Lipid-protein-partitioning (LPP) theory of skin enhancer activity: finite dose technique

Abstract

We have examined the effectiveness of pretreating human epidermis with a range of accelerants on the permeation of model drugs 5-fluorouracil (5FU) and oestradiol (ES). To complement previous steady-state investigations with these materials, we have utilised a finite dose technique with drug deposited as a dried film. We used accelerants Azone and decylmethyl sulphoxide in both propylene glycol (PG) and water vehicles, oleic acid (OA) in PG, and PG. Following accelerant pretreatments, drug permeation was monitored for 4 days. All PG-based accelerants and PG promoted 5FU penetration, 2% Azone in PG by 80-fold and PG by 12-fold (24-h results quoted). Water and aqueous-based accelerants were relatively ineffective, 3% Azone with 0.1% Tween 20 in saline producing only a 3.7-fold increase. A similar trend occurred with ES; 5% OA in PG was the most effective pretreatment, yielding a 35-fold increase, and PG produced a 9-fold effect. The aqueous-based enhancers were ineffective. With the finite dose technique, PG pretreatment increased drug penetration, contrasting with its ineffectiveness in our previous steady-state work. The glycol may solvate the tissue when it is not fully hydrated, competing with drug for hydrogen-bonding sites. Additionally, PG may aid more drug to partition into the skin. The accelerants themselves, which probably disrupt the lipid bilayers, were more effective with PG rather than with water vehicles. As PG may solvate horny cells, this suggests that both drugs may permeate the stratum corneum transcellularly to some extent. The three features of skin penetration enhancer activity (Lipid interaction, Protein alteration and Partitioning phenomena) represent the essential aspects of the LPP theory.