Entecavir patent evaluation, method for diastereomeric Impurities

Abstract

Entecavir is an oral antiviral drug used in the treatment of hepatitis B infection. Entecavir is a guanosine nucleoside analogue with selective activity against hepatitis B virus (HBV), which inhibits reverse transcription, Hepatitis B virus (HBV) is highly endemic in South Africa and across sub-Saharan Africa, where around 8% of people are chronically infected, and rates of HBV-related liver cancer are some of the highest in the world. Globally, viral hepatitis causes approximately 1.3 million deaths every year more than either malaria or tuberculosis with around 240 million people chronically infected with HBV1. The currently available anti-HBV drugs show potent antiviral activity in patients with chronic hepatitis B; however, the resistance and cross-resistance to the drugs is a major obstacle in long-term treatment. Many studies have been conducted to understand the molecular basis of drug resistance, and the mechanistic characterization and molecular modeling of anti-HBV drugs complexed with HBV RT have been reported. Although the three-dimensional X-ray structure of HBV polymerase is not available, its homology model has been reported using the X-ray structure of HIV RT as a template[1-13]. Even though the homology models may not be accurate due to the low sequence homology between the overall HIV and HBV polymerase, the sequence conservation between the RT domains of HIV and HBV polymerase enables molecular modeling of HBV RT[14]. In particular, the residues around the active site that are responsible for recognizing the template-primer or an incoming nucleoside triphosphate are highly conserved. Nucleoside analogue HBV polymerase inhibitors cause chain termination after incorporation into the growing chain in the active site of HBV polymerase and consequently inhibit viral reverse transcriptase. Thus, the HBV homology model structure based on the crystal structure of HIV polymerase serves as a useful guide for understanding the molecular basis of HBV resistance to drugs.. Department of Chemistry, IPL research center, Lucknow, India *Corresponding author: KrishnaSarmaPathy, Department of Chemistry, IPL research center, Lucknow, India, Email: drkrishnasarmapathy@yahoo.in Citation: Krishna, S .P. Process and Molecular Modelling Study of Entecavir Drug-Resistant HBV. (2018) J Pharm Pharmaceutics 5(1): 3139. Received date: May 21 2018 Accepted date: July 09 2018 Publish date: July 16 2018 Introduction The initial patent on entecavir expired in South Africa in 2011 ZA 1991/07894. Current status available on: http://patentsearch.cipc.co.za/, which should have permitted lower-cost generic competitors to enter the market. However, South Africa granted BMS three additional patents on entecavir that only expire between 2022 and 2026. Two of these patents have lapsed meaning BMS has not paid the renewal fees, and they cannot be enforced while one patent covering a lower dosage form of entecavir remains in force. This patent is currently under litigation in India Basheer S. BMS Hepatitis Patent Invalidated: A Viral Effect for India? http://spicyip.com/2013/02/bms-hepatitis-patent-invalidated-viral.html, but because it is in force in South Africa, generic suppliers may be discouraged from bringing their low-dose products to market. A more recent patent on entecavir has not yet been received or processed by the Patents Office, but it could be filed up until the end of 2014 Patent number: WO/2013/177672. Current status available on pa-tentscope.wipo.int. This patent covers the manufacturing process of entecavir, and is an example of patent ever greening where companies file patents on minor changes to an existing drug to maintain patent protection and block competition. The same patent was recently overturned in the United States for failing to meet the criteria of inventive step. However, in South Africa, since no examination of patent applications occurs, if the patent is filed, it is likely to be granted to BMS[15-18]. So long as BMS maintains a monopoly on entecavir in South Africa, the price is likely to remain high, and entecavir will remain out of reach for those who need it. But the crystalline forms of Research article DOI: 10.15436/2377-1313.18.1899 page no:31 Copyright: © 2018 Krishna, S.P. This is an Open access article distributed under the terms of Creative Commons Attribution 4.0 International License.