Novel drug formulations against HIV
Over the years, several ARVs have been developed against HIV-1. Accumulating evidence indicates that often two or more drugs need to be combined for maximum efficacy. However, the co-formulation of ARVs can be problematic due to incompatibility issues. To address this, the EU-funded MOTIF (Microbicide optimization through innovative formulation for vaginal and rectal delivery) project set out to develop a formulation containing more than one ARV for optimal tissue distribution while overcoming incompatibility. For drugs to be effective, they must efficiently penetrate the epithelium and target sub-mucosal T cells, the primary sites of HIV-1 infection. In this context, researchers investigated the role of drug transporters in the distribution of ARVs in mucosal tissue and the potential to modify formulations to maximise drug uptake. Two formulations based on dissolving films and coating of microcrystalline cellulose beads were produced that allowed the combination of two anti-HIV drugs within a single vehicle. Researchers evaluated the dissolution and stability of these two formulations alongside their drug release capacity in vivo. Both formulations were well tolerated in rabbits, which also expressed drug transporters at similar levels to humans and non-human primates. In terms of ARV efficacy, scientists tested the two formulations on human tissue explants and evaluated the drug effects on a panel of immunological markers including cytokines and chemokines. Of the drugs tested during the project, diffusion studies across epithelial cells showed a passive diffusion route. In certain cases, the administration of inhibitors against certain efflux transporters (P-glycoprotein, MRP-2) was required to maximise drug tissue permeability. Overall, the broadly applicable MOTIF formulation strategy opened new avenues for the combination of physicochemically incompatible ARVs against HIV. Furthermore, the improved knowledge of the mechanisms that determine drug distribution in tissues will undoubtedly influence the design and future dosing strategies for microbicides.
Keywords
Formulation, HIV, anti-retroviral drugs, MOTIF, cellulose beads
