Effect of Transient Heat Exposure on Drug Delivery from Transdermal and Topical Products

Abstract

Heating pads and electric blankets are widely used for relief from pain and to provide warmth, respectively. Their unintentional application simultaneously with a transdermal or topical system can result in unexpected drug levels in systemic circulation. Designing well-characterized in vitro and in vivo methods are vital to understanding the effect of heat and hence can aid in the development and evaluation of these products. The objective of this work was to evaluate the effect of heat on products with the same active pharmaceutical ingredient (API) but different inactive ingredients. Four drug molecules with different physicochemical properties were chosen. For each drug, formulations with different excipients were selected. In vivo serum drug profile and in vitro flux profile data can provide mechanistic understanding of heat effect on these formulations. Four topical diclofenac formulations were evaluated for heat effect in vitro under continuous heat exposure. Their flux profiles demonstrated the influence of formulation design and excipients on drug permeation at elevated skin temperature. Serum profiles of two different oxybutynin formulations evaluated under heat exposure showed very different magnitude of enhancement in serum levels under similar heat exposure conditions. Another objective of this work was establishing an in vitro - in vivo correlation (IVIVC) of heat effect on topical and transdermal formulations. This will help in characterizing and predicting heat effect minimizing the need of clinical trials and support the regulatory evaluation of these dosage forms. For buprenorphine patch, study design for in vitro permeation testing (IVPT) using human skin was well characterized to align with and mimic in vivo conditions of heat exposure. Level A and Level C IVIVC were established under normal as well as elevated temperature conditions. For lidocaine patches, IVIVC was observed for early heat effect. However, poor correlation was observed for late heat effect. The findings from this work determined IVPT studies can correlate with and be predictive of in vivo results under normal temperature conditions. But under suboptimal conditions like heat exposure, IVPT may have limitations and should be used in addition to other methods to evaluate heat effect.