| dc.description.abstract | Tuberculosis (TB) is the most prevalent infectious cause of death globally, affecting
approximately one-third of the world’s population (Borgdoff et al., 2002). Mycobacterium
tuberculosis (M. tuberculosis) is spread through small airborne droplets, generated through
coughing, sneezing, or even by talking to a person with pulmonary or laryngeal
TB (Knechel, 2009).
The treatment of tuberculosis with a multi-drug regimen requires therapy for a long period of
time. This is associated with risks such as poor patient compliance, treatment failure and drug
resistance. To limit these risks, the World Health Organisation and the International Union
Against Tuberculosis and Lung Disease recommend the use of fixed-dose combination
(FDC) tablets for the treatment of TB (WHO, 1999). The recommended multi-drug treatment
approach of TB includes rifampicin, isoniazid, pyrazinamide and ethambutol, daily for 2 - 3
months. The use of FDCs may hence simplify treatment and encourage patient compliance,
especially in patients who already take numerous medications, when co-infected with human
immunodeficiency virus (Panchagnula et, al., 2004, WHO, 1999).
The four current anti-TB drugs, isoniazid, pyrazinamide, ethambutol hydrochloride and
rifampicin, belong to two different classes of the Biopharmaceutical classification system
(BCS). Isoniazid, pyrazinamide and ethambutol hydrochloride belong to class I
(highly soluble and highly permeable) and rifampicin on the other hand, is the only
hydrophobic ingredient of the FDC product (Ellard & Fourie, 1999). It has been postulated
that polymorphism of rifampicin may be responsible for its variable bio-availability among
its solid oral dosage forms (Agrawal et al., 2004). Rifampicin may react adversely with
isoniazid to form isonicotinyl hydrazone (HYD) in formulation according to Singh et al
(2000). Singh & Mohan (2003) further reported that pyrazinamide and ethambutol are
catalytic towards the reaction between rifampicin and isoniazid, since FDCs that contain
four-drug combinations have shown far more chemical instability than two-drug FDCs that
only contain rifampicin and isoniazid (Singh & Mohan, 2003).
Various hypotheses have been put forward to explain inter-drug interactions that may occur
in anti-TB FDC formulations and during oral administration. Therefore, for the purpose of
this study, the latest techniques were used to determine whether such reported chemical
reactions indeed occur and under which conditions they would occur, if at all.
Hydrolysis experiments were done in distilled water to determine the extent of decomposition
of RIF and INH using single, two, three and four anti-TB APIs. The aim of the investigation
was to test the above hypotheses regarding the stability of especially RIF and INH in
combination with EMB and PZA. Assays were done at 2, 3, 6, 12, 24 and 48 hours using
solutions that were maintained at three different temperatures (5, 25, and 37°C – each ± 2°C).
The results showed that EMB together with RIF and INH showed the greatest rate of
degradation. Surprisingly the degradation of the four combination active pharmaceutical
ingredients was less than that of the above mentioned three combination. Apart from a clear
impact of INH and RIF on each other, the presence or absence of EMB and/or PZA also
influences their rate of hydrolysis in water.
The microcalorimetry results showed at 40°C that no incompatibility exists with and without
humidity. Previous studies have suggested that EMB together with humidity conditions is
mainly responsible for the RIF degradation and the so called ‘bleeding’ of the tablets.
However, it might be that the deliquescence of EMB masks any interaction or stability. It has
been suggested that in the solid-state, HYD may also be formed because of a direct
interaction between the imino group of RIF and the hydrazine group of INH. This interaction
in the solid-state is exactly what we find with the microcalorimetry results at 50°C. The
microcalorimetry results showed that an incompatibility exists between RIF and INH in the
solid-state.
The moisture sorption results confirmed the hygroscopic nature of EMB, but the question
remains is that moisture responsible for the degradation of RIF. The TAM and hydrolysis
results were not conclusive about this. From the results it is not clear if the hygroscopic
nature of EMB is solely responsible for the instability of four combination anti-TB drugs.
The stability of the anti-TB FDC tablets remains a challenge to researchers and in future
more analysis need to be proposed to solve this problem. | en_US |
