CSIR- National Chemical Laboratory (CSIR-NCL), Pune has come up with an Anti-TB cocrystal drug having improved stability. The research work by Prof A K Nangia and the team at the CSIR-NCL and the School of Chemistry, University of Hyderabad has cleared the way for the development of a stable formulation of 4-FDC (4 drugs fixed-dose combination) for TB.
A study by Prof Nangia led team has reported a new cocrystal of FDC of TB drug to address these issues in the Journal of Pharmaceutical Sciences. The team including Suryanarayana Cherukuvada, Devarapaga Maddileti, Swapna Battini, and M K Chaitanya Mannava, studied the cause for the instability of the four-FDC drug chemical structures and discovered pharmaceutically stable cocrystal by applying Crystal Engineering principles to improve the stability, so that the drug inhibits the cross-reaction between Isoniazid and Rifampicin, and thereby overcomes the formation of inactive by-products. The pharmaceutical cocrystals of INH (INH-Caffeic acid and INH-Vanillic acid) were used to improve the stability of 4-drug FDC. The team showed that the pharmaceutically stable cocrystal of INH is able to improve the stability greater than 5-fold compared to the current 4-FDC drugs. The coformer additives which stabilise the formulation are pharmaceutically accepted excipients. Stability studies were carried out under accelerated conditions of 40°C temperature and 75 per cent relative humidity. The first time improvement of stability of anti-TB 4-FDC drugs using cocrystals of INH in a fixed dose formulation was reported. Tuberculosis (TB) is an airborne infectious disease caused by a species of pathogenic bacteria Mycobacterium Tuberculosis. It is one of the top ten leading causes of death worldwide.
According to the World Health Organisation (WHO), in 2015, an estimated 10.4 million people developed TB and 1.8 million died from the disease including 0.4 million deaths among HIV-positive people.
WHO has recommended Rifampicin (RIF), Isoniazid (INH), Pyrazinamide (PZA), and Ethambutol dihydrochloride (EDH) drugs for the treatment of TB. The use of a fixed-dose combination (2-drug, 3-drug and 4-drug FDCs) for the treatment for tuberculosis was recommended in 1994 by WHO and International Union against Tuberculosis and Lung Disease (IUATLD). In 1999 the 4-drug FDC tablet was included in the WHO Model List of Essential Drugs that comprises these four drugs. The 4-FDC tablets had quality and stability issues, including poor bioavailability of rifampicin and instability during storage; this raised serious concerns on the utility of this FDC. It was essential to address the quality and stability issues.
In March 2018, a summit intended to review the progress of efforts to eradicate TB took place in Delhi named the END TB Summit 2018. On the occasion, prime minister of India called for “greater focus on financing and political will to end TB by 2030”. He stressed that all forces must come together from private and public sectors and the civil society to fight this battle. All must join hands to overcome TB. The key components to combat TB are confirmative diagnosis, early initiation of Anti TB treatment and preventing the development of multi drug resistance. “Research & Development” is a key partner component on the battle against TB.
It was stated that Inventions of Anti-TB- Drugs and improvement of Drug quality are the major areas to explore.
Prof Nangia said, “Stable cocrystal drug with longer shelf life will improve the prospects of transport logistics and inventory management of TB drugs”. In the next phase, longer-term stability data on 4-FDC will be validated with suitable excipients and polymeric additives to develop the tablet formulation in fast-track translation.