Stability of anti–tuberculosis actives in the PheroidTM delivery system / Gizela Sheen
Tuberculosis poses a serious health threat worldwide, with 9.27 million cases being reported in 2007 (WHO, 2009:1). Africa represented 31% of this figure, with South Africa ranking 5th globally. Despite an already high mortality rate of just under 2 million during 2007, resistance has also become a significant factor to reckon with in combating this disease. Poor patient compliance is reported to be the major attributing factor to formed resistance, which has necessitated the consideration of shorter treatment times. Pheroid technology is a new drug delivery system that is reported to improve absorption and enhance bioavailability. It was anticipated that its advantages could be utilised in helping to fight drug resistance. The Pheroid consists of two liquid phases (an oil– and an aqueous based phase) and a dispersed gas phase, which are allied with the dispersed fatty acid phase. Pro–Pheroid production is equal to that of the Pheroid, with the exception that the aqueous phase is omitted and that the active ingredients are included in the oil phase. This study was performed to establish the stabilities of four tuberculostatic active pharmaceutical ingredients (APIs), i.e. rifampicin, isoniazid, ethambutol and pyrazinamide, individually, as well as in combination, when incorporated into the pro–Pheroid delivery structure. For analysis, high pressure liquid chromatography was utilised, by using methods that were adjusted and validated according to ICH guidelines. The two combination products being formulated during this study were ethambutol–isoniazid in pro–Pheroid (Pyriftol IE), and pyrazinamide–rifampicin in pro–Pheroid (Pyriftol RP). These formulations were stored at stability conditions of 5ºC, 25ºC+60% RH, 30ºC+65% RH and 40ºC+75% RH, over a period of three months. The main problem with analysing Pyriftol RP was homogeneity, as this sample was very viscous. This may have caused inconsistencies during sampling of the APIs, possibly leading to the variable results obtained. Despite the low initial assay values obtained for pyrazinamide, the assay results for the four conditions over the three–month period remained stable. Most of the results complied with the required specifications of 90% - 110%. The initial results for rifampicin were within specification. Highly variable results were obtained for all the other stability intervals and no significant conclusion could be made from the results. For ethambutol, the initial result was 100%, with slightly higher results after one month. The 5°C and 40°C+75% RH results were out of specification, with values higher than 110%. For months 2 and 3, results were significantly lower than the initial results, with no value complying with specifications. The analytical technique may have caused the high variability, since a copper reaction on the column was required to determine the ethambutol contents. The initial assay results for the isoniazid sample was 85.3%. This low initial result could have been due to consistency problems during manufacturing. Throughout the stability studies, the assay values were relatively stable, but all were below the lower acceptance criterion. The results for the 5°C samples were inconsistent throughout the study. Five previous studies had confirmed the analytical problems being experienced with the Pheroid / pro–Pheroid delivery system, irrespective of the pharmaceutical active ingredient being used in these formulations. This study also emphasised the analytical, and probably also the formulation challenges within this delivery system. For future studies to be undertaken, it is advised that the development of an analytical method, suitable for analysis of this complex and unstable delivery system, be prioritised.
- ETD@PUK