Span Value as a Critical Quality Attribute for PLGA Microspheres: Controlling Burst Release and Enhancing Therapeutic Efficacy via Wet Sieving

<b>Background/Objectives:</b> Poly(lactic-co-glycolic acid) (PLGA) microspheres offer sustained drug delivery but often suffer from broad particle size distribution (PSD), leading to inconsistent release profiles. This study investigates wet sieving as a post-processing strategy to precisely control PSD, quantified by the Span value, and evaluates its impact on the performance of triamcinolone acetonide (TA)-loaded PLGA microspheres. <b>Methods:</b> Triamcinolone acetonide-loaded PLGA microspheres were prepared via emulsification-solvent evaporation. Wet sieving was employed as a post-processing strategy to obtain distinct particle size fractions and groups with defined polydispersity (Span values). The microspheres were characterized for particle size distribution, drug loading, surface morphology, and in vitro release kinetics. To establish the in vivo relevance of polydispersity control, the pharmacokinetic profiles of different Span groups were first determined using LC-MS/MS following intra-articular injection in rats. Subsequently, their therapeutic efficacy was evaluated in a rat model of knee osteoarthritis, with outcomes assessed by joint swelling measurement and histopathological analysis. <b>Results:</b> Microspheres were prepared, fractionated into distinct size groups (0-20, 20-28, 28-40, 40-50, >50 μm) and polydispersity groups (Span = 1.4, 0.8, 0.5). We identified Span as a dominant factor independent of mean particle size. Reducing the Span from 1.4 to 0.5 significantly decreased burst release (24.15% to 14.51%), prolonged mean residence time (MRT 88.52 to 123.53 h), and enhanced anti-inflammatory and cartilage-protective effects in a rat model of knee osteoarthritis. <b>Conclusions:</b> This work establishes Span ≤ 0.5 as a critical quality attribute and presents wet sieving as a simple, effective method to ensure batch-to-batch consistency and predictable in vivo performance for PLGA microsphere products.