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    Home > Active Ingredient News > Infection > Talking about: Sulfonate Drugs & Sulfonate Gene Toxicity

    Talking about: Sulfonate Drugs & Sulfonate Gene Toxicity

    • Last Update: 2021-05-02
    • Source: Internet
    • Author: User
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    WenJohnson

    In recent years, the review of genetic toxic substances by the drug review department has become stricter and more demanding.
    Are genotoxic substances detected? What is the potential risk? To what extent? It is directly related to the life and death of the project.
    However, the author believes that the "high standards and strict requirements" of the problem of gene poisoning must not give up because of choking when it comes to drug development!

    For the "sulfonate drugs" we are going to talk about today, the "sulfonic acids" required for salt formation are themselves potential hazards of genotoxic substances, but they have not affected their great help to the successful marketing of the improved drug properties, and until Today, this method of salt formation is still in use no matter at home or abroad.
    Friends who are worthy of drug research and development will study and learn from it!

    1.
    The fuse of sulfonate gene toxicity-"Nefinavir mesylate"

    1.
    The fuse of sulfonate gene toxicity-"Nefinavir mesylate"

    Nefinavir mesylate is an HIV-1 protease inhibitor for the treatment of HIV-1 infection; it was developed by Agouron, approved by the US FDA in 1997, approved by the European EMA in 1998, and approved by the Japanese PMDA in 1998 , Jointly sold by Agouron and ViiV Healthcare in the US market under the trade name Viracept®.

    On June 6, 2007, the European EMA discovered that some batches of anti-AIDS drug Viracept, that is, nelfinavir mesylate containing high doses of genotoxic impurity ~ ethyl methanesulfonate, decided to recall Roche Pharmaceuticals Viracept.
    The ethyl methanesulfonate in the medicine is a potential carcinogen.
    When the drug dose is 2.
    5g/d, up to 2.
    75mg of ethyl methanesulfonate may be ingested by the patient and affect the patient’s body.
    health.

    2.
    What are the specific varieties of sulfonate esters?

    2.
    What are the specific varieties of sulfonate esters?

    Methanesulfonic acid, benzene methanesulfonic acid and other sulfonate substances and a small amount of lower alcohols in the synthesis reaction generate alkyl sulfonate, such as methyl methanesulfonate (MMS), ethyl methanesulfonate (EMS), isopropyl Methanesulfonate (IMS), n-butyl methanesulfonate (NBMS), and arylsulfonate such as methyl benzenesulfonate (MBS), ethyl benzenesulfonate (EBS), p-toluenesulfonate (MP -TS), these substances can undergo alkylation reactions with DNA, which may become the cause of cancer.
    Therefore, it is very important to control the threshold of toxicological concern (TTC) level of such impurities in drugs.
    The European EMA issued a report on genotoxic impurities The maximum intake is 1.
    5 μg/d.

    3.
    Related important indicators-TTC

    3.
    Related important indicators-TTC

    Both the European EMA and the US FDA propose to adopt the "thresh-old of toxicological concern" (TTC) as the acceptable limit for genotoxic impurities.
    In the clinical development stage, the staged TTC is used as the limit of genotoxic impurities in the short-term medication period, as shown in the following table.
    The maximum limit of genotoxic impurities is the ratio of TTC to the maximum daily dose of the drug.
    At the same time, most genotoxic impurities are chemically active and have poor stability, which places high demands on analytical methods.

    Table 1: Acceptable limits of genotoxic impurities in the clinical phase of drugs

    Table 1: Acceptable limits of genotoxic impurities in the clinical phase of drugs

    4.
    Control & specific analysis methods

    4.
    Control & specific analysis methods

    When the solubility and stability of the sample are good, and the response is strong, the sample can be injected directly, and then gas chromatography (GC), liquid chromatography (LC) and their combined techniques are used for analysis.

    When the sample cannot meet the conditions of direct injection analysis, the sample needs to be pre-processed.
    The usual sample pre-processing methods mainly include various extraction techniques, derivatization methods, etc.
    , to separate, purify, enrich and concentrate the sample , In order to meet the requirements of analytical methods.

    The GC method is mainly used for the determination of volatile components.
    The method has high sensitivity and strong specificity.
    For example, the trace detection of mesylate compounds can use the GC method and its combined technology.
    GC method can be divided into direct injection GC method and headspace injection GC method according to different sampling methods.
    The types of detectors include FID, ECD, NPD, MS, etc.

    Compared with the GC method, the LC method can analyze the non-volatile components, and the sample load is also larger, the method is simple and feasible.
    The main methods are: high performance liquid chromatography (HPLC) method; HPLC-MS method; extraction technology and derivatization method combined with HPLC-MS; ion pair chromatography (IPC) method.

    5.
    How to avoid the production process?

    5.
    How to avoid the production process?

    Genotoxic impurities mainly come from starting materials, intermediates, reagents and reaction by-products in the synthesis of APIs.
    In addition, drugs may also degrade to produce genotoxic impurities during synthesis, storage, or formulation.
    As potential genotoxic impurities, acid ester compounds should be avoided as much as possible.
    Studies have reported the formation of sulfonate esters and various factors affecting their degradation, including temperature, alcohols, moisture, acids, alkalis, salts, etc.
    The results show that in neutral or trace amounts of alkali excess (such as 2,6-dimethyl The formation of these impurities can be avoided under the conditions of base pyridine), anhydrous, low-concentration alcohol, acids weaker than methanesulfonic acid (such as phosphoric acid), and salts (such as sodium perchlorate).
    There is currently no report indicating that sulfonate compounds are produced by degradation in other drugs.

    6.
    Global "sulfonate drugs"

    6.
    Global "sulfonate drugs"

    Through the drug crossing data query, 72 sulfonate drugs have been marketed, 3 NDA varieties, 14 clinical phase III, 17 clinical phase II, and 12 clinical phase I; in terms of treatment, they are mainly distributed in tumors and heart Cerebrovascular, nervous system, infection, respiratory system, endocrine, etc.
    ; for some drugs, see the table below for details (readers can inquire about it).

    7.
    Domestic "sulfonate drugs"

    7.
    Domestic "sulfonate drugs"

    For further inquiries, domestically developed/under-study drugs, "sulfonate drugs", have 1 approved marketed product, 2 NDA products, 5 clinical phase III products, 4 clinical phase II products, and 11 clinical phase I products; partly For drugs, see the table below for details.

    8.
    Summary

    8.
    Summary

    Be cautious of sulfonate drugs, this is right, after all, there are potential risks! But sometimes, sulfonate drugs do have better data support in pharmacy! Therefore, how to design and control in this process is very necessary!

    What I want to say here is that gene toxic substances are really annoying, but we can't stay away from it one-sidedly.
    In the process, it is good to be able to avoid nature.
    If it cannot be avoided, then we will control + study it!
    In short, don't give up eating because of choking, and in-depth research in the process, to further feel the importance of technology, there will still be a lot of fun!

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