DRUG-SURFACTANT INTERACTIONS - EFFECT ON TRANSPORT-PROPERTIES

The physico-chemical interactions between three model drugs and a vari ety of surfactants were characterized by measuring the apparent permea bility coefficients of the drugs in the presence and absence of surfac tants in vitro. The extent of interaction between the model drugs and the surfactants can best be described by the hydrophobic effect (prima rily determined by the hydrophobic surface area of the drug molecule) and the electrostatic effect (primarily determined by the charge assoc iated with the drug molecule as well as the surfactant molecules). For drugs that do not possess a significant hydrophobic surface area (tim olol and cefoxitin): their interactions can best be described based on electrostatic effects (charge effects). This interaction being strong with oppositely charged surfactants. The interactions of L-692 585 (a model drug with appreciable hydrophobic surface area) in the presence of surfactants is dominated by the hydrophobic effect, with the elect rostatic effect playing a minor secondary role. The apparent permeabil ity coefficient of timolol as a function of the amount of surfactant i n solution is modelled in light of micellar formation and entrapment a nd/or interaction of free drug with this micellar structure. Briefly, the extent of interaction as a function of amount of added surfactant for timolol indicates that initially as surfactant is added the activi ty of drug for transport declines significantly until a breaking point is reached, after which the drug activity available for transport rem ains relatively constant upon addition of more surfactant. A model is derived which is capable of describing this behavior and provides reas onable estimates for the critical micellar concentration of the surfac tant, the affinity or binding constant for the interaction cf drug wit h an equivalent micellar structure, and the loading capacity of the eq uivalent micellar structure. These observations are potentially signif icant for drug formulation of poorly bioavailable drugs. (C) 1997 Else vier Science B.V.