Concepts in topical drug delivery: Vehicle influences on the delivery of minoxidil from a solution system

Drugs intended for topical administration are generally formulated as solutions in a variety of vehicles. Due to several interrelated processes such as evaporation and absorption, the thermodynamic activity of the drug in the vehicle undergoes major changes as a function of time. The objective of this study is to assess the changes in thermodynamic activity of the drug and correlate these changes with deposition into the skin and percutaneous absorption rates. Minoxidil was used as the model drug and a 20:60:20 propylene glycol/ethanol/water solution as the prototypical formulation. Extensive in vitro and in vivo studies using hairless mouse skin were carried out and techniques to assess deposition patterns into skin were developed. The major conclusions are as follows: (1) Tape stripping of hairless mouse skin allowed estimation of the amounts of stratum corneum, drug and vehicle harvested in each strip. Vehicle treatment for more than 12 hours causes increases in tissue removed at early strippings. Thus, the penetration of drug as a function of time cannot be followed accurately by stripping profiles. (2) Despite its low vapor pressure, evaporation of propylene glycol is appreciable when applied as a thin film. As a result, minoxidil's concentration soon exceeds saturation and the drug precipitates. (3) As a consequence of supersaturation and related precipitation, minoxidil's flux obtained using a 2% formulation was only twice that seen with a 0.02% formulation after a short period of time. Drug precipitation clearly sets limits on the efficiency of drug delivery. (4) The amount of minoxidil penetrating in 24 hours was directly related to the application time. Application of vehicle alone or a second dose of formulation 12 hours following the initial application enhanced minoxidil's permeation, suggesting that precipitated minoxidil on or in the skin was solubilized and diffusionally mobilized. (5) A comparison of in vitro and in vivo results revealed far more minoxidil was deposited in the epidermis under in vitro conditions. Dermal concentrations were more comparable. Both the plasma and dermal profiles of minoxidil and propylene glycol seem to suggest a significant role exists for transappendageal absorption of the drug.