Tunable construction of multi-shelled hollow carbonate nanospheres and their potential applications.

The development of multi-shelled hollow carbonate nanospheres (MHCN) for biomedical applications is challenging, and has not been reported. In this study, a facile approach is firstly reported to synthesize hierarchically porous MHCN with controllable shell numbers using a novel strategy called layer-by-layer thermal decomposition of organic acid salts and templates. The choice of organic acid salts as the reactants is innovative and crucial. The shell numbers of porous MHCN can be easily controlled and tuned through adjusting the adsorption temperature of organic acid salts and/or the adsorption ability of the template. The synthetic method can not only open a window to prepare the multi-shelled carbonates but also provide a new strategy to synthesise other multi-shelled inorganic salts. Notably, the hierarchically porous multi-shelled hollow structures empower the carbonates with not only a large specific surface area but also good porosity and permeability, showing great potential for future applications. Herein, our in vitro/vivo evaluations show that CaCO3 MHCN possess a high drug loading capacity and a sustained-release drug profile. It is highly expected that this novel synthetic strategy for MHCN and novel MHCN platform have the potential for biomedical applications in the near future.

Quality by design: impact of formulation variables and their interactions on quality attributes of a lyophilized monoclonal antibody.

The purpose of this study was to use QbD approaches to evaluate the effect of several variables and their interactions on quality of a challenging model murine IgG3κ monoclonal antibody (mAb), and then to obtain an optimized formulation with predefined quality target product profile. This antibody was chosen because it has a propensity to precipitate and thus represents a challenge condition for formulation development. Preliminary experiments were conducted to rule out incompatible buffer systems for the mAb product quality. A fractional factorial experimental design was then applied to screen the effects of buffer type, pH and excipients such as sucrose, sodium chloride (NaCl), lactic acid and Polysorbate 20 on glass transition temperature ( [Formula: see text] ), monoclonal antibody concentration (A(280)), presence of aggregation, unfolding transition temperature (T(m)) of the lyophilized product, and particle size of the reconstituted product. A Box-Behnken experimental design was subsequently applied to study the main, interaction, and quadratic effects of these variables on the responses. Pareto ranking analyses showed that the three most important factors affecting the selected responses for this particular antibody were pH, NaCl, and Polysorbate 20. The presence of curvature in the variables' effects on responses indicated interactions. Based on the constraints set on the responses, a design space was identified for this mAb and confirmed with experiments at three different levels of the variables within the design space. The model indicated a combination of high pH (8) and NaCl (50mM) levels, and a low Polysorbate 20 (0.008 mM) level at which an optimal formulation of the mAb could be achieved. Moisture contents and other analytical procedures such as size exclusion chromatography, protein A analysis and SDS-PAGE of the pre-lyophilized and final reconstituted lyophilized products indicated an intact protein structure with minimal aggregation after formulation and lyophilization. In conclusion, experimental design approach was effective in identifying optimal concentrations of excipients and pH for this challenging monoclonal antibody formulation.