Fast-dissolving ocular films of riboflavin acetate conjugate for treatment of keratoconus in UVA-CXL procedure: ex vivo permeation, hemolytic toxicity and apoptosis detection.

Background: Attempts to facilitate corneal epithelial penetration of riboflavin (Rb) without de-epithelization, so far, include the use of penetration enhancers, to devitalize corneal epithelium in order to disturb tight epithelial interjunctional complexes and zonulae occludentes. Though such approaches result in sufficient epithelial permeability of Rb to guarantee efficacy of CXL procedure, they lack the evidences of safety. Prodrug with improved lipophilicity targeted toward esterases and amidases has proven to be an effective and promising approach to overcome lipophilic corneal epithelial barrier.

Objectives: Fast-dissolving ocular films of newly synthesized and characterized riboflavin lipid conjugate (RbLDC) were developed to overcome corneal epithelial barrier resistance for treatment of keratoconus. The safety concern of the film was assessed by in vitro hemolytic toxicity and in vitro apoptosis detection for its safe clinical use.

Results: The optimized film was tough, flexible and dissolved rapidly within 36.86 s in simulated tear fluid, pH 7.4. FE-SEM/EDX showed smooth surfaces of films and evidenced the quantitative elemental similarity, indicating drug homogeneity. The permeation profile of F18 demonstrated 13.28-fold increased permeation of RbLDC relative to Rb solution across intact cornea. Safety was confirmed by 3.74% hemolysis and 10% apoptosis.

Conclusion: Safe and efficient RbLDC fast-dissolving ocular films capable of overcoming corneal epithelial barrier resistance to avoid surgical intervention of corneal epithelial debridement were developed.