Development of antifungal fibrous ocular insert using freeze-drying technique.

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.

Novel cubosome based system for ocular delivery of acetazolamide.

Acetazolamide is the drug of choice for glaucoma treatment in an emergency. However, it is not available in any topical formulation and it is available only as systemic tablets. Despite its efficiency as a drug in decreasing intraocular pressure, it has negative systemic effects as renal toxicity and metabolic acidosis. Moreover, it suffers from poor aqueous solubility and low corneal permeability limiting its ocular bioavailability and its use topically. Cubosomes have enormous advantages as a drug delivery system, most importantly, high surface area, thermal stability, and ability to encapsulate hydrophobic, amhiphilic, and hydrophilic molecules. Herein, we have exploited the unique properties of cubosomes as a novel nano-delivery system for acetazolamide as eye drops dosage form for glaucoma treatment. Different acetazolamide-loaded cubosomes have been developed and evaluated. The best-optimized formulation (F5), was cubic shaped structure, with an average particle size of 359.5 ± 2.8 nm, surface charge -10.8 ± 3.2 mV, and 59.8% entrapment efficiency. Ex-vivo corneal permeation studies have revealed a 4-fold increase in acetazolamide permeability coefficient compared to that stated in the literature. F5 showed superior therapeutic efficacy represented by a 38.22% maximum decrease in intraocular pressure vs. 31.14 and 21.99% decrease for the commercial Azopt® eye drops and Cidamex® tablets, respectively. It also exhibited higher (AUC0-10) compared to Azopt® eye drops and Cidamex® tablets by 2.3 and 3 times, respectively. F5 showed mean residence time 4.22 h vs. 2.36 and 2.62 h for Azopt® and Cidamex® with no eye irritation observed according to the modified Draize test. To the best of our knowledge, this is the first study for developing acetazolamide-loaded cubosomes as the topical delivery system for glaucoma treatment.

Nanodispersion-loaded mucoadhesive polymeric inserts for prolonged treatment of post-operative ocular inflammation.

Mucoadhesive polymeric films incorporated with ketorolac tromethamine-loaded nanodispersion aiming the sustained delivery of the drug to the cornea have been developed and characterised for the treatment of post-operative ocular inflammation. Nanodispersions were prepared by ionic gelation method with various concentrations of chitosan and sodium tripolyphosphate. The developed nanodispersions were analysed for morphology, particle size, dispersion homogeneity, zeta potential, entrapment efficiency and drug release. The nanodispersion that showed the smallest particle size and the highest entrapment efficiency was incorporated in optimised HPMC E15 and Eudragit RL100/HPMC K4m films. The formulation with optimum physicomechanical properties was selected to study its ex vivo transcorneal permeation through freshly excised bovine cornea in comparison with the nanodispersion and the marketed eye drops (Acular®). The polymeric ocular film showed greater permeation than aqueous eye drops. Moreover, the ocular film revealed a prolonged anti-inflammatory effect compared to eye drops when applied to inflamed rabbit's eyes.

Ketoroloac tromethamine loaded nanodispersion incorporated into thermosensitive in situ gel for prolonged ocular delivery.

The present study was designed to improve the ocular availability of ketorolac tromethamine and to prolong its precorneal residence time for the treatment of postoperative ocular inflammation. Ketorolac tromethamine nanodispersions were successfully prepared by nanoprecipitation method using Eudragit(®) RL100. These nanodispersions were characterized in terms of particle size, zeta potential, entrapment efficiency and in vitro release. Consequently, the optimum nanodispersion was incorporated into thermosensitive in situ gel. The optimum gelling capacity was obtained by 20% Pluronic(®) F-127 and 14% Pluronic(®) F-127/1.5% HPMC K4m. The gelling temperature and gelation time of the in situ gels increased by decreasing the concentration of Pluronic(®) F-127. The mucoadhesive strength was significantly improved by the addition of HPMC. Incorporation of ketorolac tromethamine loaded nanodispersions into in situ gel bases sustained the release of ketorolac tromethamine, improved its ocular availability and prolonged its residence time without causing irritation to eye.