阅读说明：本技术 吲哚美辛在抗冠状病毒感染中的应用 (Application of indomethacin in resisting coronavirus infection ) 是由 徐天宏 桑托罗 于 2020-02-21 设计创作，主要内容包括：本发明涉及吲哚美辛在抗冠状病毒感染中的应用,提供了吲哚美辛抑制SARS冠状病毒的新用途及其新剂型,该新剂型为吸入制剂。吲哚美辛能够显著抑制SARS冠状病毒,因此有望成为治疗SARS冠状病毒引起的疾病的药物。(The invention relates to an application of indomethacin in resisting coronavirus infection, and provides a new application of indomethacin in inhibiting SARS coronavirus and a new dosage form thereof, wherein the new dosage form is an inhalation preparation. Indomethacin can remarkably inhibit SARS coronavirus, and is expected to be a drug for treating diseases caused by SARS coronavirus.)

1. Application of indomethacin in preparing medicine for preventing and treating coronavirus infection is provided.

2. The application of a pharmaceutical composition in preparing a medicament for preventing or treating coronavirus infection is characterized in that the pharmaceutical composition contains indometacin and a pharmaceutically acceptable carrier or excipient.

3. An indomethacin inhalant and its application in treating respiratory tract inflammation caused by coronavirus are provided.

4. The use according to claim 2, wherein said pharmaceutical composition further comprises an additional antiviral agent.

5. The product and use according to any one of claims 1 to 3, characterized in that said coronavirus is a human-infecting coronavirus.

6. The product and use according to any of claims 1-3, characterized in that the coronavirus is selected from the group consisting of SARS-CoV, SARS-CoV2, MERS-CoV or a common cold causing coronavirus.

7. Use according to any one of claims 1 to 3, wherein said coronavirus is selected from the group consisting of SARS-CoV, SARS-CoV2 or a virus belonging to the same species (speces) as it belongs to the International Commission of viral Classification (ICTV) coronavirus classification.

Technical Field

The invention belongs to the field of drug research and development, and particularly relates to application of indomethacin in resisting coronavirus infection.

Background

Coronaviruses (Coronavirus) are a class of pathogenic single-stranded RNA viruses that infect humans and other vertebrates, causing inflammation of the respiratory and digestive tracts. Coronaviruses belong to the phylogenetic group of the order of the nested viruses (Nidovirales) and the family of Coronaviridae (Coronaviridae) and belong to the genus Coronavirus (Coronavirus), a large group of viruses widely existing in nature. 2019 novel coronavirus (SARS-CoV-2) is currently known as the 7 th coronavirus that can infect humans, and the SARS-CoV coronavirus that has exploded in 2003 is genetically very close to belonging to the same virus species (Table 1) as determined by the International Committee for Classification of viruses, and the remaining 5 coronavirus that infect humans are HCoV-229E, HCoV-OC43, HCoV-NL63, HCoV-HKU1, and MERS-CoV, respectively (causing respiratory syndrome in the middle east).

TABLE 1

The existing treatment method aiming at the lack of effective treatment methods of SARS coronavirus and MERS-CoV is mainly symptomatic treatment, and the existing clinical treatment methods are mainly divided into three types: 1. immune modulatory factors, such as interferon; 2. preventing virus from invading cell molecules, such as monoclonal antibody of S protein, polypeptide aiming at key fusion region of S protein, etc.; 3. and (3) molecules for inhibiting virus replication, such as virus polymerase specific inhibitors, broad-spectrum protease inhibitors and the like. Among these methods, both immunomodulatory factors and broad-spectrum protease inhibitors are non-specific therapies, with large side effects, the sequelae that are easily left in the cured patient, and large individual differences in therapeutic effects (Al-Hazmi, 2016; Zumla et Al, 2016).

The SARS virus has strong survival ability and strong infectivity in the outside world. According to the research results, SARS virus can keep activity for a long time and can be spread in the form of aerosol in the human body common excrement sputum, excrement and blood, SARS-CoV is developed in 2003, and SARS-CoV-2 is developed in large scale in 2019, which brings serious harm to the life, production and life of people, but the therapeutic drug is not disclosed yet. Therefore, it is a great matter to find effective remedy for SARS. However, the development period of brand-new drugs is long, the cost is huge, and the drugs capable of inhibiting the coronavirus are screened from the existing approved drugs (old drugs) until the outbreak of epidemic situation cannot be dealt with.

Indomethacin, also called as indomethacin, has a structural formula shown in figure 1, is a classic non-corticosteroid anti-inflammatory antipyretic and analgesic drug, reduces Prostaglandin (PG) synthesis by inhibiting Cyclooxygenase (COX), inhibits the formation of pain nerve impulses of inflammatory tissues, inhibits inflammatory reactions including the inhibition of leukocyte chemotaxis and the release of lysosomal enzymes, and the like, thereby having antipyretic, analgesic and anti-inflammatory effects. Through search, no report on the anti-coronavirus or SARS-CoV-2 activity of indomethacin is found.

Disclosure of Invention

In order to solve the problem of poor curative effect of the drugs for treating SARS coronavirus infection in the prior art, the invention provides application of indomethacin in SARS coronavirus infection, and provides a new formulation and an inhalation formulation of indomethacin, which are used for treating pneumonia and complications thereof caused by SARS coronavirus.

Indomethacin is also called as indomethacin, and is a clinically common non-corticosteroid anti-inflammatory antipyretic and analgesic.

AI artificial intelligence technology is used to screen the inhibition of SARS-CoV-2 by thousands of old drugs through simulating the signal path of virus and host cell, and indomethacin is found to have strong potential virus inhibition. Further cell level experiments and animal experiments prove that the indomethacin can obviously inhibit the replication of the coronavirus, has an action mechanism different from 3 types of methods aiming at SARS treatment in clinic, is a brand new action mechanism, and can quickly activate protein kinase R in cells so as to activate a cell level virus defense mechanism.

The first aspect of the invention provides an application of indomethacin shown in a structural formula (A) in a medicine for preventing or treating coronavirus, wherein the coronavirus is preferably coronavirus infecting human; further, the coronavirus is preferably SARS-CoV-2, SARS-CoV or a virus of the same species, MERS-CoV

In a second aspect of the invention, there is provided a pharmaceutical composition for inhibiting coronavirus comprising indomethacin and one or more pharmaceutically acceptable excipients, fillers, binders, lubricants, disintegrants, or stabilizers.

In a third aspect of the present invention, an indomethacin inhalant is provided, which is used to increase the effective concentration of indomethacin in local lung cells, has higher bioavailability, avoids the first pass effect of liver, and more effectively treats SARS pneumonia.

The compounds of the present invention or pharmaceutical compositions containing them may be administered in unit dosage form by enteral or parenteral routes, such as by inhalation, oral, intravenous, intramuscular, subcutaneous, nasal, oromucosal, ocular, pulmonary and respiratory, dermal, vaginal, rectal, and the like. The dosage form for administration may be a liquid dosage form, a solid dosage form, or a semi-solid dosage form. The liquid dosage forms can be solution (including true solution and colloidal solution), emulsion (including o/w type, w/o type and multiple emulsion), suspension, injection (including water injection, powder injection and infusion), eye drop, nose drop, lotion, liniment, etc.; the solid dosage form can be tablet (including common tablet, enteric coated tablet, buccal tablet, dispersible tablet, chewable tablet, effervescent tablet, orally disintegrating tablet), capsule (including hard capsule, soft capsule, and enteric coated capsule), granule, powder, pellet, dripping pill, suppository, pellicle, patch, aerosol (powder), spray, etc.; semisolid dosage forms can be ointments, gels, pastes, and the like.

The dosage of the pharmaceutical composition of the compound of the present invention to be administered may vary widely depending on the nature and severity of the disease to be prevented or treated, the individual condition of the patient or animal, the route and dosage form of administration, and the like. Generally, a suitable daily dosage range for a compound of the invention is from 0.001 to 150mg/kg body weight, preferably from 0.1 to 100mg/kg body weight, more preferably from 0.5 to 60mg/kg body weight, most preferably from 1 to 30mg/kg body weight. The above-mentioned dosage may be administered in one dosage unit or divided into several dosage units, depending on the clinical experience of the physician and the dosage regimen including the use of other therapeutic means

Indomethacin has been used clinically for a long time as a classic non-cortical hormone anti-inflammatory antipyretic and analgesic, and has good safety, and the drug metabolism characteristic and the toxic and side effect are very clear. The new application of the medicine for resisting coronavirus can be quickly applied to pathogenic infection of coronavirus, and is particularly used for relieving SARS-CoV-2 serious epidemic outbreak in 2020.

Drawings

FIG. 1: molecular structural formula of indometacin

FIG. 2: in example 1, indomethacin blocked SARS-CoV infection Activity

Detailed Description