ReviewTransdermal drug delivery: Basic principles for the veterinarian
Introduction
In veterinary medicine, topical application of a wide range of pharmaceutical agents is a useful alternative to more traditional routes of drug administration. Advantages include: (i) a reduction in first pass metabolism by the liver; (ii) non-invasiveness; (iii) avoidance of the gastric route, reducing the potential for both degradation of the drug and gastric irritation, and (iv) improved owner compliance with drug administration (Magnusson et al., 2001, Roberts et al., 2002).
There is an increasing number of pharmaceutical products being registered and marketed for veterinary topical application, although limited information is available about the percutaneous penetration of the active ingredient/s or their vehicles in the intended species. It could be argued that the minimum data package required towards registration of veterinary topical formulations should contain transdermal pharmacokinetic data relevant to the species for which registration is being sought. More importantly, many of the topical preparations currently used in veterinary clinical practice, including fentanyl patches, sunscreens and anti-inflammatories, are prescribed off-label and based on human kinetic data with no information available about the penetration of drug (or vehicle) through animal skin.
The skin is the largest organ of the body, accounting for more than 10% of body mass. It has important protective and homeostatic roles and is generally regarded as a critical protective barrier to the external environment (Walters and Roberts, 2002). Extensive studies have shown that the skin is more complex than merely a barrier and this becomes apparent when agents are applied to the skin either deliberately or accidentally (Magnusson et al., 2001, Riviere and Papich, 2001, Roberts et al., 2002). The extent of absorption through the epidermis, dermis and systemically becomes important (Walters and Roberts, 2002) when we consider that drugs are applied to the skin for: (i) local effects (e.g., corticosteroids for dermatitis); (ii) transport through the skin for systemic effects (e.g., fentanyl, nicotine, oestradiol and testosterone patches); (iii) surface action (e.g., sunscreens and anti-infectives), and (iv) targeting deeper tissues (e.g., non-steroidal anti-inflammatory agents [NSAIDs] for muscle inflammation). There is also (v) the case of accidental exposure (e.g., solvents in the work place, agricultural chemical, or allergens).
Investigation of human skin has revealed that the major resistance to drug penetration is the outermost layer, the stratum corneum (SC). Several theories have been proposed for drug passage through the stratum corneum into the viable epidermis and dermis, including the “bricks and mortar” theory, representing keratinocytes held together by a lipid bilayer (Michaels et al., 1975, Menon and Elias, 1997). However, differences in skin thickness, density of appendages (hair follicles and glands), vascularity and metabolic enzymes mean that different regions of skin in the same individual display different pharmacokinetics of percutaneous drug penetration. More importantly, extrapolation of percutaneous penetration data between species is not practical (Walters and Roberts, 1993) and use of products in veterinary practice without consideration of these interspecies variations in risky.
In this review, we examine the current knowledge of transdermal drug penetration, with particular reference to differences between animal species. We look at factors that specifically affect drug movement through skin and mechanisms used to enhance transdermal drug delivery from a practical veterinary perspective.
Section snippets
Overview of the anatomy and function of the skin
The skin consists of the epidermis, the dermis and the subcutis or subcutaneous tissue which anchors the skin to underlying tissues. Each layer is physically and functionally distinct with appendages, including hair follicles, sweat ducts and sebaceous glands, bridging between the layers and the skin surface (Fig. 1). A more detailed account of skin structure and physiology can be found in some excellent reviews (Monteiro-Riviere, 1991, Walters and Roberts, 2002).
Epidermal transport
The skin is generally regarded as a physiological barrier yet pharmacological agents will penetrate into and through the skin. Studies examining the characteristics of solutes with respect to the ultrastructure of the SC have revealed that the tortuous intercellular diffusion of solutes along a concentration gradient was the pathway through the SC following topical application (Bunge et al., 1999). This led to the acceptance of the ‘bricks and mortar’ model of solute penetration (Fig. 2), with
In vitro techniques
In vitro techniques can be applied to the skin of any animal species and may become one of the most important tools in differentiating kinetic variations likely to be encountered due to permeability differences in veterinary species for commercial formulations intended for human use.
Factors affecting transdermal drug movement
Structural factors of the skin itself will influence rate and extent of movement of a particular drug molecule through skin (discussed earlier). In this section, we will discuss more specific aspects of transdermal drug penetration, including reference to physiological factors that may vary with species and breed.
Chemical penetration enhancers
Penetration enhancers are substances that can partition into, and interact with skin constituents (mainly the intercellular lipid fraction) and induce a temporary and reversible decrease in skin barrier properties (Magnusson et al., 2001). Similar to hydration, penetration enhancers possibly interact with some components of the skin to increase fluidity in the intercellular lipids, possibly inducing swelling of keratinocytes and/or leaching out of structural components, reducing the barrier
Conclusions
The ease of administration of topical formulations encourages compliance with prescribed dosing recommendations in humans and in veterinary species. However, there are significant differences in transdermal drug penetration between species (Sato et al., 1991), meaning that topical products should be formulated for the target species, whereas efficacy and/or toxicity cannot be assumed from studies in other species. In particular, the type and generally higher density of hair follicles in the
Acknowledgements
The authors acknowledge the support of the Rural Industries Research Development Corporation.
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