Formulating Resveratrol and Melatonin Self-Nanoemulsifying Drug Delivery Systems (SNEDDS) for Ocular Administration Using Design of Experiments

Abstract

Recent studies have demonstrated that Sirtuin-1 (SIRT-1)-activating molecules exert a protective role in degenerative ocular diseases. However, these molecules hardly reach the back of the eye due to poor solubility in aqueous environments and low bioavailability after topical application on the eye’s surface. Such hindrances, combined with stability issues, call for the need for innovative delivery strategies. Within this context, the development of self-nanoemulsifying drug delivery systems (SNEDDS) for SIRT-1 delivery can represent a promising approach. The aim of the work was to design and optimize SNEDDS for the ocular delivery of two natural SIRT-1 agonists, resveratrol (RSV) and melatonin (MEL), with potential implications for treating diabetic retinopathy. Pre-formulation studies were performed by a Design of Experiment (DoE) approach to construct the ternary phase diagram. The optimization phase was carried out using Response Surface Methodology (RSM). Four types of SNEDDS consisting of different surfactants (Tween® 80, Tween® 20, Solutol® HS15, and Cremophor® EL) were optimized to achieve the best physico-chemical parameters for ocular application. Stability tests indicated that SNEDDS produced with Tween® 80 was the formulation that best preserved the stability of molecules, and so it was, therefore, selected for further technological studies. The optimized formulation was prepared with Capryol® PGMC, Tween® 80, and Transcutol® P and loaded with RSV or MEL. The SNEDDS were evaluated for other parameters, such as the mean size (found to be ˂50 nm), size homogeneity (PDI < 0.2), emulsion time (around 40 s), transparency, drug content (>90%), mucoadhesion strength, in vitro drug release, pH and osmolarity, stability to dilution, and cloud point. Finally, an in vitro evaluation was performed on a rabbit corneal epithelial cell line (SIRC) to assess their cytocompatibility. The overall results suggest that SNEDDS can be used as promising nanocarriers for the ocular drug delivery of RSV and MEL.

The Therapeutic Trip of Melatonin Eye Drops: From the Ocular Surface to the Retina

“…The optimized formulation, comprising Capryol ® PGMC, Tween ® 80, and Transcutol ® P, loaded with RSV or melatonin, exhibited favorable physico-chemical parameters, including small size, homogeneity, quick emulsion time, transparency, high drug content, mucoadhesion strength, sustained drug release, and cytocompatibility with rabbit corneal epithelial cells. These findings suggest the potential of SNEDDS as effective nanocarriers for ocular drug delivery, addressing challenges associated with stability and bioavailability [ 46 ].…”

Nutraceuticals for Diabetic Retinopathy: Recent Advances and Novel Delivery Systems

“…With droplet sizes smaller than 200 nm, self-nanoemulsifying drug delivery systems (SNEDDSs) are superior for their good absorption rate and dispersion in the tissue [ 181 ]. Zingale et al developed an SNEDDS loaded with resveratrol (RSV-SNEDDS) and tested its biocompatibility in a rabbit corneal epithelial cell line (SIRC) [ 182 ]. The RSV-SNEDDS displayed improved solubility, stability, and bioavailability, suggesting that SNEDDSs can be used as promising nanocarriers for drugs to deliver toward the posterior ocular segment [ 182 ].…”

Development of a Resveratrol Nanoformulation for the Treatment of Diabetic Retinopathy

“…RSV consists of two phenolic rings linked by an ethylene bridge that can exist in both trans and cis forms, as shown in Figure 1, but it is known that the trans form is more stable and bioactive than the cis form [10,11]. However, its low solubility and bioavailability in target tissues are limited, so current studies have developed formulations to overcome these limitations and provide adequate therapeutic amounts of RSV at the site of action [12][13][14][15]. Carboxymethylcellulose (CMC) is a water-soluble anionic polymer composed of linear molecular chains obtained from the union between cellulose and monochloroacetic acid [16].…”