Tiered Testing Strategy for Assessing Thermal Effects on Transdermal Products

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Many transdermal systems are affected by temperature and are labeled with a warning against heat application. For example, heat can increase skin permeability. Heat can affect drug solubility in a formulation and drug (and excipient) release from the transdermal system. Heat can also increase dermal clearance and systemic drug absorption via the vascular network. Heat effects can be different among different transdermal delivery systems. In the FDA review process, when the reference product has a label warning against heat application, the generic product cannot be more sensitive to heat than the reference product. Different heat effects among transdermal products can be due to different drug release (and formulation release) from the products. In addition, due to the different formulation release under heat, these formulations can exert different effects on skin permeability. The different formulation release and penetration into the dermis can also affect dermal clearance for systemic drug absorption. The objectives of this project are to (a) investigate the in vitro release test conditions for identifying heat effects on transdermal delivery and (b) develop an in vitro test process to be used in the reviews of transdermal products to ensure that generic products do not introduce any additional safety risks. We will evaluate the influence of heat upon the rate of drug release from the patch using in vitro release testing of USP dissolution apparatus (tier 1), drug and formulation permeation across skin using Franz diffusion cells (tier 2), and dermal clearance analyses using an existing, state-of-the-art, skin diffusion model to determine dermis concentration and drug absorption into the vascular network in the dermis (tier 3). It is hypothesize that this tiered in vitro testing strategy will yield a scientifically-based decision tree to support the evaluation of thermal effects for ANDA approvals of transdermal products.