Investigation on the Performance of Dry Powder Inhalation System for Enhanced Delivery of Levosalbutamol Sulfate
Abstract
Chronic respiratory diseases, particularly asthma and chronic obstructive pulmonary disease (COPD), are worldwide public health challenges due to the high prevalence and mortality, affecting millions of people globally. Orally inhaled therapy through dry powder inhalation (DPI) has proven to be an effective, non-invasive, and convenient way to deliver medications to the lungs in the treatment of respiratory diseases and systemic diseases. The in-vitro performance and in-vivo efficacy of DPI systems are mainly affected by inhalers, formulations, and patients. However, the performance is not satisfactory due to variable and low lung delivery (10%-30%) of medications as well as high mouth-throat deposition. Therefore, the primary objective of the project is to investigate DPI formulation-device system to improve pulmonary delivery efficiency.
The key design parameters of a 3D-printed inhaler, including grid structure, gas inlet, grid mesh, “pierce-and-hole” design, mouthpiece length, and diameter were studied by experimental and numerical analysis, providing a comprehensive understanding of the designs in powder dispersion. Improved dispersion and aerosolization performance could be achieved by narrowing mouthpiece diameter and gas inlet size as well as generating intensive grid meshes with relatively small aperture size to introduce less vortexed airstreams and high turbulent flow. With satisfactory fine particle fraction and inhaler resistance as criteria for inhaler optimization, the final modified DPI has improved fine particle fraction (FPF) to approximately 41% compared with the model inhaler.
The influence of tertiary components on DPI formulations was investigated by particle engineering during formulation development and optimization. Spray-dried and jet-milled drug particles could achieve particle micronization with inhalable size but in spherical and irregular shapes, respectively. With 10% of fine lactose (geometric mean diametermicrons) incorporated in the formulation, the API-fine lactose-coarse lactose showed improved aerosolization performance with fine lactose physically blending with carrier lactose first. Moreover, other tertiary components, such as L-leucine and magnesium stearate, also showed their capability to improve dispersion and FPF. The optimal L-SS formulation has achieved a significantly increased FPF, up to 47%.
In summary, the levosalbutamol DPI system was successfully developed. With the optimal L-SS formulation working with the improved inhaler, the final levosalbutamol dry powder inhalation system has achieved an increased FPF to 51% with satisfactory delivery dose uniformity.