Risedronate sodium (RS) is a potent inhibitor of bone resorption, having an extreme poor permeability and limited oral bioavailability (0.62%). RS should be orally administered under fasting conditions while keeping in an upright posture for at least 30 min to diminish common gastroesophageal injuries. To surmount such limitations, novel risedronate-chitosan (RS-CS) crosslinker-free nebulizable microspheres were developed adopting the quality by design (QbD) approach and risk assessment (RA) thinking. RS:CS ratio, surfactant (Pluronic® F127) concentration, homogenization duration, speed, and temperature were identified using Ishikawa diagrams as the highest formulation and process risk factors affecting the critical quality attributes (CQAs), average particle size (PS), and entrapment efficiency (EE%). The risk factors were screened using the Plackett-Burman design, and the levels of the most significant factors were optimized using a multilevel factorial design to explore the optimized system with the least PS, maximum EE%, and a prolonged drug release profile. The optimized system (B6) was developed at a RS:CS ratio of 1:7, a surfactant concentration of 2% (w/v), and a homogenization speed of 14,000 rpm. It revealed good correlation with QbD theoretical prediction, where positively charged (47.9 ± 3.39 mV) discrete, spherical microspheres (3.47 ± 0.16 μm) having a high EE% (94.58 ± 0.19%) and prolonged RS release over 12 h (Q12 h, 89.70 ± 0.64%) were achieved. In vivo lung deposition after intratracheal instillation of B6 confirmed the delivery of high RS percentage to rat lung tissues (87 ± 3.54%) and its persistence for 24 h. This investigation demonstrated the effectiveness of QbD philosophy in developing RS-CS crosslinker-free nebulizable microspheres.
Keywords: chitosan; crosslinker-free; microspheres; quality by design (QbD); risedronate sodium.