Microemulsion based gel for topical dermal delivery of pseudolaric acid B: In vitro and in vivo evaluation

Pseudolaric acid B (PAB) possesses comparable fungicidal activity against Candida albicans to amphotericin B and antifungal activity against azole-resistant Candida species. However, its poor water solubility makes the formulation a considerable challenge for dermal permeation of PAB. The aim of this project was to improve the solubility and eventually the dermal permeability and bioavailability by developing a microemulsion based gel for PAB (PAB ME-gel). PAB ME-gel was formulated using isopropyl myristate as oil phase, cremphor EL as surfactant, transcutol P as cosurfactant, and carbopol as gel matrix, and characterized by droplet size, morphology, pH, and rheology. The 3 month storage test showed that PAB ME-gel possessed good physicochemical stability. In vitro permeation of PAB through rat skin from ME-gel was investigated in comparison with PAB microemulsion (PAB ME) and PAB hydrogel (PAB gel), and results showed that ME significantly enhanced PAB retention in the skin and permeation through the skin whether it was incorporated into the gel or not. In vivo dermatopharmacokinetics study using microdialysis further confirmed that ME-gel significantly increased PAB dermal bioavailability compared with the gel (41.95 ± 8.89 μg/ml vs. 13.90 ± 2.22 μg/ml). In vitro sensitivity against C. albicans test indicated that the antifungal activity of PAB ME-gel increased with the increase of PAB loading, and 8 mg/g of PAB ME-gel exhibited a higher antifungal activity than that of 20mg/g miconazole nitrate cream. In vivo antifungal activity evaluation in C. albicans infected guinea pigs showed that 8 mg/g of PAB ME-gel exhibited a higher efficacy than that of 20mg/g miconazole nitrate cream after 7 day treatment. Overall, the results indicated that the ME enhanced in vitro permeability, in vivo dermal bioavailability, and antifungal activity of PAB. Therefore, ME-gel may be a promising approach for topical dermal delivery of PAB to treat skin fungal infection.