Natamycin Cyclodextrin Supramolecular Complex Loaded Dissolvable Lenses for the Effective Management of Fungal Keratitis

Purpose: The only commercially available topical treatment for Fungal Keratitis (FK) that has been approved by the United States Food and Drug Administration (US FDA) is the 5% w/v suspension of Natamycin (Nat). Its very poor water solubility (~ 30–50 mg/L), which limits its absorption and therapeutic efficacy, is the main disadvantage that limits its clinical use. A lengthy dose schedule, low ocular retention, and a < 5% ocular bioavailability are the main disadvantages of topical ocular administration therapy. Methods: The present study aimed to increase the aqueous solubility of natamycin and furthermore, increase its retention at the ocular surface by incorporating it into a dissolvable lens. Novel ophthalmic formulations were formulated with Natamycin-Sulfobutylether-β-cyclodextrin (Nat/SBE-β-CD) binary complex and ternary complexes with Polyvinyl alcohol or Poloxamer 407 (Nat/SBE-β-CD/PVA and Nat/SBE-β-CD/P407, respectively). In silico molecular modelling and wet lab experiments were performed to confirm the stability and complex formation. Furthermore, the complexes were incorporated into marketed and dissolvable contact lenses (CLs) and evaluated for in vitro antifungal studies and in vivo drug distribution to investigate their therapeutic efficacy and increased precorneal retention and permeation. Results: The binary complex improved the Nat solubility up to ~ 80 fold, whereas the ternary complexes enhanced the drug solubility by ~ 107 fold and ~ 98 fold as compared to the pure drug. Cytocompatibility studies confirmed the safety and non-irritancy of the optimized formulations. The dissolvable CLs demonstrated greater drug loading, higher ex vivo transcorneal permeation, and antifungal efficacy than the soaked marketed CLs, which showed a sustained in vitro drug release. The binary dissolvable CLs showed higher in vivo corneal drug concentrations than the other CLs. Conclusion: This study demonstrates the potential of CL-loaded inclusion complexes as alternatives to the currently approved suspension therapy for treating FK.