High-safety tacrolimus nanoemulsion for dry eye disease treatment through anti-oxidant and anti-inflammatory effects

Dry eye disease (DED) is a prevalent ocular surface disorder. Left untreated, the symptoms of DED will deteriorate as a consequence of excessive inflammation and oxidative stress. Currently, only one commercial production (the ophthalmic solution containing tacrolimus) is available for the DED treatment. However, this formulation contains benzalkonium chloride (BAC), a preservative known to induce ocular irritation, and lacks components with antioxidant properties to counteract oxidative stress. To address these issues, a preservative-free nanoemulsion (FK@NE) encapsulating tacrolimus and vitamin E (VE) has been developed. The mean diameter of FK@NE was determined to be 175.7 ± 2.5 nm, accompanied by a zeta potential of -11.03 ± 0.42 mV. In this formulation, VE serves not only as the core lipid but also as an antioxidant agent. The dual functionality aims to synergistically enhance the therapeutic efficacy of FK@NE by leveraging its anti-inflammatory and antioxidant properties. Compared with the commercial production, FK@NE demonstrates superior anti-inflammatory, antioxidant, anti-apoptotic and anti-angiogenic capabilities, and can effectively promote corneal repair and the recovery of conjunctival goblet cell function. Furthermore, FK@NE shows exceptional retention on the ocular surface. Notably, FK@NE is characterized by high safety, excellent stability, and scalability for large-scale production. The Annexin V-FITC/PI assay results indicated that treatment with FK@NE significantly enhanced the viability rate of human corneal epithelial cells (HCECs) to twice that of the Talymus group (commercial tacrolimus ophthalmic solution), and concurrently decreased the apoptosis rate to one-third of that observed in the Talymus group. The stability of FK@NE was maintained for at least 150 days. These findings underscore the promising clinical potential of FK@NE for the treatment of DED.