Reduced administration frequency for the treatment of fungal keratitis: a sustained natamycin release from a micellar solution

Abstract

We report the synthesis and preparation of self-assembled poly(ethylene glycol)block-poly(glycidyl methacrylate) (PEG-b-PGMA) micelles harnessing the intrinsically hydrolysable characteristics of PGMA segments for the sustained delivery of a hydrophobic natamycin by topical administration on eye. Hydrolysis of the glycidyl groups could be achieved within physiologically relevant environment, resulting in increased drug release compared to conventional non-hydrolysable counterparts. It was found that the system provides an additional driving force for drug release by generation of hydrophilic hydroxyl groups to "push" the encapsulated hydrophobic drug away from the hydrophobic domains and into the surrounding environments. In vitro and in vivo results revealed that the drug carriers (PEG-b-PGMA micelles) and the encapsulated natamycin were not cytotoxic to human corneal epithelial cells and the released drug have strong antifungal ability to Candida albicans. Importantly, sustained natamycin release from micelles leads to the reduced administration frequency of natamycin from 8 times per day to 3 times per day in fungal keratitis (FK) rabbits. Corneal morphology of keratitis was improved by the release of natamycin from the micelle observed by anterior segment optical coherence tomography (AS-OCT) and histological analysis of the cornea. These results revealed that the use of micelle enhances the loading and delivery efficiency of natamycin and subsequently promotes the drug penetration in aqueous humor and cornea. The present study demonstrates a facile method that can greatly reduce dosing frequency of natamycin administration and thus improve long-term patient compliance.

Alternative Therapeutic Interventions: Antimicrobial Peptides and Small Molecules to Treat Microbial Keratitis

“…Various studies have been reported regarding delivery of drugs using different nanocarriers for treating ocular disorders including keratitis. Micelles are good drug carriers that entrap the drug in the hydrophobic core; whereas, hydrophilic shells form a steric barrier and prevents micelles aggregation ( Guo et al, 2020 ). Jaiswal et al reported the development of micelles to deliver itraconazole for treating fungal keratitis.…”

Emerging role of nanocarriers based topical delivery of anti‐fungal agents in combating growing fungal infections

“…Micelles are not only used to deliver the drug at a constant rate and time but also, are used to reduce the toxicity of the drugs when administered. 45…”

“…Due to the sustained release of the drug continuously for a longer duration of time, the dosing frequency and patient compliance can be improved, along with a 3‐ to 8‐fold increase in its antimicrobial activity. Micelles are not only used to deliver the drug at a constant rate and time but also, are used to reduce the toxicity of the drugs when administered 45 …”

Antifungal polymers for medical applications

“…Natamycin, an antifungal polyene, has been loaded in self‐assembled poly(ethylene glycol)‐ block ‐poly(glycidyl methacrylate) (PEG‐ b ‐PGMA) micelles, the delivery process is more prolonged than the pure natamycin, and thus, it can be used as a controlled delivery system with better pharmacokinetic profile and low cytotoxicity when being tested in corneal epithelial cells. Additionally, the natamycin‐loaded micelles required lower doses for the same activity compared to pure natamycin and a decrease in the dose frequency due to the prolonged release profile (Guo et al, 2020).…”