Tuberculosis remains a significant global health concern: in 2022, 1.3 million people died from tuberculosis-related causes.

Pretomanid (PTM) is a new nitroimidazole derivative used to treat multidrug-resistant tuberculosis. PTM is a poorly water-soluble drug compound with low bioavailability. Furthermore, PTM exhibits a significant food effect, with bioavailability doubling when taken with food. One potential formulation strategy is to simulate the food effect using lipid-based drug delivery systems, for example. We have therefore been exploring the design of self-nanoemulsifying drug delivery systems (SNEDDS) for PTM. SNEDDS are isotropic mixtures of oil, surfactant, co-surfactant, and cosolvent with dissolved drug. Upon administration, SNEDDS quickly disperse in the gastrointestinal tract to form nanoemulsion droplets containing the dissolved drug, often resulting in enhanced oral bioavailability. The application of SNEDDS is limited by the low solubility of PTM in lipid excipients. However, we have been able to increase PTM loading in SNEDDS through complexation with phospholipids.

The aim of this pilot project is to investigate the nature of the PTM-phospholipid complex in SNEDDS and the colloidal structures formed during the in vitro digestion of SNEDDS containing different drug-phospholipid complexes. The partnership will use Cryo-TEM and in vitro lipolysis at a SAXS beamline to study the formation of the PTM-phospholipid complex within SNEDDS, and correlate this with in vivo performance in preclinical studies (in rats). This should enable us to design more effective oral dosage forms with higher in vivo exposure in future.