Transdermal Acetaminophen and Caffeine for Migraine, Part 1: Solid Microneedles and Co-loaded Polymeric Gels

Abstract Purpose Acetaminophen (ACM) and caffeine (CAF) are frequently co‑administered for rapid analgesic relief for migraines, and transdermal delivery of these over-the-counter therapies could improve the patient at-home experience. In this 2-part series we examine the impact of formulation and physical enhancements on ACM and CAF skin transport. Here in part 1, we examined how polymer and solid microneedle pretreatment influence ACM and CAF release and dermal permeation from hydroxyethyl cellulose and polyvinylpyrrolidone gels. Part 2 examines impacts of dissolving microneedles and applied heat. Methods: FTIR was used to assess potential interactions between the active pharmaceutical ingredients (APIs) and polymers. Viscosity and viscoelastic parameters (G′ and G″) of the polymeric gels were measured on a rheometer. Diffusion studies were performed to quantify API release and permeation through dermatomed porcine skin, from single or dual-API loaded gels. Transepidermal water loss (TEWL) studies measured skin barrier disruption after microneedle application. Results: FTIR confirmed that both drugs remained chemically unchanged in each polymer matrix, indicating no strong drug-polymer interactions. Microneedle pretreatment significantly enhanced permeation for all formulations, with varying levels of enhancement for individual vs co‑API gels. Impact of co-delivery on permeation was dependent on API, polymer, and timing. Conclusions: Polymer structure, co-delivery, and microchannel‑mediated transport all influenced ACM and CAF delivery across intact and solid microneedle-treated skin.