The Impact of Vehicle Occlusivity on Skin Delivery and Activity of a Janus Kinase Inhibitor: Comparison of Oil-Based Formulations

<b>Background/Objectives:</b> Baricitinib, a selective JAK1/JAK2 inhibitor, shows therapeutic potential in psoriasis; however, its oral use is associated with systemic adverse effects, encouraging the development of topical formulations. This study aimed at evaluating the influence of petrolatum type on the stability, biopharmaceutical performance, and therapeutic activity of lipid-based formulations containing Baricitinib. <b>Methods</b>: Formulations were prepared with Labrafac^® Lipophile WL 1349 (L) and either liquid (LLV) or solid (LSV) petrolatum at 30% and 60% <i>w</i>/<i>w</i>. Stability, rheology, spreadability, in vitro release, ex vivo permeation, and skin retention were evaluated, along with the safety and efficacy in HET-CAM and imiquimod-induced psoriasis murine models. <b>Results</b>: Only 30% petrolatum formulations remained stable for 60 days. LLV exhibited Newtonian flow, higher spreadability, sustained release (83.7% at 50 h), and superior skin retention (94 µg/g of skin/cm²), whereas LSV showed pseudoplastic behavior, lower spreadability, and reduced release (47.4% at 50 h). Both formulations were non-irritant and improved stratum corneum hydration while reducing transepidermal water loss. In vivo, both reduced erythema, epidermal thickening, edema, and histological alterations, confirming anti-inflammatory efficacy. <b>Conclusions</b>: These results demonstrate that the vehicle occlusivity decisively modulates baricitinib's release and activity. LLV formulation favored drug retention and enhanced permeation at 24 h. Overall, excipient selection is important in designing safe and effective topical JAK inhibitor formulations.