Enhanced Transdermal Delivery of Sex Hormones in Swine with a Novel Topical Aerosol

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Abstract
This study investigated the enhanced transdermal delivery of testosterone (Tes) and estradiol (E2) in swine in vivo with novel metered-dose topical aerosols containing the penetration enhancer padimate O (PadO) and predicted the dose deliverable in humans from the calculated drug flux across the skin. Weanling swine were catheterized and castrated under general anaesthesia and used as a conscious hypogonadal model. Tes and E2 (with and without PadO) were applied once, and venous blood samples were taken over 24 h. Tes and E2 plasma levels were determined by radioimmunoassay. After daily topical dosing of Tes for 6 days, the plasma Tes levels were determined and the transdermal flux was calculated by correcting the pseudo steady-state plasma concentration versus time profile with the clearance of an iv dose within the same swine. After a single application of the E2 aerosol over 30 cm2, or the Tes aerosol over 180 cm2, the mean AUC0-24 h when PadO was included in the spray was 14.1- and 2.0-fold greater than control, respectively (p < 0.03). After the sixth application of the Tes spray with PadO, the mean flux (+/-SE, n = 4) across swine skin in vivo was 2.12 +/- 0.35 microg/cm2.h, which gave a predicted flux in humans of 0.95 microg/cm2.h. From these data the expected plasma levels of Tes in hypogonadal men would compare well with the normal diurnal Tes profile in healthy men. These novel topical aerosols are capable of enhanced transdermal delivery of sex hormones in vivo, and they have the potential to deliver clinically relevant doses to humans.