elemental mercurials for syphilis are other examples of such use in the beginning of the 20th century.²⁸ Over the past 30 years, an increasing number of medications have been formulated in transdermal delivery systems, or patches, to allow for systemic delivery of a xenobiotic. The first commercially available patch delivered scopolamine for motion sickness (1979), which was followed by nitroglycerin for chronic angina (1981) and then fentanyl for chronic pain management (1990). In the United States, the nicotine patch remains the most widely used transdermal patch, because of both the significant need for smoking cessation and its nonprescription availability. Certain medicinal xenobiotics, such as testosterone, can be administered without a patch, as a spray or gel.²² Further, xenobiotics are absorbed transdermally, as occurs with nicotine following direct exposure to moist tobacco leaf in patients with “green tobacco sickness” or following direct contact with organic phosphorus compound spraying.³

The skin is the largest organ in the body, although it is not widely used as a route for intentional xenobiotic delivery. However, there are several benefits of transdermal delivery of xenobiotics. This route provides a noninvasive means to discretely administer xenobiotics. Patches result in steady plasma concentrations that reduce side effects, particularly for xenobiotics with short half-lives. Although metabolism occurs in the skin, metabolism does not appear to be highly consequential for the majority of currently used transdermal xenobiotics.¹⁸ The patches are designed to be left in place for long periods of time, which improves compliance. Importantly, the avoidance of first-pass metabolism permits an effective means of delivery for poorly orally bioavailable xenobiotics. However, because absorption through the skin following simple application is passive, there is a large degree of variability among both patients and xenobiotics. Newer nanocarriers and minimally invasive technologies, as discussed below, attempt to overcome this limitation.^11,16

This chapter does not cover xenobiotics applied to the skin to produce an effect locally. These xenobiotics are available in patch formulation (eg, lidocaine and capsaicin) or as a directly applied preparation, such as a variety of antibiotics or acne creams (eg, tretinoin). Locally acting formulations (eg, lidocaine) typically provide only trivial amounts of systemic xenobiotic;⁶ for example, with tretinoin, despite devastating fetal complications when taken orally, these same effects do not occur when applied topically.²⁰ Some xenobiotics, such as capsaicin, have both local (for postherpetic neuralgia) and systemic (for cannabinoid hyperemesis syndrome) effects.^7,31

Passive Administration

The same hydrophobic property that allows the skin to prevent water loss hinders the ability to administer a water-soluble xenobiotic transdermally. In order to reach the systemic circulation, a xenobiotic applied to the stratum corneum (horny layer) (Fig. 17–1) must initially pass through about a dozen layers of keratinized epidermal cells and then into the dermis. This keratinaceous horny layer is highly impervious to water movement because of the presence of ceramides, fatty acids, and other lipids.⁵ This property maintains the ability of the skin to lose excess water in dry environments. Burn victims lose the capacity to regulate water loss through injury to the keratinaceous layer. In order for a xenobiotic to partition into the stratum corneum, it must be sufficiently lipid soluble. However, this same xenobiotic must subsequently partition out from the stratum corneum into the aqueous underlying tissue, and this requires sufficient hydrophilicity.²⁵ The ability to partition into these various phases (lipid and water) is described by the octanol–water partition coefficient. These vary widely among xenobiotics. For example, this coefficient for fentanyl (717) and nicotine (15) suggests sufficient ability to cross the stratum corneum, whereas morphine (0.7) cannot pass through this outer layer.

Fick’s first law describes xenobiotic permeation across the stratum corneum. In this model, steady-state flux (J) is related to the diffusion coefficient (D) of the xenobiotic based on the thickness of the stratum corneum (h), the partition coefficient (P) between the stratum corneum and the xenobiotic in its vehicle, and the xenobiotic concentration (C) that is applied, which is assumed to be constant. This equation demonstrates the influence of solubility and partition coefficient of a xenobiotic on diffusion across the stratum corneum (Equation 9–1). Molecules showing intermediate partition coefficients have adequate solubility within the lipid domains of the stratum corneum to permit diffusion through this domain while still having sufficient hydrophilic nature to allow partitioning into the lower layers (stratum granulosum, stratum spinosum, and the stratum germinativum) of the epidermis.

Permeation enhancers improve absorption by solubilizing the xenobiotic or altering the characteristics of the stratum corneum, effectively increasing the lipid solubility of the xenobiotic.^19,32 Enhancers include solvents such as ethanol, fatty acids, fatty esters, and surfactants that serve as vehicles to improve the solubility of a xenobiotic in the lipids of the stratum corneum layer.¹⁹ An alternative means of enhancing lipophilicity is the addition of organic functional groups to create a prodrug that is cleaved once absorbed.²⁹ This is similar to the significantly enhanced neurotoxicity of dimethylmercury compared to methylmercury when applied to the skin.²⁴ Additionally, the use of nanoparticles enhances xenobiotic solubility and surface contact area.³³

Few xenobiotics have the essential molecular requirements to be systemically delivered by the transdermal route. The upper limit of the molecular weight of an acceptable drug is 500 Da (fentanyl is 337 Da), and the medication must be sufficiently potent to exert the desired effect at concentrations that can reliably be obtained. Although only small quantities, typically less than 2 mg daily are delivered, the largest nicotine patch delivers 21 mg daily.

As suggested by Fick’s law, the ability to cross the dermis is related to the concentration gradient provided by the transdermal patch. To allow sufficient delivery, a large amount of xenobiotic is contained in the apparatus to maintain the concentration gradient over time. For example, the 50-mcg/hr fentanyl patch (which delivers 1.2 mg daily) contains 8.4 mg (8,400 mcg) of fentanyl in the patch.^13,36 This excess amount of drug minimizes the fluctuations in delivery over time as the concentration gradient naturally falls during movement of xenobiotic from the patch to the skin. Upon completion of the 3-day use of a fentanyl patch, the amount of fentanyl remaining in a patch ranged from 28% to 85%; at the end of use, 27% to 74% of the contents of a nicotine patch remained.^21,28 Furthermore, in order to prevent rapid movement into the skin, and also maintain a functional concentration gradient, a rate-controlling membrane is present that allows the passage of a measured amount of drug per area of skin contact surface.

Applying xenobiotic to broken skin or tissue lacking a stratum corneum, such as mucosa, results in a substantial increase in absorption, which is greater than 5- or greater than 30-fold, respectively, for fentanyl.^12,22 For example, application of salicylic acid for a treatment of hyperkeratinization disorders causes salicylate poisoning.^1,32 Because the pharmacokinetics of transmucosal delivery tend to be more predictable than by the transdermal route, certain formulations such as fentanyl citrate (Actiq, Subsys, Fentora) or nicotine (Nicorette gum) are administered transmucosally. However, the greater penetrability accounts for the toxicity associated with improper application to a mucosal surface, which lacks a stratum corneum.^5,26 A small amount of xenobiotic also enters the body by way of the skin appendages, such as the sweat glands or hair follicles.^5,25

Properties of the skin that account for pharmacokinetic variability include hydration status and temperature. Absorption varies based on the site of application on the body and on both the thickness of the stratum corneum and the blood flow.^2,29,30 Although the average skin thickness of the human body is 40 μm, it ranges between 20 and 80 μm as a result of many factors including body location, race, age, and sex. As an example, in skin samples from 8 individuals, there was more than a 50% difference in the permeability of fentanyl.¹⁷ Because the stratum corneum thickness is most relevant to diffusion rates, those areas that have similar thickness, such as the chest, extremities, and abdomen, provide the most consistent delivery and are generally used as sites for transdermal patch application.^30,33 Intertriginous areas, where skin contacts other skin (axillae, groin, inframammary, and intergluteal) allow greater absorption because of enhanced contact surface, temperature, and moisture.