Preparation and Evaluation of Upadacitinib-Loaded Binary Ethosomal Hydrogel: A Topical Delivery System with Enhanced Stratum Corneum Permeability for Improved Anti-Inflammatory Therapy in Psoriasis

Upadacitinib (UPA) is a potent antipsoriasis drug that can modulate the response of various pro-inflammatory cytokines by inhibiting the JAK-STAT pathway. The clinical application of UPA has been limited due to the systemic side effects associated with oral administration. The aim of this study was to develop upadacitinib-loaded ethanol-based carbomer hydrogel for the topical treatment of psoriasis and to improve the therapeutic efficacy against psoriasis. The ethosomes were prepared by the alcohol injection-sonication method with an average particle size of 114.42 ± 2.88 nm, an encapsulation rate of 73.75 ± 2.24%, and a drug loading capacity of 21.16 ± 0.49%. The penetration rate of binary ethosomal carbomer hydrogel was 7.04 μg/cm²·h, significantly higher than that of the cream formulation (3.12 μg/cm²·h), representing a 2.3-fold increase. Similarly, intradermal retention of the binary ethosomal carbomer hydrogel (52.19 ± 13.38 μg/cm²) was 2.9-fold greater than that of the cream (17.84 ± 9.09 μg/cm²). In vivo evaluations demonstrated that the binary ethosomal carbomer hydrogel significantly ameliorated skin phenotype and histopathologic features, while markedly suppressing pro-inflammatory cytokine levels: TNF-α decreased from 361.97 ± 17.53 to 262.11 ± 15.77 pg/mL (<i>p</i> < 0.01), IL-17 from 68.42 ± 11.59 to 49.68 ± 2.14 pg/mL (<i>p</i> < 0.05), and IL-23 from 62.64 ± 7.89 to 44.60 ± 3.08 pg/mL (<i>p</i> < 0.01) compared to the model group. In addition, upadacitinib binary ethosomal hydrogel did not show significant signs of irritation, indicating its safety for topical application. Therefore, the upadacitinib-loaded ethanol-based carbomer hydrogel developed in this study may be an effective strategy for the treatment of psoriasis.