Formulation development of a biodegradable silica depot for long-acting injectable delivery of small molecules to biologics

This thesis investigates the development and characterization of long-acting injectable (LAI) silica-based drug delivery systems, integrating sol-gel processing, formulation optimization, in vitro, and in vivo performance evaluation.The delivery platform comprises sol-gel derived silica microparticles embedded in a silica hydrogel matrix, herein referred to as the silica depot injection. The work begins by characterizing the fundamental sol-gel process for colloidal silica sols, where the sol-gel transition was characterized by time-resolved rheometry (TRR). The impact of varying silica content and pH on gelation behavior and transition times was assessed, confirming a linear increase in sol-gel transition time with solid content, and an exponential decrease with rising sol pH.The optimized TRR measurement enabled accurate monitoring of transition times and unexpectedly showed that the resulting gels exhibited viscoelastic properties typical of colloidal glasses rather than colloidal gels. The following study examined how incorporating alginate as an excipient could modulate the rheological properties of the silica depot injection. Silica microparticles containing levothyroxine were prepared by spray-drying and combined into conventional silica hydrogels and silica/alginate hydrogels. In vitro characterization demonstrated that alginate inclusion allowed lower microparticle concentrations in the depot injections while improving injectability. The in vitro and in vivo performance of a silica–triptorelin acetate depot injection is also evaluated. Triptorelin acetate, used to treat hormone-sensitive conditions such as prostate cancer, was similarly encapsulated in silica microparticles and formulated into an injectable depot. Following subcutaneous administration in Sprague-Dawley rats, pharmacokinetics and pharmacodynamics were compared to a commercial reference product (Pamorelin®). The silica depot exhibited five-fold lower maximum plasma concentrations (Cmax) and sustained triptorelin plasma concentrations over 91 days, effectively maintaining testosterone suppression, demonstrating potential as a long-acting peptide delivery system. Collectively, this thesis highlights the versatility and translational potential of silica-based LAI formulations, offering tunable rheology, prolonged drug release, and preserved biological activity for both small molecules and biologics.