Drug release from different transdermal drug delivery systems (TDDS) is governed by a number of factors including: skin condition, occlusion, exposure to heat, different inactive ingredients, sweat, age and patch design (reservoir vs. matrix). In particular, exposure to heat has been well documented to increase the peak plasma concentration and area-under the plasma concentration curve for many drugs including nicotine, fentanyl, nitroglycerine, clonidine, methyl salicylate, estradiol and testosterone, imposing critical safety issues. Most of the reported studies are limited as they focused on studying heat effect on reference or generic TDDS and almost none, according to the literature, provided direct comparison of the influence of heat effect on reference and generic products in vivo. When a reference product has a warning against applying heat, the generic product will have the same warning regardless of the dissimilarity that may exist between them (i.e., differences in inactive ingredients or type of TDDS). It is likely that the release rate of the same drug differs from different TDDS products in response to heat, as well as the skin permeation being modified due to different release rates of enhancers and cosolvents. There is an unmet need to characterize heat effects on generic vs. reference products in vitro and in vivo to develop in vitro/in vivo correlation which can be used by ANDA sponsors to predict the performance of their generic products upon heat application. This will ensure that generic products are no different than reference products with respect to their performance upon heat application and will ensure that there are no additional critical safety issues for users of generic TDDS. The objective of this proposal is to determine the best in vitro test conditions that identify the influence of heat on the permeation properties of reservoir and matrix nicotine and fentanyl patches. Nicotine and fentanyl patches are available without and with prescriptions, respectively. They are among the most used patches worldwide and they are available in both matrix and reservoir forms from different manufacturers. This project will: investigate the influence of heat effects on reference and generic nicotine and fentanyl TDDS in healthy human volunteers, investigate the influence of variable test conditions in vitro on FDA approved nicotine and fentanyl TDDS at normal and elevated temperatures, develop in vitro/in vivo correlation, and evaluate the influence of heat on FDA-approved generic products (with no available heat effect studies) and their respective reference products using our optimized in vitro test conditions. Results from these studies will help the FDA decide on which in vitro test conditions and study design ANDA sponsors will have to consider in evaluating the performance of their generic product to ensure that heat effect on their products is equivalent to that on the respective reference product. Future years of this project could include examination of the heat effect on additional drug patches, on special patient populations, and on skin with compromised barrier.

Public Health Relevance

Statement Heat can increase drug release from transdermal drug delivery systems (TDDS), as well as alter the skin permeation rate due to different release rates of enhancers and/or cosolvents. The objective of this proposal is to determine the best in vitro test conditions that predict in vivo heat effects on generic and other products. These tests would provide guidance for ANDA sponsors to ensure that their product has the same efficacy and safety profile as the reference product.

National Institute of Health (NIH)
Food and Drug Administration (FDA)
Research Project--Cooperative Agreements (U01)
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Special Emphasis Panel (ZFD1-SRC (99))
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University of Maryland Baltimore
United States
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