Liposomal Indacaterol/Ciclesonide Delivery: A Promising Strategy to Improve Pharmacodynamic Outcomes in Asthma models

Background: Asthma is a chronic inflammatory disease of the respiratory system for which there is currently no cure. The available treatments can only control and decrease the symptoms and exacerbations. Combined steroid and bronchodilator therapies are considered the first-line approach to asthma management and are preferably administered via inhalation to limit systemic side effects and reduce the required doses. Nonetheless, most currently available formulations exhibit low pulmonary deposition of active compounds. Combined with rapid mucociliary clearance and macrophage-mediated elimination, low bioavailability, and high systemic absorption, this often necessitates frequent administration and higher doses. In addition, effective asthma management relies on regular and consistent use of inhaled therapies to maintain disease control. This often results in suboptimal patient adherence to prescribed regimens, highlighting the need for simplified treatment strategies.

Purpose: Our aim is to address some of the challenges in asthma management by producing an innovative formulation containing Indacaterol/Ciclesonide (IND/CIC)-loaded liposomes, which will be converted into a dry powder for inhalation. The goal is to enhance the bioavailability of the active molecules, thereby reducing the required doses, posology, and associated side effects. This will be achieved by leveraging the targeted, local and sustained drug release provided by the biocompatible liposomal delivery system, and by optimizing pulmonary deposition of the dry powder via the use of innovative excipients such as the hydroxypropyl-beta-cyclodextrins.

Methods: We first evaluated the efficacy and pharmacological potency of IND/CIC-loaded liposomes
[1,2-dilinoleoyl-sn-glycero-3-phosphocholine (DLPC, 65%), cholesterol (Chol, 30%), distearoyl-phosphatidyl-ethanolamine-PEG2000 (DSPE-PEG, 15%)] with an ex vivo model of methacholine’s pre-contracted rat tracheal rings using an organ bath system. Subsequently, we used an acute ovalbumin (OVA)-induced mouse model of eosinophilic asthma. Balb/C mice received 10 µg OVA via intraperitoneal injection on days 1 and 8 and were challenged with OVA’s aerosol on days 24-25-26. Mice were treated from day 21 to day 26 with either liposomal or free IND/CIC formulations at two concentrations (low: IND 12.3 µg/mL, CIC 13.04 µg/mL; high: IND 123.0 µg/mL, CIC 130.4 µg/mL), and sacrificed on day 27. Lung tissue, plasma, and broncho-alveolar lavage fluid (BALF) were collected to assess the anti-inflammatory activity of CIC, while IND’s bronchodilatory efficacy was evaluated by measuring lung mechanics parameters using the FlexiVent® system.

Results: Ex vivo, liposomal IND/CIC significantly reduced methacholine-induced bronchoconstriction in rat tracheal rings and demonstrated greater potency, as reflected by lower EC₅₀, than commercial non-liposomal IND. In vivo, both low and high concentrations of liposomal formulations significantly improved lung mechanics—reducing airway resistance (Rrs), increasing compliance (Crs), decreasing elastance (Ers), and enhancing inspiratory capacity (IC)—compared to the corresponding non-liposomal treatments.
Moreover, IND/CIC liposomes at both concentrations strongly decreased BALF’s eosinophils and histological inflammation score compared to equivalent corresponding concentrations of IND/CIC solutions. Notably, low-dose IND/CIC liposomes provided comparable bronchodilatory and anti-inflammatory effects to the high-dose formulation, underscoring its improved therapeutic efficiency.

Conclusion and perspectives: Our findings demonstrate that liposomal encapsulation of IND/CIC enhances therapeutic efficacy and potency compared to non-liposomal formulations, potentially enabling dose reduction and extended duration of action. These benefits are likely driven by improved local drug retention, protection from degradation, and sustained release. Future work will aim to confirm these results and to characterize the pharmacokinetic profile of the final dry powder formulation intended for inhalation.