Jia Liyan, Zhou Kaixiang, Zhang Xuechun, Gao Xing, Kang Jijun, Shen Jianzhong, Zhu Kui
National Key Laboratory of Veterinary Public Health and Safety, College of Veterinary Medicine, China Agricultural University, Beijing, 100193, People's Republic of China.
Drug Des Devel Ther. 2025 Sep 6;19:7809-7823. doi: 10.2147/DDDT.S536132. eCollection 2025.
The rapid progression of bacterial resistance and the dearth of novel antimicrobial drug development impose a significant public health burden on the treatment of bacterial infections. Drug combination therapy has become an attractive strategy for combating multidrug-resistant bacterial infections. More importantly, matching the physicochemical properties of multiple components in formulations is essential for clinical application.
First, an enrofloxacin-colistin combination injection was developed using a tripartite strategy, defined as a three-step process involving the conversion of enrofloxacin to its salt form, the addition of 1,2-propanediol, and pH adjustment. Second, independent gradient model based on Hirshfeld surface (IGMH), nuclear magnetic resonance (NMR), and ultraviolet-visible spectroscopy (UV-vis) analysis were used to investigate the molecular mechanism of this process. Finally, the irritancy, toxicity, and efficacy of the combination injection were evaluated in vivo and in vitro.
The tripartite strategy increased the solubility of enrofloxacin by 1500-fold from 0.18 mg/mL to 272.76 mg/mL, thereby preventing enrofloxacin precipitation during 6 months at both 30°C and 4°C, maintaining colistin stability, and reducing injection-site irritation. 1,2-Propanediol enhanced hydrogen bonding with enrofloxacin and inhibited its self-aggregation. Importantly, the combination injection exhibited no significant liver and kidney toxicity while demonstrating outstanding therapeutic efficacy against pneumonia with 62.5% survival rate.
The limited solubility of enrofloxacin has long hindered its co-formulation with pH-sensitive drugs. The tripartite strategy establishes a paradigm for overcoming challenges related to the crystal precipitation of insoluble drugs and the pH limitations in complex formulations. Our findings demonstrate that the tripartite strategy effectively enhances the solubility, stability, and therapeutic efficacy of enrofloxacin-colistin combinations, offering a novel solution to overcome challenges in developing complex antibacterial formulations for veterinary use.
细菌耐药性的快速发展以及新型抗菌药物研发的匮乏给细菌感染的治疗带来了巨大的公共卫生负担。联合用药疗法已成为对抗多重耐药细菌感染的一种有吸引力的策略。更重要的是，使制剂中多种成分的物理化学性质相匹配对于临床应用至关重要。
首先，采用三方策略开发恩诺沙星 - 黏菌素联合注射液，该策略定义为一个三步过程，包括将恩诺沙星转化为其盐形式、添加1,2 - 丙二醇以及调节pH值。其次，基于 Hirshfeld 表面的独立梯度模型（IGMH）、核磁共振（NMR）和紫外 - 可见光谱（UV - vis）分析用于研究该过程的分子机制。最后，在体内和体外评估联合注射液的刺激性、毒性和疗效。
三方策略使恩诺沙星的溶解度从0.18毫克/毫升提高了1500倍至272.76毫克/毫升，从而在30°C和4°C下6个月内防止恩诺沙星沉淀，保持黏菌素稳定性，并减少注射部位刺激。1,2 - 丙二醇增强了与恩诺沙星的氢键作用并抑制其自聚集。重要的是，联合注射液在对肺炎的治疗中表现出显著疗效，生存率为62.5%，同时未表现出明显的肝肾毒性。
恩诺沙星有限的溶解度长期以来阻碍了其与pH敏感药物的共制剂开发。三方策略为克服与不溶性药物晶体沉淀以及复杂制剂中pH限制相关的挑战建立了一个范例。我们的研究结果表明，三方策略有效地提高了恩诺沙星 - 黏菌素组合的溶解度、稳定性和治疗效果，为克服兽用复杂抗菌制剂开发中的挑战提供了一种新的解决方案。
