Enhancement of propranolol hydrochloride and diazepam skin absorption in vitro. II: Drug, vehicle, and enhancer penetration kinetics.

The fluxes of representative hydrophilic (propranolol hydrochloride) and lipophilic (diazepam or indomethacin) drugs, administered as ethanolic solutions containing putative penetration enhancers (n-nonane, 1-nonanol, and 1-decanol), were measured across hairless mouse skin in vitro. Propranolol transport was augmented significantly by the presence of 4% (v/v) alkane or alkanol in the vehicle; diazepam and indomethacin, on the other hand, were enhanced only by n-nonane. Experiments with saturated solutions of the drugs as the donor phase revealed that the actions of the enhancers were taking place in the skin and were not a result of an alteration of solute thermodynamic activity in the vehicle. In separate runs, the impact of n-nonane and 1-nonanol on the percutaneous penetration of ethanol was determined. Temporal effects identical to those on the flux of propranolol were observed. A further measurement revealed that the penetration of 1-decanol, when administered as a 4% (v/v) solution in ethanol, followed a profile similar to that of the solvent (which, in turn, was comparable with that of the independently assessed propranolol hydrochloride). Thus, considerable linkage exists between the transport of a hydrophilic drug and the major vehicle component in the presence of n-nonane and 1-nonanol. The lipophilic drugs, conversely, were promoted only by n-nonane and only after most of the ethanol had been absorbed. The results show that an apparent synergy of transport between a putative enhancer and a cosolvent may not always lead to augmented drug flux. Study of the transport of all key formulation components is recommended, therefore, to optimize vehicles for transdermal drug delivery.