Purpose
Corneal ulcers, an ocular emergency and a leading cause of blindness globally, require compounded off-label topical antibiotics and/or approved fluoroquinolones at a very inconvenient hourly round-the-clock multiple day administration to prevent corneal vision loss. Jade Therapeutics is developing a topical hydrogel/hyaluronic acid (HA) biodegradable film to deliver MX in sustained-released (SR) formulation to overcome the hourly dosing challenges. Jade assessed the in vitro feasibility of this novel ocular film product, which is based on a thiolated hyaluronic acid (HA) hydrogel to deliver MX directly and locally in a continuous fashion to the ocular surface over an extended period. Prototype films of cross-linked HA containing MX were produced, sterilized, and evaluated for in vitro MX release and efficacy.
Methods
Films were fabricated using thiolated HA and poly(ethyleneglycol) diacrylate (PEGDA), as a cross-linker. The polymerized gel was dried at 37 °C overnight to create thin films. Swelling was assessed by determining film diameter and mass. For drug-loading of the film, 30 μg and 100 μg of MX were formulated into the liquid polymer solution prior to cross-linking. MX release rate was monitored in phosphate buffered saline (PBS) by measuring the UV absorption at 293 nm. Released drug amounts were calculated from the MX standard solution. MX-loaded films were sterilized under ethylene oxide (EO) gas. The efficacy of MX after the sterilization was tested against S. aureus and P. aeruginosa by Zone of Inhibition (ZOI) assays.
Results
The 6 mm diameter films, created with a hole punch, increased to 9 mm in PBS within 30 min. The mass increased as much as 600% after 10 h. MX was continuously released through Day 3, and the accumulated released drug at Day 3 was 54%. Varying the cross-linking and/or thiolation ratios did not alter the release days. The MX release profiles and the efficacy of MX remained unchanged after EO sterilization. The MX loaded films remained efficacious against both organisms through Day 3.
Conclusions
MX containing HA films yielded reproducible sustained delivery of efficacious levels of drug in vitro for 3 days. This film can ultimately lead to a commercially viable product to meet the medical needs of a single-application antibiotic to the eye. Furthermore, this system can be expanded to deliver other antimicrobials to treat other indications such as ophthalmic fungal or viral infections.
Keywords: 422 antibiotics/antifungals/antiparasitics •
482 cornea: epithelium •
479 cornea: clinical science