Enhancement of transdermal testosterone delivery by supersaturation

The objective was to evaluate supersaturation in the development of a spray formulation for transdermal testosterone delivery. The method of cosolvents was used to prepare supersaturated testosterone vehicles, the stability of which was evaluated. Drug delivery from selected formulations, and from a simpler spray, was then assessed across hairless rat skin in vitro. Supersaturated drug solutions were formed either by rapidly adding water to a drug-saturated 4:1:1 ethanol/propylene glycol (PG)/water mixture, or by maintaining the proportion of water constant, while varying the relative amounts of ethanol and PG. In the former case, only small degrees of saturation (DS) could be maintained, and drug flux was increased only modestly. The latter approach produced more stable formulations with DS = 2 to 4. A 1:1 ethanol/PG spray containing saturated testosterone delivered drug as efficiently as a supersaturated vehicle with DS = 2.5. Preparation of supersaturated testosterone formulations is possible, therefore, but significant amounts of water lead to rapid drug crystallization. As percentage PG increases, better stability results, but the practicality of using such vehicles in sprays and aerosols may be questioned. Nevertheless, a simple 1:1 ethanol/PG spray apparently induces supersaturation in situ, and further work to optimize the approach is warranted.