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Ocular drug delivery systems suffer from rapid drainage, intractable corneal permeation and short dosing intervals. Transcorneal drug permeation could increase the drug availability and efficiency in the aqueous humor. The aim of this study was to develop and optimize nanostructured formulations to provide accurate doses, long contact time and enhanced drug permeation. Nanovesicles were designed based on Box–Behnken model and prepared using the thin film hydration technique. The formed nanodispersions were evaluated by measuring the particle size, polydispersity index, zeta potential, entrapment efficiency and gelation temperature. The obtained desirability values were utilized to develop an optimized nanostructured in situ gel and insert. The optimized formulations were imaged by transmission and scanning electron microscopes. In addition, rheological characters, in vitro drug diffusion, ex vivo and in vivo permeation and safety of the optimized formulation were investigated. The optimized insert formulation was found to have a relatively lower viscosity, higher diffusion, ex vivo and in vivo permeation, when compared to the optimized in situ gel. So, the lyophilized nanostructured insert could be considered as a promising carrier and transporter for drugs across the cornea with high biocompatibility and effectiveness.

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The purpose of this manuscript was to develop and optimize Fenticonazole Nitrate (FTN)-loaded novasomes aiming to enhance drug corneal penetration and to improve its antifungal activity. Ethanol injection was used to formulate FTN-loaded novasomes adopting a central composite design. The researched factors were: stearic acid concentration (g%) (A), span 80: drug ratio (B) and cholesterol amount (mg) (C), and their effects on percent entrapment efficiency (EE%), particle size (PS), poly-dispersity index (PDI), zeta potential (ZP), and in vitro drug release after 8 hours (Q8h) were studied. Numerical optimization by Design-Expert® software was employed to select the optimum formula in respect to highest EE%, ZP (as absolute value), and Q8h >80% and lowest PS and PDI. Additional evaluation of the optimum formula was accomplished by short term stability study, effect of gamma sterilization, determination of Minimal Inhibitory Concentration and ex vivo corneal permeation study. The in vivo evaluation of the optimum formula was done to ensure its safety via in vivo ocular irritancy and in vivo corneal tolerance studies. Also, the efficacy was confirmed through in vivo corneal uptake study and susceptibility test. The optimum formula with the highest desirability value (0.738) showed EE% (94.31%), PS (197.05 nm), ZP (-66.95 mV) and Q8h (85.33%). It revealed to be safe, with augmented corneal permeation (527.98 µg/cm 2 ) that leads to higher antifungal activity. The above results confirmed the validity of novasomes to improve the corneal permeation and antifungal activity of Fenticonazole Nitrate.

The human eye is a sophisticated organ with distinctive anatomy and physiology that hinders the passage of drugs into targeted ophthalmic sites. Effective topical administration is an interest of scientists for many decades. Their difficult mission is to prolong drug residence time and guarantee an appropriate ocular permeation. Several ocular obstacles oppose effective drug delivery such as precorneal, corneal, and blood-corneal barriers. Routes for ocular delivery include topical, intravitreal, intraocular, juxtascleral, subconjunctival, intracameral, and retrobulbar. More than 95% of marketed products exists in liquid state. However, other products could be in semi-solid (ointments and gels), solid state (powder, insert and lens), or mixed (in situ gel). Nowadays, attractiveness to nanotechnology-based carries is resulted from their capabilities to entrap both hydrophilic and lipophilic drugs, enhance ocular permeability, sustain residence time, improve drug stability, and augment bioavailability. Different in vitro, ex vivo, and in vivo characterization approaches help to predict the outcomes of the constructed nanocarriers. This review aims to clarify anatomy of the eye, various ocular diseases, and obstacles to ocular delivery. Moreover, it studies the advantages and drawbacks of different ocular routes of administration and dosage forms. This review also discusses different nanostructured platforms and their characterization approaches. Strategies to enhance ocular bioavailability are also explained. Finally, recent advances in ocular delivery are described. Graphical Abstract

The aim of this work is to survey the potential of cubogel as an ocular dosage form to boost the corneal permeability of Dorzolamide Hydrochloride DZ; an antiglaucomal drug. DZ-loaded cubosomal dispersions were prepared according to Box-Behnken design, where the effect of independent variables; Monoolein MO concentration (2.5, 5 and 7.5%w/w), Pluronic V R F127 concentration (0.25, 0.5 and 0.75%w/w) and magnetic stirrer speed of (400, 800 and 1200 rpm) was studied on PS (nm), Zp (ÀmV) and Q 2 h (%) respectively. The prepared formulae were characterized via drug content DC (%), particle size PS (nm), polydispersity index PDI, zeta potential Zp (ÀmV), in-vitro drug release (Q 2 h%) and finally TEM. The optimized formulation composed of: 6.13% w/w of MO, 0.75% w/w of F127 and prepared at 1200 rpm stirring speed was chosen based on the criteria of minimum PS (nm), maximum Zp (ÀmV) and minimum Q 2 h (%). Results revealed that the optimum formula showed PS of 153.3 ± 8.4 n, Zp of 32 ± 3 ÀmV and 37.78 ± 1.3% released after 2 h. Carbopol 934 (1% w/v) as gelling agent was used to prepare the optimum cubogel, which was further evaluated by DSC, ex-vivo permeation and stability studies at 4 C for three months. Moreover, in vivo studies of the optimized cubogel include; draize test, histological examination, confocal laser scanning microscopy (CLSM) and intraocular pressure (IOP) measurement. Results revealed that the optimized cubogel was considerably safe, stable and competent to corneal delivery as assured by draize and histological examination. CLSM showed a deeper penetration of more than 2.5-fold. A higher bioavailability (288.24 mg. h/ml) was attained from cubogel compared to the market product Trusopt V R eye drops (115.40 mg. h/ml) following IOP measurement. Therefore, DZ-loaded cubogel could be considered as promising delivery system to boost the transcorneal permeation hence corneal bioavailability of DZ as antiglaucomal drug.

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