Dexamethasone intravitreal implants : characterization, manufacture, and elucidation of drug release mechanisms

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2023-08

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Abstract

Long-acting injectable products based on the biodegradable polymer poly(lactide-co-glycolide) (PLGA) have been available in the USA since 1989, with more than 20 PLGA–based formulations approved for use to date. Despite the clinical and commercial success of many of these drug products, no generic formulations have gained FDA approval at the time of this writing. The lack of PLGA–based generics can largely be attributed to the technical challenges associated with development of formulations with drug release profiles equivalent to the reference product. Despite extensive study of the drug release mechanisms of PLGA, the inherent complexity of the copolymer is largely to blame for the challenges associated with generic product development. In this work, the FDA–approved product Ozurdex (dexamethasone intravitreal implant) was used as a model system to help address the challenges associated with generic product development of PLGA–based solid implants. Ozurdex is a small, rod-shaped implant (0.46 mm diameter, 6 mm long) formulated to deliver the corticosteroid dexamethasone to the posterior segment of the eye for 3–6 months. Ozurdex was thoroughly characterized and shown to be a porous implant consisting of a two-phase system of dexamethasone crystals embedded within a PLGA matrix due to a limited drug-polymer interaction. Compositionally equivalent, reverse-engineered implants were produced using a continuous hot-melt extrusion process that required careful control to manufacture implants structurally equivalent to Ozurdex. The drug release mechanisms of the reverse-engineered implants were studied in detail using a variety of analytical techniques to examine the implant throughout the drug release period. This work also demonstrated how sourcing PLGAs with similar, but subtly different, physicochemical properties can affect the manufacture and drug release kinetics of dexamethasone intravitreal implants.

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