Sustained release gel (polymer-free) of itraconazole-loaded microemulsion for oral candidiasis treatment: time-kill kinetics and cellular uptake

Itraconazole (ICZ) was prepared in a self-microemulsifying (SM) gel. This gel was intended for use in the oral mucosa, where low volume and flow of saliva result in limited solubility and absorption of drugs that are poorly water-soluble. The drug-loaded gel formulation (ICZ-SM) was selected as a clear solution in the ternary phase diagram to improve the solubility of ICZ. Seven ratios (S1–S7) were prepared by mixing polyoxyl 35 castor oils (P35), a medium chain with a blend of mono-, di-, and triglycerides (MCT), and water. Phase separation of large-sized emulsions by countering with artificial saliva were observed in dilution tests for the formulation contained MCT, P35, and water at the ratios of 70:20:10 (S1), 10:80:10 (S3), and 20:60:20 (S4). Formulations in the ratios of 15:50:35 (S5) and 19:43:38 (S6) produced strong ICZ-SM gels, as shown by rheology tests, whereas the formulations at the ratios of 30:60:10 (S2) and 10:43:47 (S7) exhibited no elasticity. A model of zero-order kinetic (S5) and first-order kinetic (S6) were found to best fit the release kinetics of ICZ from the gels. Time-killing assays revealed that S5 and S6 required less time compared with S2 and the ICZ solution. Furthermore, S5 exhibited the highest increase in cell uptake compared with S2, S6, and the ICZ solution. These findings suggest that the ICZ-SM gel was a free polymer capable of delivering an ICZ for the treatment of oral candidiasis, and that ICZ-SM gels applied locally exhibit enhanced absorption into cells.