WO2022036774A1 - 单宁酸在制备抗呼吸道病毒药物方面的应用 - Google Patents

单宁酸在制备抗呼吸道病毒药物方面的应用 Download PDF

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WO2022036774A1
WO2022036774A1 PCT/CN2020/114432 CN2020114432W WO2022036774A1 WO 2022036774 A1 WO2022036774 A1 WO 2022036774A1 CN 2020114432 W CN2020114432 W CN 2020114432W WO 2022036774 A1 WO2022036774 A1 WO 2022036774A1
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tannic acid
parts
antiviral
medicine
virus
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PCT/CN2020/114432
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French (fr)
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付军
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广东盛普生命科技有限公司
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Priority to JP2022510808A priority Critical patent/JP7349559B2/ja
Priority to CA3149169A priority patent/CA3149169C/en
Priority to US17/630,512 priority patent/US20220354877A1/en
Priority to EP20948896.4A priority patent/EP4005575A4/en
Publication of WO2022036774A1 publication Critical patent/WO2022036774A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K20/00—Accessory food factors for animal feeding-stuffs
    • A23K20/10—Organic substances
    • A23K20/163—Sugars; Polysaccharides
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K20/00—Accessory food factors for animal feeding-stuffs
    • A23K20/20—Inorganic substances, e.g. oligoelements
    • A23K20/24—Compounds of alkaline earth metals, e.g. magnesium
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K50/00—Feeding-stuffs specially adapted for particular animals
    • A23K50/20—Feeding-stuffs specially adapted for particular animals for horses
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K50/00—Feeding-stuffs specially adapted for particular animals
    • A23K50/30—Feeding-stuffs specially adapted for particular animals for swines
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K50/00—Feeding-stuffs specially adapted for particular animals
    • A23K50/40—Feeding-stuffs specially adapted for particular animals for carnivorous animals, e.g. cats or dogs
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K50/00—Feeding-stuffs specially adapted for particular animals
    • A23K50/50—Feeding-stuffs specially adapted for particular animals for rodents
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K50/00—Feeding-stuffs specially adapted for particular animals
    • A23K50/70—Feeding-stuffs specially adapted for particular animals for birds
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K50/00—Feeding-stuffs specially adapted for particular animals
    • A23K50/70—Feeding-stuffs specially adapted for particular animals for birds
    • A23K50/75—Feeding-stuffs specially adapted for particular animals for birds for poultry
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/05—Phenols
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7024—Esters of saccharides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/06—Aluminium, calcium or magnesium; Compounds thereof, e.g. clay
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/26—Iron; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/30—Zinc; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/12—Aerosols; Foams
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs

Definitions

  • the invention belongs to the technical field of biomedicine. More specifically, it relates to the application of tannic acid in the preparation of anti-respiratory virus drugs.
  • the coronaviruses in respiratory viruses belong to the genus Nidovirales, Coronaviridae, and the genus Coronavirus.
  • Viruses of the genus Coronavirus are RNA viruses with an envelope and a linear single-stranded positive-stranded genome.
  • the coronavirus has a diameter of about 80-120 nm, a methylated cap structure at the 5' end of the genome, a poly(A) tail at the 3' end, and a full-length genome of about 27-32 kb. It is the virus with the largest genome among the known RNA viruses. .
  • Coronaviruses only infect vertebrates, including humans.
  • coronaviruses that infect humans and cause great epidemics include SARS-CoV, SARS-CoV-2, MERS-CoV, HCoV-229E, HCoV-NL63, HCoV-OC43 , HCoV-HKU1, can cause diseases of the respiratory tract, digestive tract, liver and nervous system.
  • Human coronaviruses were isolated in 1965, but until now knowledge about them is still quite limited, and the serotype and antigenic variability of coronaviruses are unclear.
  • the coronavirus can be re-infected, indicating that there are multiple serotypes (at least 4 known) and antigenic variation, its immunity is difficult, and there are no specific preventive and therapeutic drugs.
  • ⁇ zauracil ⁇ zauracil
  • ribavirin ribavirin, Virazole
  • spiroadamantane spiroadamantane
  • Remdesivir (Remdesivir, CAS: 1809249-37-3) has certain activity against coronavirus pathogens such as atypical pneumonia (SARS) and Middle East respiratory syndrome (MERS), but Remdesivir has not been approved for marketing in any country, and its safety and efficacy have not been proven. It can be seen that the current anti-coronavirus drugs all have certain safety hazards, and with the mutation of the virus and the emergence of new strains, the antiviral effect of these chemical drugs is greatly reduced, such as the new coronavirus 2019-nCoV that appeared at the end of 2019 ( SARS-CoV-2), until now no effective drug has been found.
  • the technical problem to be solved by the present invention is to overcome the defects and deficiencies of the existing anti-respiratory virus drugs and provide a new choice of anti-respiratory virus drugs, namely tannic acid (CAS: 1401-55-4).
  • tannic acid CAS: 1401-55-4
  • tannins have significant antiviral effects on respiratory viruses, especially on coronaviruses and Orthomyxoviridae influenza viruses.
  • this kind of substance exists in a variety of plants, is a natural active compound in nature, and has also been used as a food additive, with high safety, so it has a good application prospect in the preparation and development of antiviral drugs against respiratory viruses.
  • the purpose of the present invention is to provide the application of tannic acid in the preparation of anti-respiratory virus drugs.
  • Another object of the present invention is to provide the application of tannic acid derivatives or tannic acid structural analogs in the preparation of anti-respiratory virus drugs.
  • Another object of the present invention is to provide an anti-respiratory virus drug containing tannic acid.
  • tannic acid has a significant antiviral effect on respiratory viruses, especially the inhibitory effect on the new coronavirus 2019-nCoV (SARS-CoV-2) is significantly higher than that of the positive control drug Remdesivir.
  • SARS-CoV-2 new coronavirus 2019-nCoV
  • the antiviral effect of Orthomyxoviridae influenza viruses is also very significant.
  • the present invention claims the application of tannic acid in the preparation of anti-respiratory virus drugs.
  • compositions of the present invention exist in free form, or, as appropriate, as pharmaceutically acceptable derivatives.
  • pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable prodrugs, salts, esters, salts of esters, or any other that can be administered directly or indirectly according to the needs of the patient Adducts or derivatives, compounds described in other aspects of the invention, their metabolites or their residues.
  • the present invention also claims the application of tannic acid derivatives or tannic acid structural analogs in the preparation of anti-respiratory virus drugs.
  • tannic acid tannic acid derivatives, stereoisomers, geometric isomers, hydrates, solvates or pharmaceutically acceptable salts or prodrugs of tannic acid structural analogs should also be included in the present invention. within the scope of protection.
  • a “solvate” of the present invention refers to an association of one or more solvent molecules with a compound of the present invention.
  • Solvate-forming solvents include, but are not limited to, water, isopropanol, ethanol, methanol, dimethylsulfoxide, ethyl acetate, acetic acid, and aminoethanol.
  • hydrate refers to an association in which the solvent molecule is water.
  • the anti-respiratory virus includes Coronaviridae and Orthomyxoviridae.
  • Coronaviridae virus is a virus of the genus Coronavirus.
  • coronaviruses include SARS-CoV, SARS-CoV-2, MERS-CoV, HCoV-229E, HCoV-NL63, HCoV-OC43, and HCoV-HKU1.
  • the coronavirus is SARS-CoV-2.
  • Orthomyxoviridae viruses include Influenza A, Influenza B, and Influenza C.
  • the Orthomyxoviridae virus is an influenza A H1N1 influenza virus of the genus Influenza A.
  • the present invention further provides an anti-respiratory virus drug, comprising tannic acid.
  • the medicine also includes any one or both of tannic acid derivatives and tannic acid structural analogs.
  • the medicine further comprises one or both of polyphenolic compounds and antiviral metal salts.
  • antiviral metal salts include zinc salts, iron salts, calcium salts, magnesium salts, tungsten salts and rubidium salts.
  • the zinc salt is zinc sulfate or zinc gluconate
  • the iron salt is ferrous gluconate
  • the calcium salt is calcium gluconate
  • the tungsten salt is sodium tungstate
  • the rubidium salt is iodide rubidium.
  • the mass ratio of the tannic acid, tannic acid derivatives or tannic acid structural analogs to the antiviral metal salt is 1:(0.05-50).
  • polyphenolic compounds include flavonoids, stilbene, phenolic acids, lignans, and the like.
  • the mass ratio of the tannic acid, the tannic acid derivative or the tannic acid structural analog to the polyphenolic compound is 1:(0.05-50).
  • the compounds or compositions claimed in the present invention are used in the preparation of anti-respiratory virus drugs, but are not limited to, the compounds or compositions of the present invention are administered to patients in an effective amount to prepare for the prevention or treatment of diseases caused by respiratory viruses, Use of a drug for alleviating symptoms of a disease caused by a respiratory virus or delaying the development or onset of a disease caused by a respiratory virus.
  • the claimed compounds or medicaments in addition to their therapeutic benefits in humans, can also be used in veterinary treatment of pets, introduced species and farm animals, including mammals, rodents, avian animals, and the like. Examples of additional animals include horses, dogs, cats, pigs, and the like.
  • the medicine also contains pharmaceutically acceptable adjuvants, carriers, excipients, diluents, vehicles, etc., and is made into different pharmaceutical dosage forms, such as injections, oral preparations, sprays, inhalants, aerosols, etc. agent, etc.
  • Substances that can be used as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, aluminum, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, sorbitan Potassium acid, partial glyceride mixture of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silicon, magnesium trisilicate, polyethylene Pyrrolidones, polyacrylates, waxes, polyethylene-polyoxypropylene-blocking polymers, lanolin, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as carboxymethyl Sodium cellulose, ethyl cellulose and cellulose acetate; gum powder; malt; gelatin; talc; adjuvants such as
  • the principal active ingredient is mixed with a pharmaceutical excipient (or carrier) to form a solid preformulation composition comprising a homogeneous mixture of a compound of the present invention.
  • a pharmaceutical excipient or carrier
  • the active ingredient is uniformly dispersed throughout the composition so that the composition can be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules .
  • the tablets or pills of the present invention may be coated or otherwise compounded to provide a dosage form with the advantage of prolonged action, or to protect the tablet or pill from the action of acidic conditions in the stomach.
  • a tablet or pill may include an inner dose and an outer dose of ingredients, the latter having the form of a sheath over the former.
  • An enteric layer may be used to separate the two components, where the enteric layer serves to prevent disintegration in the stomach and allow the inner component to pass intact into the duodenum or be delayed release.
  • enteric layers or coatings including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate.
  • compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents, or mixtures thereof, and powders.
  • Liquid or solid compositions may contain suitable pharmaceutical excipients. Preferably, these compositions are administered by the oral or nasal respiratory route for local or systemic effect.
  • Compositions in preferred pharmaceutically acceptable solvents can be nebulized by the use of inert gases. The nebulized solution can be inhaled directly from the nebulizing device, or the nebulizing device can be attached to a mask mesh, or intermittent positive pressure breathing machine. Solutions, suspensions, or powder compositions may be administered from a device that delivers the dosage form in an appropriate manner, preferably the oral or nasal route.
  • the present invention also provides an antiviral spray, the active ingredient includes tannic acid.
  • the antiviral spray includes the following components and their parts by weight: 5-20 parts of tannic acid, 1-50 parts of polyphenolic compounds, 1-15 parts of additives and the balance of water.
  • the present invention also provides an antiviral aerosol, the active ingredient includes tannic acid.
  • tannic acid 1-20 parts of tannic acid, 0-10 parts of antiviral metal salts, 1-15 parts of additives and the balance of propellants.
  • propellant is tetrafluoroethane (HFA-134a) or heptafluoropropane (HFA-227).
  • the present invention also provides an oral antiviral agent, the active ingredient includes tannic acid.
  • tannic acid 3-20 parts of tannic acid, 1-15 parts of antiviral metal salts, 1-15 parts of additives and the balance of water.
  • additives include antioxidants and other pharmaceutically acceptable auxiliary materials.
  • antioxidants include vitamin C and rosmarinic acid.
  • tannic acid has a significant inhibitory effect on respiratory viruses including SARS-CoV-2 coronavirus, H1N1 influenza virus and other respiratory viruses, and the curative effect is exact, and has broad application in the field of preparing anti-respiratory virus drugs prospect.
  • tannic acid exists in a variety of plants and is a natural active compound that exists in nature. It has also been used as a food additive, with high safety and good foundation for drug development.
  • the present invention is further described below in conjunction with specific embodiments, but the embodiments do not limit the present invention in any form.
  • the reagents, methods and equipment used in the present invention are conventional reagents, methods and equipment in the technical field.
  • the active virus experiments of the present invention are all entrusted to the Guangdong Provincial Center for Disease Control and Prevention, and the microbial materials are provided by the Guangdong Provincial Center for Disease Control and Prevention.
  • Example 1 Determination of the toxicity of tannic acid to African green monkey kidney cells (Vero-E6 cells)
  • the maximum nontoxic dose (TD 0 ) medicinal liquid is selected for the medicine to be tested, and 12 concentrations are respectively diluted in multiple ratios with the cell maintenance liquid, and the viral infection titer is 100TCID 50 ;
  • tannic acid showed high anti-SARS-CoV-2 virus activity, its IC50 value against SARS-CoV-2 virus was 0.0032 ⁇ M, and its SI was 7343.75, which was significantly higher than that of the positive control group.
  • Desivir has antiviral activity and a high selectivity index.
  • Example 3 Determination of the toxicity of tannic acid to canine kidney epithelial cells (MDCK cells)
  • Drugs experimental group, tannic acid; control group, ribavirin (purchased from Nord Pharmaceutical (Jiangsu) Co., Ltd.);
  • MDCK cells canine kidney epithelial cells
  • Embodiment 4 Anti-influenza A H1N1 influenza virus drug efficacy test of tannic acid
  • Drugs experimental group, tannic acid; control group, ribavirin (purchased from Nord Pharmaceutical (Jiangsu) Co., Ltd.);
  • MDCK cells canine kidney epithelial cells
  • tannic acid showed high anti-influenza A H1N1 virus activity, its IC 50 value against influenza A H1N1 virus was 0.0032 ⁇ M, and the SI was 7343.75, which was significantly higher than that of ribavir in the positive control group
  • the antiviral activity of the forest was also high, and the selection index was also high.
  • Example 5 Determination of the toxicity of tannic acid composition on African green monkey kidney cells (Vero-E6 cells)
  • the tannic acid composition showed higher anti-SARS-CoV-2 virus activity, which was significantly higher than that of the positive control group Remdesivir, and the selection index was also higher.
  • Example 7 Determination of toxicity of tannic acid composition on canine kidney epithelial cells (MDCK cells)
  • Example 8 Drug efficacy test of tannic acid composition against influenza A H1N1 virus
  • the tannic acid composition exhibited higher anti-influenza A H1N1 virus activity, which was significantly higher than that of ribavirin in the positive control group, and the selection index was also higher.
  • Embodiment 9 A kind of antiviral spray
  • An antiviral spray contains the following components and their weight percentages: 10% of tannic acid, 5% of catechin, 3% of vitamin C and the balance of deionized water.
  • Embodiment 10 A kind of antiviral spray
  • An antiviral spray contains the following components and their weight percentages: 5% of tannic acid, 5% of resveratrol, 3% of rosmarinic acid and the balance of deionized water.
  • Embodiment 11 A kind of antiviral aerosol
  • An antiviral aerosol contains the following components and their weight percentages: 5% of tannic acid, 1% of zinc gluconate, 8% of deionized water, 2% of ethanol, and the balance is propellant tetrafluoroethane.
  • Embodiment 12 A kind of antiviral oral agent
  • An antiviral oral preparation contains the following components and their weight percentages: 10% of tannic acid, 10% of zinc gluconate, 2% of auxiliary materials and the balance of distilled water.

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Abstract

单宁酸在制备抗呼吸道病毒药物方面的应用。经过活病毒实验显示，单宁酸对包括SARS-CoV-2的冠状病毒、甲型H1N1流感病毒等呼吸道病毒均具有显著的抑制效果，疗效确切，在制备抗呼吸道病毒药物领域中具有广阔的应用前景。而且单宁酸存在于多种植物中，是自然界存在的天然活性化合物，同时也已作为食品添加剂应用，安全性高，开发药物基础好。

Description

单宁酸在制备抗呼吸道病毒药物方面的应用 技术领域
本发明属于生物医药技术领域。更具体地，涉及单宁酸在制备抗呼吸道病毒药物方面的应用。
背景技术
病毒引起的疾病基本上都具有一定的传染性，其爆发或流行都将给人类的健康和生活带来巨大的影响。目前，病毒感染的防治主要依赖于疫苗接种和/或抗病毒药物治疗。但是，是临床应用中，疫苗的价格较高，需要低温储存，使其难以广泛应用；另一方面，目前的许多病毒都具有变异性，特别是呼吸道病毒(如冠状病毒、正粘病毒科病毒等)更容易发生变异，疫苗的研发难以跟上病毒的变异。因此，抗病毒药物已经逐渐成为治疗病毒性传染病的主要手段。
其中，呼吸道病毒中的冠状病毒在系统分类属套式病毒目(Nidovirales)、冠状病毒科(Coronaviridae)、冠状病毒属(Coronavirus)。冠状病毒属的病毒是具囊膜(envelope)、基因组为线性单股正链的RNA病毒，是自然界广泛存在的一大类病毒。冠状病毒直径约80～120nm，基因组5′端具有甲基化的帽状结构，3′端具有poly(A)尾，基因组全长约27～32kb，是目前已知RNA病毒中基因组最大的病毒。冠状病毒仅感染脊椎动物，包括人，目前已知感染人并带来极大疫情的冠状病毒有SARS-CoV、SARS-CoV-2、MERS-CoV、HCoV-229E、HCoV-NL63、HCoV-OC43、HCoV-HKU1，可引起呼吸道、消化道、肝脏和神经系统产生疾病。人冠状病毒在1965年已被分离出来，但直至目前对它们的认识仍相当有限，冠状病毒的血清型和抗原变异性还不明确。且冠状病毒可以发生重复感染，表明其存在有多种血清型(已知至少有4种)并有抗原的变异，其免疫较困难，尚无特效的预防和治疗药物。
目前仅在实验研究中发现，氮尿嘧啶(αzauracil)及利巴韦林(病毒唑，ribavirin，Virazole)，螺金刚烷(spiroadamantane)对冠状病毒有明显的抑制作用(向倩,王睿.冠状病毒感染特点与防治[J].中华医院感染学杂志,2003,013(011):1097-1100.)。但是上述药物容易出现腹泻、贫血、头晕头痛、虚弱乏力等不良反应。另外，临床研究发现，瑞德西韦(Remdesivir，CAS：1809249-37-3) 对非典型性肺炎(SARS)和中东呼吸综合征(MERS)等冠状病毒科病毒病原体均有一定的活性，但是瑞德西韦尚未在任何国家获得批准上市，其安全性和有效性也未被证实。可见，目前的抗冠状病毒药物均存在一定的安全隐患，并且随着病毒的变异和新毒株的出现，这些化药的抗病毒效果大打折扣，比如2019年底出现的新型冠状病毒2019-nCoV(SARS-CoV-2)，直到目前尚未发现疗效确切的药物。
发明内容
本发明要解决的技术问题是克服现有抗呼吸道病毒药物的缺陷和不足，提供一种抗呼吸道病毒药物的新选择，即单宁酸(Tannic acid，CAS：1401-55-4)。发明人经过大量的探索和研究发现，单宁酸对呼吸道病毒，尤其是对冠状病毒、正粘病毒科流感病毒的抗病毒效果显著。且该类物质存在于多种植物中，是自然界存在的天然活性化合物，同时也已作为食品添加剂应用，安全性高，因此在制备开发针对呼吸道病毒的抗病毒药物方面具有很好的应用前景。
本发明的目的是提供单宁酸在制备抗呼吸道病毒药物方面的应用。
本发明另一目的是提供单宁酸衍生物或单宁酸结构类似物在制备抗呼吸道病毒药物方面的应用。
本发明另一目的是提供一种包含单宁酸的抗呼吸道病毒的药物。
本发明上述目的通过以下技术方案实现：
本发明研究显示，单宁酸对呼吸道病毒具有显著的抗病毒作用，特别是对于新型冠状病毒2019-nCoV(SARS-CoV-2)的抑制效果要显著高于阳性对照药物瑞德西韦，对正粘病毒科流感病毒的抗病毒效果也非常显著。基于上述成果，本发明要求保护单宁酸在制备抗呼吸道病毒药物方面的应用。
本发明所述单宁酸存在自由形态，或合适的、作为药学上可接受的衍生物。根据本发明，药学上可接受的衍生物包括，但并不限于，药学上可接受的前药，盐，酯，酯类的盐，或能直接或间接地根据患者的需要给药的其他任何加合物或衍生物，本发明其他方面所描述的化合物，其代谢产物或他的残留物。
因此，本发明还要求保护单宁酸衍生物或单宁酸结构类似物在制备抗呼吸道病毒药物方面的应用。
进一步地，单宁酸、单宁酸衍生物、单宁酸结构类似物的立体异构体、几何 异构体、水合物、溶剂化物或药学上可接受的盐或前药也应在本发明保护范围之内。
本发明的“溶剂化物”是指一个或多个溶剂分子与本发明的化合物所形成的缔合物。形成溶剂化物的溶剂包括，但并不限于，水、异丙醇、乙醇、甲醇、二甲亚砜、乙酸乙酯、乙酸和氨基乙醇。术语“水合物”是指溶剂分子是水所形成的缔合物。
进一步地，所述抗呼吸道病毒包括冠状病毒科病毒和正粘病毒科病毒。
更进一步地，所述冠状病毒科病毒为冠状病毒属病毒。
具体目前已证实的所述冠状病毒属病毒包括SARS-CoV、SARS-CoV-2、MERS-CoV、HCoV-229E、HCoV-NL63、HCoV-OC43、HCoV-HKU1。
优选地，所述冠状病毒属病毒为SARS-CoV-2。
进一步地，所述正粘病毒科病毒包括甲型流感病毒属、乙型流感病毒属、丙型流感病毒属。
优选地，所述正粘病毒科病毒为甲型流感病毒属的甲型H1N1流感病毒。
基于此，本发明进一步提供一种抗呼吸道病毒的药物，包含单宁酸。
更进一步地，所述药物还包含单宁酸衍生物、单宁酸结构类似物中的任意一种或两种。
进一步地，所述药物还包含多酚类化合物、抗病毒金属盐中的一种或两种。
更进一步地，所述抗病毒金属盐包括锌盐、铁盐、钙盐、镁盐、钨盐和铷盐。
优选地，所述锌盐为硫酸锌或葡萄糖酸锌；所述铁盐为葡萄糖酸亚铁；所述钙盐为葡萄糖酸钙；所述钨盐为钨酸钠；所述铷盐为碘化铷。
进一步地，所述单宁酸、单宁酸衍生物或单宁酸结构类似物与抗病毒金属盐的质量比为1：(0.05～50)。
更进一步地，所述多酚类化合物包括类黄酮、芪、酚酸和木酚素等。
进一步地，所述单宁酸、单宁酸衍生物或单宁酸结构类似物与多酚类化合物的质量比为1：(0.05～50)。
本发明要求保护的化合物或组合物应用于制备抗呼吸道病毒药物，但不限于，使用本发明的化合物或药物组合物的有效量对患者给药来制备用于预防或治疗呼吸道病毒引发的疾病，减轻呼吸道病毒引发的疾病症状或者延缓呼吸道病毒引发的疾病的发展或发作的药品的用途。
本发明要求保护的化合物或药物除了对人类治疗有益以外，还可应用于兽医治疗宠物、引进品种的动物和农场的动物，包括哺乳动物，啮齿类，禽类动物等等。另外一些动物的实例包括马、狗、猫、猪等。
更进一步地，所述药物还含有药学上可接受的辅料、载体、赋形剂、稀释剂、媒介物等，制成不同的药物剂型，如注射剂、口服剂、喷剂、吸入剂、气雾剂等。
可作为药学上可接受载体的物质包括，但并不限于，离子交换剂，铝，硬脂酸铝，卵磷脂，血清蛋白，如人血清蛋白，缓冲物质如磷酸盐，甘氨酸，山梨酸，山梨酸钾，饱和植物脂肪酸的部分甘油酯混合物，水，盐或电解质，如硫酸鱼精蛋白，磷酸氢二钠，磷酸氢钾，氯化钠，锌盐，胶体硅，三硅酸镁，聚乙烯吡咯烷酮，聚丙烯酸脂，蜡，聚乙烯-聚氧丙烯-阻断聚合体，羊毛脂，糖，如乳糖，葡萄糖和蔗糖；淀粉如玉米淀粉和土豆淀粉；纤维素和它的衍生物如羧甲基纤维素钠，乙基纤维素和乙酸纤维素；树胶粉；麦芽；明胶；滑石粉；辅料如可可豆脂和栓剂蜡状物；油如花生油，棉子油，红花油，麻油，橄榄油，玉米油和豆油；二醇类化合物，如丙二醇和聚乙二醇；酯类如乙基油酸酯和乙基月桂酸酯；琼脂；缓冲剂如氢氧化镁和氢氧化铝；海藻酸；无热原的水；等渗盐；林格(氏)溶液；乙醇，磷酸缓冲溶液，和其他无毒的合适的润滑剂如月桂硫酸钠和硬脂酸镁，着色剂，释放剂，包衣衣料，甜味剂，调味剂和香料，防腐剂和抗氧化剂。
为了制备固体组合物如片剂，将主要的活性组分与药物赋形剂(或载体)进行混合以形成固体预配制组合物，其包含本发明的化合物的均匀混合物。当称这些预配制组合物为均匀的时候，它是指活性组分被均匀分散在整个组合物中，以致组合物可以容易地被细分成相同有效的单位剂型如片剂、丸剂以及胶囊剂。
本发明的片剂或丸剂可以被涂布或用其它方式被复合以提供一种具有延长作用优点的剂型，或保护片剂或丸剂免受胃中酸性条件的作用。例如，片剂或丸剂可以包括内剂量和外剂量成分，后者具有在前者之上的外皮的形式。可以用肠溶层来分隔两种成分，其中肠溶层用来阻止在胃中的崩解以及允许内成分完整进入十二指肠或被延迟释放。各种材料可以用于这样的肠溶层或涂层，上述材料包括许多高分子酸以及高分子酸与这样的材料如虫胶、十六烷醇、以及醋酸纤维素的混合物。
用于吸入法或吹入法的组合物包括在药学上可接受的含水溶剂或有机溶剂、或其混合物中的溶液和悬浮液，以及散剂。液体或固体组合物可以包含适宜的药 用赋形剂。优选地，通过口服或鼻呼吸途径给予这些组合物以获得局部或全身效应。可以通过使用惰性气体来雾化在优选的药学可接受的溶剂中的组合物。可以直接从雾化装置吸入雾化溶液，或雾化装置可以连接于面罩帐状物、或间歇正压呼吸机。可以由以适当方式递送剂型的装置，优选口服或鼻途径，给予溶液、混悬剂、或散剂组合物。
基于此，本发明还提供了一种抗病毒喷剂，有效成分包括单宁酸。
进一步地，所述一种抗病毒喷剂包括以下组分及其重量份数：单宁酸5～20份、多酚类化合物1～50份、附加剂1～15份和余量水。
本发明还提供了一种抗病毒气雾剂，有效成分包括单宁酸。
进一步地，包括以下组分及其重量份数：单宁酸1～20份、抗病毒金属盐0～10份、附加剂1～15份和余量抛射剂。
进一步地，所述抛射剂为四氟乙烷(HFA-134a)或七氟丙烷(HFA-227)。
本发明还提供了一种抗病毒口服剂，有效成分包括单宁酸。
进一步地，包括以下组分及其重量份数：单宁酸3～20份、抗病毒金属盐1～15份、附加剂1～15份和余量水。
进一步地，所述附加剂包括抗氧化剂和其它药学上允许添加的辅料。
更进一步地，所述抗氧化剂包括维生素C和迷迭香酸。
本发明具有以下有益效果：
本发明研究结果显示，单宁酸对包括SARS-CoV-2的冠状病毒、甲型H1N1流感病毒等呼吸道病毒均具有显著的抑制效果，疗效确切，在制备抗呼吸道病毒药物领域中具有广阔的应用前景。而且单宁酸存在于多种植物中，是自然界存在的天然活性化合物，同时也已作为食品添加剂应用，安全性高，开发药物基础好。
具体实施方式
以下结合具体实施例来进一步说明本发明，但实施例并不对本发明做任何形式的限定。除非特别说明，本发明采用的试剂、方法和设备为本技术领域常规试剂、方法和设备。
本发明活性病毒实验均为委托广东省疾病预防控制中心进行，微生物材料由广东省疾病预防控制中心提供。
除非特别说明，以下实施例所用试剂和材料均为市购。
实施例1单宁酸对非洲绿猴肾细胞(Vero-E6细胞)毒性的测定
1、实验材料
(1)药物：实验组，单宁酸；对照组，瑞德西韦(购于上海陶素生化科技有限公司)；
(2)细胞株：非洲绿猴肾细胞(Vero-E6细胞)；
(3)其他：MEM培养基；96孔培养板。
2、实验步骤
(1)采用微量培养法进行细胞培养。
(2)药物稀释：分别于12支离心管内将单宁酸、瑞德西韦用细胞培养液【成分要求：MEM培养基(Gibco Invitrogen)、1％双抗(Gibco Invitrogen)、2％胎牛血清(FBS；Gibco Invitrogen)】倍比稀释成共计12个浓度的单宁酸、瑞德西韦溶液。
(3)每个浓度设置3个平行复孔，同时设细胞对照孔(不加药，仅加培养液)。
(4)48小时后每100ul细胞培养液中加入10ul CCK-8，37℃孵育1小时后，用分光光度计测量OD 450，计算单宁酸和瑞德西韦的最大无毒浓度(TC 0)和半数有毒浓度(TC 50)。
3、实验结果
表1单宁酸及瑞德西韦对非洲绿猴肾细胞毒性的测定结果
组别 TC 0(μM) TC 50(μM)
单宁酸 11.8 23.5
瑞德西韦 52.8 105.6
实施例2单宁酸抗SARS-CoV-2病毒药效试验
1、实验材料：
(1)药物：实验组，单宁酸；对照组，瑞德西韦(购于上海陶素生化科技有限公司)；
(2)细胞株：非洲绿猴肾细胞(Vero-E6细胞)；
(3)病毒：SARS-CoV-2病毒；
(4)其它：MEM培养基；96孔培养板。
2、实验步骤
(1)预先用96孔培养板将Vero-E6细胞培养成单层细胞(细胞数量为：2×10 4细胞/孔)；
(2)将待检药物选用最大无毒剂量(TD 0)药液，用细胞维持液分别倍比稀释12个浓度，病毒感染滴度为100TCID 50；
(3)药物每个浓度3孔，病毒吸附1小时后，弃去病毒液，用PBS洗一次后，各孔补加0.2ml含药物的维持液。同时设置细胞对照(仅加维持液)、药物对照(不加病毒)、病毒对照(不加药液)，置37℃，5％CO 2孵箱内培养。
(4)48小时后收取细胞培养上清液用于病毒核酸提取，利用COVID-19荧光定量PCR试剂盒(已获临床医疗器械注册证)进行病毒相对定量，计算单宁酸对抑制SARS-CoV-2病毒的影响；计算半数抑制浓度(IC 50)及选择指数(SI)等参数。
选择指数(SI)＝TC 50/IC 50
TC 50(50％毒性浓度)：采用Reed-Muench公式计算
IC 50(半数抑制浓度)：采用Reed-Muench公式计算
3、实验结果：
如表2所示，单宁酸表现出较高的抗SARS-CoV-2病毒活性，其对SARS-CoV-2病毒的IC 50值为0.0032μM，SI为7343.75，显著高于阳性对照组瑞德西韦的抗病毒活性，且选择指数也较高。
表2单宁酸、瑞德西韦对病毒的活性参数
组别 IC 50(μM) SI
单宁酸 0.0032±0.0002 ** 7343.75
阳性对照(瑞德西韦) 0.651±0.013 * 162.21
注：与阳性对照组相比， *P<0.05， **P<0.01。
实施例3单宁酸对犬肾上皮细胞(MDCK细胞)毒性的测定
1、实验材料
(1)药物：实验组，单宁酸；对照组，利巴韦林(购于诺德药业(江苏)有限公司)；
(2)细胞株：犬肾上皮细胞(MDCK细胞)；
(3)其他：DMEM培养基；96孔培养板。
2、实验步骤
(1)采用微量培养法进行细胞培养。
(2)药物稀释：分别于12支离心管内将单宁酸、利巴韦林用细胞培养液【成分要求：DMEM培养基(Gibco Invitrogen)、1％双抗(Gibco Invitrogen)、10％胎牛血清(FBS；Gibco Invitrogen)】倍比稀释成共计12个浓度的单宁酸、利巴韦林溶液。
(3)将各稀释度药物分别加入MDCK细胞孔中，每个稀释度3个复孔，每孔100μL，同时设置正常细胞对照孔，37℃、5％CO 2培养箱培养。
(4)每日观察细胞病变并记录：(—)，无细胞病变；(+)，0～1/4的细胞病变；(++)，1/4～1/2的细胞病变；(+++)，1/2～3/4的细胞病变；(++++)，3/4～1的细胞病变。以不出现细胞病变的药物最小稀释倍数为药物的最大无毒浓度(TC 0)，利用Reed-Muench公式计算药物的半数有毒浓度(TC 50)。
3、实验结果
表3单宁酸及利巴韦林对犬肾上皮细胞毒性的测定结果
组别 TC 0(μM) TC 50(μM)
单宁酸 376.21 752.41
利巴韦林 655.17 1310.34
实施例4单宁酸抗甲型H1N1流感病毒药效试验
1、实验材料：
(1)药物：实验组，单宁酸；对照组，利巴韦林(购于诺德药业(江苏)有限公司)；
(2)细胞株：犬肾上皮细胞(MDCK细胞)；
(3)病毒：甲型H1N1流感病毒；
(4)其它：DMEM培养基；96孔培养板。
2、实验步骤
(1)0.25％胰酶消化单层MDCK细胞，以1×10 5个/mL的细胞浓度接种培养，待细胞长满所需密度(80％～90％)时吸去培养液，PBS洗两遍；
(2)分为细胞组、病毒组、利巴韦林组和单宁酸组，将待检药物选用最大无毒剂量(TD 0)药液，制成倍比稀释12个浓度的含药血清；
(3)用100TCID50/100μL甲型H1N1流感病毒感染各组细胞(细胞组不感染，加维持液100μL)；进行培养箱吸附、PBS清洗等操作后，分别加入利 巴韦林血清、单宁酸血清、细胞维持液，药物每个浓度3孔，100μL/孔，置37℃，5％CO 2孵箱内培养；
(4)48小时后收取细胞培养上清液用于病毒核酸提取，利用甲型H1N1流感病毒荧光定量PCR试剂盒进行病毒相对定量，计算单宁酸对抑制甲型H1N1病毒的影响；计算半数抑制浓度(IC 50)及选择指数(SI)等参数。
选择指数(SI)＝TC 50/IC 50
TC 50(50％毒性浓度)：采用Reed-Muench公式计算
IC 50(半数抑制浓度)：采用Reed-Muench公式计算
3、实验结果：
如表4所示，单宁酸表现出较高的抗甲型H1N1流感病毒活性，其对甲型H1N1流感病毒的IC 50值为0.0032μM，SI为7343.75，显著高于阳性对照组利巴韦林的抗病毒活性，且选择指数也较高。
表4单宁酸、瑞德西韦对病毒的活性参数
组别 IC 50(μM) SI
单宁酸 0.17±0.02 ** 4425.94
阳性对照(利巴韦林) 22.60±0.04 * 57.98
注：与阳性对照组相比， *P<0.05， **P<0.01。
实施例5单宁酸组合物对非洲绿猴肾细胞(Vero-E6细胞)毒性的测定
1、实验材料：
(1)药物：实验组，将单宁酸分别与儿茶素、白藜芦醇、葡萄糖酸锌按照质量比1:1混合，制成3种药物组合物；对照组，瑞德西韦(购于上海陶素生化科技有限公司)；
(2)其它实验材料同实施例1。
2、实验步骤：参考实施例1。
3、实验结果：
表5单宁酸组合物对非洲绿猴肾细胞毒性的测定结果
组别 TC 0(μg/ml) TC 50(μg/ml)
单宁酸+儿茶素 21.562 43.132
单宁酸+白藜芦醇 22.177 44.350
单宁酸+葡萄糖酸锌 15.132 30.265
瑞德西韦 31.816 63.633
实施例6单宁酸组合物抗SARS-CoV-2病毒药效试验
1、实验材料：
(1)药物：同实施例5；
(2)其它实验材料同实施例2。
2、实验步骤：参考实施例2。
3、实验结果：
如表6所示，单宁酸组合物表现出较高的抗SARS-CoV-2病毒活性，显著高于阳性对照组瑞德西韦的抗病毒活性，且选择指数也较高。
表6单宁酸组合物对SARS-CoV-2病毒的活性参数
组别 IC 50(μg/ml) SI
单宁酸+儿茶素 0.00412±0.00003 ** 10468.93
单宁酸+白藜芦醇 0.00335±0.00004 * 13238.81
单宁酸+葡萄糖酸锌 0.00124±0.00007 ** 24407.26
瑞德西韦 0.392±0.003 ** 162.21
注：与阳性对照组相比， *P<0.05， **P<0.01。
实施例7单宁酸组合物对犬肾上皮细胞(MDCK细胞)毒性的测定
1、实验材料
(1)药物：同实施例5；
(2)其它实验材料同实施例3。
2、实验步骤：参考实施例3。
3、实验结果
表7单宁酸组合物及利巴韦林对犬肾上皮细胞毒性的测定结果
组别 TC 0(μg/ml) TC 50(μg/ml)
单宁酸+儿茶素 650.01 1300.56
单宁酸+白藜芦醇 665.43 1330.68
单宁酸+葡萄糖酸锌 573.35 1147.21
利巴韦林 160.00 320.01
实施例8单宁酸组合物抗甲型H1N1流感病毒药效试验
1、实验材料：
(1)药物：同实施例5；
(2)其它实验材料同实施例4。
2、实验步骤：参考实施例4。
3、实验结果：
如表8所示，单宁酸组合物表现出较高的抗甲型H1N1流感病毒活性，显著高于阳性对照组利巴韦林的抗病毒活性，且选择指数也较高。
表8单宁酸、瑞德西韦对病毒的活性参数
组别 IC 50(μg/ml) SI
单宁酸+儿茶素 0.24±0.02 ** 5419.00
单宁酸+白藜芦醇 0.19±0.01 ** 7003.58
单宁酸+葡萄糖酸锌 0.11±0.01 ** 10429.20
利巴韦林 5.52±0.03 * 57.98
注：与阳性对照组相比， *P<0.05， **P<0.01。
实施例9一种抗病毒喷剂
一种抗病毒喷剂，含有以下组分及其重量百分数：单宁酸10％、儿茶素5％、维生素C 3％和余量去离子水。
实施例10一种抗病毒喷剂
一种抗病毒喷剂，含有以下组分及其重量百分数：单宁酸5％、白藜芦醇5％、迷迭香酸3％和余量去离子水。
实施例11一种抗病毒气雾剂
一种抗病毒气雾剂，含有以下组分及其重量百分数：单宁酸5％、葡萄糖酸锌1％、去离子水8％、乙醇2％、余量为抛射剂四氟乙烷。
实施例12一种抗病毒口服剂
一种抗病毒口服剂，含有以下组分及其重量百分数：单宁酸10％、葡萄糖酸锌10％、辅料2％和余量蒸馏水。
上述实施例为本发明较佳的实施方式，但本发明的实施方式并不受上述实施例的限制，其他的任何未背离本发明的精神实质与原理下所作的改变、修饰、替代、组合、简化，均应为等效的置换方式，都包含在本发明的保护范围之内。

Claims (16)

  1. 单宁酸在制备抗呼吸道病毒药物方面的应用。
  2. 单宁酸衍生物或单宁酸结构类似物在制备抗呼吸道病毒药物方面的应用。
  3. 根据权利要求1或2所述应用，其特征在于，所述抗呼吸道病毒包括冠状病毒科病毒和正粘病毒科病毒。
  4. 根据权利要求3所述应用，其特征在于，所述冠状病毒科病毒为冠状病毒属病毒，包括SARS-CoV、SARS-CoV-2、MERS-CoV、HCoV-229E、HCoV-NL63、HCoV-OC43、HCoV-HKU1。
  5. 根据权利要求3所述应用，其特征在于，所述正粘病毒科病毒包括甲型流感病毒属、乙型流感病毒属、丙型流感病毒属。
  6. 一种抗呼吸道病毒的药物，其特征在于，所述药物包含单宁酸。
  7. 根据权利要求6所述药物，其特征在于，所述药物还包含单宁酸衍生物、单宁酸结构类似物中的任意一种或两种。
  8. 根据权利要求6所述药物，其特征在于，所述药物还包含多酚类化合物、抗病毒金属盐中的一种或两种。
  9. 根据权利要求8所述药物，其特征在于，所述抗病毒金属盐包括锌盐、铁盐、钙盐、镁盐、钨盐和铷盐。
  10. 根据权利要求9所述药物，其特征在于，所述药物为口服剂、喷剂、气雾剂或注射剂。
  11. 一种抗病毒喷剂，其特征在于，有效成分包括单宁酸。
  12. 根据权利要求11所述抗病毒喷剂，其特征在于，包括以下组分及其重量份数：单宁酸5～20份、多酚类化合物1～50份、附加剂1～15份和余量水。
  13. 一种抗病毒气雾剂，其特征在于，有效成分包括单宁酸。
  14. 根据权利要求13所述抗病毒气雾剂，其特征在于，包括以下组分及其重量份数：单宁酸1～20份、抗病毒金属盐0～10份、附加剂1～15份和余量抛射剂。
  15. 一种抗病毒口服剂，其特征在于，有效成分包括单宁酸。
  16. 根据权利要求15所述抗病毒口服剂，其特征在于，包括以下组分及其重量份数：单宁酸3～20份、抗病毒金属盐1～15份、附加剂1～15份和余量水。
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