Translating ophthalmologic drug delivery systems from the bench to clinical trials
Glaucoma is a debilitating and insidious disease and is the world’s leading cause of irreversible blindness. There have been many proposed innovations in the ophthalmology space though few have successfully been implemented in humans. The gap between proof of concept studies and market launch has been termed the “valley of death.” The Blake, Ayyala, and John research group have been endeavoring to bring two drug delivery systems through this “valley of death” for the last ten years. These products aim to solve a common problem in glaucoma surgery: post-surgical fibrosis resulting in the need for revision surgery. The two drug systems are a poly(hydroxyl ethyl methacrylate) hydrogel loaded with mitomycin C and a biodegradable poly(lactic-co-glycolic acid) matrix loaded with 5-fluorouracil and mitomycin C. These anti-fibrotics, when released into the surgical site, successfully reduced scar tissue formation in animal models. To translate these technologies to market, we created methods to interrogate their synthesis, studied their properties after sterilization, and performed longitudinal studies to determine their stability. For the pHEMA-based drug delivery system, we introduced a new casting method and compared it to previous studies. This new method reduced casting time two-fold and increased lot-to-lot reproducibility. We also developed an assay for quantifying the amount of drug loaded into each hydrogel. Using this assay, we reduced the loading time of the hydrogels two-fold by more than 5 days. The product was then gamma and e-beam sterilized to determine how sterilization would affect the hydrogel. We showed that the hydrogel releases mitomycin C more slowly after gamma irradiation than after e-beam and that both releases were slower than unsterilized material. This indicates that the hydrogel has cross-linked during the sterilization process. For the PLGA-based drug delivery system, we developed a solvent extraction method for quantifying the amount of drug in each piece. We then used this assay to interrogate different steps in the manufacturing process. We discovered the need for a new casting method using a positive displacement pipette. We tested the homogeneity of the 5-fluorouracil within the polymer matrix and discovered that drug distribution in our films was uniform. We ensured that we could reproducibly create lots of these films. Then, we tested the stability of this drug delivery system after gamma irradiation. We performed a longitudinal shelf-life study to see how temperature and the presence of air could affect the system during 3 months of storage. We then lyophilized our product and compared e-beam and gamma sterilization techniques. These studies contributed to an investigational new drug filing with the FDA which is the next milestone for a drug product before first-in-human trials.