Characterization of a dextran-budesonide prodrug for inhalation therapy

Reducing the dosing frequency of corticosteroids may increase compliance and increase pulmonary targeting. The objective of this study was to evaluate whether a high molecular weight dextran-budesonide conjugate might be suitable for pulmonary slow release of the otherwise fast absorbed budesonide. An array of dextran-spacer-budesonide conjugates was prepared that differed in the molecular weight of dextran (20 kDa or 40 kDa) and the length of the dicarboxylic spacer (succinic, glutaric, and adipic anhydride). The conjugates were characterized for identity by proton nuclear magnetic resonance (¹H NMR) and Fourier-transform infrared spectroscopy (FTIR), the degree of dextran-hydroxyl conjugation, purity, and physiological activation (release of budesonide). The 40 kDa dextran-succinate-budesonide conjugate was formulated as a dry powder for pulmonary delivery and characterized for particle size distribution, particle morphology, and aerodynamic particle size. The degree of substitution (grams of budesonide in 100 g of conjugate) ranged from 4 to 10% for all six dextran-spacer-budesonide conjugates. Incubation at 37 °C and pH 7.4 in phosphate buffered saline resulted in release of 25-75% of the conjugated budesonide over an 8-hour period with the rate of release increasing with molecular weight of dextran and the length of the spacer. Modeling of the concentration time profiles of the released budesonide and budesonide-21-hemisucinate in phosphate buffered saline, suggested that budesonide is generated either directly or via the budesonide-21-hemisucinate pre-cursor. Data also suggested that the rate of budesonide generation likely depends on the position of budesonide on the dextran molecule. Spray-drying the 40 kDa dextran-succinate-budesonide produced respirable particles of the conjugate with a mass median aerodynamic particle size (MMAD) of 4 μm. The slow generation of budesonide from the chemical delivery system might further improve the pharmacological profile of budesonide.