Particle engineering of montelukast and budesonide for preparation of respirable dry powder and in vitro characterization

Abstract

Introduction: Asthma is a hypersensitivity syndrome of the respiratory system which leads to airflow obstruction. Combination of inhaled corticosteroids (ICS), such as budesonide, with montelukast show promising effect in asthma control. Aims: The current study used different methodologies for particle engineering of montelukast and budesonide to prepare inhalable dry powder formulations. Also, a model was generated correlating the inhaler device properties, inhalation flow rate, particle characteristics and drug/excipient physico-chemical properties with the resultant fine particle fraction. Methods: Spray drying, ball milling, jet milling and electrospraying methods were used to produce engineered particles of montelukast and budesonide and their combined formulation. The produced drug particles were characterized using various analyzing methods. In vitro drug deposition pattern was assessed using next generation impactor, and the dissolution profile of the selected formulations was characterized via modified diffusion Franz cell method. The pharmacological effects of combined formulation were assessed by measuring its power to inhibit the production of reactive oxygen species in human lung cells. In the current study, a model was constructed to correlate the inhaler device properties, inhalation flow rate, particle characteristics and drug/excipient physico-chemical properties with the resultant fine particle fraction. Results: Jet milling and electrospraying resulted in improving the FPF values of montelukast from 9 to 55 and 45, respectively. The FPF value for the co-electrosprayed formulation of montelukast-budesonide was 38% with a significantly enhanced dissolution rate for budesonide compared to the budesonide alone formulations. The combination of montelukast and budesonide showed a synergistic intracellular anti-inflammatory effect. The constructed correlation between the mentioned descriptors and FPF values showed appropriate power of predictivity. Conclusion: The findings in the current study emphasize that jet milling and electrospraying are suitable particle engineering methods to produce inhalable dry powder formulations of montelukast. Moreover, using montelukast associated with budesonide not only has greatly improved the aerosolization behavior and dissolution rate of budesonide but also has resulted in synergistic pharmacological effects, indicating the suitability of this combination as an anti-asthmatic therapeutic. The authors believe that this model is capable of predicting the lung deposition pattern of a formulation with an acceptable precision