Combination of Nanomicellar Technology and In Situ Gelling Polymer as Ocular Drug Delivery System (ODDS) for Cyclosporine-A

A combination of in situ gelling systems and a loaded drug self-assembling nanomicellar carrier was chosen in this study as a new potential Ocular Drug Delivery System (ODDS) for Cyclosporine-A (CyA), a poorly water-soluble drug. Two non-ionic surfactants (d-α-tocopherol polyethylene glycol succinate, VitE-TPGS and polyoxyl 40 hydrogenated castor oil, RH-40) were used to produce the nanomicelles. The physical–chemical characterization of the nanomicelles in terms of CyA entrapment (EE%) and loading efficiency (LE%), cloud point (CP), regeneration time (RT), size and polydispersity index (PI) allowed us to select the best combination of surfactant mixture, which showed appropriate stability, high CyA-EE (99.07%), very small and homogeneous dimensions and favored the solubilization of an amount of CyA (0.144% w/w) comparable to that contained in marketed emulsion Ikervis^®. The selected nanomicellar formulation incorporated into optimized ion-sensitive polymeric dispersions of gellan gum (GG-LA: 0.10, 0.15 and 0.20% w/w) able to trigger the sol–gel transition after instillation was characterized from technological (osmolality, pH, gelling capacity, rheological behavior, wettability, TEM and storage stability at 4 and 20 °C) and biopharmaceutical points of view. This new combined approach allowed us to obtain clear aqueous dispersions that were easy to instill and able to form a viscous gel when in contact with the tear fluid, improving CyA ocular bioavailability. Furthermore, this new ODDS prevented CyA transcorneal permeation, exhibited low cytotoxicity and prolonged the CyA resident time in the precorneal area compared to Ikervis^®.

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or continue reading here: Terreni, E.; Zucchetti, E.; Tampucci, S.; Burgalassi, S.; Monti, D.; Chetoni, P. Combination of Nanomicellar Technology and In Situ Gelling Polymer as Ocular Drug Delivery System (ODDS) for Cyclosporine-A. Pharmaceutics 2021, 13, 192. https://doi.org/10.3390/pharmaceutics13020192

Conclusions
The present data demonstrate the potential of VitE-TPGS/RH-40 polymeric micelles in ocular drug delivery for their ability to improve CyA solubility and to enhance its residence time in tear fluid, above all when instilled as an in situ gelling system. VitE-TPGS is a widely used commercial adjuvant in drug delivery; as a potent P-gp inhibitor, it has been used by several authors both to promote the interaction with the ocular structures allowing the drug transport through the corneal epithelium and to maintain a high drug concentration at the ocular level. Several diseases of the surface of the eye, such as dry eye disease, could take advantage of the presence of a high drug concentration in the epithelium. Surfactant nanomicelles, in addition to technological advantages such as optimal size for ocular application and high capacity of drug encapsulation, can be strengthened in their effectiveness by associating them with in situ gelling systems. In particular, starting from the knowledge of the great impact of gelation phenomena on ocular bioavailability, we optimized the formulations both from qualitative and quantitative points of view, selecting the concentration of GG-LA and the percentage of mono- and divalent ions able to promote the gelation of the instilled eye drops. These new formulations, while providing the same ease of instillation as conventional eye drops, appear to be a valid alternative in ophthalmic therapy due to their ability to enhance drug residence time in the precorneal area, representing a useful innovative ODDS for the treatment of several affections of the anterior segment of the eye.

Materials and Methods
The following materials were used as received: Cyclosporine A; D-α-Tocopherol polyethylene glycol succinate (VitE-TPGS, Kolliphor®TPGS) and Polyoxyl 40 Hydrogenated Castor Oil (RH-40, Kolliphor®RH-40), Gellan Gum (GG-LA, Kelcogel CG-LA)