Development of ion-triggered <i>in situ</i> gel containing ketoconazole/hydroxypropyl-β-cyclodextrin for ocular delivery: <i>in vitro</i> and <i>in vivo</i> 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 <i>in situ</i> gel (ISG) of KET to promote its ocular bioavailability in topical application. The solubility of KET in water was increased by complexation with hydroxypropyl-β-cyclodextrin (HPβCD), then KET-HPβCD inclusion complex (KET-IC) was fabricated into an ion-sensitive ISG triggered by sodium alginate (SA). The <i>in vitro</i> 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 <i>ex vivo</i> rabbit corneal permeation studied demonstrated higher permeability of KET-IC-ISG formulation (<i>P_app</i> of (6.34 <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mrow><mml:mo>±</mml:mo></mml:mrow></mml:math>0.21) <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mrow><mml:mo>×</mml:mo></mml:mrow></mml:math>10^-4cm/h) than pure KET (<i>P_app</i> of (3.09 <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mrow><mml:mo>±</mml:mo></mml:mrow></mml:math> 0.09) <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mrow><mml:mo>×</mml:mo></mml:mrow></mml:math>10^-4cm/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.