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Published on: August 28, 2015
Nanoformulation of Polymyxin E Through Complex Coacervation: A Pharmacokinetic Analysis
Xiaobao Chen1, Li Liu1, Weidan Wang1
1Scindy Pharmaceutical Co., Ltd., Suzhou Industrial Park, Suzhou 215125, China.
Abstract:
Objectives: 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. Methods: 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. Results: 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. Conclusions: 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.
Insights
New nanoformulations of Polymyxin E (PME) were created using complex coacervation. These PME nanoformulations reduce toxicity while maintaining potent antibacterial activity against resistant infections.
Area of Science:
- Pharmaceutical Sciences
- Nanotechnology
- Infectious Diseases
Background:
- Polymyxin E (PME) is a critical antibiotic for treating multidrug-resistant Gram-negative bacteria.
- Nephrotoxicity is a significant dose-limiting side effect of PME therapy.
- Innovative formulation strategies are needed to mitigate PME's adverse effects while preserving efficacy.
Purpose of the Study:
- To develop PME nanoformulations using complex coacervation to reduce toxicity.
- To evaluate if charge neutralization during formulation impacts PME's efficacy, pharmacokinetics, and tissue distribution.
- To assess the safety and therapeutic effectiveness of the developed PME nanoformulations.
Main Methods:
- Complex coacervation was employed using three negatively charged polyions (potassium sucrose octasulfate, polytamic acid, sodium hyaluronate) with PME.
- Characterization of PME-polyion nanocomplexes, including size and polydispersity index (PDI).
- Evaluation of nanoformulations through minimum inhibitory concentration (MIC) assays, in vivo efficacy studies in a mouse model, pharmacokinetic analysis, tissue distribution, and toxicity assessments.
Main Results:
- Successfully formed PME nanoformulations (<30 nm, PDI < 0.3) with varying polyions and charge ratios.
- PME nanoformulations demonstrated equivalent or enhanced antibacterial activity compared to standalone PME.
- In vivo studies showed increased maximum tolerated dose, reduced adverse reactions, and comparable pharmacokinetic profiles to standalone PME.
Conclusions:
- Complex coacervation is an effective method for developing PME nanoformulations.
- The developed nanoformulations mitigate PME's inherent positive charge, reducing toxicity.
- These nanoformulations offer a promising strategy to improve PME's therapeutic index for treating resistant infections.
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