Abstract
Purpose :
Moxifloxacin 0.5% (Vigamox®) is indicated for the treatment bacterial keratitis and conjunctivitis, as well as a pre- and post-operative prophylactic. While, topical eye drops are the current preferred delivery route of choice for patients, resolution of ocular infection often requires a high frequency of application to avoid bacterial resistance or permanent visual damage if the infection is not resolved. A single-dose sustained-release injectable that supplies the antibiotic for the course of treatment could drastically improve infection outcomes without eye drops.
Methods :
Hydrophobic ion-pairing with disodium pamoic acid was used to transform moxifloxacin hydrochloride (MOX) into a water-insoluble (MOX-PAM) complex. We then generated moxifloxacin crystals by evaporative crystallization and modulated size via either dry or wet milling. A nanosuspension formulation was generated via wet milling of MOX-PAM. We measured in vitro dissolution rates of MOX nanosuspension, nanocrystals and microcrystals and measured pharmacokinetics of each in rabbits. We tested the antibacterial capacity of each in models of Staphylococcus aureus ocular infection -- a corneal scratch model in rat and an intracameral injection model in both rat and rabbit with comparison to topical moxifloxacin eye drops.
Results :
We found a size-dependent correlation in in vitro dissolution. The microcrystals released the slowest (14 days), while the crystalline nature of the nanocrystals prolonged dissolution from 3 days in the nanosuspension to 5 days. In PK studies in rabbit following a single subconjunctival injection, we found that the nanocrystals were the only able to achieve therapeutic concentrations in relevant sites of ocular infection (aqueous humor, vitreous humor, cornea) at least 5-10 fold above the MIC of moxifloxacin for S. aureus at one week. Efficacy studies compared the nanocrystal formulation to topical and intracameral MOX and showed that the single injectable dose was able to treat infection favorably to 3X daily MOX over 1 week and prevent infection similarly to intracameral MOX.
Conclusions :
A subconjunctival injectable MOX nanocrystal formulation improved infection outcomes with reduced frequency of application. Packaging a treatment's worth of antibiotic into a single dose can signifcantly improve ocular infection outcomes in the clinic.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.