Optimization, In Vitro, and In Silico Characterization of Theophylline Inhalable Powder Using Raffinose-Amino Acid Combination as Fine Co-Spray-Dried Carriers

<b>Background/Objectives</b>: Dry powder inhalation is an attractive research area for development. Therefore, this work aimed to develop inhalable co-spray-dried theophylline (TN) microparticles, utilizing raffinose-amino acid fine carriers intended for asthma therapy. The study addressed enhancing TN's physicochemical and aerodynamic properties to ensure efficient lung deposition. <b>Methods</b>: The process involves spray-drying each formulation's solution using a mini spray drier. A rigorous assessment was conducted on particle size distribution, structural and thermal analysis, morphology study, in vitro and in silico aerodynamic investigation, and aerodynamic particle counter in addition to the solubility, in vitro dissolution, and diffusion of TN. <b>Results</b>: The carriers containing leucine and glycine revealed superior characteristics (mass median aerodynamic diameter (MMAD): 4.6-5 µm, fine particle fraction (FPF): 30.6-35.1%, and amorphous spherical structure) as candidates for further development of TN-DPIs, while arginine was excluded due to intensive aggregation and hygroscopicity, which led to poor aerodynamic performance. TN co-spray-dried samples demonstrated fine micronized particles (D [0.5]: 3.99-5.96 µm) with predominantly amorphous structure (crystallinity index: 24.1-45.2%) and significant solubility enhancement (~19-fold). Formulations containing leucine and leucine-glycine revealed the highest FPF (45.7-47.8%) and in silico lung deposition (39.3-40.1%), rapid in vitro drug release (~100% within 10 min), and improved in vitro diffusion (2.29-2.43-fold), respectively. Moreover, the aerodynamic counter confirmed the development of fine microparticles (mean number particle size = 2.3-2.02 µm). <b>Conclusions</b>: This innovative formulation possesses enhanced physicochemical, morphological, and aerodynamic characteristics of low-dose TN for local asthma treatment and could be applied as a promising carrier for dry powder inhaler development.