Fluconazole-loaded thermosensitive system: In vitro release, pharmacokinetics and safety study

Fluconazole (FCZ) is a broad spectrum anti-fungal drug and categorized as a BCS class-I molecule because of its readily soluble and highly permeable properties. Oral delivery of FCZ is associated with teratogenic effects. Thus, other routes of administration needs to be investigated for improved efficacy of the drug. The purpose of this study was to prepare and characterize FCZ loaded thermosensitive system (FCZ-TSS) for rectal administration with sustained release and improved bioavailability. The ingredients of FCZ-TSS were optimised by preparing different formulations using various concentrations of Poloxamer 407 (P-407), Poloxamer 188 (P-188), Tween 80 (Tw-80) and FCZ. The FCZ-TSS was liquid at room temperature and converted into gel at body temperature. The rheological properties of the FCZ-TSS were determined including, gelation temperature, gel strength, gelation time and mucoadhesive force. In vitro release and in vivo pharmacokinetic studies of the optimised formulation was performed and compared with the drug solution. P-407 and Tw-80 reduced the gelation time and gelation temperature of FCZ-TSS, but increased the mucoadhesive force and gel strength. Optimised FCZ-TSS was liquid at room temperature which upon increase in temperature converted into gel at approximately 30.16 °C. The gel formation took around 1.23 min and exhibited its easy administration and quick gelation inside the body. FCZ-TSS released the drug over a time period of 24 h, displaying sustained behaviour as compared with the drug solution which take only 4 h for complete release of the drug. Moreover, the higher Cmax and AUC values of FCZ-TSS as compared to FCZ solution showed increased bioavailability of FCZ. Furthermore, in vivo safety study demonstrated safe profile of FCZ-TSS when compared with FCZ solution, after their application to rectal mucosa. These results confirmed that TSS has the potential to improve the bioavailability of FCZ with increased safety.