Heating-driven self-assembled glycyrrhizin nanomicelles loading bisdemethoxycurcumin: Preparation, characterization, and efficacy evaluation on experimental dry eye.

In this study, a simple but novel preparation method was developed by heating a mixture of dipotassium glycyrrhizinate (DG) and bisdemethoxycurcumin (BDMC) in aqueous solution, and a DG self-assembled nanomicelles-loading BDMC (named B@DNM) ophthalmic solution was successfully fabricated with this heating-driven process. AutoDock simulation analysis revealed that Pi-Alkyl hydrophobic interactions between BDMC and DG played important role in this self-assembled B@DNM. The optimized B@DNM, with a DG:BDMC mass ratio of 40:1 and heating time of 6 h, had a high encapsulation efficacy of 96.70 ± 0.13 % and particle sizes of 117.50 ± 6.07 nm. The apparent solubility of BDMC in B@DNM was significantly improved from bare BDMC (10.40 ± 0.16 µg/ml to 1405.60 ± 6.78 µg/ml) in artificial tears after 4 h incubation. B@DNM had great storage stability as an aqueous ophthalmic solution. B@DNM showed significantly improved in vitro antioxidant activity. Ex vivo hen's egg test-chorioallantoic membrane assay and long-term in vivo mouse eye tolerance evaluation showed that B@DNM had good ocular safety profiles. B@DNM showed improved in vivo corneal permeation profiles in the mouse eyes. Topical administration of B@DNM achieved a significantly improved efficacy on a mouse model of dry eye disease (DED), including accelerating corneal wound healing, restoring corneal sensitivity, and inhibiting corneal neovascularization. Regulation of the high mobility group box 1 signal pathway was involved in B@DNM's strong therapeutic effects. These findings demonstrate that heating is a simple method to prepare ocular nanoformulation with DG, and B@DNM might be a potential ocular drug for treating DED.

Ocular topical application of alpha-glucosyl hesperidin as an active pharmaceutical excipient: in vitro and in vivo experimental evaluation.

Alpha-glucosyl hesperidin (GH) is an aqueous soluble, amphipathic hesperidin derivative with several pharmacological effects, and it is postulated in this manuscript that GH could potentially be utilized as an active pharmaceutical excipient in eyedrops. The ocular safety of GH was evaluated according to in vitro cytotoxicity and in vivo ocular tolerance. The in vivo corneal permeation of coumarin-6 (Cou-6) with or without GH was characterized, and the in vivo inducing corneal wound healing using bisdemethoxycurcumin (BDMC) with or without GH was also evaluated to determine whether GH is an active pharmaceutical excipient in eyedrops. The results demonstrated that as high as 30 mg/ml of GH exhibits high-level in vitro and in vivo safety profiles according to four in vitro and in vivo evaluations. GH improved the corneal permeation of Cou-6 in mice, as well as demonstrated in vitro antioxidant activity. Concerning in vivo activity, a BDMC-GH suspension was shown to be synergistic in promoting corneal wound healing in mice, as well as restoring corneal sensitivity, promoting corneal epithelial wound healing, and restoring the corneal tissue structure without inflammatory cell infiltration. Overall, GH could be a novel and promising active excipient in eyedrops.

Multienzyme-Like Nanozyme Encapsulated Ocular Microneedles for Keratitis Treatment.

Keratitis, an inflammation of the cornea caused by bacterial or fungal infections, is one of the leading causes of severe visual disability and blindness. Keratitis treatment requires both the prevention of infection and the reduction of inflammation. However, owing to their limited therapeutic functions, in addition to the ocular barrier, existing conventional medications are characterized by poor efficacy and low bioavailability, requiring high dosages or frequent topical treatment, which represents a burden on patients and increases the risk of side effects. In this study, manganese oxide nanocluster-decorated graphdiyne nanosheets (MnOx/GDY) are developed as multienzyme-like nanozymes for the treatment of infectious keratitis and loaded into hyaluronic acid and polymethyl methacrylate-based ocular microneedles (MGMN). MGMN not only exhibits antimicrobial and anti-inflammatory effects owing to its multienzyme-like activities, including oxidase, peroxidase, catalase, and superoxide dismutase mimics but also crosses the ocular barrier and shows increased bioavailability via the microneedle system. Moreover, MGMN is demonstrated to eliminate pathogens, prevent biofilm formation, reduce inflammation, alleviate ocular hypoxia, and promote the repair of corneal epithelial damage in in vitro, ex vivo, and in vivo experiments, thus providing a better therapeutic effect than commercial ophthalmic voriconazole, with no obvious microbial resistance or cytotoxicity.