This paper demonstrates the usefulness of an equilibria-cotransport model for understanding the isopropyl alcohol-enhanced transport of an ionizable model compound, terbutaline in its sulfate salt form, through human skin in vitro. With the same isopropyl alcohol concentrations (0 - 80% v/v) present at both sides of skin, the permeation experiments were conducted using split-thickness skin and dermis membranes. The equilibria-cotransport model was consistent with total terbutaline flux and a terbutaline-to-sulfate flux ratio, both increased with increasing isopropyl alcohol and/or terbutaline sulfate concentrations. From the saturated drug solutions, aqueous isopropyl alcohol enhanced terbutaline skin flux about 10 - 100-fold with the maximum at 60 - 80% isopropyl alcohol. This overall flux enhancement was qualitatively separated into the contributions of isopropyl alcohol effects on both equilibrated donor concentrations and skin permeabilities of protonated terbutaline, terbutaline-sulfate ion pair anion, and neutral terbutaline-sulfate (2:1) ion triplet. In addition to altering the species equilibria, isopropyl alcohol was found to enhance the transport of both neutral and ionic species of terbutaline sulfate across stratum corneum.

Atorvastatin is an oral lipid-lowering agent. A Small Tablet (ST) formulation and a Chewable Tablet (CT) formulation have recently been developed and tested in two single-dose bioequivalent (BE) studies (10 mg and 80 mg), each in 76 healthy volunteers. Plasma samples were only analyzed for atorvastatin in ST studies, and simultaneously for both atorvastatin and ortho-hydroxyatorvastatin in CT studies. The results showed the ST and the CT formulations were each bioequivalent to the current Marketed Tablet (MT) formulation, at the lowest (10 mg) and the highest (80 mg) doses. For the CT formulation, both atorvastatin and its metabolite achieved BE at both doses. Although the metabolite BE is not warranted, supportive metabolite data may be needed depending on the degree of divergence in formulations from its MT formulation. Furthermore atorvastatin has linear PK with respect to AUC; however, C max is nonlinear with a greater than dose-proportional increase. Therefore, to ensure the desired sensitivity to detect formulation differences, BE studies with atorvastatin should be conducted at the highest dose.