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Hawe, Andrea (2006): Studies on Stable Formulations for a Hydrophobic Cytokine. Dissertation, LMU München: Faculty of Chemistry and Pharmacy
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Abstract

The goal of the thesis was to analyze the impact of the formulation conditions on the stabilization of a hydrophobic cytokine. A standard way to formulate the cytokine at physiological pH is using Human Serum Albumin (HSA) as excipient. Based on a lyophilized formulation with mannitol as bulking agent and HSA as stabilizer analogous to commercially available systems, the impact of HSA-stabilizers, NaCl and pH on particle formation and stability of the cytokine in the liquid state was elucidated. As NaCl can impact the freezing and lyophilization behavior, the impact of NaCl on the behavior of mannitol-HSA placebo mixtures based on the cytokine-HSA formulations was studied. The goal was to understand how freezing, lyophilization and a subsequent storage of the formulations are influenced by NaCl and the HSA-stabilizers. The use of HSA as excipient is related to the risk of blood born pathogens, enhanced immunogenicity, as well as to analytical difficulties. Therefore, approaches to replace HSA in the cytokine formulation and to achieve stable HSA-free formulations were developed. For the lyophilized formulations HSA was replaced by sucrose as amorphous stabilizer and the physico-chemical properties of the system mannitol–sucrose during freezing and lyophilization were analyzed. To achieve a stable HSA-free formulation, cytokine adsorption and its low solubility were the major issues that had to be overcome. Overall, it was feasible to stabilize the cytokine without the use of HSA at low pH as liquid and lyophilized formulation. By using glass type I+ vials, respectively adding polysorbate 20 it was possible to minimize protein adsorption. Thus, the studies provided an extensive characterization of the hydrophobic cytokine, its stabilization with HSA and the pH dependent instability of HSA-containing systems. As an alternative a stable HSA-free formulation for the cytokine could be presented. Especially for the lyophilized formulations it could be shown that subtle changes of excipients e.g. in the NaCl content can have a detrimental impact.