SC1: Special Considerations

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.³¹ Mustard seed plaster for chest congestion, releasing allyl isothiocyanate, and topical elemental mercurials for syphilis are other examples from the early 20th century.²⁴ 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 delivery system both because of the high need for smoking cessation and its nonprescription availability. Certain medicinal xenobiotics, such as testosterone, can be administered topically without a patch as a spray or gel.¹⁸ Furthermore, nonmedicinals can be absorbed transdermally, as occurs with nicotine after direct exposure to moist tobacco leaf in patient with "green tobacco sickness" or with organic phosphorus pesticides.³

The skin is the largest organ in the body, although it is not generally used as a route for intentional xenobiotic delivery. However, there are several benefits of transdermal delivery of systemic medication. This route provides a noninvasive means to discreetly administer medications. Patches result in steady serum concentrations that reduce side effects particularly for xenobiotics with short half-lives. The patches can be left in place for long periods of time, which improves compliance. Importantly, the avoidance of first-pass metabolism permits a means to effectively deliver poorly orally bioavailable xenobiotics. However, because all absorption through the skin is passive, there is a large degree of variability among both patients and xenobiotics.

This chapter does not cover xenobiotics applied to the skin to produce an effect locally. These xenobiotics can be available in patch formulation (eg, lidocaine and capsaicin) or as a directly applied preparation, such as a variety of antibiotics or acne creams. Locally acting formulations (eg, lidocaine) typically provides only trivial amounts of systemic xenobiotic;⁶ with tretinoin, despite devastating fetal complication when taken orally, these same effects do not occur when applied topically.¹⁶

Passive Administration

The same hydrophobic property that allows the skin to prevent water loss hinders the ability to administer a water-soluble xenobiotic transdermally. To reach the systemic circulation, a xenobiotic applied to the stratum corneum (horny layer) (Fig. 18–1) 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 both physiologically maintains the ability to lose excess water in dry environments and pathologically is lost in burn victims. For a xenobiotic to partition into the waxy stratum corneum, it must be sufficiently lipid soluble. However, this same xenobiotic must subsequently partition out of the stratum corneum into the aqueous underlying tissue, and this requires sufficient hydrophilicity.²² 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 and logP for fentanyl (717; 2.53) and nicotine (15; 1.18) suggests sufficient ability to cross the stratum corneum, but morphine (0.7, -0.15) cannot pass through this outer layer.

Fick's first law can be used to describe 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. Molecules showing intermediate partition coefficients (log P of 1–3) have adequate solubility within the lipid domains of the stratum corneum to permit diffusion through this domain still having sufficient hydrophilic nature to allow partitioning into the viable tissues 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.²⁷ Approaches include optimizing the solubility of the xenobiotic or enhancing the properties of the skin itself.⁵ 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.⁵ An alternative means of enhancing lipophilicity is the addition of organic functional groups to create a prodrug that is cleaved after being absorbed.²⁵ This is similar to the significantly enhanced neurotoxicity when dimethylmercury is applied to the skin and compared with methylmercury.²⁰ Additionally, the use of nanoparticles enhances xenobiotic solubility and surface contact area.²⁸

Few xenobiotics have the correct molecular requirements to be able to be systemically delivered by the transdermal route. The upper limit of the molecular weight (MW) of an acceptable xenobiotics is 500 Da (fentanyl is 337 Da), and the xenobiotic must be sufficiently potent to exert its 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 delivery apparatus. 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-μg/h fentanyl patch (which delivers 1.2 mg daily) contains 8.4 mg (8400 μg) of fentanyl in the patch.^12,31 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 24% to 85%; at the end of use, 27% to 74% of the contents of a nicotine patch may remain.^17,24,32 Furthermore, to prevent rapid movement into the skin and maintain a functional concentration gradient, a rate-controlling membrane is present that allows a measured amount of drug to pass per area of skin contact surface.

Applying xenobiotic to broken skin or tissue lacking a stratum corneum, such as the mucosa, results in a substantial increase in its absorption which may be more than five- and more than 30–fold, respectively, for fentanyl.^11,18 However, because the pharmacokinetics of transmucosal delivery tend to be more predictable than by the transdermal route, certain formulations such as fentanyl citrate (Actiq or Fentora) or nicotine (Nicorette gum) may be administered transmucosally. However, the greater penetrability accounts for the toxicity associated with improper application to a mucosal surface.^5,23 A small amount of xenobiotic can enter the body by way of the skin appendages, such as the sweat glands or hair follicles.^5,22 Furthermore, application of salicylic acid for treatment of hyperkeratinization disorders can cause salicylate poisoning.^1,27

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 is based on both thickness of the stratum corneum and blood flow.^2,25,26 Although the average skin thickness of the human body is 40 microns, it ranges between 20 and 80 microns because of many factors, including body location, race, age, and sex. As an example, in skin samples from eight individuals, there was more than a 50% difference in the permeability of fentanyl.¹⁵ Because the stratum corneum thickness may be 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 device application.^26,28 Intertriginous areas, where skin contacts other skin (axillae, groin, inframammary, and intergluteal), may allow greater absorption because of enhanced contact surface, temperature, and moisture.

Active Administration

The passive approach requires the optimization of formulation or xenobiotic carrying vehicle to increase skin permeability. However, passive methods do not greatly improve the permeation of xenobiotics with MWs greater than 500 Da. In contrast active methods, normally involving physical or mechanical methods of enhancing delivery are generally superior. The delivery of xenobiotics of differing lipophilicity and MW, including proteins, peptides, vaccines, and oligonucleotides, is improved by active energy-requiring techniques such as iontophoresis, electroporation, and ultrasonography.^10,21 In general, these techniques are not yet in wide use (Tables SC1–1 and SC1–2).

Patch Technology

In most current patches, the xenobiotic to be delivered is incorporated into the adhesive layer. There may be multiple layers of adhesive separated by membranes that serve to regulate the release. To allow a longer duration of drug delivery, a reservoir may be added. This compartment contains the xenobiotic in solution or suspension, and a rate-regulating membrane ensures that the release follows zero order kinetics to avoid fluctuations in concentration. Increasing the surface area of contact by enlarging the patch proportionally increases the amount of xenobiotic delivered. The membrane itself is not altered. Removal of the rate-regulating membrane, however, results in rapid absorption of toxic quantities of xenobiotic.⁷

The initial fentanyl patch (Duragesic) used a reservoir that contained a large quantity of xenobiotic. This reservoir could have been accessed inadvertently by a child chewing the patch or intentionally by a person seeking to abuse the liquid contents.¹⁹ Cutting the reservoir patch could disperse the fentanyl and result in either overdose or loss of analgesia. Patch construction defects also occurred that potentially allowed leakage.¹³ Alternatively, by incorporating the xenobiotic into a fabric mesh, the matrix patch eliminates the reservoir and reduces the risk for abuse. The matrix patch may be cut to change dosage delivered, based on surface contact area, without risking spillage of any liquid content. The clinical pharmacology of the matrix fentanyl patch is similar to that of the reservoir patch.⁸

Pharmacokinetics

The initial detection of a xenobiotic in the serum after transdermal application is not surprisingly delayed compared with other routes of administration. The delay depends on the properties of the xenobiotic, the skin, and the environment. Very lipophilic xenobiotics form a depot in the subcutaneous tissue as they slowly dissolve in the aqueous tissue for diffusion to allow vascular uptake. Highly hydrophilic xenobiotics slowly penetrate the lipid layers of the epidermis, which is why ionic (salt) forms of xenobiotics are administered by a subcutaneous or intramuscular route. For example, fentanyl will not be detected in the serum before 1 to 2 hours after placement of a patch, and the peak concentration may not occur for one day or longer. For this reason, the use of a fentanyl patch is not indicated for the treatment of acute pain, particularly postoperative pain.¹⁹ Because the natural history of acute pain is to rapidly improve over several days, during which time the fentanyl concentrations continue to rise, the risk of toxicity rises.²⁹ However, in patients with chronic pain, this pharmacokinetic profile may be beneficial as long as opioids are indicated and safe use is monitored. Furthermore, as noted, permeation enhancers may alter the xenobiotic or the skin sufficiently to alter the absorption kinetics.

The pharmacokinetic profiles of serial doses of patches is based on removal of the patch after the specified time period and application of a new patch to a different location.¹⁹ This is important to allow a new subcutaneous depot to form while the existing depot is absorbed rather than adding a bolus dose from the adhesive to the existing depot.

Washing the skin or removing the patch will not result in a rapid fall in serum concentrations or a reduction in clinical effect.¹² Rather, these will resolve over several hours because of the persistence of the dermal depot.¹⁹ For example, the effective half-life of fentanyl after removal of a fentanyl patch is approximately 18 hours.¹² Therefore, simple removal of the fentanyl patch will not be sufficient treatment of a patient experiencing respiratory depression, and respiratory support or naloxone should be used.

Adverse Effects

Because transdermal administration places the xenobiotic in close contact with the environment, there is substantial risk of variation in absorption because of changes in ambient conditions. For example, patches exposed to heat, from heating blankets or saunas, can release xenobiotic at a rate greater than expected under conventional ambient conditions.⁴ Exposed patches may be damaged, either during the manufacturing process or subsequently, which can alter their release profile, resulting in toxicity.¹³ Certain patches, such as those with a metal backing, can get exceedingly hot during exposure to magnetic resonance imaging studies and result in burns.

Despite these techniques to enhance xenobiotic delivery, transdermal systems require that large amounts of xenobiotic be present externally to maximize the transcutaneous gradient. Much of the xenobiotic typically remains in the patch when it is removed after its intended course of therapy,¹⁷ raising concerns for safe disposal, especially around children,³⁰ and abuse potential among others.¹⁴ This latter issue is of greatest concern with the fentanyl reservoir patch.¹⁹

Perhaps the most insidious adverse effect associated with patches is their complicated pharmacology. Because many prescribers are unfamiliar with the dosing and initiation of therapy with transdermal products, those xenobiotics with consequential adverse effects in overdose, such as fentanyl, are commonly linked to poor outcomes even with intended therapeutic use.^9,19

• Few xenobiotics have the appropriate chemical properties, such as lipophilicity and potency, to permit transdermal absorption.

• Transdermal delivery of a xenobiotic has certain therapeutic advantages over other routes, such as bypassing first-pass hepatic metabolism and providing a discreet administration.

• The pharmacokinetics of transdermal xenobiotic delivery are unique compared with other routes. Absorption is typically slower but more prolonged, which is potentially beneficial in situations in which long-term, continuous dosing is required.

References