S. Prodduturi, A. M. Wokovich, B. J. Westenberger, L. F. Buhse, W. H. Doub, DPA, OTR, CDER, FDA, St. Louis, MO
Background: Fentanyl is a potent opioid used in the palliative treatment of late-stage cancer and chronic pain. There are currently two approved Fentanyl Transdermal Systems (FTS). Innovator Duragesic FTS (D-FTS) is a reservoir system with a rate-control membrane while generic Mylan FTS (M-FTS) is a drug-in-adhesive system without a rate-control membrane.
Methods: Novel technique to study skin/membrane permeability was developed using a modified USP-5 paddle-over-disk apparatus. Four membranes with different permeabilities- two silastic (75, 125 microns) and two ethylene vinyl acetate (EVA) membranes (9%, 19% vinyl acetate content) were evaluated.
Results: The steady state output rates calculated using EVA (9% vinyl acetate) membrane for 25 µg/hr dose Mylan and Duragesic patches were 21.3 and 20.4 µg/hr, respectively. The release rate before steady state was higher from D-FTS (34.5 µg/hr) than M-FTS (24.6 µg/hr). When other membranes (silastic and EVA 19% vinyl content) having higher permeabilities were used, the steady state output rates from matrix M-FTS were very high when compared to reservoir D-FTS.
Conclusions: The higher observed initial release rate (pre-steady state) with the reservoir D-FTS might be due to its saturated drug-containing adhesive layer and/or due to alcohol incorporated as a penetration enhancer. The higher fluxes obtained from M-FTS relative to D-FTS when using high permeability membranes may indicate that matrix and reservoir FTS are not bioequivalent when the skin is compromised. EVA membrane (9% vinyl acetate) seems to be a good model to predict skin permeability. However, confirmatory experiments using cadaver skin are currently underway.