Enhanced pulmonary delivery of spray-dried theophylline: investigation of the trehalose and amino acid combinations as innovative fine carriers

The emergence of novel carrier systems for dry powder inhalers is an attractive research subject. Additionally, the site-specific pulmonary delivery of theophylline (THN) remains challenging. Therefore, the present research aims to assess the potential enhancement of THN local delivery to the deep lung via powder inhalation for asthma treatment by developing appropriate fine carriers utilizing the well-established spray-drying technique.

The preliminary study aimed to develop novel trehalose-based carrier systems combined with amino acids leucine, glycine, and arginine. Aqueous feedstock solutions were spray-dried, and the obtained microparticulate carriers were assessed. Subsequently, therapeutic powders were produced by spray drying ethanol 10 % solutions of THN combined with candidate-developed carriers. Following each sample preparation, it was subjected to structural, thermal, morphological, rheological, aerodynamic, and particle size distribution characterization. Furthermore, THN solubility was determined. In vitro drug release and diffusion, in vitro and in silico simulated lung deposition, and aerodynamic particle count were analyzed by applying samples equivalent to 10 mg of THN.

To summarize the outcomes, carriers composed of trehalose with either leucine or a leucine-glycine combination demonstrated superior respirable properties and were considered candidates for further development. THN co-spray-dried samples showed less crystalline structure and particle size of 4–5 µm, leading to profound solubility enhancement (⁓20 fold) and rapid drug release compared to the pure THN (⁓100 % in 5 min). The in vitro and in silico aerodynamic measurements demonstrated that the THN-trehalose-leucine combination had a significantly enhanced fine particle fraction (43 %), leading to higher deep lung deposition (36 %), and the aerodynamic counter confirmed the development of fine particles (mean=3.61 µm). Moreover, the in vitro experiments on the A549 cells demonstrated that the optimized formulation has a low cytotoxicity profile.

In conclusion, the acquired characteristics suggest that inhalable co-spray-dried THN with the trehalose-leucine fine carrier may be a practical approach for local asthma therapy.