Strategy to counteract the pyrazinamide induced hepatotoxicity by developing naringin based Co-amorphous system with supplementary benefits

Abstract

Pyrazinamide (PZA) is one of the first-line drugs used in the multi-drug regimen treatment for tuberculosis (TB). Hepatotoxicity and liver damage was found to be the major adverse event associated with the PZA containing anti-tubercular treatment. The success rate of the anti-TB treatment is getting highly affected due to the hepatotoxic effects of PZA, which needs to be solved with new drug development ideas. In the present study, a new co-amorphous system (CAM) of PZA was developed using naringin (NGN) as a co-former. Chemically, NGN is a flavonoid of herbal origin with antioxidant and hepatoprotective effects. Three CAMs were prepared by taking PZA and NGN in different ratios like 1:1, 1:2, and 2:1 successively. Further, the amorphous nature of the developed CAM products was confirmed by using DSC, PXRD, and FT-IR. The CAM 1:1 was found to be the most superior in terms of solubility, dissolution rate as well as permeability. Solubility of the drug enhanced up to 25-fold. In the dissolution study, about 97.2% release at 30 min and100% release at 1 h was observed. The apparent permeability of the CAM 1:1 was found to be 3.41 times that of the pure drug. Apart from these supplementary benefits, evaluation of the pharmacodynamic hepatoprotective effect of the developed CAM demonstrated that the developed formulation could be a better alternative for currently available formulations of PZA concerning for to hepatotoxicity.