(T1030-12-83) Preparation and Aerodynamic Performance Evaluation of PLGA Microparticle with Dimple Surface

Purpose: This study aimed to prepare and evaluate dimple surface microspheres (MSs) as a carrier-based formulation for pulmonary drug delivery using the Handihaler® device. The MSs are composed of Poly(lactic-co-glycolic acid) 503H (PLGA 503H) and budesonide, and they are prepared through the o/w emulsion-solvent evaporation method.

Methods: The dimple MSs (MSs) were prepared using the o/w emulsion-solvent evaporation method. PLGA 503H and budesonide were dissolved in a mixture of dichloromethane and methanol. The emulsion was formed by injecting this solution into a 0.2% polyvinyl alcohol (PVA) solution at a controlled rate using a high-speed dispersion homogenizer. Different shear stress levels were applied during the solvent evaporation step, achieved by using a mechanical stirrer at various rpm values for over 3 hours at 37 °C. To obtain the dimple surface MSs, the emulsion was centrifuged to eliminate non-encapsulated budesonide particles, and the supernatant was collected. The collected supernatant was then subjected to further centrifugation, and the resulting dimple surface MSs were washed multiple times with distilled water. After filtration, the dimple surface MSs were treated and lyophilized at -75°C for two days. To evaluate the aerosol performance of the carrier-based formulations with the Handihaler® device, an 8-stage nonviable Anderson cascade impactor (ACI) was used following the specifications outlined in the USP Chapter < 601 >. The flow rate was set at 60 L/min using a flow meter, and silicone oil was used to prevent particle bounce and re-entrainment during the test. Gelatin capsules filled with the carrier-based formulations were aerosolized using the Handihaler®, and the drug amount remaining in the capsules and deposited onto each stage's collection plate was quantified using modified HPLC methods. The aerosol performance was assessed based on the emitted dose (ED) and the fine particle fraction (FPF). The ED represented the percentage difference between the initial and remaining drug weights in the capsule after aerosolization. The FPF indicated the proportion of drug amount collected at stages 1 through 6 (which have aerodynamic cut-off diameters of 8.6 µm to 0.54 µm) in the ED, specifically evaluating the ability of particles to reach the respirable region (with aerodynamic size ≤ 5.0 μm).

Results: Budesonide-PLGA MSs with dimple surfaces were prepared using the o/w emulsion method, resulting in uniform spherical particles. The drug-polymer ratio and the mechanical stirrer rates during particle formation influenced the surface shape of the MS. MSs with increased drug ratios and specific stirrer rates exhibited dimple surfaces, which were found to have improved aerodynamic behavior compared to smooth surface MS. The aerodynamic performance of the prepared formulations was evaluated using an Andersen Cascade Impactor with a Handihaler® DPI device. The dimple surface MSs showed better aerodynamic behavior, except for the emitted dose (ED), compared to smooth surface microspheres. The changes in aerodynamics around the dimple surface MSs are believed to positively impact particle travel, facilitating deeper lung penetration. Moreover, the dimple surface influenced particle-particle interactions, reducing cohesion and adhesion forces, which could affect the ED value. Overall, the study demonstrated that MSs with dimple surfaces have the potential for improving aerosol drug delivery to the deep lung. For future formulations, the appropriate surface roughness should be carefully considered to develop even higher aerodynamic efficiency.

Conclusion: Dimple surface MSs were prepared using the o/w solvent evaporation method, and they exhibited a uniform spherical shape with dimple surfaces. Both dimple surface and smooth surface MSs showed an amorphous state and had similar size distributions. The aerodynamic behavior of the dimple surface MSs was demonstrated through ACI parameters such as MMAD and FPF. The results confirmed that the presence of dimples on the MSs improved the deep lung delivery of the drug by altering the flow around the particles. However, despite the observed improvement in aerodynamic behavior, the absolute inhalation efficiency was found to be low. This is attributed to various factors, including the electrostatic forces between the polymer and capsules, as well as the inhaler device itself. These factors need to be considered and addressed in future studies to develop more effective dry powder inhalation formulations.

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).

Scheme of preparing dimple microparticles

SEM images of microspheres according to mechanical stirrer rates (A) 100RPM (B) 600RPM (C) 1000RPM (D) 2000RPM.