Formulation of a Dry Powder for Inhalation Combining Ciclesonide and Indacaterol

Introduction
Dry powder inhalers (DPIs) effectively deliver medication directly to the lungs for conditions like asthma and chronic obstructive pulmonary disease (COPD), offering drug stability and no propellant gases. Particle engineering, particularly via spray-drying technology, enhances DPI characteristics, improving aerodynamic performance and dispersibility, ultimately increasing their effectiveness [1,2]. This research aims to develop an inhalable dry powder with ciclesonide (CIC) and indacaterol maleat (IND) using spray-drying. Due to CIC's high hydrophobicity and previous studies demonstrating the beneficial effects of a deflated morphology for aerosolization performance, cyclodextrins are used to enhance solubility, and suspension atomization will be explored. The main goal is to compare the drying outcomes of solutions and suspensions while developing an innovative formulation with improved lung deposition profiles.
Materials and Methods
Spray-drying: A 5 and 10 % (w/w) atomized liquids are formulated. The suspension includes hydroxy-propyl-β-cyclodextrin, which does not allow the solubilization of a high quantity of CIC, along with a surfactant agent (Tween® 80). Solubilization is improved with Crysmeb, a methyl-β-cyclodextrin, based on phase-solubility test results. Both liquids are spray dried using a Procept 4 M8-Trix spray-dryer (Procept, Zelzate, Belgium) with a bi-fluid nozzle (0.4 mm) under optimized parameters [1].
Powder Characterization: Analyses include yield determination, particle size distribution measured by laser diffractometer Mastersizer 3000, moisture content via thermogravimetric analysis (TGA), and particle morphology characterized by scanning electron microscopy (SEM) after metallization with Au. Homogeneity of CIC and IND is assessed by collecting 10 samples from the powder bed, and drugs recovery rates post-drying process in each sample is determined by HPLC assay. Raman hyperspectral imaging (R-HSI) experiments were conducted using a Labram HR Evolution (Horiba Scientific).
Aerodynamic Properties Characterization: Pulmonary deposition profiles were determined using a Next Generation Impactor (NGI, Copley Scientific, UK) at airflow rates of 60 and 100 L/min for 2,4s with Breezhaler® device. The PreciseInhale® device was also use at airflow rates of 60 L/min to study the aerosolization properties of powders.
Stability studies: Stability studies in accordance with ICH guidelines were conducted over a period of 3 months on the best-performing powder.
Results and discussion
The engineered spray-dried powders feature deflated morphology, particle sizes below 5 µm, and around 5 % water content, making them suitable for inhalation [3]. Yet, drying suspensions yields larger particles compared to solutions. Active pharmaceutical ingredients (API) homogeneity evaluation revealed consistent distribution, with a coefficient of variation below 5 %. However, CIC recovery rates after suspension drying were lower due to its non-solubilized state, possibly causing drug loss on drying chamber walls. R-HIS studies confirmed this, showing uniform distribution in spray-dried solutions and distinct CIC signatures in suspensions. The in vitro aerosolization performance of powders from solutions shows high fine particles fractions (FPF) values: 58.27 ± 7.49 % and 56.25 ± 1.24 % for CIC at 5 and 10 % (w/w) respectively, and 54.25 ± 2.99 % and 53.27 ± 4.17 % for IND, indicating uniform API deposition. These powders enhance the FPF of IND by nearly 15 % compared to Onbrez®, a DPI on the Belgian market, improving lung deposition due to the absence of a carrier and optimized powder properties. Conversely, atomized suspensions showed lower FPF values: 35.16 ± 4.68 % and 26.86 ± 4.59 % for CIC at 5 and 10 % (w/w), and 42.88 ± 7.96 % and 36.28 ± 5.53 % for IND, attributed to larger particle size and less uniform API distribution, causing increased upper respiratory tract impaction. Aerosolization of the powders is deemed acceptable, and the stability results are encouraging, indicating that the powders remain stable over time.
Conclusion
Varying solid content from 5 to 10 % had minimal impact on powder properties and lung deposition. However, atomized solutions produced powders with better inhalation properties, leading to higher lung deposition. Furthermore, spray-dried powders achieved nearly 15 % higher pulmonary deposition than Onbrez®, highlighting the importance of active ingredient solubilization and particle engineering for enhanced lung drug delivery and therapeutic efficacy. Future perspectives include improving powder flowability, currently deemed poor, by exploring options such as lactose blending or self-agglomeration, while assessing the stability of active ingredients over time [4].
References
[1] Lechanteur, A., et al. (2023). Inhalation powder development without carrier: How to engineer ultra-flying microparticles? European Journal of Pharmaceutics and Biopharmaceutics, 191, 26–35.
[2] Alhajj, N., et al. (2021). Designing enhanced spray dried particles for inhalation: A review of the impact of excipients and processing parameters on particle properties. In Powder Technology (Vol. 384, pp. 313–331). Elsevier B.V.
[3] Lechanteur, A., et al. (2022). Engineered-inhaled particles: Influence of carbohydrates excipients nature on powder properties and behavior. International Journal of Pharmaceutics, 613.
[4] Gresse, E., et al. (2024). Enhancement of inhaled micronized powder flow properties for accurate capsules filling. Powder Technology, 437, 119576.