Chen Xiaobao, Liu Li, Wang Weidan, Yuan Yuan, Wang Wei
Scindy Pharmaceutical Co., Ltd., Suzhou Industrial Park, Suzhou 215125, China.
Center for Pharmacy, University of Bergen, 5020 Bergen, Norway.
Pharmaceutics. 2025 Jan 8;17(1):76. doi: 10.3390/pharmaceutics17010076.
Polymyxin E (PME), a polymyxin antibiotic, serves as a final resort against antibiotic resistance. Nephrotoxicity is the primary concern when employing PME. To alleviate this issue, researchers have explored strategies including dosing adjustments and innovative formulations. This study employed complex coacervation to create PME nanoformulations, capitalizing on PME's charge properties. The research question and hypothesis posed pertained to whether neutralization of PME's positive charge during formulation would reduce its antibiotic efficacy and alter its tissue distribution and other pharmacokinetic parameters. Our objective was to evaluate the capability of complex coacervation to mitigate the adverse effects of PME while preserving its antibacterial potency and therapeutic effectiveness. Three negatively charged polyions: potassium sucrose octasulfate, polytamic acid, and sodium hyaluronate, were used for formulation. We performed characterization on the nanocomplex formed by the polyions and PME. The nanoformulations underwent several tests, including minimum inhibitory concentration, in vivo efficacy on an infected mouse model, pharmacokinetic assessments, tissue distribution, and toxicity. the three polyions formed coacervation complexes with PME at varying charge ratios, yielding nanoparticles smaller than 30 nm with low polydispersity (PDI < 0.3). The results demonstrated that complex coacervation-mediated PME nanoformulations exhibited equivalent or superior antibacterial activity, increased maximum tolerant dose, and fewer adverse reactions in animal tests. Utilizing complex coacervation, PME nanoformulations were developed, demonstrating efficacy in the formulation process. Pharmacokinetic assessments revealed absorption and distribution profiles akin to those of standalone PME. The positive charge inherent in PME causing its toxicity was mitigated after complex coacervation.
多粘菌素E（PME）是一种多粘菌素类抗生素，是对抗抗生素耐药性的最后手段。使用PME时，肾毒性是主要关注点。为缓解这一问题，研究人员探索了包括调整剂量和创新制剂等策略。本研究利用复凝聚法制备PME纳米制剂，利用了PME的电荷特性。所提出的研究问题和假设涉及制剂过程中PME正电荷的中和是否会降低其抗生素疗效并改变其组织分布及其他药代动力学参数。我们的目标是评估复凝聚法减轻PME不良反应同时保留其抗菌效力和治疗效果的能力。使用了三种带负电荷的聚离子：蔗糖八硫酸钾、聚谷氨酸和透明质酸钠进行制剂。对聚离子与PME形成的纳米复合物进行了表征。对纳米制剂进行了多项测试，包括最低抑菌浓度、对感染小鼠模型的体内疗效、药代动力学评估、组织分布和毒性测试。这三种聚离子与PME以不同电荷比形成凝聚复合物，产生小于30 nm且多分散性低（PDI < 0.3）的纳米颗粒。结果表明，复凝聚介导的PME纳米制剂在动物试验中表现出同等或更高的抗菌活性、增加的最大耐受剂量以及更少的不良反应。利用复凝聚法开发了PME纳米制剂，在制剂过程中证明了其有效性。药代动力学评估显示其吸收和分布概况与单独的PME相似。复凝聚后，PME固有的导致其毒性的正电荷得到了减轻。
