Inhalable delivery of salmeterol xinafoate-ciclesonide co-amorphous for asthma treatment: prediction, preparation and...

The combination therapy of long acting β₂ agonists and inhaled corticosteroids is considered the first line treatment for asthma. However, the formulation development is challenged by poor water solubility and dose ratio accuracy. In this work, co-amorphous technology was employed to solve the problem. Guided by multi-approach theoretical predictions including molecular dynamics simulations coupled with molecular docking, novel co-amorphous systems combining salmeterol xinafoate (SX) with either ciclesonide (CIC) or betamethasone dipropionate (BP) were prepared. Compared to co-amorphous SX-BP (COAM SX-BP), co-amorphous SX-CIC (COAM SX-CIC) was preferred for further development because of the higher dissolution rate and synchronous release behaviour. The ratio of SX and CIC critically influenced the stability under high temperature and high humidity environments. To meet the needs of clinical application, the ratio of SX and CIC was optimized at 1:1.5. COAM SX-CIC exhibited good aerodynamic performance, with approximately 34 % of COAM SX-CIC being able to deposit in small airways. The cytotoxicity of COAM SX-CIC (IC₅₀ = 3.97 × 10^-5 M) was higher than that of SX (IC₅₀ = 3.15 × 10^-4 M) and CIC (IC₅₀ = 6.74 × 10^-4 M), which would not limit the application of COAM SX-CIC due to the high activity and low dosage of SX and CIC. The safety and efficacy of COAM SX-CIC was verified by in vitro anti-inflammation activity evaluation experiments. COAM SX-CIC had significant therapeutic effects in asthma models, manifested by the downregulation in TNF-α levels by about 60 % and improvement inflammatory lesions in both the airway and alveolar region. COAM SX-CIC achieved synchronous release of the two components with accurate dose ratio and demonstrated improved asthma therapeutic effects compared with raw materials, revealing the potential of co-amorphous technology in combination therapy.