Ocular Distribution of Papaverine Using Non-aqueous Vehicles.

Papaverine, a poorly soluble opium alkaloid, has recently been shown to reduce retinal inflammation due to which it may have therapeutic application in the management of Leber's hereditary optic neuropathy. In this study, papaverine eyedrops based on medium chain triglycerides were prepared and the effect of diethyl glycol monoethyl ether (DGME) on their ocular distribution was evaluated using an ex vivo porcine eye model. The route of drug penetration was also studied by orienting the eye to expose either only the cornea or the sclera to the formulation. Furthermore, in vivo studies were performed to confirm ocular tolerability and evaluate ocular drug distribution. Our results showed increased papaverine concentrations in the cornea and sclera in the presence of DGME but with a slight reduction in the retina-choroid (RC) drug concentration when administered via the corneal route, suggesting that DGME enhances drug accumulation in the anterior ocular tissues but with little effect on posterior drug delivery. In vivo, the papaverine eyedrop with DGME showed good ocular tolerability with the highest drug concentration being observed in the cornea (1.53 ± 0.28 µg/g of tissue), followed by the conjunctiva (0.74 ± 0.18 µg/g) and sclera (0.25 ± 0.06 µg/g), respectively. However, no drug was detected in the RC, vitreous humor or plasma. Overall, this study highlighted that DGME influences ocular distribution and accumulation of papaverine. Moreover, results suggest that for hydrophobic drugs dissolved in hydrophobic non-aqueous vehicles, transcorneal penetration via the transuveal pathway may be the predominant route for drug penetration to posterior ocular tissues. Graphical abstract.

Brinzolamide-loaded nanoemulsions: ex vivo transcorneal permeation, cell viability and ocular irritation tests.

The aim of this study was to investigate the corneal penetration of brinzolamide (BZ) nanoemulsions (NEs) and evaluate their in vitro and ex vivo irritancy potential. Twelve BZ NEs were prepared by the spontaneous emulsification method and ex vivo permeability studies were conducted using excised bovine corneas fixed onto Franz diffusion cells. To confirm the safety of the formulations for ophthalmic use, preparations were examined for potential ocular irritancy using a cell viability assay on retinal cells, the Hen's Egg Test-Chorio-Allantoic Membrane (HET-CAM) and the bovine corneal opacity-permeability (BCOP) test. Seven BZ NEs exhibited superior penetration across isolated bovine cornea compared to the marketed BZ suspension. The half maximal inhibitory concentration (IC50) values of various surfactants and oils determined using the sulforhodamine B cell viability assay on retinal cells showed that Transcutol P, Cremophor RH40 and Triacetin were the least toxic excipients and may be safely used in the eye at various concentrations. HET-CAM and BCOP tests revealed that NE6B and NE4C did not result in any irritation and were thus considered safe for ocular use. Our finding suggests that optimized NEs can be a safe and effective vehicle for ocular delivery of BZ.

Light-responsive in situ forming injectable implants for effective drug delivery to the posterior segment of the eye.

INTRODUCTION: Frequent intravitreal injections are currently the preferred treatment method for diseases affecting the posterior segment of the eye. However, these repeated injections have been associated with pain, risk of infection, hemorrhages, retinal detachment and high treatment costs. To overcome these limitations, light-responsive in situ forming injectable implants (ISFIs) may emerge as novel systems providing site-specific controlled drug delivery to the retinal tissues with great accuracy, safety, minimal invasiveness and high cost efficiency. AREA COVERED: Complex ocular barriers, routes for drug delivery, types of injectable implants, ocular application of light and benefits of light-responsive systems are discussed with regards to challenges and strategies employed for effective drug delivery to the posterior segment of the eye. In particular, we have highlighted photoresponsive moieties, photopolymerization mechanisms and different development strategies with their limitations as well as recent advancements in the field. EXPERT OPINION: Biodegradable light-responsive ISFIs are promising drug delivery systems that have shown a high degree of biocompatibility with sustained drug release in a number of applications. However, their use in intravitreal drug delivery is still in the very early stages. Issues related to the biocompatibility of the photoinitiator and the elimination of photo-degraded by-products from the ocular tissues need careful consideration, not only from a chemistry standpoint, but also from a biological perspective to improve the suitability of these systems for clinical applications.