Development of novel polymeric delivery systems for the controlled release of therapeutic agents to prevent the spread of Zoonotic diseases

Abstract

The agricultural revolution and related activities have led to new connections between humans and farm animals, which are expected to expand due to the global trade of livestock and growth in the demand for animal protein for human consumption. Ireland is a globally recognised trading nation, providing high-quality meat, milk, and dairy products. In order to remain viable and grow over time, the Irish agricultural sector will need to focus on animal health to maximise productivity, mainly because parasitic infections represent a major production-limiting issue with the possibility of transmission within animal populations and from animal to human populations. Repidose® Ready Pulse bolus is the only orally administered anthelmintic intraruminal delivery device for grazing cattle in Ireland. Therefore, the aim of this research was to develop novel controlled-release solid dispersion formulations for the safe and efficient delivery of benzimidazole anthelmintics to cattle, achieved through processing the active ingredient with biodegradable polymers via hot-melt processing technologies. To accomplish this goal, five specific objectives were defined (i) to improve the poor water solubility of fenbendazole using a biocompatible, biodegradable, and hydrophilic polymer; (ii) to identify and analyse other polymers compatible with fenbendazole; (iii) to design and manufacture fenbendazole extended-release extruded formulations; (iv) to design and mould solid dispersion formulations for the extended-release of fenbendazole; and (v) to upgrade the solid dosage form with oxfendazole as is present in the commercial Repidose® bolus. The results achieved during this research revealed that (i) solid dispersions of fenbendazole and PEO are physically and chemically compatible, with higher percentages of PEO processed at lower screw speed being more effective in enhancing the drug dissolution properties; (ii) Kolliphor® P 407, PCL, and PLA are compatible with fenbendazole and have potential for further application in the development of solid dosage forms; (iii) melt-extruded matrices showed that the drug release rate from a PEO/PCL blend can be tailored by altering the ratio of PEO and PCL; (iv) moulded tablets of amorphous solid dispersions improved the dissolution properties of fenbendazole, with the PEO/PCL blend-based matrices showing an extended-release profile; and (v) hot-melt extrusion coupled with micro-injection moulding produced extended-release amorphous solid dispersion of oxfendazole, which is a novel pharmaceutical strategy with the potential to improve upon the Repidose® bolus. This research project successfully demonstrated the application of a semi-continuous manufacturing process for the production of plasticised solid dispersion tablets of oxfendazole as a potentially viable alternative to the current tablet formulation present in the Repidose® bolus, thus this technology could be viable on the market to provide effective parasite control.