Approach for Development of Topical Ketoconazole-Loaded Microemulsions and Its Antifungal Activity

Abstract

Loading ketoconazole in microemulsions can enhance the solubility and permeation of ketoconazole into the skin. The systematic approach as quality by design (QbD) can help for better product and process understanding. This study aimed to develop topical ketoconazole-loaded microemulsions (KME) based on the QbD approach. After risk assessment, the design of experiment was utilized to determine the optimal ratio of water, isopropyl myristate, and surfactant mixture (polysorbate 80 and ethanol), which were chosen as critical material attributes. The particle size and polydispersity index, selected as critical quality attributes, were evaluated as responses. Then, characterizations, in vitro permeation, cytotoxicity, and antifungal activity studies were tested. As result, the equations from the D-optimal mixture design model successfully predicted the composition of the optimized formulation and obtained the acceptable design space. The optimized KME was 16.00 % w/w of isopropyl myristate, 73.50 % w/w of surfactant mixture, and 8.50 % w/w of water resulted in a water-in-oil system. The particle size and polydispersity index of KME were 21.1 ± 1.6 nm and 0.329 ± 0.020, respectively. KME showed prolonged skin retention after 24 h and was non-toxic. KME exhibited a broader zone of inhibition and lower inhibition concentration compared to unloaded ketoconazole against dermatophytes, indicating that KME enhanced effectiveness in antifungal activity for skin infection. The results of the KME meeting the quality target indicated a well-designed and suitable microemulsion for topical usage. Therefore, employing QbD in identifying the process and formulation is a promising approach for future development of high-quality topical KME products. HIGHLIGHTS The topical ketoconazole-loaded microemulsions (KME) were developed based on quality by design approach for further industrial production The D-optimal mixture design model successfully predicted the design space of desired KME formulation KME showed prolonged skin retention after 24 h KME was non-toxic for a topical dosage form KME exhibited antifungal activity greater than unloaded ketoconazole GRAPHICAL ABSTRACT