ABSTRACT
In the search for ways to improve the topical delivery of drugs for local or
systemic effects, two approaches have received the most attention recently: devices
and penetration enhancers (1). Lost in the attention paid to those two approaches
has been the prodrug approach that could be an attractive alternative to devices
and penetration enhancers (2). A prodrug is a transient, inactive chemical
derivative of a known parent drug, which improves some physicochemical
property such as low solubility, metabolic instability, or other problematic proper-
ties of the drug, so that the active drug is delivered more effectively to the target
tissue. One reason that the prodrug approach has not been explored as extensively
as it might have been, based on its theoretical promise, may be that many of the
reported improvements in transdermal delivery by prodrug approaches were
modest, at best only two-to fourfold (3). However, since an increase in
transdermal delivery is linked to an increase in dermal delivery, an improvement
in transdermal delivery of two-to fourfold, and hence in dermal delivery for a
local effect, can make the difference between a successful product or not. Similar
improvements in oral delivery have made a difference in the success of oral
products (4). On the other hand, transdermal delivery through a relatively small
surface area, but for a systemic effect, will require a much larger improvement
because a much larger dose is required for a systemic effect. Thus, a prodrug
approach may be more ideally suited to solving local rather than systemic delivery
problems, while possibly too much emphasis has been placed on using prodrugs
topically to improve systemic delivery in the past. In this chapter, we will discuss
the development of design directives to optimize the physicochemical properties
of the prodrug to optimize the delivery of the active drug, discuss the results of the
application of the design directives to model drugs, give examples of prodrugs
that have been approved for topical use, and give examples of soft drugs that have
been approved for topical use.
