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Gabriele Thumann, George Mihov, Jens Thies, Anja Kemp, Katharina Morawa, Martina Kropp; Slow-release intraocular drug delivery by injectable PEA microfibrils (DSM, NL). Invest. Ophthalmol. Vis. Sci. 2013;54(15):5045.
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Ophthalmic drug therapy of the posterior segment requires that effective concentrations of drug reach the target tissue, a goal complicated by limited penetration, short half-life of many drugs and difficult access to the posterior segment. Generally drug delivery to the posterior segment of the eye is accomplished by intravitreal (ivt) injection, often requiring frequent injections, e.g. AMD treatment with ranibizumab or aflibercept. Continuous drug delivery systems would be useful to avoid frequent administration and to deliver the drug at a more physiological concentration. Here we report properties of biodegradable amino acid polyester amide (PEA) polymers (DSM, NL) that can deliver a spectrum of drugs in a sustained, zero-order behavior and degrade via an enzyme-mediated pathway.
Deformability and in vitro degradation of the PEA fibrils (120-300 µm in diameter) was analyzed by incubation at 37o C in PBS, in α-chymotrypsin, in human, rabbit and bovine vitreous. In vivo biocompatibility and degradation was analyzed by subconjunctival (sc) and ivt implantation in normal and VEGF-treated rabbits that simulate blood-retinal barrier breakdown. Drug release by single PEA fibrils loaded with 10% dexamethasone was analyzed in vitro.
During the first 2 hours the fibrils decreased in length 57% in PBS, 62% in rabbit vitreous and 59% in human vitreous; the decrease in length was accompanied by an increase in diameter. Degradation by chymotrypsin depended on the amino acid composition of the PEA. Degradation in normal vitreous was slight but increased in vitreous from VEGF-treated rabbits. Sc and ivt PEA fibrils were well tolerated with no evidence of inflammation, retinal damage or changes in IOP. After an initial peak dexamethasone was released at a constant rate of 0.05-1.0 µg/ml for 140 days, whereas PLGA 75/25 did not release significant amounts of dexamethasone during the first 120 days, followed by 90% release from day 120 to day 140.
PEA polymers (DSM, NL) are well tolerated in the ocular environment, degrade slowly intravitreally and can be loaded with drugs that are released with zero-order kinetics over a period of months. Since PEAs are well tolerated in the ocular environment and can be manufactured to be loaded with different classes of drugs, these materials would be ideal for sustained delivery of drugs to the posterior segment.
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