Formulation optimization, in vitro and in vivo correlation, and long-acting analgesic efficacy of dezocine-loaded microspheres overcoming the “quick sand” phenomenon

Abstract

Polymeric acids and their copolymer-based microspheres constitute a critical platform for extended and controlled-release drug delivery systems. However, the precipitated drug crystals (commonly termed “quick sand” phenomenon) during microsphere fabrication significantly limits their application for specific drug molecules, leading to suboptimal drug loading (DL) and encapsulation efficiency (EE) in final products. In this study, dezocine-loaded microspheres (Dez-Ms) were fabricated using microfluidic reactor technology. The formulation and process parameters were systematically optimized through single-factor screening and orthogonal experimental design. Three distinct formulations with high, medium, and low release profiles (designated as Dez-Ms-H, Dez-Ms-M, and Dez-Ms-L) were characterized for mean particle size, DL, and EE. The optimized formulations exhibited mean particle sizes of 55.99 ± 0.02 μm, 62.42 ± 0.01 μm, and 52.93 ± 0.16 μm, DL values of 25.96 ± 0.14 %, 25.02 ± 0.23 %, and 23.12 ± 0.52 %, and EE values of 86.65 ± 0.28 %, 86.33 ± 0.66 %, and 79.72 ± 2.00 %, respectively. Physicochemical characterization via X-ray powder diffraction, differential scanning calorimetry, and Fourier transform infrared spectroscopy revealed alterations in the drug’s melting point, crystalline form, and infrared absorption peaks post-encapsulation, suggesting intermolecular interactions between the polymeric carrier and the drug within the microspheres. Pharmacokinetic analysis demonstrated that, compared to the dezocine solution group (Dez-Sol), the microsphere groups (Dez-Ms-H, Dez-Ms-M, and Dez-Ms-L) exhibited significantly elevated maximum drug concentrations (C_max) and clearance rates (CL), alongside prolonged time to peak concentration (T_max), elimination half-life (T_1/2), and mean residence time (MRT) (p < 0.05), confirming sustained in vivo release kinetics. An internally validated in vitro-in vivo correlation (IVIVC) model demonstrated robust predictive capability for the microspheres’ pharmacokinetic behavior, establishing a foundation for achieving Level A IVIVC compliance. Additionally, a significant delay in pain response latency (p < 0.05) was observed in the Dez-Ms groups compared to Dez-Sol, indicating sustained analgesic efficacy. Preliminary stability studies further identified optimal storage conditions for Dez-Ms as hermetically sealed containers under dry, low-temperature, and light-protected environments. In conclusion, this study successfully optimized Dez-Ms formulations to overcome the “quick sand” limitation, achieving high EE, validated IVIVC, and prolonged analgesic activity. These findings advance the development of polymeric microsphere systems for controlled drug delivery applications.