No abstract

An in vitro dissolution model, the so-called EyeFlowCell (EFC), was developed to test intravitreal dosage forms, simulating parameters such as the gel-like consistency of the vitreous body. The developed model consists of a stereolithography 3D-printed flow-through cell with a polyacrylamide (PAA) gel as its core. This gel needed to be coated with an agarose sheath because of its low viscosity. Drug release from hydroxypropyl methylcellulose-based implants containing either triamcinolone acetonide or fluorescein sodium was studied in the EFC using a schematic eye movement by the EyeMovementSystem (EyeMoS). For comparison, studies were performed in USP apparatus 4 and USP apparatus 7. Significantly slower drug release was observed in the PAA gel for both model drugs compared with the compendial methods. Drug release from fluorescein sodium-containing model implants was completed after 40 min in USP apparatus 4, whereas drug release in the gel-based EFC lasted 72 h. Drug release from triamcinolone acetonide-containing model implants was completed after 35 min in USP apparatus 4 and after 150 min in USP apparatus 7, whereas this was delayed until 96 h in the EFC. These results suggest that compendial release methods may overestimate the drug release rate in the human vitreous body. Using a gel-based in vitro release system such as the EFC may better predict drug release.

The characterization of intravitreal dosage forms with regard to their behavior in vivo is usually explored in preclinical development through animal studies. In vitro vitreous substitutes (VS) to simulate the vitreous body for preclinical investigations have so far been insufficiently studied. To determine a distribution or concentration in the mostly gel-like VS, extraction of the gels is required in many cases. This destroys the gels, which makes a continuous investigation of the distribution impossible. In this work, the distribution of a contrast agent in hyaluronic acid agar gels and polyacrylamide gels was studied by magnetic resonance imaging and compared with the distribution in ex vivo porcine vitreous. The porcine vitreous served as a surrogate for human vitreous since both are similar in their physicochemical properties. It was shown that both gels do not completely represent the porcine vitreous body, but the distribution in the polyacrylamide gel is similar to that in the porcine vitreous body. In contrast, the distribution throughout the hyaluronic acid agar gel is much faster. It was also shown that anatomical features such as the lens and the interfacial tension to the anterior eye chamber could have an influence on the distribution that is difficult to reproduce using in vitro VS. However, with the presented method, new in vitro VS can be investigated continuously without destruction in the future, and thus their suitability as a substitute for the human vitreous can be verified.