Enhancement of Transdermal Delivery and Vaccine Effect via Chemical Permeation Enhancers Integrated Solid-in-Oil...

Needle-free transdermal vaccination is an attractive alternative to hypodermic injection but its use remains limited because of the poor skin permeability of macromolecular antigens. Here, we integrated chemical penetration enhancers (CPEs) into solid-in-oil (S/O) dispersions to improve transdermal delivery and vaccine efficacy. The 24 different CPEs spanning five chemical classes were screened in fluorescein isothiocyanate-ovalbumin permeation assays using excised mouse skin. Fatty acids produced the strongest effects, with decanoic acid and linoleic acid yielding >3-fold increases in permeation, whereas long-chain aldehydes and alcohols showed negligible or modest activity. A random-forest model trained on CPE physicochemical descriptors identified the pK_a value as the dominant determinant of enhancement, motivating evaluation of pH-responsive alkylamines. Alkylamine-loaded S/O formulations achieved permeation comparable to fatty acids, and decanoic acid, linoleic acid, and decylamine were selected for further study. FT-IR analysis of stratum corneum sheets after treatment with isopropyl myristate loaded with decanoic acid, linoleic acid, or decylamine indicated that there was increased lipid fluidity consistent with CPE insertion into the intercellular lipid matrix. In vivo, CPE-containing formulations caused only transient increases in transepidermal water loss and no histological damage, indicating acceptable skin tolerability. Notably, S/O patches containing decylamine or linoleic acid elicited antiovalbumin IgG titers in mice comparable to subcutaneous injection. These findings establish CPE-loaded S/O dispersions as a promising platform for safe, needle-free transdermal vaccination.