Abstract
Tuberculosis (TB), which killed 1.8 million patients in 2015, is still a real threat to public health despite the current therapy. The therapeutic success is limited due to, in part, mycobacterial resistance and side-effects related to the current regimen. Clofazimine (CFM) has activity against several species of mycobacteria and has not been clinically reported to be resisted by Mycobacterium tuberculosis which makes it ideal for multidrug-resistant TB (MDR-TB) and extensively drug-resistant TB (XDR-TB) cases. However, it is classified as third-line agent for TB treatment due to poor pharmacokinetic properties and serious side-effects accompanying its oral delivery. Solid lipid microparticles (SLMs) is a delivery system that contains lipid and surfactant, and it can improve the incorporation and bioavailability of hydrophobic drugs such as clofazimine. |In this project, we believe that inhaled clofazimine delivery in the form of SLMs would be ideal to overcome the challenges of current TB treatment. |A variety of lipids and surfactants were formulated with curcumin as a drug model to estimate how they will behave with clofazimine. Anti-solvent precipitation technique (ASP) followed by spray drying (SD) or freeze drying (FD) was used to produce SLMs. These SLMs were characterized for batch yield, particle size distribution, physical state, and stability. Based in curcumin’s results, it was determined that SD do not change the particle size distribution of the formulations after ASP, while FD may increase the particle size. Also, FD keep high batch yield comparing to SD. |Clofazimine was formulated with eligible lipids and surfactants to produce SLMs. As a drying method, FD was able to keep high batch yield and drug content more than SD especially with formulations containing lipids. Lipids improved drug content more than surfactants, but they made larger particles with multi-modal distribution. All clofazimine formulations were physically stable, chemically intact, and in crystalline form. Four out of fourteen clofazimine formulations showed excellent aerodynamic properties with mass median aerodynamic diameter (MMAD) < 5 μm in acceptable geometric standard deviation (GSD) and free particle fraction (%FPF). These formulations were FD and SD CFM: Dipalmitoylphosphatidylcholine, FD CFM: Palmitic acid: Lecithin, and SD CFM: Palmitic acid: Choline Chloride.