(448e) Formulation and Scale-up of Delamanid Nanoparticles Via Emulsification for Oral Tuberculosis Treatment

Delamanid is a small molecule anti-tuberculosis therapeutic used to treat drug-resistant tuberculosis (DR-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 due to trifluoromethyl and nitro groups present on delamanid. 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.

Depending on the stabilizer, emulsification produced stable particles 100-600 nm in diameter, which were spray dried to produce a dried powder. A 1:1 mass ratio of lecithin and HPMC was found to be optimal in producing smaller particles (250 nm) which were also robust enough for spray drying. An in vitro dissolution assay revealed that the dried emulsion formulations produced enhanced dissolution kinetics compared to bulk crystalline delamanid, and the powders remained stable against aging-induced crystallization at elevated temperature and humidity. Solid state NMR measurements confirmed that the spray-dried emulsions were semicrystalline but more robust to temperature and humidity induced crystallization than a comparable amorphous solid dispersion.