Optimization of topical formulations using a combination of in vitro methods to quantify the transdermal passive diffusion of drugs

Publication from Health
Biomedizinisches Gewebemonitoring

Joanna Hummer, Thomas Birngruber, Frank Sinner, Leanne Page, Frank Toner, Clive S. Roper, David J. Moored, Mark B. Baker, Mila Boncheva Bettexe

International Journal of Pharmaceutics , 4/2022


This paper describes a new approach to the early-stage optimization of topical products and selection of lead formulation candidates. It demonstrates the application of open flow microperfusion in vitro in conjunction with the Franz diffusion cell to compare time-resolved, 24-hour profiles of diclofenac passive diffusion through all skin layers (including the skin barrier, dermis, and subcutis) resulting from nine topical formulations of different composition. The technique was successfully validated for in vitro sampling of diclofenac in interstitial fluid. A multi-compartmental model integrating the two datasets was analyzed and revealed that the passive diffusion of diclofenac through the dermis and subcutis does not correlate with its diffusion through the skin barrier and cannot be predicted using Franz diffusion cell data alone. The combined application of the two techniques provides a new, convenient tool for product development and selection enabling the comparison of topical formulation candidates and their impact on drug delivery through all skin layers. This approach can also generate the experimental data required to improve the robustness of mechanistic PBPK models, and when combined with clinical sampling via open flow microperfusion – for the development of better in vivo-in vitro correlative models.

Keywords: open flow microperfusion in vitro Franz diffusion cell topical diclofenac passive diffusion formulation optimization