Self-emulsifying drug delivery systems containing hydrophobic ion pairs of polymyxin B and agaric acid: A decisive strategy for enhanced antimicrobial activity

Aamir Jalil,Mulazim Hussain Asim,Imran Nazir,Barbara Matuszczak,Andreas Bernkop-Schnürch

doi:10.1016/j.molliq.2020.113298

Aamir Jalil, Mulazim Hussain Asim + Show 3 more

Open Access

https://doi.org/10.1016/j.molliq.2020.113298

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Abstract

The aim of the study was to develop self-emulsifying drug delivery systems (SEDDS) providing a synchronized delivery of an antibiotic drug and a complexing agent for enhanced antimicrobial efficacy. Polymyxin B (PMB) was ion paired with agaric acid (AA) serving as complexing agent and lipophilic counter ion and incorporated into SEDDS. Resazurin assay was performed to assess toxicity of SEDDS having been diluted with minimum essential medium. SEDDS were diluted 1:10 in 0.01 M NaOH and evaluated for their ability to bind Ca2+ and Mg2+ as well as for enhanced antimicrobial activity using E. coli as model germ. Resazurin assay revealed that >80% of Caco-2 cells remain viable up to a SEDDS concentration of 0.5% (v/v) within 4 h. SEDDS showed chelating properties by binding 18.7 ± 0.7 g of Ca2+ and 12.0 ± 0.6 g of Mg2+ per mol of AA accumulating to a high extent on the surface of the oily droplets. SEDDS containing the PMB-AA complex and AA exhibited 36- and 13- fold enhanced antimicrobial activity compared to SEDDS containing just AA or the PMB-AA complex, respectively. The combination of PMB with a complexing agent serving also as lipophilic counter ion for hydrophobic ion pairing seems to be a promising strategy to enhance the antimicrobial activity of this antibiotic.

Highlights

In the last century, discovery of antibiotics radically improved the treatment of microbial infection [1]
hydrophobic ion pairs (HIPs) of Polymyxin B (PMB) were formed by using anionic agaric acid as lipidizing agent
The interaction between the positively charged PMB and negatively charged agaric acid (AA) resulted in the formation of stable HIPs

Summary

Introduction

Discovery of antibiotics radically improved the treatment of microbial infection [1]. In order to achieve a high antimicrobial activity, the antibiotic should ideally reach together with citric acid the target site which is from the drug delivery point of view a great challenge. To achieve this goal, both active species have to be incorporated into a single delivery system capable of efficiently reaching the target site and providing their synchronized release there. A promising strategy to achieve a synchronized release is the formation of complexes between cationic antibiotics with citric acid. Its potential use as potentiating agent for antibiotics has not been evaluated at all

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