Abstract
The treatment of enteric bacterial infections using oral bacteriophage therapy can be challenging since the harsh acidic stomach environment renders phages inactive during transit through the gastrointestinal tract. Solid oral dosage forms allowing site-specific gastrointestinal delivery of high doses of phages, e.g., using a pH or enzymatic trigger, would be a game changer for the nascent industry trying to demonstrate the efficacy of phages, including engineered phages for gut microbiome modulation in expensive clinical trials. Spray-drying is a scalable, low-cost process for producing pharmaceutical agents in dry powder form. Encapsulation of a model Salmonella-specific phage (Myoviridae phage Felix O1) was carried out using the process of spray-drying, employing a commercially available Eudragit S100® pH-responsive anionic copolymer composed of methyl methacrylate-co-methacrylic acid formulated with trehalose. Formulation and processing conditions were optimised to improve the survival of phages during spray-drying, and their subsequent protection upon exposure to simulated gastric acidity was demonstrated. Addition of trehalose to the formulation was shown to protect phages from elevated temperatures and desiccation encountered during spray-drying. Direct compression of spray-dried encapsulated phages into tablets was shown to significantly improve phage protection upon exposure to simulated gastric fluid. The results reported here demonstrate the significant potential of spray-dried pH-responsive formulations for oral delivery of bacteriophages targeting gastrointestinal applications.
Highlights
The emergence of antibiotic resistance in pathogenic bacteria is a serious global health threat
The aim of the present study was to investigate the effect of spray-drying temperatures and formulation parameters, varying the amount of trehalose and the pH-responsive polymer Eudragit S100® to produce stable dry powders having a high amount of encapsulated phage and good storage stability
A log-phase culture of Salmonella at an optical density (OD) of 0.2 (this typically equates to a viable cell count of ~108 colony-forming units (CFU)/mL) was inoculated with Felix O1 at a multiplicity of infection (MOI) of 0.01
Summary
The emergence of antibiotic resistance in pathogenic bacteria is a serious global health threat. Common enteric bacterial pathogens are becoming progressively resistant to frontline antibiotics. The pipeline for the development of new classes of broad-spectrum antibiotics is not looking promising [1]. In addition to treating gastrointestinal infections in humans, a safe and low-cost strategy to reduce pathogen carriage in livestock and poultry is needed. National health agencies are increasingly banning general antibiotic use in animals grown for human consumption, e.g., see the European Union (EU) directive on additives for use in animal nutrition [2]. There is an increasing awareness of the need to move away from broad-spectrum antibiotics and use more specific treatments which do not cause dysbiosis of the microbiome [3]
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