Development of ion-triggered in situ gel containing ketoconazole/hydroxypropyl-β-cyclodextrin for ocular delivery: in vitro and in vivo evaluation

The application of ketoconazole (KET) in ocular drug delivery is restricted by its poor aqueous solubility though its broad-spectrum antifungal activity. The aim of this study is to develop an ion-sensitive in situ gel (ISG) of KET to promote its ocular bioavailability in topical application. The solubility of KET in water was increased by complexation with hydroxypropyl-beta-cyclodextrin (HP beta CD), then KET-HP beta CD inclusion complex (KET-IC) was fabricated into an ion-sensitive ISG triggered by sodium alginate (SA). The in vitro drug release and antifungal activities investigations demonstrated that the KET-IC-ISG formulation increased drug release and anti-fungal activities compared to pure KET. The ex vivo rabbit corneal permeation studied demonstrated higher permeability of KET-IC-ISG formulation (Papp of (6.34 +/- 0.21) x10-4 cm/h) than pure KET (Papp of (3.09 +/- 0.09) x10-4 cm/h). The cytotoxicity assay and the ocular irritation study in rabbits confirmed the KET-IC-ISG safety and well tolerance. The ocular pharmacokinetics of KET in rabbits was investigated and the results showed that the KET-IC-ISG increased its bioavailability in cornea by 47-fold. In conclusion, the KET-IC-ISG system promoted the precorneal retention, the ocular drug bioavailability and the developed formulation is a potential strategy to treat mycotic keratitis.