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

Yizhen Bian; Xingyu Liu; Qianlin Xu; Ke Yang; Qian Zhou; Ming-Hui Qi; Bin Zhu; Guo-Bin Ren; Minghuang Hong

doi:10.1016/j.ijpharm.2025.125876

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

Int J Pharm. 2025 Jun 18:681:125876. doi: 10.1016/j.ijpharm.2025.125876. Online ahead of print.

Authors

Yizhen Bian¹, Xingyu Liu¹, Qianlin Xu¹, Ke Yang¹, Qian Zhou¹, Ming-Hui Qi¹, Bin Zhu¹, Guo-Bin Ren², Minghuang Hong³

Affiliations

¹ Laboratory of Pharmaceutical Crystal Engineering & Technology, State Key Laboratory of Bioreactor Engineering, Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Engineering Research Centre of Pharmaceutical Process Chemistry, Ministry of Education, School of Pharmacy, East China University of Science and Technology, No. 130 Meilong Road, Shanghai 200237, China.
² Laboratory of Pharmaceutical Crystal Engineering & Technology, State Key Laboratory of Bioreactor Engineering, Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Engineering Research Centre of Pharmaceutical Process Chemistry, Ministry of Education, School of Pharmacy, East China University of Science and Technology, No. 130 Meilong Road, Shanghai 200237, China. Electronic address: rgb@ecust.edu.cn.
³ Laboratory of Pharmaceutical Crystal Engineering & Technology, State Key Laboratory of Bioreactor Engineering, Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Engineering Research Centre of Pharmaceutical Process Chemistry, Ministry of Education, School of Pharmacy, East China University of Science and Technology, No. 130 Meilong Road, Shanghai 200237, China. Electronic address: mhhong@ecust.edu.cn.

PMID: 40541627
DOI: 10.1016/j.ijpharm.2025.125876

Abstract

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.

Keywords: Asthma; Ciclesonide; Co-amorphous; Salmeterol xinafoate.