Optimization of the fine particle fraction of a lyophilized lysozyme formulation for dry powder inhalation.

ABSTRACT

PURPOSE: A new dry powder inhalation technology creates inhalable particles from a coherent lyophilized bulk at the time of inhalation. The aim of this study was to evaluate several approaches to improve the fine particle fraction (FPF) and to understand underlying mechanisms. METHODS: Lysozyme was chosen as model drug. Phenylalanine and valine were added, and the freezing process was varied. Lyophilisate characteristics as well as aerosolization behavior was analyzed. RESULTS: The addition of the crystalline amino acids rendered a dose independent three-fold increase of the FPF. This is possibly due to enhanced fracture properties of the lyophilisates upon impact of the air stream and reduced particle agglomeration/cohesion caused by a rougher surface. This positive effect was well preserved over 3 months of storage. The structure of the lyophilisate was influenced by the freezing process which in turn affected the aerosolization behavior. Liquid nitrogen and vacuum-induced freezing performed best, doubling the FPF. The special cake morphology with elongated channels enabled easy disintegration. The resulting large porous particles comprise a low density being advantageous for a high FPF. CONCLUSION: The variation of the lyophilization process and formulation utilizing excipients enabled an optimization of the FPF of the novel lyophilisate based DPI system.