Flexible and dispersible paediatric oral formulations produced via extrusion spheronisation for the treatment of tuberculosis

Until now, there has been a lack of suitable formulations for combined tuberculosis (TB) therapy to treat paediatric populations. The objective of this research was the development and manufacture (at small scale) of an age-appropriate flexible dose combination of dispersible spherical pellets of isoniazid (INH), pyrazinamide (PZD) and rifampicin (RIF) for TB treatment. These pellets were prepared using either crospovidone (XPVP) alone or XPVP in combination with microcrystalline cellulose (MCC) as an extrusion-spheronisation (ES) aid (ES-aid). Each drug was incorporated into ES-aid separately at various APIs/ES-aid proportions: 0:100, 10:90, 40:60, and 60:40, to make spherical pellets using ES. Average Feret diameter (d_Fer.ave), Raman spectroscopy, texture analysis, disintegration and dissolution testing were used to assess/characterize the formulations produced with a view to enable the production of high-quality pellets with sufficiently high drug loading. Pellets prepared with XPVP alone demonstrated a slightly larger d_Fer.ave compared to those made with MCC. Although d_Fer.ave increased as drug loading rose, pellets maintained acceptable sphericity, highlighting the robustness of the formulation process. The most notable distinction between the batches was the rapid disintegration of spheronised pellets containing INH, PZD, RIF, and XPVP within 20-30 s in Simulated Salivary Fluid (SSF) at 37 °C, in contrast to the MCC-based pellets, which remained intact under identical conditions. The dissolution profiles, particularly for RIF and PZD, were significantly faster with XPVP-formulated pellets compared to MCC. These findings aligned with tensile strength data, where XPVP-based pellets, both drug-free and drug-loaded, were less hard than MCC-based pellets, contributing to their superior disintegration and dissolution performance. Age-appropriate flexible dose combination spherical pellets were developed and their properties make them a promising formulation strategy for combination therapy to improve the overall TB treatment in paediatric populations.