Abstract
Roflumilast is currently administered orally to control acute exacerbations in chronic obstructive pulmonary disease (COPD). However, side effects such as gastrointestinal disturbance and weight loss have limited its application. This work aimed to develop an inhalable roflumilast formulation to reduce the dose and potentially circumvent the associated toxicity. Roflumilast was cospray-dried with trehalose and L-leucine with varied feed concentrations and spray-gas flow rates to produce the desired dry powder. A Next-Generation Impactor (NGI) was used to assess the aerosolization efficiency. In addition, different devices (Aerolizer, Rotahaler, and Handihaler) and flow rates were used to investigate their effects on the aerosolization efficiency. A cytotoxicity assay was also performed. The powders produced under optimized conditions were partially amorphous and had low moisture content. The powders showed good dispersibility, as evident by the high emitted dose (>88%) and fine particle fraction (>52%). At all flow rates (≥30 L/min), the Aerolizer offered the best aerosolization. The formulation exhibited stable aerosolization after storage at 25 °C/15% Relative Humidity (RH) for one month. Moreover, the formulation was non-toxic to alveolar basal epithelial cells. A potential inhalable roflumilast formulation including L-leucine and trehalose has been developed for the treatment of COPD. This study also suggests that the choice of device is crucial to achieve the desired aerosol performance.
Highlights
Chronic obstructive pulmonary disease (COPD) is a progressive airflow obstruction associated with chronic lung inflammation, which impairs a patient’s quality of life, and acute exacerbation can lead to death [1]
Bronchodilators, corticosteroids, muscarinic antagonists, methylxanthines, phosphodiesterase-4 (PDE4) inhibitors, and mucolytic agents currently constitute the treatment for COPD [3]
An increase in feed concentration increased the process yield, whereas the spray-drying gas flow rate did not have any effect on the yield (Figure 1, Table 3)
Summary
Chronic obstructive pulmonary disease (COPD) is a progressive airflow obstruction associated with chronic lung inflammation, which impairs a patient’s quality of life, and acute exacerbation can lead to death [1]. Bronchodilators, corticosteroids, muscarinic antagonists, methylxanthines, phosphodiesterase-4 (PDE4) inhibitors, and mucolytic agents currently constitute the treatment for COPD [3]. The PDE4 inhibitor shows particular promise against COPD as PDE enzymes hydrolyze and inactivate cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP), which regulate smooth muscle relaxation and inflammatory mediator release [4]. Roflumilast (3-cyclo-propylmethoxy-4-difluoromethoxy-N-[3,5-dichloropyrid-4-yl]benzamide) is a selective PDE4 inhibitor used to control acute exacerbations in patients with severe COPD [3]. The current roflumilast oral therapy has a clear purpose in Pharmaceutics 2021, 13, 1254.
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