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Abstract
The aim of the study was to optimize and characterize high therapeutic payload large respirable powders prepared by spray-drying technique for maximum fine particle fraction with minimum quantities of excipients. Influence of formulation components was optimized by a three-factor, five-level central composite design having different proportions of L-leucine (X1), tobramycin sulfate (X2), and poloxamer-188 (X3) as the independent variables and fine particle fraction as a response variable (Y). Large respirable powders were characterized for particle size, size distribution, moisture, crystallinity, and morphology. In vitro aerosol performance of powders was determined by an eight-stage Andersen cascade impactor using the Rotahaler. Mathematical model elucidated for Y was Y = 56.2068 + 5.7481 X1 - 3.0531 X2 + 0.8468 X3 + 1.1737 X1 X2 − 0.5012 X1 X3 − 0.7412 X2 X3 − 0.7149 X12 − 1.9212 X22 − 1.6187X32. The component of greatest influence on product performance (response variable) was found to be L-leucine. Lack of fit was not significant (p = 0.08), and regression equation predicted response for Y was in reasonably good agreement with experimental values (p = 0.01; R2 = 0.92). The optimal model predicted with a fine particle fraction of 62.8 ± 2.6% with X1, X2, X3 levels of 20, 45.71, and 5.51 respectively. Large respirable powders with TB load of 45.7% w/w were prepared; they had smooth surface texture, dimpled spherical shape, roundness value close to 1(1.048 ± 0.032) and were found to possess bulk tap densities of 0.04 g/cc, geometric particle sizes of 6–7 μm, and emitted dose of 92%. The results of the studies suggest that in vitro aerosol performance was affected significantly by small and deliberate change of specific formulation components and its proportions. It may be concluded that appropriate type and proportion of excipients is necessary to obtain maximum fine particle fraction of large respirable powders containing high therapeutic payloads.