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Toxicity and gut associated lymphoid tissue translocation of polymyxin B orally administered by alginate/chitosan
Gilberto Coppi1, Moreno Bondi, Andrea Coppi
1Department of Pharmaceutical Sciences, University of Modena and Reggio Emilia, Via Campi 183, 41100 Modena, Italy. coppi.gilberto@unimore.it
Abstract:
Fluorescent calcium alginate/chitosan microparticles, prepared using a spray-drying technique followed by crosslinking reactions with calcium ions and chitosan, were assayed in-vivo for polymyxin B (PMB) oral toxicity, uptake by Peyer's patches and PMB oral absorption. A single PMB dose (300 mg kg(-1)), loaded in microparticles or dissolved in water, was administered to rats by oral gavage under fasted and fed conditions. By monitoring incidence of mortality, animal behaviour, clinical signs and abnormality in several organs, PMB in water solution was found lethal at a dose lower than the LD50 (790 mg kg(-1)) in the fasted state and toxic for the gastrointestinal tract in the fed state. However, no signs of acute toxicity at the level of the gastrointestinal tract were observed when animals were administered PMB loaded in microparticles under fasted and fed conditions. A lower PMB dose (125 mg kg(-1)), loaded in microparticles or dissolved in water, was given to rats in a fed state to determine PMB levels in Peyer's patches, urine and serum as well as to detect the loaded microparticles inside Peyer's patches for three days after dosing. Abnormalities were observed at gut level only when PMB was dosed in a water solution. Detectable antibiotic levels in Peyer's patches and urine as well as more constant PMB serum concentrations were provided by dosing PMB loaded in microparticles. Therefore, the use of alginate/chitosan microparticles to target the lymphatic system could improve safety when administering PMB orally.
Insights
Oral administration of polymyxin B (PMB) in alginate/chitosan microparticles significantly reduced toxicity compared to free PMB. This novel delivery system enhanced PMB uptake by Peyer's patches, improving safety and targeting the lymphatic system.
Area of Science:
- Biomaterials Science
- Pharmacology
- Drug Delivery Systems
Background:
- Polymyxin B (PMB) is a critical antibiotic, but its oral administration is limited by toxicity.
- Alginate/chitosan microparticles offer a potential solution for targeted oral drug delivery.
- Investigating the in-vivo safety and efficacy of PMB-loaded microparticles is crucial.
Purpose of the Study:
- To evaluate the oral toxicity of PMB when loaded into alginate/chitosan microparticles.
- To assess the uptake of PMB and microparticles by Peyer's patches.
- To determine the oral absorption and serum concentration of PMB delivered via microparticles.
Main Methods:
- Spray-drying technique to prepare fluorescent calcium alginate/chitosan microparticles.
- In-vivo studies in rats comparing PMB in microparticles versus water solution under fasted and fed conditions.
- Monitoring mortality, clinical signs, organ abnormalities, and quantifying PMB levels in serum, urine, and Peyer's patches.
Main Results:
- PMB in water solution showed significant oral toxicity and gastrointestinal damage, especially when fasted.
- PMB-loaded microparticles demonstrated no acute gastrointestinal toxicity in either fasted or fed states.
- Microparticle delivery resulted in detectable PMB in Peyer's patches and urine, with more consistent serum concentrations.
Conclusions:
- Alginate/chitosan microparticles effectively mitigate the oral toxicity of polymyxin B.
- This delivery system enhances targeted uptake by Peyer's patches, suggesting lymphatic system targeting.
- Microparticle formulation represents a safer oral delivery strategy for polymyxin B.
