Abstract
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Development of regulatory science tools to facilitate and accelerate accessibility to complex generic drug products continues to be the focus of significant research activity. The application of confocal Raman spectroscopy to the assessment of cutaneous drug pharmacokinetics is a particular example and has been exploited here to compare two approved topical creams (the reference-listed drug product and a generic) of doxepin hydrochloride with an intentionally non-equivalent, laboratory-made solution of the drug. Experiments involved administration of the formulations to pig skin ex vivo for 6 or 12 h (the uptake phase) followed by 2 and 4 h of clearance to generate Raman-assessed absorption-elimination profiles at nominal depths of 5 μm and 25 μm into the skin. This was achieved, despite overlap between spectral features of the drug with those from the skin, using a background signal removal strategy that also allowed the two functional excipients of the laboratory-made solution to be independently tracked. The areas under the Raman signal versus time absorption-elimination profiles showed (as expected) that the two creams were very similar but that the laboratory-made solution was distinctly different. First-order elimination rate constants describing the clearance phase post-application of doxepin from the superficial skin layers into the deeper tissue were also derived from the spectral data. While the experimental design was insufficiently powered to assess bioequivalence, the data background signal separation paradigm notably expands the potential value of the approach to a broader range of chemical species than had been originally envisaged.