title: Promising ion-sensitive in situ ocular nanoemulsion gels of terbinafine hydrochloride: design, in vitro characterization and in vivo estimation of the ocular irritation and drug pharmacokinetics in the aqueous humor of rabbits.
abstract: Terbinafine hydrochloride (T-HCl) is recommended for the management of fungal keratitis. To maintain effective aqueous humor concentrations, frequent instillation of T-HCl drops is necessary. This work aimed to develop alternative controlled-release in situ ocular drug-loaded nanoemulsion (NE) gels. Twelve pseudoternary-phase diagrams were constructed using oils (isopropyl myristate/Miglyol 812), surfactants (Tween 80/Cremophor EL), a co-surfactant (polyethylene glycol 400) and water. Eight drug-loaded (0.5%, w/v) NEs were evaluated for thermodynamic stability, morphology, droplet size and drug release in simulated tear fluid (pH 7.4). Following dispersion in gellan gum solution (0.2%, w/w), the in situ NE gels were characterized for transparency, rheological behavior, mucoadhesive force, drug release and histopathological assessment of ocular irritation. Drug pharmacokinetics of sterilized F31 [Miglyol 812, Cremophor EL: polyethylene glycol 400 (1:2) and water (5, 55 and 40%, w/w, respectively)] in situ NE gel and oily drug solution were evaluated in rabbit aqueous humor. The NEs were thermodynamically stable and have spherical droplets (<30 nm). The gels were transparent, pseudoplastic, mucoadhesive and showed more retarded zero-order drug release rates. F31 in situ NE gel showed the least ocular irritation potential and significantly (P<0.01) higher C(max), delayed T(max), prolonged mean residence time and increased bioavailability.
authors: Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Cairo University, Cairo, Egypt.
authors: Saadia Ahmed
authors: SA
authors: Tayel
authors: Mohamed Ahmed
authors: MA
authors: El-Nabarawi
authors: Mina Ibrahim
authors: MI
authors: Tadros
authors: Wessam Hamdy
authors: WH
authors: Abd-Elsalam
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000737:chemistry / Q000493:pharmacokinetics; D001082:Aqueous Humor / Q000187:drug effects / Q000378:metabolism*; D001682:Biological Availability; D002851:Chromatography, High Pressure Liquid; D003315:Cornea / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D003692:Delayed-Action Preparations; D004305:Dose-Response Relationship, Drug; D004337:Drug Carriers / Q000737:chemistry*; D004339:Drug Compounding; D015195:Drug Design; D004355:Drug Stability; D004655:Emulsions; D005782:Gels; D007509:Irritants / Q000008:administration & dosage* / Q000009:adverse effects / Q000737:chemistry / Q000493:pharmacokinetics; D008297:Male; D046529:Microscopy, Electron, Transmission; D053758:Nanoparticles / Q000737:chemistry*; D009281:Naphthalenes / Q000008:administration & dosage* / Q000009:adverse effects / Q000737:chemistry / Q000493:pharmacokinetics; D010316:Particle Size; D011817:Rabbits; D012212:Rheology; D012995:Solubility; D013499:Surface Properties; D000077291:Terbinafine
chemical_list: D000935:Antifungal Agents; D003692:Delayed-Action Preparations; D004337:Drug Carriers; D004655:Emulsions; D005782:Gels; D007509:Irritants; D009281:Naphthalenes; D000077291:Terbinafine