Reducing burst release and enhancing sustained release in SAIB-based implants: The role of polyphenol-modification

Xue Wang; Zao Ji; Di Wu; Tengfei Zhou; Yongjun Wang; Lu Liu; Guangqi Yan

doi:10.1016/j.ejmech.2025.117958

Reducing burst release and enhancing sustained release in SAIB-based implants: The role of polyphenol-modification

Eur J Med Chem. 2025 Jul 9:297:117958. doi: 10.1016/j.ejmech.2025.117958. Online ahead of print.

Authors

Xue Wang¹, Zao Ji², Di Wu³, Tengfei Zhou⁴, Yongjun Wang⁵, Lu Liu⁶, Guangqi Yan⁷

Affiliations

¹ Department of Orthodontics, School of Stomatology, China Medical University, Shenyang, 110002, China.
² Department of Otolaryngology, The First Hospital of China Medical University, Shenyang, 110001, China.
³ Department of Cardiology, The First Hospital of China Medical University, Shenyang, 110001, China.
⁴ Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang, 110016, China.
⁵ Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang, 110016, China. Electronic address: wangyongjun@syphu.edu.cn.
⁶ Department of Preventive Dentistry, School and Hospital of Stomatology, Liaoning Provincial Key Laboratory of Oral Diseases, China Medical University, Shenyang, 110002, China. Electronic address: lliu82@cmu.edu.cn.
⁷ Department of Oral and Maxillofacial Surgery, School and Hospital of Stomatology, Liaoning Provincial Key Laboratory of Oral Diseases, China Medical University, Shenyang, 110002, China. Electronic address: gqyan@cmu.edu.cn.

PMID: 40652672
DOI: 10.1016/j.ejmech.2025.117958

Abstract

Sucrose acetate isobutyrate (SAIB)-based in situ forming implants (SADS) are promising for long-acting drug delivery but suffer from undesirable burst release. Here, we propose a molecular-level strategy to mitigate burst release by covalently modifying the antipsychotic drug aripiprazole (ARP) with polyphenols-specifically 4-hydroxybenzoic acid (HBA), protocatechuic acid (PCA), and gallic acid (GA). These moieties form strong hydrogen bonds with SAIB, enhancing drug-matrix interactions. Among them, ARP-GA exhibited the best performance, showing a significant reduction in burst release (8.99 ± 2.10 %) compared to unmodified ARP (22.84 ± 1.03 %) and sustained release over 30 days in vitro. In vivo pharmacokinetics in rats confirmed prolonged circulation with a 2.5-fold increase in AUC (1466.59 ± 139.35 vs. 592.66 ± 157.68 ng/mL•d), extended T_max (6.40 ± 2.97 vs. 0.29 ± 0.42 days), and lower C_max/C_S (2.32 vs. 3.41), indicating improved release control. Rheological and porosity analysis supported the enhanced drug retention mechanism via hydrogen bonding. This approach also proved effective for six additional drugs, suggesting broad applicability. These findings demonstrate that polyphenol modification of APIs offers a carrier-compatible, drug-centric solution for burst release regulation. Overall, this strategy significantly enhances the safety and efficacy of SAIB-based long-acting injectable systems.

Keywords: Aripiprazole derivative; Burst release suppression; Long-acting drug delivery; Pharmacokinetic enhancement; Polyphenol-modified prodrug; SAIB-Based in situ implant.