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Keil, Tobias W. M.; Zimmermann, Christoph; Baldassi, Domizia; Adams, Friederike; Frieß, Wolfgang; Mehta, Aditi and Merkel, Olivia M. (2021): Impact of Crystalline and Amorphous Matrices on Successful Spray Drying of siRNA Polyplexes for Inhalation of Nano-in-Microparticles. In: Advanced Therapeutics, Vol. 4, No. 6, 2100073

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To develop stable and inhalable dry powder formulations with long shelf life, polyplexes consisting of siRNA and a polyethylenimine (PEI)-based block copolymer in presence of mannitol or trehalose are spray dried. The effect of inlet (T-In) and outlet (T-Out) temperature on the recovery of siRNA and adsorption effects within the tubing material are investigated. Choosing a low abrasion silicon tubing prevented siRNA loss due to adsorption. Mannitol and trehalose formulations preserved siRNA integrity regardless of excipient concentration and temperature at T-Out below the siRNA melting temperature. Trehalose formulations allowed full siRNA recovery whereas mannitol formulations resulted in spray drying induced losses of approximate to 20% siRNA and of 50-60% polymer. Mannitol formulations showed optimal aerodynamic characteristics as confirmed by next generation impaction analysis based upon siRNA content. All spray dried formulations resulted in green fluorescent protein (GFP) silencing comparable or better than freshly prepared polyplexes. To test if the observed results could be transferred, formulations of siRNA and transferrin-PEI conjugates are spray dried, characterized, and used to transfect primary human T cells ex vivo. Results confirmed successful silencing of the transcription factor GATA3 in primary CD4(+) T cells with spray dried formulations as a potential treatment for severe asthma.

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