| The morphology and physico-chemical properties of inhaled particles can have a significant effect on in vitro and in vivo performance of dry powder aerosols. It is proposed that particle engineering techniques can optimize these properties and may be correlated to in vivo performance of an anticholinergic bronchodilator. The specific aims addressing this hypothesis include: generation and characterization of suitable respirable particles, particle engineering to attain sustained release properties and demonstration of pharmacodynamic effect.; Engineered particles suitable for inhalation were generated and characterized. The crystalline primary particles (ipratropium bromide (IPB)/glycine) exhibited a hollow, spherical morphology. Experimental design techniques were employed to identify critical process parameters and optimize the spray drying process to generate engineered particles. Two sustained release formulation strategies were explored and primary particle coating with polylactic acid (PLA) was chosen as the optimum approach. Crystalline, stable particles with a range of dissolution profiles were created by application of different amounts of PLA coating. (1, 5, 10, 15, 30 and 50%w/w). A novel, robust, modified Type IV dissolution method was developed to discriminate between different formulations and strategies. An empirical composite index was established for evaluation of tablet/capsule powder flow properties that was correlated (R2 = 0.9931) with a statistical principal components analysis (PCA) that explained 72.75% of variability in data. When applied to inhalation blends, PCA accounted for 81.68% of data variability. An improvement in blend content uniformity was noted with improved flow but no correlation with dispersion could be demonstrated. Preliminary studies in guinea pigs showed a large difference in duration of bronchodilatory effect for IPB powders alone (11.0 min) when compared to 5% (13.5 min) and 30% PLA coated particles (56.3 min) particles. Statistical differences (p < 0.05) between 5% PLA and 15% PLA treatments as compared to a negative control were demonstrated in additional guinea pig studies.; These are the first studies to compare physicochemical properties of hollow, spherical, engineered respirable particles to in vitro and in vivo performance. Novel methods of characterizing particle dissolution and inhalation blend macroscopic flow properties were developed. A trend between in vitro dissolution properties and pharmacodynamic effect is apparent but a correlation cannot be inferred from the data. |
