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Ramesh Ayyala, MD, Katherine Freer, Mitchell Fullerton, Diane Blake; Optimizing drug release in sterilized drug delivery devices to prevent post-operative fibrosis. Invest. Ophthalmol. Vis. Sci. 2021;62(8):2771.
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Glaucoma drainage device (GDD) implantation has a 5-year failure rate of ~50% because of post-operative fibrosis. Our group has developed two drug delivery devices that reduced fibrosis after GDD implantation in an animal model (TVST 2015;4(3)4). This study advances these devices toward clinical trials by characterizing the effects of FDA-approved sterilization methods on drug release.
We compared drug release in unsterilized (US), gamma sterilized (GS), and e-beam sterilized (EBS) PHEMA and PLGA devices (n=8). Devices were manufactured and lyophilized in a GMP facility, then sterilized using gamma or e-beam irradiation. The PHEMA-device contained mitomycin C (MMC) and the PLGA device contained 5-fluorouracil (5-FU). We used UV/Vis spectroscopy to quantify drug release into saline over a 30-day period.
Plots of 5-FU released vs time in the PLGA device had sigmoidal character and were fitted to a variant of the Hill equation, where “KA” was redefined as “T1/2”, the time of 50% drug release, and the “Hill coefficient” was redefined as the “sigmoidicity coefficient” (SC). A lower SC indicates that similar quantities of drug are released over equal time intervals. Mean values of the T1/2 for GS, US, EBS sterilized PLGA were 23.04, 27.67, 29.55 days . The T1/2 of the GS product was significantly lower (p<0.0001) that the US or EBS material. We hypothesize that GS (at 15 kGy) introduced free radicals that enhanced PLGA degradation. Lower energy (10.5 kGy) EBS provided a product with an SC significantly lower (p<0.013) than that of the GS or the US product (4.57, 6.32 and 7.92, respectively). The slower, more gradual drug release provided by the EBS product may be advantageous, since optimal drug release from this product would extend over 20-30 days in order to attenuate the post-op wound-healing response. MMC release from PHEMA followed a one-phase exponential decay. GS and EGS increased polymer crosslinking, which significantly slowed drug release (p<0.0001). T1/2 was 2.12, 4.17, and 5.79 days for the US, EBS and GS PHEMA, respectively
PHEMA and PLGA devices respond differently to sterilization. EBS led to a more gradual drug release from PLGA. Both GS and EBS slowed drug release from PHEMA. Both devices can be manufactured in a GMP facility, which provides a path for these devices to enter clinical trials.
This is a 2021 ARVO Annual Meeting abstract.
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