Transdermal drug delivery is increasingly popular in veterinary medicine due to ease of administration, prolonged delivery and avoidance of a first-pass effect. Not all drugs can be applied topically, with size, iconicity and lipophilicity of a compound all determining its potential for transdermal delivery. Furthermore, species and regional (on the body) differences in skin, including thickness of the skin layers, hair type and density, and cutaneous blood flow, suggest that formulations developed for one species (or body region) may have different pharmacokinetics and pharmacodynamics when applied to other species. This paper will provide an overview of the underlying basic principles determining the movement of topically applied molecules into and through the skin. Emerging advances and future technologies will also be covered.
Movement of Drugs through Skin
The skin is the largest organ of the body, accounting for more than 10% of body mass (Walters and Roberts 2002). 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 effects (e.g., sunscreens and anti-infectives); (iv) to deeper target tissues [e.g., non-steroidal anti-inflammatory agents (NSAIDs) for muscle inflammation]; and (v) accidental exposure (e.g., solvents in the work place, agricultural chemical, or allergens) (Mills and Cross, 2006).
The primary barrier to transdermal drug penetration is the stratum corneum (Walters and Roberts 2002). Hence, compounds suitable for transdermal penetration must be relatively small (≤ 500 daltons), nonionic and relatively lipophilic (log P < 2.6). Drug molecules will move between individual corneocytes within the stratum corneum (Figure 1), traversing intercellular lipids along a concentration gradient towards the underlying dermis. The fractional area of hair follicles represents approximately 0.1% of skin surface in humans, so unlikely to contribute significantly to transdermal drug penetration. However, the considerably greater hair follicle density in some domestic species suggests that appendageal transport may be feasible in veterinary species, although few studies have investigated this aspect.
|Figure 1. A diagrammatic representation of the layer types and distribution in skin|
Factors Affecting Drug Movement through Skin
(1) Skin Metabolism
The skin possesses Phase I and Phase II metabolic activity, reducing the bioavailability of topically applied drugs, although the extent of metabolic activity is species dependent (Hotchkiss 1998). The effect of metabolism is less for drugs where parent drug and metabolites are active, such as methylsalicylate (Mills et al. 2005a), while pro-drugs may be activated by passing through skin (Hotchkiss 1998).
(2) Vehicle and Formulation
The vehicle consists of inert excipients, solvents, preservatives, fragrances and stabilizers, within which the active drug is contained at a known concentration. The rate and extent of active drug leaving the vehicle and moving through the skin will depend on the relative and absolute solubility of the drug between both phases, and the diffusivity (the speed the drug can move through skin, which is limited by binding of the drug to corneocytes, the viscosity of the intercellular environment and the tortuosity of the pathway of the drug in the two phases, vehicle and skin) (Roberts et al. 2002). The formulation of the vehicle will therefore have a major role in determining movement of drug into and through skin, including the consideration that some vehicles will interact with skin, further affecting transdermal drug movement (Mills and Cross 2002).
(3) Integrity of the Skin
Any damage to the stratum corneum will limit its barrier capacity. For example, solvents have been shown to remove intercellular lipid and enhance subsequent transdermal drug delivery (Monteiro-Riviere et al. 2001). This has particular relevance to veterinary species, since compounds used to clean skin, such as chlorhexidine, or skin following removal of adhesive bandages is significantly more permeable to compounds applied topically (Mills and Cross 2006). Importantly, drugs used to treat skin diseases, such as corticosteroids, have been shown to penetrate skin more readily (Ahlstrom et al. 2011), greatly enhancing the local and potential systemic concentrations of these drugs.
(4) Skin Blood Flow and Regional Differences
The flow of blood in the upper dermis acts as a sink to remove solutes that have penetrated through the upper skin layers (Roberts et al., 2002). Interruption of cutaneous blood flow will therefore reduce local clearance of solute and, consequently, initiate a peripheral accumulation of active drug below the site of application. In contrast, skin overlying body regions with lower than normal blood flow, such as the lower leg of the horses, will have relatively lower uptake of topically applied drugs than other more well-perfused regions (Mills and Cross 2007). Similarly, our laboratory has shown regional differences in the transdermal penetration of alcohols, hydrocortisone and testosterone. For example, fentanyl (within a patch) penetrated skin from the groin region of dogs more rapidly and with a shorter lag time, compared to skin from the neck (where fentanyl patches are normally applied) and thorax (Mills et al. 2004).
(5) Hydration of the Skin
Corneocytes swell as they absorb water into the intracellular keratin matrix, disrupting the organized layers of the stratum corneum and substantially increasing permeability (Roberts et al. 2002). This has relevance when drugs are applied under an occlusive dressing, which captures insensible water loss, effectively hydrating the skin (Riviere and Papich 2001). Similarly, transdermal delivery systems or 'patches' enhance transdermal drug penetration, and subsequent systemic drug concentrations, by providing a microclimate of hydration under the patch. A range of drugs are available or in development as a patch, although these are generally used off-label in veterinary medicine (Mills and Cross 2006).
Methods to Enhance Transdermal Penetration
(1) 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 (Mills and Cross 2006). 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 function of the stratum corneum (SC). It has been suggested that penetration enhancers may significantly increase skin permeability to macromolecules (approximately 1-10 kDa), including heparin, luteinising hormone releasing hormone (LHRH) and oligonucleotides.
Early penetration enhancers tended to be disruptive keratolytic agents that destroyed the SC and were nonspecific in their penetration enhancement. These included dimethylsulfoxide (DMSO) and dimethylformamide, which accelerated the penetration of many drugs, including antibiotics, steroids and local anaesthetics, but have practical drawbacks, such as toxicity, irritancy and odour. Newer penetration enhancers include propylene glycol, alcohols and surfactants. However, there remains a correlation between the efficacy of a penetration enhancer and its ability to cause irritation.
(2) Physical Action on the Drug
Iontophoresis uses a small electrical current (~ 0.5 mA/cm2), applied between two electrodes, in contact with the skin, to drive a charged molecule through the barrier. The efficiency of iontophoresis depends on the polarity, valency and mobility of the drug molecule, plus the electrical cycle and formulation containing the drug. Iontophoresis has been reported to enhance the delivery through the stratum corneum of proteins, oligonucleotides, lidocaine and fentanyl (Guy 2010).
(3) Physical and/or Mechanical Energy Applied to the Barrier
1. Ultrasound uses energy waves to disturb the stratum corneum layers by cavitation, with low frequency ultrasound (~ 20 kHz) potentially able to enhance the penetration of drugs, such as insulin, erythropoietin and interferon by up to 1000 fold.
2. Thermal poration involves using energy to create pores in the skin. Electroporation involves the application of short (µsec or msec) electrical pulses (~ 100–1000 V/cm) to the skin to create transient aqueous pores, which permits drugs, such as vaccines, liposomes and microspheres, to penetrate more readily.
3. Microneedle (MN) arrays temporarily disrupt the barrier function of the skin, and thereby enhance transdermal drug delivery. A large number of MN types have synthesised arrays, with micron-sized needles ranging in size from 25 to 2000 µm in height and composed of various compounds, including silicon, metal and biodegradable polymers. The needles puncture the skin and create a number of aqueous channels through which larger drug molecules can pass. The needles usually penetrate only to the viable epidermis, so are essentially painless since they avoid many of the nerves in the dermis.
Topical application can be extremely useful in veterinary medicine for recalcitrant animals, for large scale applications and to improve owner compliance. Technology to enhance the movement of larger molecules through animal skin is advancing, increasing the range of drugs that may be applied topically. Significant differences exist between species in the rate and extent of transdermal drug penetration, so the target species should always be considered when developing new formulations.
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