TOWARDS IMPROVING THE BIOAVAILABILITY OF ORALLY DELIVERED MALARIAL ANTIMICROBIALS THROUGH NANOPARTICLE FORMULATIONS

Abstract

Malaria poses a major burden on human health; there were 212 million casesworldwide in 2016, resulting in 429,000 deaths. Malaria is becoming increasingly difficultto treat due to the development of antimicrobial resistance. The resistance issue isexacerbated by the lack of patient adherence to long-term dosing regimens, which resultsin rapid resistance development to newly-developed antimalarial therapies. Due to thiscrisis, there is an urgent motivation for the development of new antimalarial treatments thatare less susceptible to the development of resistance. One such promising candidate formalaria treatment is OZ439, developed by the Medicines for Malaria Venture, which hasdemonstrated both safety and efficacy in human trials, including against resistant strains.OZ439 is intended as a single-dose oral therapeutic against malaria, which, if effective,will preclude the possibility of resistance resulting from a lack patient adherence.Oral drug delivery is the most preferred method for drug delivery and is favoredbecause of the ease of administration, minimal pain and versatility, which are also factorsthat increase patient adherence - particularly for administration to children. However,OZ439 is a hydrophobic organic compound with poor solubility in the gastrointestinal tractand requires high dosage amounts for efficacy as a single-dose treatment. The developmentof an inexpensive, continuous and scalable process to produce OZ439 nanoparticles hasthe potential to improve drug bioavailability. Polymer stabilized nanoparticles can be usedto encapsulate hydrophobic drugs and can improve drug solubility, prolong half-life,prevent degradation and allow sustained release. In collaboration with the Bill and MelindaGates Foundation and the Medicines for Malaria Venture, here we appliednanoencapsulation technologies to formulate improved OZ439 forms. A polymer-directed self-assembly process, Flash NanoPrecipitation (FNP), was successfully used to formstable nanoparticles of 50-400 nm in size with two different physical forms of OZ439.OZ439 mesylate salt first had to be ion-paired to a hydrophobic oleate salt and OZ439 freebase had to be formulated with vitamin E succinate to increase drug hydrophobicity forprecipitation in the FNP process. The identity and amount of excipients/polymer stabilizerswere tuned to optimize the stability of the OZ439 nanoparticles and yielded nanoparticlesthat were stable for as long as several days, using inexpensive and FDA-approved foodexcipients. Promising formulations of OZ439 nanoparticles were lyophilized with a varietyof different cryoprotectants and optimized to successfully yield dry powders for long-termstorage. The release rates of encapsulated OZ439 were determined in bio-relevant mediaand compared to the release rates of the unencapsulated drug. These studies indicated thatOZ439 nanoparticles exhibit sustained and several-fold higher release concentrationscompared to the unencapsulated drug. This work utilized nanoprecipitation techniques todevelop new formulations of OZ439 with improved function, that may be a solution tocombat antimicrobial resistant malaria.