Estimation of transdermal permeation parameters in non-stationary diffusion experiments. Application to pre-treatment studies with terpenes.

Purpose: To estimate the applicability of transdermal drug permeation parameters in a finite-dose model for skin pre-treated with terpenes and to evaluate the enhancing effect of some terpene formulations on alprazolam permeation.

Methods: In vitro enhancement of alprazolam human skin permeation was investigated using a pretreatment with different terpene solutions. Vertical diffusion, Franz-type cells were used. Intrinsic drug permeation was also investigated. Transdermal permeation parameters were estimated from the permeation tabulates using different theoretical approaches for their calculation. Two groups of permeation parameters were calculated: modelistic (diffusion of a finite-dose of drug model) and parameters nondependent of a diffusional model.

Results: In control experiments, all approaches of data treatment satisfactorily described the experimental permeation profiles. When skin pre-treatment was investigated, the fitting of a mathematical sigmoid function was much better than the diffusional approach. Pre-treatment of the skin with Limonene dissolved in ethanol / propylene glycol and Menthol dissolved in propylene glycol increased 15 and 10 times respectively the permeation parameters of alprazolam.

Conclusions: Using enhancers that are rapidly cleared from the skin, skin permeability does not remain constant during the permeation experiment and therefore it is not possible to calculate parameters that are usually true coefficients or definite values. In this case, non-modelistic parameters can be used to estimate an enhancing effect.