Repurposing Losartan as Dry Powder Inhalation (DPI) for Asthma Related Cardiovascular Complications

Abstract

Our previous work published suggests that systemic administration of losartan is effective against asthma and asthma related implications. Dry powder inhalation (DPI) formulations as dosage forms are gaining momentum because of their propellant‐free nature, improved physical and chemical stability, low drug dose requirements and high systemic absorption. We developed a dry powder inhalation (DPI) formulation of losartan to treat the symptoms of asthma‐related cardiovascular complications. In this study, we evaluated the compatibility of some common DPI excipients with losartan and their ability to improve critical aerodynamic properties of the formulation to make it suitable for pulmonary drug delivery. There are different manufacturing techniques available for developing DPI formulations including milling, freeze‐drying, and spray drying (SD). We used SD in the current study to develop our formulation. The screening studies were performed by following one factor at a time approach (OFAT). We used amino acids and sugars, either alone or in combination to develop the DPI formulation by using SD technique. The SD conditions were kept constant at 110°C inlet temperature, 100% aspiration, 10% (approx. 3ml/min) pump rate, and 601 liters/hour gas flow rate. The developed formulations were characterized for their physicochemical, aerodynamic, and solid‐state properties. Particle size (<5μm) is critical to understand the deposition behavior of the DPI. Our formulations have the particle size distribution of the 50% of the particles (Dx50) below the respirable range that is <6μm. The fine particle fraction (2.2 – 3.4μm) of our formulation is 53.72%, which is the amount of dose that is actually reaching the lungs and shows therapeutic activity. The respirable fraction (3.4 – 5.3 μm) of our formulation is 70.90%, which is the amount of drug that is within the inhalable range. The solid‐state characterization studies, including differential scanning calorimetry, powder X‐ray diffraction studies indicate the drug in the formulation is amorphous, and the excipients and carrier used help to keep the formulation stable. The drug‐excipient compatibility was proved by quantitatively and qualitatively analyzing the samples using High‐Performance Liquid Chromatography (HPLC) and Fourier Transform Infrared Spectroscopic (FT‐IR). The developed formulations showed good aerosol performance and can be used for preclinical work for further evaluation of therapeutic efficacy of the losartan in asthma models.