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    Home > Medical News > Latest Medical News > Is the second upgrade of tenofovir a strategy or a real improved drug?

    Is the second upgrade of tenofovir a strategy or a real improved drug?

    • Last Update: 2019-09-18
    • Source: Internet
    • Author: User
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    Nearly 90 million people with HBV infection define China as a big country of hepatitis B; the huge number of HBV infection has led to nearly half of the world's liver cancer patients in China; hepatitis b curative drugs are urgently needed in clinical practice, entecavir has occupied the market for many years; the introduction of "4 + 7" has greatly improved the use of drugs for HBV patients; in 2016, tenofovir eilatamine was approved for listing, known as "the best at present" So, what are the characteristics of the current optimal tenofovir and eilatamine? Can shake the domestic hepatitis B treatment drug market? 1 Basic information of the drug: tenofovir, also known as propotenofovir The original research company is Gilead, a nucleoside reverse transcriptase inhibitor, which is the prodrug of tenofovir Compared with tenofovir dipivoxil (TDF), this product has stronger antiviral activity and more effective access to lymphoid tissue In vitro experimental data showed that there was no significant difference between the antiviral effect of taf25mg and that of tdf300mg Compared with TDF, the antiviral effect of taf25mg reached the main end point of non inferiority At first, the original research company started the development of the compound in 2001; in 2004, due to the "internal project evaluation", the company stopped the project (think it has no advantage over Viread); six years later, the company changed its original intention, and announced the discovery of tenofovir-a-phenamine (to resist the global patent challenge to Viread); at the 2011 medical conference, the research results in 2003 were disclosed In November 2016, it was approved by the FDA for listing (the only new drug approved by the FDA in the past 10 years to treat chronic hepatitis B), and the trade name is vemlidy ® In 2017, the European Society of Hepatology (EASL) updated the clinical practice guide of the European Society of Hepatology 2017: management of HBV infection For the first time, TAF, ETV and TDF were listed as the preferred drugs for the treatment of chronic hepatitis B In 2017, global sales reached 122 million US dollars, and in 2018, global sales reached 321 million US dollars 2 Single drug / compound drug - entered the market in 2015, 10 mg TAF, 150 mg etigrevir, 150 mg drug enhancer corcistad, 200 mg ntrastabine, which was approved by FDA for listing, was used to treat HIV-1 infection in adults and children weighing at least 25 kg; TAF entered the market for the first time with drug ingredients In 2016, 25mg TAF, 25mg ribavirin and 200mg etrastabine were combined to form a compound, which was approved by FDA for listing, and was used for HIV-1 infected people over 12 years old who had not received antiviral treatment In 2016, 25mg TAF and 200mg etrastabine were combined to treat adults and adolescents (≥ 12 years old, weight ≥ 35kg) with HIV-1 infection In 2016, TAF was approved by FDA as a single drug for the treatment of adult patients with chronic hepatitis B In 2018, 10mg TAF, 800mg darunavir, 150mg corcistadine and 200mg ntrastabine were combined to form a compound, which was approved by FDA for listing, and used to treat HIV-1 infection in adults and adolescents (12 years old and above, weight at least 40kg) In 2018, 25mg TAF, 50mg bioctegravir and 200mg ntrastabine formed a compound, which was approved by FDA for listing and used to treat adult HIV-1 infection 3 Statistics of patent data: as the original research company, Gilead applied for the patent application of tenofovir and elaphenamine, which respectively claimed to protect its general formula compound, specific compound, salt, preparation method and combination drug composition, forming a hierarchical protection for the drug In recent years, the global patent application statistics of tenofovir and elaphenamine are shown in the figure below The compound compound patent (wo0208241a2, 2001) protects the compound tenofovir and fumarate The scope of protection includes not only salts, tautomers or free bases and their general formula compounds, but also their pharmaceutical compositions and uses in the preparation of drugs for the prevention or treatment of tumors or viral diseases, in which viral diseases are HIV infection China matures in July 2021; the US matures in May 2022 (with a 291 day extension) The crystal form patent (2012, 201280039891) protects tenofovir and its crystal form, composition and use in the treatment of HIV infection According to the patent application document, the non enantiomeric impurities in the prepared tenofovir-a-phenamine-half-fumaric acid salt are removed to less than 1 / 10 of the initial concentration Compared with tenofovir-a-phenamine-monofumaric acid salt, it has stronger impurity removal ability and shows better chemical and thermodynamic stability The inventiveness of the patent application has been disputed in China, and it was rejected by the patent office on December 2, 2016 when it was put forward that it does not possess inventiveness in the real trial stage The applicant submitted a request for reexamination in March 2017, which is currently in the reexamination stage PS: homologous patents have been authorized in the United States, Europe, Australia, Japan, South Korea and other countries and regions The patent for preparation method (case No 200410097845) protects the preparation method of tenofovir-a-phenamine, in particular to claim 1, "a method for using hydrocarbon magnesium, including the reaction of 9 - (2-hydroxypropyl) adenine (HPA) or 9 - (2-hydroxyethyl) adenine (HEA), hydrocarbon magnesium and protected p-toluenesulfonyloxymethyl phosphonate." The patent application was authorized in 2008, and the patent term is until July 20, 2021 The patent for key intermediate preparation method (application No 201280048965) protects the preparation method of key intermediate of tenofovir eilatamine, which is a compound with at least 90% non enantiomeric purity The method provided in the patent application document can obtain higher yield, easier operation, or lower use cost and toxicity The patent application was authorized in 2017 4 Domestic registration declaration statistics Through the simultaneous search of "tenofovir and elaphenamine" and "phosphopropotenofovir", the data shows that: the original Gilead company has been approved for import with chemical medicine category 5.1 (and has obtained the domestic priority review); only two companies of Zhengda Tianqing Pharmaceutical Group Co., Ltd and Jiangxi Qingfeng Pharmaceutical Co., Ltd have applied for anda with chemical medicine category 3 5 Summary: Based on the efficacy and safety, the launch of tenofovir and elapamine is more an update of the original research company's product line; in terms of patents, the review of crystal patents has provided opportunities for domestic imitation enterprises; Imitated declaration: although only Zhengda Tianqing and Qingfeng pharmaceutical have registered and declared this product in China, many enterprises' products have been in the state to be declared; in general, tenofovir and elaphenamine are not inferior drugs in the traditional sense, but it still needs a lot of foreshadowing to shake the position of entecavir in the domestic hepatitis B market! 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