Biphasic testosterone delivery profile observed with two different transdermal formulations

Abstract

Purpose. Our long-term goal is to develop formulations for pulsatile testosterone (T) delivery. T has been reported earlier to show biphasic pharmacokinetics in humans by Mazer et al, as well as biphasic permeation across excised rat skin by our group. We examined two kinds of formulations to evaluate their delivery profiles and to assess whether differences in the formulation approach affect pharmacokinetics in animal models. Methods. One formulation consisted of T and a polymer blend dissolved in isopropanol; administered by dispensing the solution on the skin to cast a film in situ. The other was an adhesive-dispersion patch. In vitro release from the patch was evaluated using a flow-through cell interfaced with an HPLC pump and UV detector. Single dose pharmacokinetics were evaluated in castrated Wistar rats and bonnet monkeys immunized against gonadotropin-releasing hormone to deplete endogenous T. Results. Two maximas were observed in the T release profile from the patch and in serum concentration versus time profiles in both animal models on application of either formulation. The relative magnitudes of the two maximas and the time interval separating them were different in the case of each formulation. Conclusions. Both formulations result in biphasic pharmacokinetics of T in the animal models studied. Discrete maximas presumably correlate with 'burst' and 'sustained' phases of drug release.