Development of direct compression tablets for microencapsulated bacteriophages prepared by spray drying

The outbreak of COVID-19 demonstrated the depth of global pandemic and the extent to which it can affect various aspects of human life, from direct health issues to indirect economic and social damages. Antimicrobial resistance, one of the world's most health threatening issues, could have very similar effects. Phage Therapy has been demonstrated as a possible alternative to antibiotics in the former Soviet Union but has only recently gained attention elsewhere. Several factors are preventing the fast commercialisation of bacteriophages as an alternative to antibiotics. This work addressed two of these issues through a series of studies, the stability and drug dosage form. Spray drying bacteriophage, Salmonella Felix O1, using a 2:1 ratio of trehalose and Eudragit polymers (S100 and L100) at an outlet temperature of 80°C, significantly improved phage stability during the encapsulation process, storage, and once exposed to the acidic environment. Tableting of encapsulated phages using the direct compression tableting method was achieved without damaging the encapsulated phages. It also further improved acid stability and provided additional protection during storage under 65% relative humidity (RH). Phage viability and tablet quality are both dependent on the excipients used for encapsulation and those used before tableting. The addition of 2% Magnesium Stearate (Mg-St) reduced friability and improved phage viability during the storage compared with those with lower content. Tableting of PS21-S100 powders was possible using a maximum of 15 kN compaction pressure, without damaging the phage while for PS21-L100 no damage was observed up to 20 kN. The disintegration of tablets each weighing 290 mg with a diameter of 10 mm was affected both by the compaction pressure. The disintegration of tablets was reduced with an increase in compaction pressure. Also, the excipients influence the disintegration with PS21-S100 experiencing lower mass loss in comparison with PS21-L100. In both formulations, friability was modified by increasing compaction pressure from 5 kN to 10 kN, acid protection was possible even at pH 1 and no batch-to-batch variation was observed in powders and tablets. Storage of powder and tablets indicated low temperature and humidity conditions are most suitable for storing encapsulated phages for the long term. Samples stored under 4°C and 0% RH and 20°C (uncontrolled RH) experienced one log drop over six months while those stored at 30°C and 65% RH underwent three log drops for the same period. Storage of samples at 30°C and 0% RH resulted in improved stability and demonstrated the adverse effect of moisture absorption on phage viability. The investigation into moisture content revealed moisture absorption occurred in samples stored at 20°C and 30°C and 65% RH, explaining the decline in phage viability under these conditions. Finally, drying of samples using vacuum drying without damaging the phages to 3% moisture content was possible but did not result in improved stability at 30°C + 0% RH. From these studies, it can be concluded that the current formulation and encapsulation methods can improve phage viability and acid protection and enhance long term storage. Also, tableting provides additional protection in extreme conditions of acidic and very humid environment. Finally, PS21-L100 samples performance was better during long term storage suggesting the possibility of eliminating the cold supply chain.