Improving corneal permeability of dexamethasone using penetration enhancing agents: First step towards achieving topical drug delivery to the retina.

With an ever-increasing burden of vision loss caused by diseases of the posterior ocular segment, there is an unmet clinical need for non-invasive treatment strategies. Topical drug application using eye drops suffers from low to negligible bioavailability to the posterior segment as a result of static and dynamic defensive ocular barriers to penetration, while invasive delivery systems are expensive to administer and suffer potentially severe complications. As the cornea is the main anatomical barrier to uptake of topically applied drugs from the ocular surface, we present an approach to increase corneal permeability of a corticosteroid, dexamethasone sodium-phosphate (DSP), using a novel penetration enhancing agent (PEA). We synthesised a novel polyacetylene (pAc) polymer and compared its activity to two previously described cell penetrating peptide (CPP) based PEAs, TAT and penetratin, with respect to increasing transcorneal permeability of DSP in a rapid ex-vivo porcine corneal assay over 60 min. The transcorneal apparent permeability coefficients (Papp) for diffusion of pAc, and fluorescein isothiocyanate (FITC) conjugated TAT and penetratin were up to 5 times higher (p < 0.001), when compared to controls. When pAc was used in formulation with DSP, an almost 5-fold significant increase was observed in Papp of DSP across the cornea (p = 0.0130), a significant 6-fold increase with TAT (p = 0.0377), and almost 7-fold mean increase with penetratin (p = 0.9540). Furthermore, we investigated whether the PEAs caused any irreversible damage to the barrier integrity of the corneal epithelium by measuring transepithelial electrical resistance (TEER) and immunostaining of tight junction proteins using zonula occludens-1 (ZO-1) and occludin antibodies. There was no damage or structural toxicity, and the barrier integrity was preserved after PEA application. Finally, an in-vitro cytotoxicity assessment of all PEAs in human retinal pigment epithelium cells (ARPE-19) demonstrated that all PEAs were very well-tolerated, with IC50 values of 64.79 mM for pAc and 1335.45 µM and 87.26 µM for TAT and penetratin, respectively. Our results suggest that this drug delivery technology could potentially be used to achieve a significantly higher intraocular therapeutic bioavailability after topical eye drop administration, than currently afforded.

Penetration Enhancers for Topical Drug Delivery to the Ocular Posterior Segment-A Systematic Review.

There is an unmet clinical need for eye drop formulations to efficiently treat the diseases of the posterior ocular segment by non-invasive topical administration. Here, we systematically reviewed the literature on ocular penetration enhancers and their ability to transfer drugs to the posterior segment of the eye in experimental studies. Our aim was to assess which penetration enhancer is the most efficient at delivering drugs to the posterior segment of the eye, when topically applied. We conducted a comprehensive search in three electronic databases (Ovid Embase, Ovid MEDLINE, and PubMed) to identify all the relevant manuscripts reported on ocular penetration enhancers based on the PRISMA guidelines. We identified 6540 records from our primary database search and filtered them per our inclusion/exclusion criteria to select a final list of 14 articles for qualitative synthesis. Of these, 11 studies used cell penetrating peptides (CPPs), 2 used chitosan, and 1 used benzalkonium chloride (BAC) as the penetration enhancer. Cationic and amphipathic CPPs, transactivator of transcription (TAT), and penetratin can be inferred to be the best among all the identified penetration enhancers for drug delivery to the fundus oculi via topical eye drop instillation. Further high-quality experimental studies are required to ascertain their quantitative efficacy.