Fungal infections are a growing global health problem. Therefore, our group has synthetized and characterized an improved antimycotic by co-crystallization of ketoconazole and para-amino benzoic acid, named KET-PABA. The aim was to increase bioavailability, biocompatibility, and efficiency of the parent drug–ketoconazole. Based on our previous results showing the cocrystal improved physical properties, such as stability in suspension, solubility, as well as antimycotic efficiency compared to ketoconazole, the current study investigated the local possible side effects induced on the skin of BALBc mice by the application of KET-PABA cocrystal, in view of a further use as a topically applied antimycotic drug. A specific test (mouse ear-swelling test) was used, combined with the histopathological examination and the measurement of pro and anti-inflammatory cytokines and inflammation mediators. KET-PABA application was safe, without signs of skin sensitization shown by the mouse ear sensitization test, or histopathology. KET-PABA strongly inhibited proinflammatory cytokines such as IL1 α, IL1 β, IL6 and TNF α, and other proinflammatory inducers such as NRF2, compared to vehicle. KET-PABA had no effect on the levels of the anti-inflammatory cytokine IL10, or proinflammatory enzyme COX2 and had minimal effects on the activation of the NF-κB pathway. Overall, KET-PABA application induced no sensitization, moreover, it decreased the skin levels of proinflammatory molecules. The lack of skin sensitization effects on BALBc mice skin along with the inhibition of the proinflammatory markers show a good safety profile for topical applications of KET-PABA and show promise for a further clinical use in the treatment of cutaneous mycosis.

真菌感染是一个日益严重的全球健康问题。因此，我们小组通过酮康唑和对氨基苯甲酸的共结晶合成并表征了一种改进的抗真菌剂，称为 KET-PABA。目的是提高母体药物酮康唑的生物利用度、生物相容性和效率。基于我们之前的结果显示，与酮康唑相比，共晶改善了物理性质，例如悬浮稳定性、溶解性以及抗真菌效率，目前的研究调查了应用 KET 对 BALBc 小鼠皮肤引起的局部可能的副作用-PABA 共晶，考虑到进一步用作局部应用的抗真菌药物。使用了特定的测试（小鼠耳胀测试），结合组织病理学检查和促炎和抗炎细胞因子和炎症介质的测量。KET-PABA 应用是安全的，没有小鼠耳敏试验或组织病理学显示的皮肤敏化迹象。与载体相比，KET-PABA 强烈抑制促炎细胞因子，如 IL1 α、IL1 β、IL6 和 TNF α，以及其他促炎诱导剂，如 NRF2。KET-PABA 对抗炎细胞因子 IL10 或促炎酶 COX2 的水平没有影响，对 NF-κB 通路的激活影响很小。总体而言，KET-PABA 应用不会引起致敏，而且，它降低了促炎分子的皮肤水平。