Abstract

Confocal Raman spectroscopy is being assessed as a tool with which to quantify the rate and extent of drug uptake to and its clearance from target sites of action within the viable epidermis below the skin’s stratum corneum (SC) barrier. The objective of this research was to confirm that Raman can interrogate drug disposition within the living layers of the skin (where many topical drugs elicit their pharmacological effects) and to identify procedures by which Raman signal attenuation with increasing skin depth may be corrected and normalized so that metrics descriptive of topical bioavailability may be identified. It was first shown in experiments on skin cross-sections parallel to the skin surface that the amide I signal, originating primarily from keratin, was quite constant with depth into the skin and could be used to correct for signal attenuation when confocal Raman data were acquired in a “top-down” fashion. Then, using 4-cyanophenol (CP) as a model skin penetrant with a strong Raman-active C≡N functionality, a series of uptake and clearance experiments, performed as a function of time, demonstrated clearly that normalized spectroscopic data were able to detect the penetrant to at least 40–80 μm into the skin and to distinguish the disposition of CP from different vehicles. Metrics related to local bioavailability (and potentially bioequivalence) included areas under the normalized C≡N signal versus depth profiles and elimination rate constants deduced post-removal of the formulations. Finally, Raman measurements were made with an approved dermatological drug, crisaborole, for which delivery from a fully saturated formulation into the skin layers just below the SC was detectable.
Original languageEnglish
Pages (from-to)5910-5920
Number of pages11
JournalMolecular Pharmaceutics
Volume20
Issue number11
Early online date6 Oct 2023
DOIs
Publication statusPublished - 6 Nov 2023

Bibliographical note

Funding Information:
This project was supported by the Food and Drug Administration (FDA) of the U.S. Department of Health and Human Services (HHS) as part of the financial assistance award (1-U01-FD006533) totaling $1.25M with 100% funded by FDA/HHS. The contents are those of the author(s) and do not necessarily represent the official views of, nor an endorsement, by the FDA/HHS or the U.S. Government. Valuable insight from and stimulating discussions with Drs. Priyanka Ghosh, Sam Raney, and Markham Luke from the FDA’s Office of Generic Drugs and from Professor Jane White at the University of Bath are gratefully acknowledged. N.A.B. thanks the Community for Analytical Measurement Science for a 2020 CAMS Fellowship Award funded by the Analytical Chemistry Trust Fund.

Keywords

  • Raman spectroscopy
  • skin uptake
  • skin clearance
  • skin penetration
  • topical bioavailability

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmaceutical Science
  • Drug Discovery

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