An engineered porous silica particle for sustained intravitreal delivery of mycophenolic acid

Abstract

Purpose : Mycophenolate mofetil (MMF) is a strong immunosuppressant used for refractory autoimmune uveitis through oral administration. However, roughly 30% of patients cannot tolerate this prodrug. MMF is converted by the liver to the active ingredient mycophenolic acid (MPA). We hypothesize that an intravitreal sustained delivery system will provide long-term therapeutic MPA at the disease site while eliminating systemic side effects.

Methods : Spherical porous silica (pSiO2) were obtained from Silicycle (Quebec City, QB) measuring 15µm in diameter with 10 nm pores. In order to load hydrophobic MPA, the pSiO2 particles were chemically grafted with alkyl chains (C8) to render them hydrophobic. 60mg of the grafted pSiO2 particles was then soaked in MPA solution (10mg/mL in methanol) for 60 hours for loading. The loaded particles finally were briefly washed before drying for in vitro release and in vivo intravitreal injection. In vitro release was performed in a dynamic dissolution chamber with the infusion rate of 1 µL per minute. The sample was collected daily and stored at -80°C until mass spectrometry analysis. For in vivo study, one eye of each four rabbits was injected with MPA-loaded pSiO2 particles. After the injection, slit-lamp, tonometry, indirect ophthalmoscopy, and ERG were performed for two weeks.

Results : C8 grafting was confirmed by Fourier Transform Infra-Red spectrometry. Both C8 grafting and MPA loading were quantified by thermogravimetric analysis (Figure 1) and were determined to be 11% in mass for C8 grafting and 16.7% in mass for MPA loading. The in vitro release demonstrated a Cmax of 1.05 µg/mL, Tmax of day 1, and the concentration at day 14 was 682 ng/mL. The intravitreal injected MPA-loaded pSiO2 particles ranged from 4.5mg to 2.7 mg per eye. No toxicity was observed clinically and ERG at day 14 was normal compared with the fellow eyes (flicker ERG 38.1±6.1 vs. 41.8±6.1µV, p=0.42 paired t-test). Intraocular pressure for the injected eyes was 10.5±1.4 mmHg versus 10.2±1.4 mmHg for the fellow eyes, p=0.63, paired t-test.

Conclusions : MPA can be successfully loaded into C8 grafted pSiO2 particles and the intravitreal injection was well tolerated. This delivery system may be highly valuable for the management of refractory autoimmune uveitis.

This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.