File Entry: Entecavir Patent Evaluation, Method for Diastereomeric Impurities

Created: 2018-06-29 10:47:08      Last updated: 2018-06-29 10:48:15
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Entecavir Patent Evaluation, Method for Diastereomeric Impurities


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, 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 2014Patent 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. 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 entecavir and its performances are not researched and reported in the above-mentioned patent. The review relates to analogues of 2′-cyclopentyl deoxyguanosine, especially relates to entecavir, its preparation and the pharmaceutical composition and uses thereof. This method was capable to detect Entecavir and its diastereomeric impurities at a level below 0.009% with respect to test concentration of 500 μg ml-1 for a 20 μL injection volume. The method has shown good, consistent recoveries for diastereomeric impurities (95-105%). The test solution was found to be stable in the diluent for 48 h. The drug was subjected to stress conditions. The mass balance was found close to 99.5%.Entecavir also helps to prevent the hepatitis B virus from multiplying and infecting new liver cells, is also indicated for the treatment of chronic hepatitis B in adults with HIV/AIDS infection.
Method Details: C18 stationary phase (150 x 4.6 mm, 3.5 microns particles) with the economical and simple mobile phase combination delivered in an isocratic mode at a flow rate of 1.0 ml min-1 at 254 nm. In the developed method, the resolution between Entecavir and its diastereomeric impurities was found to be greater than 2.0. Regression analysis shows an r2 value (correlation coefficient) greater than 0.999 for Entecavir and for its diastereomeric impurities.
 

 

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