Evaluation of in vitro percutaneous absorption of olanzapine and fluoxetine HCl: enhancement properties of olanzapine

Abstract

The diffusion characteristics of fluoxetine HCl (FLX HCl) and olanzapine (OLZ) alone and in combination with each other were studied to determine their in vitro permeation behavior across a series of gelling agents through a cellulose membrane and human cadaver skin. Klucel 0.5% was selected as the optimal formulation to study their diffusion through human cadaver skin. The release profiles of drugs acting alone and in combinations were identical in the case of the cellulose membrane. However, with human cadaver skin, the permeation of FLX HCl in combination with OLZ drastically increased (732 µg) compared with the release of FLX HCl alone (43.7 µg), while the release of OLZ remained the same whether alone or in combination with FLX HCl (183.7 µg). The results indicate that OLZ enhances the diffusion of FLX HCl through the cadaver skin. Follow-up studies with OLZ were conducted to further investigate this phenomenon and have shown that OLZ enhancement properties are skin reversible as well as concentration dependent. Also, a variety of experiments with different hydrophilic and lipophilic molecules were conducted, and it was found that OLZ enhances the permeation of hydrophilic compounds, while it has no influence on lipophilic compounds. Finally, a number of compounds structurally related to OLZ were investigated as enhancers, and it was determined that piperazine ring attached to the tricyclic system of OLZ is essential for enhancement of FLX HCl (1,837 µg).