CSIR-NCL develops Anti-TB 4-FDC drug

ST Correspondent
Sunday, 6 May 2018

The research work has cleared way for the development of a stable formulation of 4-FDC for TB 

Pune: In a boost to the treatment of Tuberculosis, CSIR-National Chemical Laboratory (CSIR-NCL), Pune, has come up with an anti-TB cocrystal drug having an improved stability. The research work was done by Prof AK Nangia, Director, NCL, along with a team of researchers and the School of Chemistry, University of Hyderabad.

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 Organization (WHO), in the year 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.

The research work has cleared the way for the development of a stable formulation of 4-FDC (4 drugs fixed-dose combination) for TB. The team studied the cause for the instability of the 4-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 byproducts.

“The pharmaceutical cocrystals of INH (INH-Caffeic acid and INH-Vanillic acid) were used to improve the stability of 4-drug FDC”, said Nangia, adding, “In the current drug formula, the four drugs would react with each other reducing the impact or effect of the drug. The drug effect would go down from say 100 per cent to 70 per cent affecting the treatment vis-a-vis the patient,” he said.

The team showed that the pharmaceutically stable cocrystal of INH was able to improve the stability greater than 5-fold compared to the current 4-FDC drugs. TB is the biggest challenge before us and with PM’s call for the eradication of it, the treatment regime from 2 drug formula went to 3 drugs and now to 4 drugs.

“The coformer additives, which stabilise the formulation, are pharmaceutically accepted excipients,” he said, adding, “The stability studies were carried out under accelerated conditions of 40°C temperature and 75% 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.”

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 included Suryanarayana Cherukuvada, Devarapaga Maddileti, Swapna Battini and MK Chaitanya Mannava.

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 Narendra Modi 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 a confirmative diagnosis, early initiation of Anti TB treatment and preventing the development of multidrug 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.

About 4-FDC
† WHO has recommended Rifampicin (RIF), Isoniazid (INH), Pyrazinamide (PZA), and Ethambutol dihydrochloride (EDH) drugs for the treatment of TB. The use of 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 above 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.

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