Friday, October 18, 2024
10/18/2024
Microbial keratitis (MK) is a serious ophthalmic infection that can cause visual impairment and even blindness. The MK infection is commonly treated by the fourth-generation fluoroquinolones such as moxifloxacin or combination therapy including tobramycin and vancomycin or gentamycin and vancomycin. The frequency of drop instillation for severe infections is every 5 min for the first 30 min followed by half-hourly drops or hourly drops for the first 24-72 hours including night. Subsequently, the frequency decreases to once every 2 or 4 hours. The high instillation frequency is required because of rapid eye drop clearance resulting in a low bioavailability of 1-5%. The total number of drops for this therapy could be as high as about 100 over 1-week of treatment. While efficacious, the patients have difficulties in complying with this high frequency application of eye drops resulting in poor prognosis. We will address this unmet need by designing a novel sustained release contact lens drug delivery system for delivering antibiotics (moxifloxacin (monotherapy) and tobramycin and vancomycin (combination therapy)) to treat MK. Contacts lenses offer many advantages over eye drops including extended release that will improve compliance by replacing 100 drops with 1-2 lenses and higher bioavailability that will lead to higher and more consistent concentrations in ocular tissues resulting in improved therapy and reducing the possibility of development of resistance that is becoming a major problem. We have developed a novel, patented approach for extended delivery by incorporation of vitamin E (a tocopherol) nanobarriers in commercial silicone hydrogel contact lenses. Use of commercial contact lenses that are already approved by the FDA reduces barriers to translation. Our preliminary results have shown that nanobarrier contact lenses (NB-CL) increase the drug release duration of moxifloxacin, while maintaining all key properties of the contact lenses including transparency, wettability, UV-blocking, oxygen and ion permeability, low protein binding, and young’s modulus. Specifically, we showed that incorporation of 20% (w/w) on dry basis of vitamin E in Acuvue Oasys lenses increases the release duration of moxifloxacin from a few hours to about 50 hours. Also, validated mathematical model suggests that an Oasys lens loaded with 30% VE and 500 µg of moxifloxacin will result in drug concentrations in aqueous humor comparable to the tedious drop regimen of numerous drops over 3 days. This research aims to manufacture and characterize the antibiotic-loaded nanobarrier lenses in Aim 1 and test pharmacokinetics and efficacy in New Zealand white rabbits in Aim 2. The approach will provide insights into sustained drug delivery and efficacy with acute wear NB-CL, and lead to a novel device to treat MK. Our approach promises to increase bioavailability, reduce dosage amount to improve compliance and minimize drug variations to reduce the potential for development of antibiotic-resistance. If successful, NB-CL for sustained drug delivery will revolutionize MK treatment by replacing about 100 drops with 1-2 contact lenses. The approach is applicable to other drugs individually or in combination for many other indications including other infections, glaucoma, wound-healing, inflammation, cystinosis, etc. The validated model will establish the fundamental design principles and serve as an optimization tool.
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