(M1530-03-17) Improving Aerodynamic Performance with Spray-Dried Corrugated Chitosan Microparticles

Purpose: The aim of this study was to prepare corrugated chitosan microparticles as carriers for dry powder inhalers and to evaluate its physicochemical and aerodynamic properties.

Methods: Corrugated chitosan microparticles were prepared using a laboratory-scale spray dryer (EYELA SD-1000, Rikakikai Co. Ltd., Tokyo, Japan) with an organic acid solution containing levofloxacin. The chitosan-organic acid solution was prepared with three different types of organic acid (formic acid - HMF, acetic acid - HMA, propionic acid - HMP) and various molecular ratios (17.5, 87.5, and 175 mmol). The chitosan microparticles were then evaluated to confirm the surface morphology, as well as the number and depth of wrinkles, using scanning electron microscopy (SEM) and atomic force microscopy (AFM). The particle size distribution and true density were measured using Mastersizer 3000 and Ultrapyc 1200e, respectively. The aerodynamic performance was assessed using Andersen cascade impactor™ (ACI) system, while the particle image velocimetry (PIV) system was used to directly confirm the actual movement of the aerosolized particles. Furthermore, the in vivo dissolution test was conducted using the Franz diffusion cell system.

Results: The formation of roughness was influenced by type of organic acid and the molecular ratios. As the molecular ratios of organic acid increased, wrinkles also increased. When compared at 175 mmol, the microparticles prepared with a propionic acid solution exhibited a higher degree of corrugation than those prepared with a formic acid solution. This difference can be attributed to the higher boiling point of propionic acid, which results in a slower formation of the shell during particle drying compared to formic acid and acetic acid. The slower drying process tends to produce microparticles with lower density shells, as opposed to the faster drying process. The aerodynamic performance of corrugated microparticles was significantly increased in ACI results. The emitted dose (ED)% values for all samples high, range from 90.9 to 95.3 %. A more corrugated structure is considered to have better aerodynamic performance than a less corrugated structure, and HMP showed significant improvement in the FPF, MMAD, GSD values compared to HMF. For HMF, the FPF( < 4.4 μm) was 25.6 ± 7.7%, MMAD was 2.4 ± 0.1, and GSD was 3.0 ± 0.1. On the other hand HMP showed FPF ( < 4.4 μm) as 41.3 ± 3.9 %, MMAD was 2.2 ± 0.0, and GSD was 2.8 ± 0.0. Corrugated microparticles also showed better aerosolization, with decreased x-axial velocity and variable angle. Rapid dissolution profiles of drugs in the prepared formulations were observed within 30 minutes.

Conclusion: The controlled preparation of wrinkled chitosan microparticles using organic acid has the potential to serve as a micro-carrier for dry powder inhalers, offering improved inhalation efficiency and dissolution profiles. This study shows promising possibilities in developing a microcarrier that can enhance drug deposition and achieve rapid dissolution in the deep lung.

Acknowledgements: This research was also supported by "Regional Innovation Strategy (RIS)" through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (MOE)(2021RIS-001).

Figure 1. (A) SEM images of corrugated microparticle according to type of organic acid and various molecular ratios. (B) Relationship between molecular ratio of organic acid and wrinkles.

Figure 2. HMF175 L20 and HMP175 L20 results of (A) Dissolution profiles (n=5). (B) and (C) ACI. (D) PVI. T-test; * < 0.05, ** < 0.005, *** < 0.0005