Surface-coated silica microparticles: In vitro and ex vivo evaluation of a preclinical extended release platform conceived for intravitreal injection

Current standard pharmacological treatment of retinal vascular diseases requires frequent intravitreal injection every 4-12 weeks. Active pharmaceutical ingredients (APIs) with better pharmacokinetics (PK), allowing less frequent administrations, remain to be discovered and developed. In preclinical stage mostly small molecule New Chemical Entities (NCEs) and peptides represent promising candidates. However, they typically suffer from fast clearance from the eye upon intravitreal injection, which confines support of animal models as sufficient exposure over 1-4 weeks in the eye is not reached. Addressing this need of extended-release (XR) formulations to enable such animal models, we hereby present chitosan embedded silica particles in suspension (CHESS). We identified non-mesoporous silica matrix particles as suitable biodegradable XR formulation and established a preparation method to control their degree of condensation, erosion rate and finally the release rate. Applicability for different API candidates was demonstrated by successful embedding of two model small molecules and one model peptide at high drug loads of >20 %, respectively. The ability to control release rate was demonstrated in vitro. High intravitreal mobility, which is a disadvantage of uncoated silica microparticles and other intravitreally applied XR microparticle formulations, was reduced by surface-coating with a polycationic chitosan-derivative. This leads to formation of stable depots in the vitreous after injection, which can be easily separated from the retina, facilitating PK analysis and pharmacodynamic (PD) readouts. Furthermore, we showed good tolerability and low toxicity on ARPE-19 cells.