Improved Topical Ophthalmic Natamycin Suspension for the Treatment of Fungal Keratitis.

Purpose: Natamycin (NT) is used as a first-line antifungal prescription in the treatment of fungal keratitis (FK) and is commercially available as a 5% w/v ophthalmic suspension. NT shows poor water solubility and light sensitivity. Thus, the present investigation is aimed to enhance the fraction of NT in solution in the commercial formulation by adding cyclodextrins (CDs), thereby improving the delivery of the drug into deeper ocular tissues. Methods: The solubility of NT in different CDs, the impact of ultraviolet (UV) light exposure, stability at 4°C and 25°C, in vitro release, and ex vivo transcorneal permeation studies were performed. Results: NT exhibited the highest solubility (66-fold) in randomly methylated-ß-cyclodextrin (RM-ßCD) with hydroxypropyl-ßCD (HP-ßCD) showing the next highest solubility (54-fold) increase in comparison to market formulation Natacyn® as control. The stability of NT-CD solutions was monitored for 2 months (last-time point) at both storage conditions. The degradation profile of NT in NT-RM-ßCD and NT-HP-ßCD solutions under UV-light exposure followed first-order kinetics exhibiting half-lives of 1.2 h and 1.4 h, respectively, an almost 3-fold increase over the control solutions. In vitro release/diffusion studies revealed that suspensions containing RM-ßCD and HP-ßCD increased transmembrane flux significantly (3.1-fold) compared to the control group. The transcorneal permeability of NT from NT-RM-ßCD suspension exhibited an 8.5-fold (P < 0.05) improvement compared to Natacyn eyedrops. Furthermore, the addition of RM-ßCD to NT suspension increases the solubilized fraction of NT and enhances transcorneal permeability. Conclusion: Therefore, NT-RM-ßCD formulations could potentially lead to a decreased frequency of administration and significantly improved therapeutic outcomes in FK treatment.

Cannabidiol Loaded Topical Ophthalmic Nanoemulsion Lowers Intraocular Pressure in Normotensive Dutch-Belted Rabbits.

Cannabidiol (CBD) is the major non-psychoactive and most widely studied of the cannabinoid constituents and has great therapeutic potential in a variety of diseases. However, contradictory reports in the literature with respect to CBD's effect on intraocular pressure (IOP) have raised concerns and halted research exploring its use in ocular therapeutics. Therefore, the current investigation aimed to further evaluate CBD's impact on the IOP in the rabbit model. CBD nanoemulsions, containing Carbopol® 940 NF as a mucoadhesive agent (CBD-NEC), were prepared using hot-homogenization followed by probe sonication. The stability of the formulations post-moist-heat sterilization, in terms of physical and chemical characteristics, was studied for three different storage conditions. The effect of the formulation on the intraocular pressure (IOP) profile in normotensive Dutch Belted male rabbits was then examined. The lead CBD-NEC formulation (1% w/v CBD) exhibited a globule size of 259 ± 2.0 nm, 0.27 ± 0.01 PDI, and 23.2 ± 0.4 cP viscosity, and was physically and chemically stable for one month (last time point tested) at 4 °C, 25 °C, and 40 °C. CBD-NEC significantly lowered the IOP in the treated eyes for up to 360 min, with a peak drop in IOP of 4.5 mmHg observed at the 150 min time point, post-topical application. The IOP of the contralateral eye (untreated) was also observed to be lowered significantly, but the effect lasted up to the 180 min time point only. Overall, topically administered CBD, formulated in a mucoadhesive nanoemulsion formulation, reduced the IOP in the animal model studied. The results support further exploration of CBD as a therapeutic option for various inflammation-based ocular diseases.

Design of Topical Ocular Ciprofloxacin Nanoemulsion for the Management of Bacterial Keratitis.

Bacterial keratitis (BK) is a critical ocular infection that can lead to serious visual disability. Ciprofloxacin (CIP), moxifloxacin (MOX), and levofloxacin (LFX) have been accepted as monotherapies by the US Food and Drug Administration for BK treatment. CIP is available commercially at 0.3% w/v concentration as an ophthalmic solution and as an ointment for ocular delivery. Because of solubility issues at physiological pH, CIP precipitation can occur at the corneal surface post instillation of the solution dosage form. Consequently, the ocular bioavailability of CIP is reduced. The ointment dosage form is associated with side effects such as blurred vision, itching, redness, eye discomfort, and eye dryness. This study aimed to design a CIP loaded nanoemulsion (NE; CIP-NE) to facilitate drug penetration into the corneal layers for improved therapeutic outcomes as well as to overcome the drawbacks of the current commercial ophthalmic formulations. CIP-NE formulations were prepared by hot homogenization and ultrasonication, using oleic acid (CIP-O-NE) and Labrafac® Lipophile WL 1349 (CIP-L-NE) as the oily phase, and Tween® 80 and Poloxamer 188 as surfactants. Optimized CIP-NE was further evaluated with respect to in vitro release, ex vivo transcorneal permeation, and moist heat sterilization process, using commercial CIP ophthalmic solution as a control. Optimized CIP-O-NE formulation showed a globule size, polydispersity index, and zeta potential of 121.6 ± 1.5 nm, 0.13 ± 0.01, and -35.1 ± 2.1 mV, respectively, with 100.1 ± 2.0% drug content and was spherical in shape. In vitro release and ex vivo transcorneal permeation studies exhibited sustained release and a 2.1-fold permeation enhancement, respectively, compared with commercial CIP ophthalmic solution. Autoclaved CIP-O-NE formulation was found to be stable for one month (last time-point tested) at refrigerated and room temperature. Therefore, CIP-NE formulation could serve as an effective delivery system for CIP and could improve treatment outcomes in BK.