Abstract

The current study has focused on the local delivery of furazolidone to the gut with the aim of generating alternative approaches for the treatment of Helicobacter pylori (H. pylori). Furazolidone has proven antibacterial activity against H. pylori, which has a unique niche in the stomach mucus. This drug was chosen as it is not currently used for the treatment of H. pylori and thus resistance is not expected to be a problem.
Chitosan micro-particles were formulated by the spray drying technique, followed by optimization of mucoadhesion and drug release profiles using glutaraldehyde crosslinking agent at two pH values (1.3 and 4.5). Results revealed that increasing glutaraldehyde decreased the mucin adsorption and at low pH drug release was increased. For liposomal formulations, the effects of furazolidone concentration, chitosan and cholesterol on encapsulation efficacy and in vitro drug release were evaluated. It was found that increasing the pH from 1.3 to 4.5 increased the mucoadhesive behaviour of chitosan coated liposomes from 42% to 60%. Also, increasing the furazolidone amount from 4mg to 5mg increased encapsulation efficiency. A combination of two antibiotics (including furazolidone) was prepared in muco-penetrative liposomal formulations; N-acetylcysteine was used for the muco- penetration effect with Pluronic F-127. These formulations were investigated for their charge effect on muco-penetration and drug encapsulation. The data showed that neutral liposomes easily diffuse through the mucus layer.
Escherichia coli was selected to establish the assay protocol for Helicobacter pylori. The microdilution approach was used for assaying the furazolidone minimum inhibitory concentration (MIC), which was found to be 16 μg/ml for E. coli and 4
μg/ml for H. pylori. In time-dependent killing studies, it was possible to observe
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complete killing of the bacteria. Increasing furazolidone concentration by two fold of its MIC, reduced the time required to kill bacteria. The mucoadhesive drug formulations also increased the residence time of furazolidone in the stomach mucus from 2- 3 hours to 4-6 hours; this time period would then be appropriate for killing the bacteria in the stomach. For mucopenetration study complete killing was achieved in 2.5 hours when furazolidone with 1 % minimum inhibitory concentration of NAC which was used. Which was otherwise six hours when NAC was not added for augmentation.
To conclude, delivery of furazolidone was via application of novel liposomal and spray dried formulations to either increase movement across gastric mucosa (via a muco-penetration effect) or to increase binding to the mucus (via mucoadhesive action). Hence, the various approaches used in this research have showed success (to deliver effective amounts of furazolidone locally into the stomach mucus) and the co-encapsulation of furazolidone and N-acetylcysteine is a novel approach for the delivery of antimicrobial agents to the stomach.