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

The fluxes of representative hydrophilic (prapranolol 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 hydrophiiic 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 transtiermal drug delivery.