PURPOSE: Fluconazole is a bis-triazole antifungal agent with a low molecular weight (306 Da). It is hydrophilic in nature and has low protein binding. It is available as eye drops for the treatment of ocular mycoses, the second most common cause of blindness in developing countries. However, its administration often results in poor patient compliance and limited use due to its short half-life (15-30 min) and a low log P (0.25). Therefore, fluconazole was incorporated into a novel sorbitan (spans) based elastic (spanlastic) vesicular system with intent to achieve a prolonged and better effect. Spanlastics are to niosomes what Transfersomes(®) are to liposomes. METHODS: Developed spanlastics consisted of spans and an edge activator prepared by the ether injection method. Developed vesicles were characterized for size, shape, and the number of vesicles/ml by optical microscopy. Entrapment efficiency was determined by the dialysis method, and the ex vivo corneal permeability study was performed using porcine cornea. A 3-tier safety of the novel formulation was established by the Ames test, the 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay, and in rabbits according to the OECD guidelines 404 and 405. RESULTS: Spanlastics were smaller in size (3 times) and showed a better permeation in comparison to a corresponding niosomal formulation. The system showed an increase (3-fold) in the apparent permeability coefficient compared to the marketed formulation Zocon(®) (0.3% w/v solution of fluconazole) due to its elastic nature. The developed system was found to be stable for 2 months under refrigerated conditions and under extreme storage conditions. Safety was established in terms of genotoxicity (Ames test), cytotoxicity (MTT assay; mouse peritoneal macrophages), acute dermal/eye irritation/corrosion, and chronic eye irritation/corrosion tests (OECD guidelines). CONCLUSION: The developed system is novel and provides an effective and safe formulation of fluconazole.
PURPOSE:Fluconazole is a bis-triazole antifungal agent with a low molecular weight (306 Da). It is hydrophilic in nature and has low protein binding. It is available as eye drops for the treatment of ocular mycoses, the second most common cause of blindness in developing countries. However, its administration often results in poor patient compliance and limited use due to its short half-life (15-30 min) and a low log P (0.25). Therefore, fluconazole was incorporated into a novel sorbitan (spans) based elastic (spanlastic) vesicular system with intent to achieve a prolonged and better effect. Spanlastics are to niosomes what Transfersomes(®) are to liposomes. METHODS: Developed spanlastics consisted of spans and an edge activator prepared by the ether injection method. Developed vesicles were characterized for size, shape, and the number of vesicles/ml by optical microscopy. Entrapment efficiency was determined by the dialysis method, and the ex vivo corneal permeability study was performed using porcine cornea. A 3-tier safety of the novel formulation was established by the Ames test, the 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay, and in rabbits according to the OECD guidelines 404 and 405. RESULTS: Spanlastics were smaller in size (3 times) and showed a better permeation in comparison to a corresponding niosomal formulation. The system showed an increase (3-fold) in the apparent permeability coefficient compared to the marketed formulation Zocon(®) (0.3% w/v solution of fluconazole) due to its elastic nature. The developed system was found to be stable for 2 months under refrigerated conditions and under extreme storage conditions. Safety was established in terms of genotoxicity (Ames test), cytotoxicity (MTT assay; mouse peritoneal macrophages), acute dermal/eye irritation/corrosion, and chronic eye irritation/corrosion tests (OECD guidelines). CONCLUSION: The developed system is novel and provides an effective and safe formulation of fluconazole.
Authors: Nabil A Alhakamy; Shaimaa M Badr-Eldin; Hibah M Aldawsari; Anas Alfarsi; Thikryat Neamatallah; Solomon Z Okbazghi; Usama A Fahmy; Osama A A Ahmad; Basma G Eid; Wael Ali Mahdi; Adel F Alghaith; Sultan Alshehri; Shadab Md Journal: AAPS PharmSciTech Date: 2021-06-14 Impact factor: 3.246