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

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 Cmax, delayed Tmax, prolonged mean residence time and increased bioavailability.

(1) Pseudoternary phase diagram; (2) drug-loaded NE; (3) gellan gum solution; (4) drug-loaded in situ NE gel; (5) gamma sterilization; (6) histopathological assessment of rabbit's ocular tissues; cornea and (7) aqueous humor concentration–time profiles of T-HCl following ocular instillation of F31 in situ NE gel and the oily drug solution in rabbits (mean ± SD, n = 5).Figure optionsDownload high-quality image (132 K)Download as PowerPoint slide