A controlled release formulation of a budesonide prodrug for asthma inhalation therapy

Budesonide is a non-halogenated glucocorticoid steroid that is currently prescribed to provide the anti-inflammatory therapy for maintenance treatment of asthma. Reducing the asthma therapy dosing regimen may increase compliance and, consequently improve upon the prophylactic maintenance treatment of asthma. A controlled release drug that can be retained in the lung and release the active drug over time may address this problem.;The overall objective of this study was to synthesize a budesonide prodrug and to spray-dry the prodrug for inhalation. The prodrug synthesis included the conjugation of budesonide to three spacer molecules and to two dextran carrier polymers. The prodrugs were tested for their chemical activation by the release of budesonide and the budesonide-21-hemiester in phosphate buffer (pH 7.4 and 37°C) with and without esterase. The measured release of budesonide and the budesonide-21-hemiester concentration-time profiles were then evaluated by multi-compartmental modeling. A selected prodrug was then spray-dried with a lipid and evaluated for particle morphology, particle size, thermodynamic response, encapsulation, chemical stability, and aerodynamics.;The total amount of budesonide released over 8 hours in phosphate buffer was the greatest for the prodrugs containing the longer chain spacer molecules with 50-80% of the conjugated budesonide released. Four models were evaluated for goodness of fits using the coefficient of determination, Akaike Information Criterion (AIC), and area under the curve (AUC) between the measured and model-predicted concentration-time profiles for budesonide and budesonide-21-hemisuccinate. The model with parallel activation of the prodrug (Model 3 and 4) proved to be the more representative model of the measured budesonide and budesonide-21-hemisuccinate concentration-time profile data.;Spray drying the budesonide prodrug with lactose produced smooth spherical particles, while the addition of a lipid caused the particles to have an irregular spherical shape. The spray-dried particles produced respirable size particles with a mass median aerodynamic diameter (MMAD) less than 5 mum. The lipid-containing spray-dried budesonide prodrug had a delayed release of budesonide while the spray-dried budesonide prodrug without lipid released nearly 33% (w/w) of its available conjugated budesonide in phosphate buffer. Spray-drying the budesonide prodrug with a lipid achieved a controlled release budesonide prodrug formulation with an inhalable particle size for asthma inhalation therapy.