PurposeIntravitreal (IVT) therapies are a standard of care for many ocular diseases. Frequent administration and injection‐based adverse events pose a hurdle for effective upkeep of ocular health. Developing improved effective treatment durations has gained significant traction. This study investigated if a near water‐insoluble drug, BAY224, could be encapsulated in biodegradable silica microparticles (SMP) and exhibit sustained controlled in vitro and in vivo release through a surface eroding SMP‐silica hydrogel composite (silica‐silica composite).MethodsBAY224 was encapsulated in a silica matrix by sol‐gel chemistry and spray drying. In vitro silica dissolution and BAY224 release from silica‐silica composite was analyzed followed by studying in vivo IVT release in rabbits. In vitro silica dissolution was studied in sink conditions colorimetrically. Cumulative release and total BAY224 content were analyzed by HPLC. In vivo release was studied by LC‐MS/MS of sample vitreous humor up to 55 days post 30 µl IVT injections.ResultsBAY224 was encapsulated, and silica‐silica composite was made at a load of 1 mg/50 µL (5.7 wt‐%). BAY224‐SMPs were sterilized using γ‐irradiation (26.8–47.5 kGy) not affecting in vitro dissolution. Burst release of BAY224 was >9 wt‐% in SMP and silica‐silica composite. Release of API was controlled by silica matrix surface erosion. In accelerated in vitro dissolution, the release time of BAY224 from SMP was 8–9 days. The silica‐silica composite prolonged release to 9–10 days. With the relevant in vitro‐in vivo correlation factor, in vivo release of 3 months was hypothesized. In vivo PK data showed sustained release of BAY224 in vitreous for at least 55 days. Daily API release (calculated from the API remnant in depot) was ca. 5–8 µg/day.ConclusionsEfficient encapsulation of a near insoluble drug was achieved with a silica‐silica composite with no burst release and a long‐acting release in‐vivo of >55 days in line with the in‐vitro dissolution results.