Exploring the influence of magnesium stearate content and mixing modality on the rheological properties and in vitro aerosolization of dry powder inhaler.

Since carrier-based dry powder inhalers (DPIs) suffer from inadequate drug deposition in the lung, an increasing number of marketed products have added magnesium stearate (MgSt) to improve the aerosolization, dispersion, and stability against moisture of DPI. However, for carrier-based DPI, there is a lack of examination of the optimal MgSt content as well as the mixing modality, and there is also a need to verify the applicability of rheological properties to predict the in vitro aerosolization of DPI formulations containing MgSt. Therefore, in this work, DPI formulations were prepared using fluticasone propionate as a model drug and commercial crystalline lactose Respitose® SV003 as a carrier within 1% MgSt content, the effect of MgSt content on the rheological and aerodynamic properties were investigated. After the optimal MgSt content was determined, the effects of mixing modality, mixing order, and carrier size on formulation properties were further investigated. Meanwhile, correlations were established between rheological parameters and in vitro drug deposition parameters, and the contribution of rheological parameters were determined using principal component analysis (PCA). The results showed that the optimal content of MgSt in DPI formulations is 0.25%-0.5% under both high-shear and low-shear, using medium-sized carriers (D50 around 70 µm) and low-shear mixing are beneficial for improving in vitro aerosolization. Good linear relationships between powder rheological parameters such as basic flow energy (BFE), specific energy (SE), Permeability and fine particle fraction (FPF) were established, PCA showed that both flowability and adhesion are key properties affecting FPF. In conclusion, both MgSt content and mixing modality can influence rheological properties of the DPI, which can be used as a screeing tool for DPI formuluation and preparation process optimization.

Predicting in vitro lung deposition behavior of combined dry powder inhaler via rheological properties.

Dry powder inhaler (DPI) for pulmonary delivery is currently the primary treatment for asthma and COPD (chronic obstructive pulmonary disease), an increasing number of combined DPIs (containing two or more drugs in one inhaler) have been developed to complement the effect of single DPIs. Based on our previous studies, the rheological properties can be a potential tool used to predict the in vitro lung deposition behavior of DPI formulations. However, it is unknown whether such a prediction model is suitable for combination systems. Therefore, this study aimed to verify the applicability of using powder rheological properties to predict in vitro drug deposition behavior in combined DPI formulations. Two drugs (fluticasone propionate and salmeterol xinafoate) and their combination of DPI formulations were prepared using fine lactose content (in the range of 1%-20%) as a variable. The physicochemical properties of the powder mixtures such as particle size and content uniformity were characterized. The rheological properties of the powder mixtures were measured by FT4 rheometer, the aerodynamic behavior of the DPI formulations was evaluated by a new generation impactor (NGI), and the effect of flowability and adhesion on the deposition of the fine particle fraction (FPF) was investigated by principal component analysis (PCA). The results showed that the combined DPI formulations with larger particle interaction forces have certain differences from the aerodynamic behavior of the single DPI formulations. The regularity of rheological properties affecting FPF revealed in single DPI is still applicable to combined DPI, the parameters basic flowability energy (BFE), representing flowability, and flow factor (ff), Cohesion representing adhesion, can be well linearly related to the FPF. The results of the principal component analysis showed that better flowability and suitable adhesion contributed to higher in vitro deposition of the drug in the formulation, and the contribution of adhesion (75.42%) was greater than that of flowability (24.58%). In conclusion, rheological properties is an effective tool for predicting the deposition behavior of DPI not only in single but also in combined DPIs.