Nanoformulation of Polymyxin E Through Complex Coacervation: A Pharmacokinetic Analysis

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.