Formulation and Scale-up of Delamanid-Loaded Nanoparticles for Oral Multi-Drug Resistant Tuberculosis (MDR-TB) Treatment

Abstract

Nanoparticle encapsulation is a promising technique to improve the bioavailability and drug delivery of therapeutics for various diseases, such as tuberculosis. Tuberculosis is one of the top 10 leading causes of death worldwide. Delamanid is a small molecule anti-tuberculosis therapeutic used to treat multi-drug resistant tuberculosis (MDR-TB), a strain of the disease associated with higher mortality rates and the need for harsher therapies. However, the bioavailability of delamanid is limited by its hydrophobicity and crystallinity. Nanoparticle encapsulation is an attractive route to increase the bioavailability of delamanid by increasing the specific surface area available for drug dissolution and by forming an amorphous drug core. Initial investigation of nanoprecipitation as a formulation route revealed significant incompatibility between the solid drug core and commonly employed nanoparticle stabilizers. To address this, emulsification was investigated as a route to form stable drug-loaded nanoparticles while avoiding the in situ formation of a solid drug core, as the delamanid remained solubilized in a liquid core during emulsification. Inexpensive, naturally derived emulsifiers, including lecithin and functionalized cellulosics, were employed as stabilizers. Initial formulation screening was conducted at batch scale using probe-tip sonication, and scale-up studies were conducted using high-pressure homogenization. The size stability of the resulting nanoparticles was characterized over time using dynamic light scattering. Depending on the stabilizer used, emulsification produced stable particles with average diameters ranging from 100-600 nm. Subsequent spray drying and redispersion studies were conducted to produce a dried powder. Combinations of lecithin and cellulose stabilizers were found to be beneficial in producing smaller particles (~250 nm) which were also robust enough for spray drying without significant aggregation. An in vitro dissolution assay revealed that the dried emulsion formulations produced significantly enhanced dissolution kinetics compared to bulk crystalline delamanid.