Abstract
Purpose :
Intravitreally (IVT) injected therapies are a standard of care for many ocular diseases. Frequent administration and injection based adverse events pose a challenge for effective maintenance of ocular health. The need to develop treatments with improved effective durations has gained significant attention. The purpose of this study was to investigate if a limited solubility drug, BAY224, could be encapsulated in biodegradable silica microparticles and demonstrate sustained and controlled in vitro and in vivo release through a surface eroding silica microparticle-silica hydrogel composite (silica-silica composite).
Methods :
BAY224 was encapsulated in a silica matrix by sol-gel chemistry and spray drying. The in vitro silica dissolution and BAY224 release rate of silica-silica composite were analyzed followed by in vivo characterization of the IVT release in the rabbit. In vitro silica dissolution was studied in sink conditions colorimetrically. The cumulative release and total BAY224 content were analyzed by HPLC. The in vivo release was investigated by LC-MS/MS analysis of harvested vitreous humor up to 55 days post 30 µl IVT injections.
Results :
BAY224 is a practically insoluble small molecule drug in water. Yet it was encapsulated, and silica-silica composite was produced at a load of 1mg/50µL (5.7 wt-%). BAY224-Silica microparticles were sterilized using gamma-irradiation (26.8-47.5 kGy doses) without affecting the in vitro dissolution profiles. Burst release of BAY224 was below 9 wt-% in both microparticle and silica-silica composite. Also, the release of BAY224 was controlled by silica matrix surface erosion. In the accelerated in vitro dissolution, the release time of BAY224 from microparticles was 8-9 days. The silica-silica composite prolonged the release up to 9-10 days. Based on the appropriate in vitro-in vivo correlation factor, an estimated in vivo release of 3 months was hypothesized. In vivo PK data demonstrated sustained release of BAY224 in vitreous for at least 55 days. The daily API release (calculated from the remaining API in depot) was ca. 5-8 µg/day.
Conclusions :
Efficient encapsulation of a practically insoluble drug was achieved with a silica-silica composite achieving no burst release and ensuring a long acting release in-vivo for more than 55 days correlating with the in-vitro dissolution experiments.
This is a 2020 ARVO Annual Meeting abstract.