Formulation of amorphous solid dispersion of clofazimine, an extremely water-insoluble basic drug, via hot-melt...

Clofazimine (CFZ) is an anti-leprosy and anti-tuberculosis drug listed on the World Health Organization's (WHO) Model List of Essential Medicines, but it is extremely water-insoluble and has major dissolution and bioavailability issues, and presumably for these reasons, its only commercially available formulation, Lamprene®, was withdrawn from the US market by its manufacturer. The present investigation was undertaken to develop amorphous solid dispersions (ASDs) of CFZ using hot-melt extrusion (HME) to increase its dissolution rate. The process was, however, challenging because CFZ has a high melting point of 224 ℃, requiring high processing temperatures, at which the drug and the polymer used could degrade. Moreover, dissolution of CFZ from ASDs was low and incomplete. These issues were resolved by interacting the basic CFZ with glutaric acid (GA) using the acid-base supersolubilization (ABS) principle, enabling HME at 120 ℃ and achieving high drug dissolution. The final ASDs consisted of a mixture of CFZ (10% w/w), GA (11% w/w), poloxamer 407 (10% w/w), and either Kollidon® VA64 or HPMCAS-LG (69% w/w). The dissolution of 5-mg and 50-mg doses of the formulations with both polymers was studied in 250 mL of fed-state intestinal fluid (FeSSIF-V2, pH 5.8) over 2 h. While only 30-40% of the 50-mg dose dissolved under these conditions, the 5-mg dose dissolved completely (100%). It is postulated that the bioavailability of CFZ would be much higher from new ASDs, thereby reducing the dose.