Ethanol and other alcohols: old enhancers, alternative perspectives

Alcohols, such as ethanol and propylene glycol, are among the most intensively studied penetration enhancers in the field of topical drug delivery. Much has been written concerning the use of these versatile solvents with generally positive results being produced and alcohols featuring in a number of commercially available products. Much has also been published regarding the mechanisms underpinning penetration enhancement. In the first instance, ethanol is typically used as a co-solvent in order to increase the donor concentrations of poorly soluble drugs in aqueous solutions. This would thus provide increased fluxes by creating a higher chemical potential within the vehicle. At the tissue level, numerous papers have focussed on processes occurring within the stratum corneum as a consequence of the applied alcoholic formulation. A common theme relates to the modulation of skin lipid domains, which become more leaky thus facilitating increased drug partitioning and permeation. Such processes are sometimes claimed to be reversible within a short timescale, which does not fit well with other observations of the leaching of skin lipids, particularly when high levels of alcohols are dosed to the skin. In addition to reviewing the aforementioned, this Chapter seeks to offer some alternative perspectives relating to the mechanisms by which penetration enhancement is achieved by alcohols and probably other chemical permeation enhancers too. It is proposed that interactions and modulations within the stratum corneum are only part of the process and that a fuller picture only emerges when the permeation of the drug is viewed alongside the permeation of enhancer/vehicle. Firstly, dissolution is a thermodynamic process – energy is released as a solute undergoes solvation – and to reverse the process requires input of equal or more energy. Secondly, it is known that alcohols penetrate the skin. Thirdly, studies on the relationship between levels of alcohol and solute penetrating the skin indicate that co-permeation/drag effects are of key importance