Skin is a primary area of body contact with the environment, and is the route by which chemicals enter the body. Introduction of chemicals in the body via skin occurs through passive contact with the environment and through direct application of chemicals on the body for the purposes of medical therapy (skin disease, transdermal drug delivery), and cosmetics. In most cases, the toxicity of chemicals is low, likely because the bioavailability (rate and amount of absorption) of the chemical is too low to cause an immediate response; however, some chemicals when applied to the skin have produced toxicity.
For topically applied drug products, drug release from the formulation is also considered important. They fall into two major categories:
- transdermal systems, that are designed to allow entry of the drug substance into the systemic circulation and
- topical dermatological drug products such as creams, ointments, gels, and lotions, that are designed to treat local skin disorders with minimal systemic exposure.
Topical dermatological drug products are semisolid preparations such as creams, ointments, and gels. They deliver drugs to the skin to prevent or treat disease and/ or to alleviate symptoms. Such preparations include antibacterials, antifungals, antivirals, corticosteroids, and retinoids. The onset, duration, and magnitude of therapeutic response for any topical drug product depend on the relative efficiency of three sequential processes:
- release of the drug substance from the product
- penetration/diffusion of the drug through the stratum corneum
- activation of the desired pharmacological effect at the site of action.
Assuring the quality of a topical dermatologic product requires a complex set of studies that maintain continuing equivalence of the product relative to the clinical trial material on which the documentation of safety and efficacy was based. These include bioavailability BA and bioequivalence BE studies, and many other types of studies as well. Transdermal products are also applied topically but are designed to achieve system effect. Commonly used methods for documenting the BE of oral dosage forms are generally not applicable to topical dermatological drug products. Currently, comparative clinical studies are used to establish bioequivalence for most topical formulations, with the exception of corticosteroids. Documentation of BE for topical dermatological drug products has posed an important challenge for manufacturers and regulators. Several methods have been developed for documenting BE of these types of formulations and are currently being used. A number of methods, such as the tape stripping technique for measuring drug concentrations in the SC termed dermatopharmacokinetics, imaging technique, confocal Raman spectroscopy, the blister fluid technique, microdialysis, are under investigation, while still others have been deemed inadequate. Because a topical dermatological product will generally be applied to diseased skin, formulation/excipient factors may play a much larger role in how the drug moves to the primary site of action within the epidermis or dermis than in the case of a solid oral dose form administered orally, for which drug excipient interactions after absorption are generally thought not to occur. Despite these and other differences between drugs administered orally and topically, many of the same general methods employed to establish BE for both types of formulations.
Dermatological drug products after topical drug application do not produce concentration that can be easily measured in an accessible biologic fluid. Given local action, the focus on systemic absorption may relate more to safety than to local efficacy. For these reasons, plasma blood-level pharmacokinetic measurement for a topical drug product is used as a surrogate for possible toxicity.
Pharmacokinetics applied to drug concentration measurements in the SC is termed DPK. DPK measures drug levels in the SC as a function of time post application and post removal using tape stripping procedure. The tape stripping is thus analogous to an in vivopharmacokinetic studies, using drug concentrations in the SC to determine drug uptake and elimination from the SC. Whereas a plasma pharmacokinetic study assesses BE after oral administration, DPK measures drug concentration in the vicinity of the site of action following application of a topic product.
Application of drugs to the skin offers both unique opportunities and special challenges to the pharmaceutical scientist and regulator interested in evaluation of bioequivalence of topical dermatologic products. While new approaches are needed.
A small confirmatory clinical trial might use, perhaps in association with a pharmacokinetic blood level study for toxicity. But the primary documentation of BE for these formulations would turn instead either to a DPK approach and/or to an entirely in vitro approachsuch as the diffusion cell.