QbD-guided development of stearylamine-coated TPGS nanomicelles for enhanced ocular delivery of rosmarinic acid in fungal keratitis

Fungal keratitis is a vision-threatening corneal infection for which topical therapy is often limited by poor corneal penetration and rapid precorneal drug elimination. This study aimed to develop and optimize stearylamine-coated TPGS nanomicelles (SRATM) for ocular delivery of rosmarinic acid (RA) using a Quality by Design (QbD) approach. A face-centered central composite design was employed for formulation optimization. The optimized SRATM exhibited a particle size of 19.7 ± 2.21 nm, a zeta potential of + 18.2 ± 3.2 mV, and an entrapment efficiency of 97.16 ± 2.6%. The formulations exhibited physicochemical characteristics suitable for topical ocular administration, sustained drug release, and increased mucoadhesive interaction. Ex vivo corneal permeation studies demonstrated significantly enhanced RA permeation from SRATM compared with RA suspension and uncoated RA-loaded TPGS nanomicelles (RATM). The nanomicellar formulations also exhibited enhanced antifungal activity against Candida albicans , with SRATM showing the lowest minimum inhibitory concentration and the highest zone of inhibition among the RA-containing formulations. HET-CAM and histopathological evaluations indicated good ocular tolerability under the experimental conditions. In vivo pharmacodynamic evaluation in a rat model of C. albicans -induced fungal keratitis demonstrated greater improvement in clinical signs with SRATM compared with RA suspension and RATM. These findings support the potential of stearylamine-coated TPGS nanomicelles as an ocular delivery platform for RA and warrant further investigation for fungal keratitis.