Abstract
Understanding a drug candidate’s pharmacokinetic (PK) parameters is a challenging but essential aspect of drug development. Investigating the penetration and distribution of a topical drug’s active pharmaceutical ingredient (API) allows for evaluating drug delivery and efficacy, which is necessary to ensure drug viability. A topical gel (BPX-05) was recently developed to treat moderate to severe acne vulgaris by directly delivering the combination of the topical antibiotic minocycline and the retinoid tazarotene to the pilosebaceous unit of the dermis. In order to evaluate the uptake of APIs within human facial skin and confirm accurate drug delivery, a selective visualization method to monitor and quantify local drug distributions within the skin was developed. This approach uses fluorescence lifetime imaging microscopy (FLIM) paired with a multicomponent phasor analysis algorithm to visualize drug localization. As minocycline and tazarotene have distinct fluorescence lifetimes from the lifetime of the skin’s autofluorescence, these two APIs are viable targets for distinct visualization via FLIM. Here, we demonstrate that the analysis of the resulting FLIM output can be used to determine local distributions of minocycline and tazarotene within the skin. This approach is generalizable and can be applied to many multicomponent fluorescence lifetime imaging targets that require cellular resolution and molecular specificity.
Highlights
Understanding a drug candidate’s pharmacokinetic (PK) parameters is a challenging but essential aspect of drug development
Visualizing and quantifying the properties of multi-compound interactions within such formulations would allow for more accurate drug dosimetry resulting from improved understanding of where, when, and how active pharmaceutical ingredient (API) diffuse in the skin
These EEMs revealed that the two APIs have different, but overlapping, maximum excitation peaks (MNC at 480 nm and TAZ at 410 nm) while showing similar maximum emission spectra (MNC at 510 nm and TAZ at 490 nm, Fig. S1 in the Supplementary Information)
Summary
Understanding a drug candidate’s pharmacokinetic (PK) parameters is a challenging but essential aspect of drug development. In order to evaluate the uptake of APIs within human facial skin and confirm accurate drug delivery, a selective visualization method to monitor and quantify local drug distributions within the skin was developed This approach uses fluorescence lifetime imaging microscopy (FLIM) paired with a multicomponent phasor analysis algorithm to visualize drug localization. We demonstrate that the analysis of the resulting FLIM output can be used to determine local distributions of minocycline and tazarotene within the skin This approach is generalizable and can be applied to many multicomponent fluorescence lifetime imaging targets that require cellular resolution and molecular specificity. This is a result of phasor algebra, where multi-exponential fluorescence lifetimes are a linear combination of their individual lifetime components This allows for computation of relative signal contribution of exogenous or endogenous references to the test sample and an accompanying visual map of signal across the tissue sample. Compared to previous analysis methods, such as arbitrary thresholding techniques, and tedious multiexponential fitting, this newly applied approach is highly robust and yields complete drug uptake maps without missing tissue regions that otherwise would be ignored in other multicomponent phasor analysis protocols
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