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Development of antifungal fibrous ocular insert using freeze-drying technique
Hoda E Teba1, Islam A Khalil1, Rana M Gebreel1
1Department of Pharmaceutics, Faculty of Pharmacy and Drug Manufacturing, Misr University for Science and Technology, 12566, 6th of October, Giza, Egypt.
Abstract:
Candida species is one of the pathogenic fungi of the eye responsible for keratitis that frequently causes vision impairment and blindness. Effective treatment requires long-term use of antifungal drugs, which is opposed by the defensive mechanisms of the eye and inadequate corneal penetration. The objective of this study was to develop a carrier for prolonged ocular application of fluconazole (FLZ) to treat keratitis. FLZ was encapsulated into chitosan fibrous matrices (F1-F4) using different chitosan concentrations (0.02, 0.1, 0.5, and 1%w/v, respectively) by freeze-drying as a single-step technique. Studying the morphology and surface properties of the inserts revealed a porous matrix with fibrous features with a large surface area. Thermal stability and chemical compatibility were confirmed by DSC/TGA/DTA and FT-IR, respectively. Loading capacity (LC) and entrapment efficiency (EE) were determined. According to the in vitro release study, F4 (0.11 mg mg-1 LC and 87.53% EE) was selected as the optimum insert because it had the most sustained release, with 15.85% burst release followed by 75.62% release within 12 h. Ex vivo corneal permeation study revealed a 1.2-fold increase in FLZ permeation from F4 compared to FLZ aqueous solution. Also, in the in vivo pharmacokinetic study in rabbits, F4 increased the AUC0-8 of FLZ by 9.3-fold and its concentration in aqueous humor was maintained above the MIC through the experimentation time. Studies on cytotoxicity (MTT assay) provide evidence for the safety and biocompatibility of F4. Therefore, the freeze-dried FLZ-loaded chitosan fibrous insert could be a promising candidate for treating ocular keratitis.
Insights
This study developed a novel chitosan fibrous insert for sustained delivery of fluconazole (FLZ) to treat fungal keratitis. The optimized insert demonstrated enhanced corneal penetration and prolonged drug release, showing promise for effective ocular infection treatment.
Area of Science:
- Ophthalmology
- Pharmaceutics
- Biomaterials Science
Background:
- Fungal keratitis, often caused by Candida species, leads to significant vision impairment and blindness.
- Current antifungal treatments for ocular infections face challenges due to the eye's defense mechanisms and poor drug penetration.
- Prolonged drug delivery systems are needed to overcome these limitations and improve therapeutic outcomes.
Purpose of the Study:
- To develop and evaluate a chitosan-based fibrous matrix for sustained ocular delivery of fluconazole (FLZ).
- To assess the physicochemical properties, drug release kinetics, and ocular penetration of the developed formulation.
- To investigate the in vivo pharmacokinetics and safety of the fluconazole-loaded chitosan insert.
Main Methods:
- Fluconazole (FLZ) was encapsulated into chitosan fibrous matrices using freeze-drying.
- Formulations were characterized for morphology, thermal stability, chemical compatibility, loading capacity (LC), and entrapment efficiency (EE).
- In vitro drug release, ex vivo corneal permeation, in vivo pharmacokinetics in rabbits, and cytotoxicity assays were performed.
Main Results:
- The optimized F4 formulation exhibited a porous, fibrous structure with high surface area, LC (0.11 mg mg⁻¹), and EE (87.53%).
- F4 showed sustained drug release over 12 hours (75.62% release after 15.85% burst release) and a 1.2-fold increase in corneal permeation.
- In vivo studies demonstrated a 9.3-fold increase in AUC₀₋₈ and sustained therapeutic concentrations of FLZ in rabbit aqueous humor, with no observed cytotoxicity.
Conclusions:
- Freeze-dried fluconazole-loaded chitosan fibrous inserts represent a promising strategy for sustained ocular drug delivery.
- The developed formulation enhances corneal penetration and maintains therapeutic drug levels, offering a potential new treatment for fungal keratitis.
- The safety and biocompatibility of the chitosan insert support its potential clinical application.
