Transdermal Therapeutics

Transdermal drug delivery (TDD) is a novel technique for drug administration and is an active area of research in human medicine. Although there is some precedent for use of TDD in veterinary species, most of this use is based on empirical information. There are limited reports of active research or controlled trials investigating this modality in the veterinary medical literature.

The skin is considered the largest organ system in the body. Due to its easy access and ability to maintain applied formulations for prolonged periods of time, the skin is a likely target for drug delivery techniques. The physical structure of the skin itself provides a basic barrier to the agents utilized in TDD techniques. The skin is divided into three layers: the epidermis, dermis, and subdermis. The epidermis is further divided into five layers: the stratum corneum, stratum lucidum, stratum granulosum, stratum spinosum, and stratum basale. The barrier created by the unique structure of the stratum corneum appears to provide the rate-limiting point for transdermal drug absorption.^1–5 The cornified layer of the stratum corneum was once thought to be inert, but it is now known to actively oppose absorption from outside and loss from within.^1–4

Absorption via the transdermal route primarily occurs by passive diffusion. The rate of diffusion is governed by the properties described in Fick’s Law of Diffusion. This law describes the interactions of several factors, including the diffusion coefficient of the drug, the partition coefficient of the drug, the concentration of the drug applied, the surface area of the skin over which the drug is applied, and the thickness of the epidermis itself.²⁶ In addition, other factors that may influence drug absorption across the skin include physical differences between the structure of skin in different species, the presence and physical characteristics of the hair coat of a given species or breed, and differences in skin characteristics on different parts of the body.³⁶ Even the process of shaving hair may affect drug absorption. Age, gender, body temperature, body composition, and blood supply are all facets that must be considered to have an impact on drug absorption. The result is that even with a specific formulation, absorption may vary dramatically between individuals. This variability in absorption can even be found within the same patient, depending on the physical characteristics and site of formulation placement.^1–46 This variability, compounded by the lack of defined pharmacokinetic/dynamic information on many of these products, can severely impact on therapeutic efficacy.

Not all drugs are good candidates for TDD. There are a number of physical properties that make certain compounds ideal candidates for transdermal application. The ideal compounds have a low molecular weight (≤400 Daltons), are lipophilic but soluble in oil and water, and have a high melting point and partition coefficient.^1–6 In addition, other factors such as drug stability, the use of different transdermal delivery carriers, and different penetration enhancers may impact absorption.

The major advantages of using a transdermal application include ease of administration, patient tolerance, treatment (owner) compliance, bypass of the gastrointestinal tract, and hepatic first pass biotransformation and metabolism.^1–6 The major disadvantages of this route of administration include the possibility of localized cutaneous reactions, systemic toxicity, lag time between application and absorption, and a general lack of understanding of the pharmacokinetics of many of the drugs being compounded for transdermal delivery.^1–6

Currently there are several planned and ongoing investigations with transdermal agents such as methimazole, amitriptyline, buspirone, diltiazem, and ondansetron. A recent retrospective study evaluating the use of transdermal methimazole for treatment of feline hyperthyroidism in 13 cats showed promising results, with serum thyroxine concentrations returning to normal in most cats evaluated at 4-week and 6-month follow-up times.⁷ However, another study was unable to demonstrate detectable serum concentrations of methimazole in four of six healthy cats after transdermal administration.⁸ This may imply that multiple dosages of transdermal drugs may be required before systemic levels can be detected.

Nitroglycerin and fentanyl are examples of agents that have successful track records of being utilized via the transdermal route of administration in veterinary species. Several studies have been performed using the fentanyl patch in dogs and cats.^9–11 Recently, metoclopramide was evaluated for transdermal administration in the dog, but measurable serum concentrations were not detected.¹²

A recent Internet search indicated over 100 compounding pharmacies offering a large variety of agents in a transdermal form. The majority of these agents are compounded in a Pluronic lecithin organogel (PLO) carrier that allows transdermal application. Pluronic F127 is a polymeric surfactant that enhances the formation of drug micelles in a gel matrix.¹³¹⁴ Pluronic gels have been shown to modulate the release and permeation of drugs such as propranolol, metronidazole, cephalexin, nifedipine, diclofenac, and insulin.^813–18 Lecithin (i.e., phosphatidylcholine) is an emulsifying agent that forms into a viscous gel with the addition of water. This ointment forms spaghetti-like structures with the stratum corneum and allows absorption through this layer.¹⁹ Other carrier agents available include Lipoderm and Vanderm.¹³

An abbreviated list of agents currently available as transdermal applications includes aminophylline, amitriptyline, amoxicillin, buprenorphine, buspirone, chloramphenicol, chlorpromazine, cisapride, clindamycin, cyproheptadine, diclofenac, diltiazem, diphenhydramine, doxycycline, enalapril, enrofloxacin, famotidine, furosemide, hydroxyzine, ibuprofen, itraconazole, ivermectin, ketoprofen, lorazepam, methimazole, metronidazole, phenylbutazone, phenylpropanolamine, prednisolone, prednisone, and ursodiol. While readily available, most of these agents have had little or no work done to establish efficacy or to elucidate pharmacokinetics when delivered via this route.

When considering the use of TDD, there are important questions the clinician must ask. Is the transdermal route the most appropriate for this patient? Do you know the properties of the therapeutic agent, and has the transdermal route been evaluated for this agent? What is the carrier vehicle? Some carrier agents may contain dimethyl sulfoxide (DMSO), which may have side effects,¹³ and soy lecithin has been reported as a known allergen.²⁰ What is the shelf life of the agent? And can this patient tolerate therapeutic failure? (i.e., Is this a life-threatening disease?) It may be best to use these agents in stable patients when there is a known or measurable endpoint for therapy.

At this point in time, although TDD has exciting possibilities, controlled studies evaluating the many drugs being suggested for use via this route in both dogs and cats need to be performed before recommendations can be confidently made. The use of transdermal agents empirically cannot be recommended at this time. If these agents are deemed necessary and appropriate by the attending clinician, the pet owner must be reminded that these agents are considered off-label drug use. As such, the veterinarian should obtain informed client consent prior to use.