Shelf-life and Injectability Study of Syringes Filled With a Biodegradable Silica-Silica Composite Used in the Parenteral Administration of Pharmaceutical Agents

摘要

This thesis was carried out with the collaboration of DelSiTech Ltd, which is a leading silica-based drug delivery technology and drug development company based in Finland. In the beginning of this study, spray dried silica gel microparticles, used as a carrier material for therapeutic agents, were mixed together with a sol-gel derived silica sol. It was paramount that the mixing was performed before the initial silica sol had been allowed to form a hydrogel. This ensured the creation of a homogenous mixture. In the end, the mixture was filled into syringes and allowed to form a stable and injectable silica microparticle-silica hydrogel composite product. The continuous hydrogel matrix of the composite elicits excellent shear-thinning characteristics, and as a result, could facilitate the parenteral administration of therapeutic agents encapsulated within the silica microparticles. Throughout the study, the formulation of the sol-gel derived silica sol was kept constant at an R-value of 400 (molar ratio of water to silica alkoxide). In contrast, the volume concentration of silica microparticles ranged from 0.5 to 1 g/ml, which was noticed to affect the gelation rate of the silica-silica composite. This indicated that the microparticles act as nucleating agents in the formation of the three-dimensional gel structure. In order to optimize the manufacturing process of the composite and to define the applicability of the final product, three objectives were set: determine the time-frame in which to mix the composite as well as fill the syringes, evaluate the shelf-life of the final product and to assess the injectability of the product through various needle gauges (23G, 27G, and 30G). The mixing and filling time-frames were evaluated by determining the gel-point of the composite under small angle oscillatory shear. Process parameters, such as temperature, evaporation and the age of the initial silica sol were examined to optimize the filling process. The broadest time-fame was achieved by utilizing unaged silica sols in sealed process systems at refrigerator temperatures (4-8 °C). Respectively, the shelf-life of the final product was also characterized by oscillatory measurements, which indicated that the composite retained its viscoelastic characteristics for at least 30 days, regardless of changing microparticle concentrations. Lastly, the final product was injected out of 1ml syringes through thin needles to evaluate the injectability of the product. Ultimately, a microparticle concentration of 0.75 g/ml exhibited the most prominent injectability characteristics out of all the concentrations investigated.