Characterization of suspension-based metered dose inhaler formulations composed of spray-dried budesonide microcrystals dispersed in HFA-134a.

Abstract

Purpose. To assess the physicochemical characteristics and aerosol properties of suspensions of lipid-coated budesonide microcrystals dispersed in HFA-134a. Methods. Lipid-coated budesonide microcrystals were prepared by spray-drying an emulsion-based feedstock. Physicochemical characteristics of spray-dried particles were assessed by electron microscopy, laser diffraction, and differential scanning calorimetry. Purity and content were determined by reverse-phase HPLC. Particle aggregation and suspension stability were assessed visually, and aerosol performance was assessed by Andersen cascade impaction and dose content uniformity. Results. Spray-drying of micronized budesonide microcrystals in the presence of phospholipid-coated emulsion droplets results in the production of low-density lipid-coated microcrystals with low surface energy. These spray-dried particles form stable suspensions in HFA-134a. This translates into good uniformity in the metered dose across the contents of the inhaler and acceptable aerodynamic particle size distributions (MMAD = 3.2 to 3.4 μm). The formulation was observed to maintain its performance over 6 months at 40°C/75% RH and 16 months at 25°C/60% RH. No effect of storage orientation was observed on the content of first sprays following storage (i.e., no Cyr effect). The fine particle dose was found to be linear out to suspension concentrations of about 2% wt/vol, and FPD4.7μm values approaching 400 μg can be delivered in a single inhalation. Conclusions. Engineered particles comprised of lipid-coated microcrystals may provide an acceptable alternative formulation technology for metered dose inhalers in the new hydrofluoroalkane propellants.