Purpose: The pulmonary route has gained significant attention for drug delivery systems due to its excellent control of local symptoms associated with respiratory diseases and the high permeability of the lungs and their large area for drug absorption, which allow drugs to be effectively and rapidly delivered to the systemic circulation. The purpose of this study is to maximize the aerodynamic performance of fluticasone propionate (FP) by modifying lactose carriers and to investigate the effect of lactose carriers on the aerodynamic performance of FP. Methods: An amorphous lactose solid dispersion (ALSD) prepared by co-spray drying lactose with magnesium stearate (MgSt). Supertab®SD11, tomahawk-shaped Lactohale® 200 (LH® 200), and spherical spray-dried lactose w/wo MgSt were used as references. A design of experiments (DoE) approach was employed to optimize the amounts of MgSt and the blending time on in vitro aerodynamic performance as measured by the emitted dose and the fine particle fraction (FPF). Solid state characterization of the lactose particles was performed using PXRD, DSC, TGA, and scanning electron microscope. Particle size distribution (PSD) analysis was conducted using a laser diffraction particle size analyzer. The flowability of lactose carriers was tested by measuring the bulk density and tapped density following European 6.0 < 2.9.34. > and US Pharmacopoeia 34 < 616 >. An 8 stage of next generation impactor (NGI) was used to evaluate the aerodynamic performance such as fine particle fraction (FPF), recovered dose, emitted dose, and fine particle dose. The amounts of FP on each stage were measured by HPLC. Results: The ALSD was prepared by co-spray drying lactose with MgSt. PXRD suggested that the ALSD is amorphous lactose, and the SEM showed that the ALSD was spherical and had smooth surface. SuperTab®SD11 exhibits a similar size distribution to that of LH® 200, a commercially available lactose carrier for DPI. However, LH® 200 has a tomahawk shape with a flat surface, whereas SuperTab®SD11 is spherical with a rough surface. The FPF of LH® 200 was 34.64% while that of SuperTab®SD11 was 16.48%, suggesting that the morphology of lactose carriers plays an important role in determining the FPF. In terms of morphology, both SuperTab®SD11 and spray-dried lactose were spherical but exhibited significantly different FPFs due to their surface properties, which were modified by mixing them with MgSt. Because the spray-dried lactose and the physical mixture of spray-dried lactose with 0.2% MgSt are the same size, the effect of surface modification was clearly observable. It appeared that flakes of MgSt were inserted between the spray-dried lactose particles or covered the surface of the spray dried lactose particles. Interestingly, the FPF for the physical mixture of spray-dried lactose with 0.2% MgSt was 29.88% which was lower than that of spray-dried lactose (39.94%) and the ALSD containing 0.2% MgSt ( >55%).
Based on DoE results, the amount of MgSt was set at 0.2%, and the design space for the blending time was set from 5 min to 30 min. An ALSD containing 0.2% MgSt produced an FPF (59.62%) that was about 25% and 41% higher than LH® 200 (34.53%) with 0.2% MgSt and SuperTab®SD11 (18.30%) with 0.2% MgSt, respectively. It is interesting to note that the physical mixture of the ALSD with MgSt, which is similar in terms of size, shape, and surface topology, had a significantly lower FPF and poor flowability compared to the ALSD alone. Although MgSt is frequently used as a lubricant in manufacturing processes, it can act as a tackifier, especially when mixed with materials of a similar size. Conclusion: In this study, we demonstrated the importance of the size, morphology, and surface properties of lactose carriers and blending time in a dry powder inhaler (DPI) system and the importance of understanding the relationships between these factors in optimizing the performance of the system. The ALSD developed in this study greatly improved the aerodynamic performance of FP in the DPI system and can be used as a promising carrier.
