Abstract
A scalable low-shear membrane emulsification process was used to produce microencapsulated Escherichia coli-phages in a solid oral dosage form. Uniform pH-responsive composite microparticles (mean size ~100 µm) composed of Eudragit® S100 and alginate were produced. The internal microstructure of the gelled microcapsules was studied using ion-milling and imaging, which showed that the microparticles had a solid internal core. The microencapsulation process significantly protected phages upon prolonged exposure to a simulated gastric acidic environment. Encapsulated phages that had been pre-exposed to simulated gastric acid were added to actively growing bacterial cells using in vitro cell cultures and were found to be effective in killing E. coli. Encapsulated phages were also shown to be effective in killing actively growing E. coli in the presence of human epithelial cells. Confocal microscopy images showed that the morphology of encapsulated phage-treated epithelial cells was considerably better than controls without phage treatment. The encapsulated phages were stable during refrigerated storage over a four-week period. The process of membrane emulsification is highly scalable and is a promising route to produce industrial quantities of pH-responsive oral solid dosage forms suitable for delivering high titres of viable phages to the gastrointestinal tract.
Highlights
The emergence of antibiotic resistance in bacteria is a serious global threat to human health
Epithelial cells treated with Simulated gastric fluid (SGF)-exposed encapsulated phages showed clear differences compared with untreated controls
We have shown that Eudragit Eudragit® S100 (ES100) co-formulated with medium viscosity alginate in 100-μm microcapsules protected the phages exposed to SGF at pH 2 for an exposure period of 2 h (Figure 5)
Summary
The emergence of antibiotic resistance in bacteria is a serious global threat to human health. Virulent bacteriophages (phages) are viruses that infect and kill bacteria in a highly specific manner They represent a promising approach to targeting bacterial infections in a treatment known as phage therapy [5,6,7,8]. In instances of enteric bacterial infections where the causative agent and strain may be suitably diagnosed, treatment with a sufficiently high initial phage dose could promote rapid in situ phage multiplication and killing of the targeted bacteria [10,11,12]. We report here for the first time the use of a scalable membrane emulsification platform technology to encapsulate phages suitable for targeted delivery to the gastrointestinal tract. The small size of the microcapsules is useful for efficacy testing of encapsulated phages via oral delivery using small-bore gavage tubes for testing in animal models such as in mice and rats
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