Anti-Influenza Virus Drug-Oseltamivir Phosphate Passed the Consistency Evaluation

Oseltamivir phosphate is a kind of specific influenza virus neuraminidase inhibitor, and it is an effective way to treat influenza virus clinically. Recently, a Chinese pharmaceutical company’s oseltamivir phosphate capsule (75mg) passed the consistency evaluation for the first time, which enabled it to gain advantages in future market expansion and medical insurance payment. The supplementary application for the consistency evaluation of the capsule was accepted by the CDE on June 15, 2018, with the acceptance number CYHB1850080, and the consistency evaluation was completed in February 2019.

The first company approved by the National Food and Drug Administration to pass the consistency evaluation was Dongyang Sunshine Pharmaceutical’s Oseltamivir Phosphate Capsule (75mg). The original manufacturer was Roche and the trade name was Tamiflu. Tamiflu has a patent in my country. Due to the large-scale outbreak of influenza in 2005 and under the pressure of the government’s compulsory production license, Roche Group authorized the production and sales of oseltamivir to Shanghai Pharmaceutical Group and Shenzhen in 2005 and 2006 respectively. East Sunshine Industrial Development Co., Ltd. The successful consistency evaluation of the drug is an authoritative recognition of the company’s R&D capabilities, production and drug quality, and drug efficacy. Because companies need to go through multiple steps from development to final completion of consistency evaluation, including reference reagent selection and procurement, pharmaceutical research, BE testing, and submission of consistency evaluation applications, it can be difficult and difficult to achieve.

Requirements for consistency evaluation in the research and development of generic drugs

The significance of the consistency of generic drugs includes two aspects, one is pharmacy equivalence, and the other is biological equivalence, so as to achieve clinical efficacy equivalent to the original drug and realize the replacement of the original drug. Pharmaceutical research involves research on the crystal form and particle size of the raw material drug, formulation and technology, product quality and stability, etc., and finally achieves the same in vitro dissolution behavior as the reference formulation. If it is inconsistent, a research on the formulation process change is required. After the pharmaceutical research is completed and confirmed, the BE test can be performed.

The ultimate goal of the BE test is to make the difference between the absorption rate and degree of absorption of the drug in the test preparation and the reference preparation within an acceptable range, and the pharmacokinetic parameters Cmax and AUC are usually selected for evaluation. After the BE test is completed and the bioequivalence is confirmed, the data can be sorted and submitted to the CFDA for consistency evaluation. Medicilon Biopharmaceuticals has successfully completed a number of quality consistency evaluation cases in the quality consistency evaluation of generic drugs. It has rich experience in the research and development of generic drugs and can provide customers with professional consistency evaluation services.

The mechanism of action of oseltamivir phosphate

The main component of oseltamivir phosphate is oseltamivir, a new type of antiviral drug, which can reduce the spread of influenza A or B viruses by inhibiting the release of the virus from infected cells. The best time to administer it is within 2 days (ie within 48 hours) of the onset of flu symptoms, but it will have a certain effect when used 4 days after the onset (ie, 96 hours).

Oseltamivir phosphate is a prodrug of its active metabolite, and its active metabolite (oseltamivir carboxylate) is a potent and selective influenza virus neuraminidase inhibitor. Neuraminidase is a glycoprotease on the surface of the virus. Its activity is essential for the release of newly formed virus particles from infected cells and the further spread of infectious virus in the human body. The active metabolite of oseltamivir phosphate can inhibit the neuraminidase activity of influenza A and B viruses, and the half inhibitory concentration of viral neuraminidase activity in vitro is as low as nanograms. Active metabolites can be observed in vitro to inhibit the growth of influenza virus, and in vivo can also be observed to inhibit influenza virus replication and pathogenicity. Moreover, clinical studies have shown that the amino acid sequence at the site of action of oseltamivir phosphate capsules has a strong conservative type, which can effectively avoid the development of drug resistance in patients. Therefore, it is necessary to apply oseltamivir phosphate to the treatment of viral colds. Good results will be achieved.

Research on the anti-influenza virus of oseltamivir in animals

Some researchers have carried out the characteristics of the pharmacokinetic parameters of oseltamivir in tree shrews and its anti-influenza virus efficacy in tree shrews [1]. The method was that the tree shrews were taken orally with oseltamivir phosphate and the plasma was used for pharmacokinetic analysis, and compared with the pharmacokinetic parameters of human, ferret, mice, and rats.

Tree shrews were infected with human influenza virus A/California/04/2009H1N1 and avian influenza virus H9N2 mutant strain Y280-PB2-E627K via nasal inoculation, and were treated with oseltamivir. The nasal symptoms were observed and collected at 1, 3, and 5 days after infection. Nasal lavage fluid and sediment were tested for virus TCID50 and cell classification count respectively, and the serum neutralizing antibody titers were tested 21 days after infection. The results showed that the pharmacokinetic parameters of oseltamivir in tree shrews were: Cmax: 1.34μg/mL, Tmax: 0.75h, T1/2: 2.03h, AUC0-12: 1.76mg•h/liter. Oseltamivir has no obvious inhibitory effect on the nasal detoxification of tree shrews infected with A/California/04/2009H1N1 virus, but the high-dose group oseltamivir can significantly inhibit the nasal detoxification of tree shrews infected with H9N2Y280-PB2-E627K virus on the first day , To reduce the total number of cells in the nasal lavage fluid on the third day. The antibody titer produced after infection with the A/California/04/2009H1N1 virus was significantly higher than the antibody titer of the H9N2Y280-PB2-E627K avian influenza virus. Oseltamivir antiviral treatment has no effect on the serum antibody titer among the groups infected with the same virus. Influence.

Therefore, the pharmacokinetic parameters of oseltamivir in tree shrews are different from model animals such as humans or ferrets, but its drug plasma clearance half-life and peak time are similar to mice; oseltamivir can be effective in terms of pharmacodynamics Inhibit nasal virus detoxification and inflammation in tree shrews infected with H9N2Y280-PB2-E627K influenza virus.

Although oseltamivir can reduce flu symptoms in patients, it also has side effects. The main side effect is nausea and vomiting, and patients have reported experiencing headaches, mental disorders and even kidney disease. Therefore, they should be prescribed by a doctor and should not be used indiscriminately. When using oseltamivir, on the one hand, patients should not blindly reserve oseltamivir, and should use it rationally based on clinical diagnosis; on the other hand, the public media should not amplify the mental adverse reactions of oseltamivir and the The interpretation of the guide catalogue caused public panic.

[1] Pharmacokinetics and pharmacodynamic application research of oseltamivir in tree shrews[J]