The potential for physicochemical driving forces facilitating topical transport of the lipid-soluble drug oxaprozin (OXA) was investigated using surface-enhanced Raman spectroscopy (SERS) in this study. Azone, iontophoresis (IP), and sonophoresis (SP) were combined and performed on mouse skin for the OXA transdermal penetration, and the synergistic effect was analyzed using Raman spectroscopy. The data of characteristic peak intensity were processed with overlapping peak resolving and standard normalization. The results showed that Azone promoted the transdermal penetration of OXA (5.9-fold greater than the OXA concentration of normal penetration); SP enhanced OXA transdermal penetration (5.5-fold); IP enhanced OXA transdermal penetration (4.2-fold); the combined application of Azone and SP (Azone+SP) and SP+IP can improve the enhancement coefficient of OXA transdermal penetration (8.4-fold and 6.1-fold, > 5.9, > 5.5, > 4.2), and their combined application has a synergistic effect; Azone+IP does not have a synergistic effect while the enhancement coefficient of Azone+IP (5.3-fold, < 5.9) and Azone+SP+IP (7.2-fold, < 8.4) was slightly reduced. As for the drug OXA, Azone+SP is an effective method of transdermal penetration.
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