CN111905011A - Antiviral composition and preparation as well as preparation method and application thereof - Google Patents

Antiviral composition and preparation as well as preparation method and application thereof Download PDF

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Publication number
CN111905011A
CN111905011A CN202010830080.9A CN202010830080A CN111905011A CN 111905011 A CN111905011 A CN 111905011A CN 202010830080 A CN202010830080 A CN 202010830080A CN 111905011 A CN111905011 A CN 111905011A
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parts
antiviral
virus
extract
preparation
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付军
齐婧
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Guangdong Shengpu Life Technology Co ltd
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Guangdong Shengpu Life Technology Co ltd
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    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/73—Rosaceae (Rose family), e.g. strawberry, chokeberry, blackberry, pear or firethorn
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    • A61K31/19—Carboxylic acids, e.g. valproic acid
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Abstract

The invention belongs to the technical field of medicines, and particularly relates to an antiviral composition, an antiviral preparation, a preparation method and application thereof. The formula of the composition contains the roxburgh rose or the extract thereof, can effectively inhibit virus invasion and harm human bodies, remarkably inhibit virus replication, has broad-spectrum antiviral activity and remarkable antiviral effect; moreover, the roxburgh rose belongs to a medicinal and edible material, has the advantages of naturalness, safety, no side effect and the like, and has good application value in the aspect of developing antiviral drugs, particularly developing preventive preparations aiming at respiratory viruses such as coronavirus and the like.

Description

Antiviral composition and preparation as well as preparation method and application thereof
Technical Field
The invention belongs to the technical field of medicines. More particularly, relates to an antiviral composition and preparation, and a preparation method and application thereof.
Background
Diseases caused by viruses are basically infectious, and outbreaks or epidemics of the diseases bring great influence on health and life of human beings. Currently, prevention and treatment of viral infections is largely dependent on vaccination and/or anti-viral drug therapy. However, in clinical application, the price of the vaccine is high, and low-temperature storage is needed, so that the vaccine is difficult to be widely applied; on the other hand, many viruses at present have variability, and particularly respiratory viruses are more prone to change, and the development of vaccines is difficult to keep up with the change of the viruses. Thus, antiviral drugs have gradually become a major means for treating viral infectious diseases. Among them, most of antiviral drugs interfere with virus replication by inhibiting transcription of viral genome, for example, chinese patent application CN109071467A discloses an acyclic antiviral drug which can inhibit reverse transcriptase of virus, viral encapsidated glycoprotein 120, etc., thereby inhibiting virus replication. However, since viruses mainly depend on host cells for viral genome replication, such drugs often have certain cytotoxicity and strong specificity at the same time, and can only be used for treating a part of viruses with similar structures, and the antiviral spectrum is narrow. Therefore, it is highly desirable to provide an antiviral drug with high safety.
In addition, "prevention" is more important for the prevention and control of viruses with strong infectivity. In the aspect of prevention and control of pathogeny and epidemic situation, plant extracts in the traditional Chinese medicine concept are always better in expression, particularly plant/tissue extracts with homology of medicine and food, have the advantages of nature, safety and no side effect, and are very suitable for developing prevention products.
Disclosure of Invention
The invention aims to solve the technical problems of low safety and narrow antiviral spectrum of the existing antiviral drugs, provides a medicinal and edible plant extract with broad-spectrum antiviral and higher safety, and develops and prepares an antiviral preparation which has a better effect on preventing and resisting viral infection.
The invention aims to provide an antiviral composition.
The invention also aims to provide the application of the composition in preparing antiviral drugs.
It is another object of the present invention to provide three antiviral agents.
The invention also aims to provide a preparation method of the antiviral preparation.
The above purpose of the invention is realized by the following technical scheme:
the invention provides an antiviral composition, which comprises roxburgh rose.
The rosa roxburghii tratt is a perennial deciduous bush plant in rosa of rosaceous, and is a medicinal and edible material with high safety. The Rosa roxburghii fruit contains multiple active ingredients such as polysaccharide, flavone, SOD, polyphenol, triterpenes, vitamin C, etc., and has antioxidant, antibacterial, toxic substance removing, atherosclerosis resisting, and anti-tumor effects. The research of the invention shows that the roxburgh rose and the extract thereof have better antiviral effect and have very good application value in the aspect of developing antiviral products for preventing virus infection.
Specifically, the antiviral range of fructus Rosae Normalis and its extract includes coronavirus, orthomyxoviridae virus, enterovirus, hepacivirus, rabies virus, herpesviridae virus, and Flaviviridae virus.
Preferably, the roxburgh rose and the extract thereof have remarkable antiviral effects on viruses of coronavirus family and orthomyxoviridae family.
More preferably, the viruses of the family Coronaviridae include 2019-nCoV, SARS-CoV, MERS-CoV, HCoV-229E, HCoV-NL63, HCoV-OC43, HCoV-HKU 1.
Therefore, the application of the roxburgh rose and the extract thereof in preparing the antiviral drug also falls within the protection scope of the invention.
In addition, in particular use, it is preferred to use the Rosa roxburghii extract for the preparation of an antiviral product.
Preferably, the roxburgh rose extract is a roxburgh rose aqueous extract and/or a roxburgh rose alcohol extract.
Further, the preparation method of the rosa roxburghii tratt aqueous extract comprises the following steps: drying and crushing the roxburgh rose, adding water in an amount which is 5-50 times the weight of the roxburgh rose, performing reflux extraction for 1-3 h, filtering, concentrating and drying filtrate to obtain the roxburgh rose beverage.
Further, the preparation method of the rosa roxburghii alcohol extract comprises the following steps: drying and crushing the roxburgh rose, adding an ethanol solution with the weight of 5-20 times that of the roxburgh rose, performing reflux extraction for 0.5-2 h, filtering, concentrating and drying filtrate, thus obtaining the roxburgh rose.
Preferably, the concentration of the ethanol solution is 50-80 vol%.
Preferably, the rosa roxburghii aqueous extract and rosa roxburghii alcohol extract can be extracted by assistance of ultrasound, microwave, electric field and the like during extraction.
Preferably, the roxburgh rose aqueous extract and the roxburgh rose alcohol extract can be extracted for 1-2 times by the same method, and the filtrate is combined, concentrated and dried to obtain the roxburgh rose alcohol extract.
Preferably, the rosa roxburghii alcohol extract or rosa roxburghii water extract can be purified by macroporous resin chromatography, membrane separation and other methods and then used.
Preferably, the rosa roxburghii aqueous extract and rosa roxburghii alcohol extract can be prepared by the following method:
drying and crushing the roxburgh rose, adding an ethanol solution with the weight 5-20 times that of the roxburgh rose, performing reflux extraction for 0.5-2 h, filtering, adding water with the weight 5-50 times that of the roxburgh rose into the obtained filter residue, performing reflux extraction for 1-3 h, filtering, combining the two filtrates, concentrating and drying to obtain the roxburgh rose beverage.
Preferably, the rosa roxburghii aqueous extract and the rosa roxburghii alcohol extract can also be a mixture of the rosa roxburghii aqueous extract and the rosa roxburghii alcohol extract according to a certain proportion.
Still further, the antiviral composition further comprises a metal salt and/or sialic acid.
Preferably, the mass ratio of the roxburgh rose extract to the metal salt is 1 (0.05-15).
Further, the metal salt includes zinc salt, iron salt, calcium salt, magnesium salt, tungsten salt, and rubidium salt.
Preferably, the zinc salt is zinc sulfate or zinc gluconate; the ferric salt is ferrous gluconate; the calcium salt is calcium gluconate; the tungsten salt is sodium tungstate; the rubidium salt is rubidium iodide.
Preferably, the mass ratio of the roxburgh rose extract to the sialic acid is 1 (0.02-20).
Preferably, the source of sialic acid may be mammalian mandibular extract, cubilose, breast milk, cow milk, egg, cheese, and the like. The mammal may be derived from cattle, pig, etc.
Still more preferably, the mammal is a pig or a cow.
The use of the claimed compositions in the manufacture of a medicament for use in the treatment of viral diseases, including, but not limited to, the use of an effective amount of a composition of the invention for administration to a patient in the manufacture of a medicament for the prevention or treatment of viral diseases, for the alleviation of symptoms of viral diseases or for the delay of progression or onset of viral diseases.
In addition to being beneficial for human treatment, the presently claimed compositions find application in veterinary treatment of pets, animals of the species of import and farm animals, including mammals, rodents, and the like. Examples of other animals include horses, dogs, cats, and the like.
Based on the above results, the antiviral composition can be properly compounded with appropriate excipients to prepare different pharmaceutical dosage forms.
The invention provides an antiviral oral liquid containing the composition.
Further, the antiviral oral liquid comprises the following components in parts by weight: 10-25 parts of roxburgh rose extract, 5-20 parts of metal salt, 8-20 parts of sialic acid, 8-25 parts of antioxidant and 5-25 parts of sweetener.
The anti-virus oral liquid provided by the invention has reasonable compatibility of components, and the antioxidant can inhibit the oxidation of the composition, stabilize the performance of the composition and play a role in adjusting the taste of the composition; the sweetening agent is capable of imparting sweetness to the composition, so that it tastes good; the components are combined synergistically to play a remarkable synergistic effect, have remarkable and broad-spectrum antiviral efficacy, are beneficial to treatment and rehabilitation of virus infected patients, improve the life quality, and can be used as an effective method for daily protection and prevention of virus infected diseases of normal people.
Preferably, the antiviral oral liquid comprises the following components in parts by weight: 15-25 parts of roxburgh rose extract, 5-15 parts of metal salt, 15-20 parts of sialic acid, 8-15 parts of antioxidant and 5-15 parts of sweetener.
More preferably, the antiviral oral liquid comprises the following components in parts by weight: 20 parts of rosa roxburghii tratt extract, 10 parts of metal salt, 18 parts of sialic acid, 8 parts of antioxidant and 6 parts of sweetener.
Preferably, the antioxidants include ascorbic acid, sodium ascorbate and D-erythorbic acid and sodium D-erythorbate.
Preferably, the sweetener comprises aspartame, stevia, sucrose, sorbitol mannitol, maltitol, glucose, and AK sugar.
Further, the preparation method of the antiviral oral liquid comprises the following steps: fully dissolving the roxburgh rose extract, the metal salt, the sialic acid, the antioxidant or the sweetener in the water according to the weight parts.
The invention also provides an antiviral spray containing the composition.
Further, the antiviral spray comprises the following components in parts by weight: 5-20 parts of rosa roxburghii tratt extract, 3-18 parts of metal salt, 5-18 parts of sialic acid, 1-12 parts of solvent, 6-16 parts of glycerol and 1-10 parts of essence.
Preferably, the rosa roxburghii tratt extractive comprises 10-20 parts of rosa roxburghii tratt extractive, 5-18 parts of metal salt, 10-18 parts of sialic acid, 5-12 parts of solvent, 8-16 parts of glycerol and 1-5 parts of essence.
More preferably, the rosa roxburghii tratt extract comprises 18 parts of rosa roxburghii tratt extract, 10 parts of metal salt, 15 parts of sialic acid, 6 parts of solvent, 10 parts of glycerin and 2 parts of essence.
Further, the solvent is a volatile solvent.
The vehicle may be selected according to its conditions of use, and when used to prepare a pharmaceutical for oral administration, a food grade vehicle is selected.
Still more preferably, the solvent is ethanol.
According to the invention, through scientific and reasonable matching, all components of the antiviral spray are mutually compatible and optimally combined, so that an obvious synergistic interaction effect can be exerted, wherein ethanol is used as a good organic solvent, glycerol is used as a good wetting agent, so that the antiviral spray can be well wetted on an application object, and the essence can generate a pleasant smell; the antiviral composition has remarkable broad-spectrum antiviral efficacy, is beneficial to the treatment and rehabilitation of patients infected by viruses, improves the living quality, can be used as an effective method for daily protection and prevention of virus infection diseases of normal people, and has better antiviral effect on coronavirus and orthomyxoviridae viruses; the Rosa roxburghii extract is derived from the traditional Chinese medicine Rosa roxburghii, has no toxic or side effect, and the antiviral spray has the advantages of simple preparation method, large-scale production and convenient use.
Further, the preparation method of the antiviral spray comprises the following steps: fully dissolving the roxburgh rose extract, the sialic acid, the metal salt, the solvent, the glycerol and the essence in deionized water according to the weight parts.
An antiviral ophthalmic agent containing the composition.
Further, the antiviral ophthalmic medicament comprises the following components in parts by weight: 6-18 parts of rosa roxburghii tratt extract, 2-18 parts of metal salt, 2-5 parts of osmotic pressure regulator, 0.2-5 parts of antioxidant, 1-10 parts of solubilizer, 0.1-0.5 part of bacteriostatic agent, 0.1-5 parts of tackifier, 0.1-0.5 part of borneol and the balance of water for injection.
Preferably, the antiviral ophthalmic medicament comprises the following components in parts by weight: 10-18 parts of roxburgh rose extract, 8-15 parts of metal salt, 3-5 parts of osmotic pressure regulator, 1-5 parts of antioxidant, 1-5 parts of solubilizer, 0.1-0.3 part of bacteriostatic agent, 1-5 parts of tackifier, 0.2-0.5 part of borneol and the balance of water for injection.
More preferably, the antiviral ophthalmic medicament comprises the following components in parts by weight: 15 parts of rosa roxburghii tratt extract, 10 parts of metal salt, 4 parts of osmotic pressure regulator, 2 parts of antioxidant, 3 parts of solubilizer, 0.2 part of bacteriostatic agent, 2 parts of tackifier, 0.3 part of borneol and the balance of water for injection.
Still further, the tonicity modifier includes, but is not limited to, sodium chloride or boric acid; antioxidants include, but are not limited to, ascorbic acid, sodium ascorbate and D-erythorbic acid, sodium D-erythorbate, sodium bisulfite, sodium sulfite, sodium thiosulfate, sodium metabisulfite; the solubilizer includes but is not limited to tween-80, tween-20; such bacteriostatic agents include, but are not limited to, benzalkonium chloride or benzalkonium bromide; the viscosity increasing agent includes, but is not limited to, sodium hyaluronate, hypromellose, methylcellulose, povidone, polyvinyl alcohol.
Further, the preparation method of the antiviral ophthalmic agent comprises the following steps:
dissolving fructus Rosae Normalis extract with water for injection, and filtering; dissolving metal salt, dissolving borneol in ethanol, adding into the filtrate, sequentially adding osmotic pressure regulator, antioxidant, solubilizer, tackifier and bacteriostatic agent, stirring, adjusting pH to 6.0-8.0, adding water for injection to adjust volume to 1L, filtering, packaging the filtrate, and sterilizing.
The invention has the following beneficial effects:
the invention provides an antiviral composition, which has reasonable compatibility of all components in the formula, optimized combination, can effectively inhibit virus invasion and harm human bodies, remarkably inhibits the replication of viruses, has broad-spectrum antiviral activity and remarkable antiviral effect; the roxburgh rose in the formula of the composition belongs to a medicinal and edible material, and has the advantages of nature, safety, no side effect and the like; has good application value in the development of antiviral drugs, particularly in the development of prevention and treatment preparations for respiratory viruses such as coronavirus and the like.
The invention also provides three antiviral preparations based on the composition, the preparation method is simple, the cost is low, the three antiviral preparations are beneficial to the treatment and the rehabilitation of virus infected patients, the life quality is improved, and meanwhile, the three antiviral preparations can also be used as an effective method for daily prevention and treatment of normal people and respiratory system infection diseases, and have good prevention and control significance for the spread and harm of diseases caused by virus infection of human bodies.
Detailed Description
The present invention is further illustrated by the following examples, which are not intended to limit the invention in any way. The reagents, methods and apparatus employed in the present invention are conventional in the art, unless otherwise specified.
Unless otherwise indicated, reagents and materials used in the following examples are commercially available.
EXAMPLE 1 preparation of Rosa Roxburghii extract
The roxburgh rose extract is a roxburgh rose aqueous extract and is prepared by the following steps:
drying and crushing the roxburgh rose, weighing 50g of roxburgh rose powder, adding 500mL of water, carrying out reflux extraction for 2h, filtering, adding 500mL of water into filter residue, carrying out reflux extraction for 2h, filtering, combining the two filtrates, concentrating and drying to obtain the roxburgh rose water extract.
Example 2 preparation of Rosa roxburghii extract
The roxburgh rose extract is an alcohol extract of roxburgh rose and is prepared by the following steps:
drying and crushing roxburgh rose, weighing 50g of roxburgh rose powder and 500mL of 60 vol% ethanol solution, performing reflux extraction for 1h, filtering, and concentrating and drying filtrate to obtain the roxburgh rose powder.
EXAMPLE 3 preparation of Rosa Roxburghii extract
The roxburgh rose extract is prepared by the following steps:
drying and crushing roxburgh rose, weighing 50g and 500mL of 60 vol% ethanol solution of roxburgh rose powder, carrying out reflux extraction for 1h, filtering, adding 500mL of water into obtained filter residue, carrying out reflux extraction for 2h, filtering, combining two filtrates, concentrating and drying to obtain the roxburgh rose powder.
EXAMPLE 4 preparation of antiviral oral liquid 1
The antiviral oral liquid 1 is prepared from the following components in parts by weight: example 1 Rosa roxburghii extract 20 parts, zinc sulfate 10 parts, sialic acid 18 parts, ascorbic acid 8 parts, aspartame 6 parts, distilled water 150 parts.
Dissolving the roxburgh rose extract, zinc sulfate, sialic acid, ascorbic acid and aspartame in parts by weight in distilled water, and subpackaging to obtain the antiviral oral liquid 1.
EXAMPLE 5 preparation of antiviral oral liquid 2
The antiviral oral liquid 2 is prepared from the following components in parts by weight: example 1 Rosa roxburghii extract 16 parts, calcium gluconate 16 parts, sialic acid 15 parts, ascorbic acid 10 parts, stevioside 10 parts, and distilled water 240 parts.
Dissolving the roxburgh rose extract, calcium gluconate, sialic acid, ascorbic acid and stevioside in parts by weight in distilled water, and subpackaging to obtain the antiviral oral liquid 2.
EXAMPLE 6 preparation of antiviral oral liquid 3
The antiviral oral liquid 3 is prepared from the following components in parts by weight: example 2 Rosa roxburghii extract 18 parts, zinc gluconate 12 parts, sialic acid 10 parts, sodium ascorbate 12 parts, sorbitol 12 parts, distilled water 450 parts.
Dissolving the rosa roxburghii tratt extract, the zinc gluconate, the sialic acid, the sodium ascorbate and the sorbitol in the distilled water according to the parts by weight, and subpackaging to obtain the antiviral oral liquid 3.
EXAMPLE 7 preparation of antiviral oral liquid 4
The antiviral oral liquid 4 is prepared from the following components in parts by weight: example 2 Rosa roxburghii extract 10 parts, ferrous gluconate 20 parts, sialic acid 8 parts, ascorbic acid 5 parts, sucrose 15 parts, and distilled water 100 parts.
Dissolving the roxburgh rose extract, ferrous gluconate, sialic acid, ascorbic acid and sucrose in parts by weight in distilled water, and subpackaging to obtain the antiviral oral liquid 4.
EXAMPLE 8 preparation of antiviral oral liquid 5
The antiviral oral liquid 5 is prepared from the following components in parts by weight: example 3 Rosa roxburghii extract 25 parts, sodium tungstate 5 parts, sialic acid 20 parts, D-isoascorbic acid 20 parts, maltitol 22 parts, distilled water 750 parts.
Dissolving the roxburgh rose extract, sodium tungstate, sialic acid, D-isoascorbic acid and maltitol in parts by weight in distilled water, and subpackaging to obtain the antiviral oral liquid 5.
EXAMPLE 9 preparation of antiviral oral liquid 6
The antiviral oral liquid 6 is prepared from the following components in parts by weight: example 3 Rosa roxburghii extract 21 parts, rubidium iodide 10 parts, sialic acid 16 parts, D-sodium erythorbate 25 parts, mannitol 25 parts, and distilled water 420 parts.
Dissolving the roxburgh rose extract, rubidium iodide, sialic acid, D-sodium erythorbate and mannitol in the weight parts in distilled water, and subpackaging to obtain the antiviral oral liquid 6.
Example 10 preparation of antiviral spray 1
The antiviral spray 1 is prepared from the following components in parts by weight: example 1 Rosa roxburghii extract 18 parts, zinc sulfate 10 parts, sialic acid 15 parts, ethanol 6 parts, glycerol 10 parts, essence 2 parts and deionized water 180 parts.
Fully dissolving the roxburgh rose extract, zinc sulfate, sialic acid, ethanol, glycerol and essence in parts by weight in deionized water, and then subpackaging 50mL per bottle in an aerosol bottle to obtain the antiviral spray 1.
Example 11 preparation of antiviral spray 2
The antiviral spray 2 is prepared from the following components in parts by weight: example 1 Rosa roxburghii extract 10 parts, grape calcium carbonate 15 parts, sialic acid 18 parts, ethanol 8 parts, glycerol 8 parts, essence 2 parts and deionized water 200 parts.
Fully dissolving the roxburgh rose extract, the calcium gluconate, the sialic acid, the ethanol, the glycerol and the essence in the deionized water in parts by weight, and then filling the solution into aerosol bottles according to 50mL per bottle to obtain the antiviral spray 2.
Example 12 preparation of antiviral spray 3
The antiviral spray 3 is prepared from the following components in parts by weight: example 2 Rosa roxburghii extract 15 parts, grape zinc carbonate 12 parts, sialic acid 12 parts, ethanol 10 parts, glycerin 9 parts, essence 1 part and deionized water 450 parts.
And (3) fully dissolving the roxburgh rose extract, the zinc gluconate, the sialic acid, the ethanol, the glycerol and the essence in the deionized water in parts by weight, and then filling 50mL of the solution in each bottle into an aerosol bottle to obtain the antiviral spray 3.
Example 13 preparation of antiviral spray 4
The antiviral spray 4 is prepared from the following components in parts by weight: example 2 Rosa roxburghii extract 5 parts, sodium tungstate 18 parts, sialic acid 18 parts, ethanol 12 parts, glycerin 12 parts, essence 5 parts and deionized water 150 parts.
And (3) fully dissolving the roxburgh rose extract, sodium tungstate, sialic acid, ethanol, glycerol and essence in the deionized water in parts by weight, and then subpackaging 50mL of each bottle into an aerosol bottle to obtain the antiviral spray 4.
Example 14 preparation of antiviral spray 5
The antiviral spray 5 is prepared from the following components in parts by weight: example 3 Rosa roxburghii extract 20 parts, ferrous gluconate 3 parts, sialic acid 10 parts, ethanol 1 part, glycerin 16 parts, essence 3 parts and deionized water 250 parts.
And (3) fully dissolving the roxburgh rose extract, the ferrous gluconate, the sialic acid, the ethanol, the glycerol and the essence in the deionized water in parts by weight, and then subpackaging the solution into aerosol bottles according to 50mL per bottle to obtain the antiviral spray 5.
Example 15 preparation of antiviral spray 6
The antiviral spray 6 is prepared from the following components in parts by weight: example 3 Rosa roxburghii extract 12 parts, rubidium iodide 5 parts, sialic acid 16 parts, ethanol 12 parts, glycerol 6 parts, essence 10 parts and deionized water 240 parts.
Fully dissolving the roxburgh rose extract, rubidium iodide, sialic acid, ethanol, glycerol and essence in the weight parts in deionized water, and then subpackaging 50mL of each bottle in an aerosol bottle to obtain the antiviral spray 6.
EXAMPLE 16 preparation of antiviral ophthalmic agent 1
The antiviral eye medicament 1 is prepared from the following components in parts by weight: example 1 Rosa roxburghii extract 15g, zinc sulfate 10g, osmotic pressure regulator sodium chloride 4g, antioxidant sodium bisulfite 2g, solubilizer Tween 3ml, bacteriostatic agent benzalkonium chloride 0.2g, tackifier sodium hyaluronate 2g, borneol 0.3g, ethanol 1ml, and the balance of water for injection.
Dissolving fructus Rosae Normalis extract with water for injection, and filtering; dissolving zinc sulfate, dissolving Borneolum Syntheticum in ethanol, adding into the above filtrate, sequentially adding osmotic pressure regulator, antioxidant, solubilizer, tackifier, and bacteriostatic agent, stirring, adjusting pH to 6.0-8.0, adding water for injection to adjust volume to 1L, filtering, packaging the filtrate, and sterilizing to obtain ophthalmic preparation 1.
EXAMPLE 17 preparation of antiviral ophthalmic agent 2
The antiviral eye medicament 2 is prepared from the following components in parts by weight: example 1 Rosa roxburghii extract 18g, zinc gluconate 8g, osmotic pressure regulator sodium chloride 5g, antioxidant ascorbic acid 3g, solubilizer Tween 5ml, bacteriostatic agent benzalkonium bromide 0.5g, tackifier sodium hyaluronate 3g, borneol 0.1g, ethanol 1ml, and the balance of water for injection.
Preparation method referring to example 16, ophthalmic preparation 2 was obtained.
EXAMPLE 18 preparation of antiviral ophthalmic agent 3
The antiviral eye medicament 3 is prepared from the following components in parts by weight: example 2 Rosa roxburghii extract 10g, calcium gluconate 16g, osmotic pressure regulator sodium chloride 4g, antioxidant ascorbic acid 1g, solubilizer Tween 6ml, bacteriostatic agent benzalkonium bromide 0.2g, tackifier sodium hyaluronate 2g, borneol 0.3g, ethanol 1ml, and the balance is water for injection.
Preparation method referring to example 16, ophthalmic preparation 3 was obtained.
EXAMPLE 19 preparation of antiviral ophthalmic agent 4
The antiviral eye medicament 4 is prepared from the following components in parts by weight: example 3 Rosa roxburghii extract 6g, ferrous gluconate 18g, osmotic pressure regulator boric acid 2g, antioxidant sodium ascorbate 0.2g, solubilization agent Tween 3ml, bacteriostat benzalkonium chloride 0.2g, tackifier polyethylene 5g, borneol 0.5g, ethanol 1ml, the rest is water for injection.
Preparation method referring to example 16, ophthalmic preparation 5 was obtained.
EXAMPLE 20 preparation of antiviral ophthalmic agent 5
The antiviral eye medicament 5 is prepared from the following components in parts by weight: example 3 Rosa roxburghii extract 18g, sodium tungstate 2g, osmotic pressure regulator boric acid 2g, antioxidant D-isoascorbic acid 5g, solubilizer temperature 10ml, bacteriostatic agent benzalkonium chloride 0.5g, tackifier polyvidone 0.1g, borneol 0.1g, ethanol 1ml, and the balance of water for injection.
Preparation method referring to example 16, ophthalmic preparation 5 was obtained.
EXAMPLE 21 preparation of antiviral ophthalmic agent 6
The antiviral eye medicament 6 is prepared from the following components in parts by weight: example 3 Rosa roxburghii extract 6g, rubidium iodide 18g, osmotic pressure regulator sodium chloride 5g, antioxidant D-sodium erythorbate 0.2g, solubilizer Tween 1ml, bacteriostatic agent benzalkonium chloride 0.4g, tackifier povidone 3g, borneol 0.3g, ethanol 1ml, and the balance of water for injection.
Preparation method referring to example 16, ophthalmic preparation 6 was obtained.
Comparative example 1 an oral liquid
Different from example 4, comparative example 1 does not contain the rosa roxburghii tratt extract, and the rest of the parameters and operations refer to example 4.
Comparative example 2 an oral liquid
Except for example 4, comparative example 2 did not contain the rosa roxburghii tratt extract and zinc sulfate, and the rest of the parameters and operation were referred to example 4.
Comparative example 3 an oral liquid
Unlike example 4, comparative example 3 does not contain the rosa roxburghii tratt extract, zinc sulfate and sialic acid, and the rest of the parameters and procedures refer to example 4.
Comparative example 4 an oral liquid
The difference from example 4 is that the part by weight of the rosa roxburghii tratt extract of comparative example 4 is 5 parts (the content is too low), and the rest parameters and operation refer to example 4.
Comparative example 5 an oral liquid
The difference from example 4 is that in comparative example 5, the rosa roxburghii tratt extract is 5 parts by weight (too low content), the sialic acid is 5 parts by weight (too low content), and the rest of the parameters and operations refer to example 4.
Comparative example 6 spray
Except for example 10 that comparative example 6 does not contain the rosa roxburghii tratt extract and zinc sulfate, and the rest of the parameters and operation refer to example 10.
Comparative example 7 spray
Except for example 10 that comparative example 7 did not contain the rosa roxburghii tratt extract, zinc sulfate and ethanol, and the rest of the parameters and operation refer to example 10.
Comparative example 8 spray
Unlike example 10, comparative example 8 does not contain the rosa roxburghii tratt extract, zinc sulfate, ethanol and sialic acid, and the rest of the parameters and operations refer to example 10.
Comparative example 9 an ophthalmic drug
Unlike example 16, comparative example 9 does not contain the Rosa roxburghii extract, and the rest of the parameters and operations refer to example 16.
Comparative example 10 an ophthalmic drug
Except for example 16 that comparative example 10 did not contain zinc sulfate, and the remaining parameters and operation were in reference to example 16.
Experimental example 1 oral liquid cytotoxicity test
1. Experimental methods
In this experimental example, an MTT method is used to test the toxicity of the antiviral oral liquid prepared in embodiments 4 to 6 of the present invention to cells, and the specific experimental steps are as follows:
(1) by 1 × 105Concentration per well, human embryonic kidney cells 293(HEK293 cells) were seeded into 96-well plates and 100. mu.L DMEM medium was added thereto at 37 ℃ with 5% CO2Culturing until a monolayer of cells is formed;
(2) discarding the culture solution, washing with PBS for 2 times, performing gradient dilution on the antiviral oral liquid prepared by the embodiment of the invention with DMEM, inoculating on cells at 100 μ L/well, setting control group with same concentration in each well with concentration of more than 4, and setting 5% CO at 37 deg.C2Culturing for 48 h;
(3) mu.L of MTT solution (2.5mg/mL) was added to each well at 37 ℃ with 5% CO2Incubating for 4 h; discarding the supernatant, adding 120 μ L DMSO/well, and shaking for 20 min;
(4) the absorbance (OD) at 490nm of each well was measured on a multifunctional reader and the 50% toxic concentration was calculated as the drug median Toxic Concentration (TC) by the Reed-Muench method50)。
2. Results of the experiment
The TC of the antiviral oral liquid prepared in the embodiments 4-6 of the invention for HEK293 cells is measured by using an MTT method50Values were 129.33 μ g/mL, 130.21 μ g/mL, 138.50 μ g/mL, respectively; the antiviral oral liquid prepared by the invention has no cytotoxicity (the toxicity is low and can be ignored).
Experimental example 2 in vitro antiviral Performance test of oral liquid
1. Experimental methods
This experimental example was conducted to examine the in vitro antiviral (coronavirus family: 2019-nCoV, MERS-CoV; orthomyxoviridae: influenza A H1N 1; Enterovirus: poliovirus; hepadnaviridae: hepatitis A, hepatitis B, rabies: rabies; herpesviridae: herpes simplex virus 1; flaviviridae: encephalitis B, dengue) experiments of the Rosa roxburghii extract prepared in examples 1 to 2 and the antiviral oral liquid prepared in examples 4 to 6 of the present invention, and the concrete experimental steps were as follows:
(1) HEK293 cells were plated at 4.5X 104The individual cells/well concentration were added to a 96 well plate in DMEM with 1% fetal bovine serum at 37 ℃ with 5% CO2Culturing for 24 h;
(2) discard the supernatant and add 100TCID to each well separately502019-nCoV, MERS-CoV, influenza A H1N1, poliovirus, Japanese encephalitis virus, dengue fever virus, rabies virus, hepatitis A virus, hepatitis B virus and herpes simplex virus type 1 virus liquid, 5% CO at 37 DEG C2Adsorbing for 2 h;
(3) discarding supernatant, washing cells with PBS, diluting the oral liquid and fructus Rosae Normalis extract with DMEM, adding into each well, setting as experimental group, adding DMEM into blank control group, and adding 5% CO at 37 deg.C2Incubating for 72h, and collecting virus supernatant;
(4) HEK293 cells were plated at 2X 106One cell/well, seeded in 12-well plates, 5% CO at 37 ℃2Culturing for 24 h;
(5) diluting the virus supernatant collected in step (3) by 10 times gradient, inoculating to HEK293 cells, and culturing at 37 deg.C with 5% CO2Adsorbing for 2 h;
(6) the supernatant was discarded and the cells were washed with PBS, 2mL of 1% (w/v) methylcellulose-DMEM overlay was added, 5% CO at 37 deg.C2Culturing for 72 h;
(7) removing the methylcellulose-DMEM covering, washing the cells 2 times with PBS, and fixing the cells with 10% formaldehyde at room temperature for 30 min;
(8) discarding the supernatant, washing the cells with PBS for 2 times, adding 0.5% crystal violet, staining for 5min at room temperature, washing with deionized water for 2 times, drying, counting plaques, and calculating the half Inhibitory Concentration (IC) of 50% virus-inhibited drug by Reed-Muench method50)。
2. Results of the experiment
The results of the in-vitro inhibitory activity of the rosa roxburghii tratt extract and the antiviral oral liquid prepared in the embodiment of the invention on viruses are shown in tables 1-3. As shown in the table, the rosa roxburghii tratt extract prepared by the invention has good in-vitro inhibitory activity to the 10 viruses, but is lower than the inhibitory effects of the antiviral oral liquids 1, 2 and 3.
TABLE 1 in vitro inhibitory Activity results (titer lg PFU/mL) of oral liquids against 2019-nCoV, MERS-CoV, influenza A H1N1, and poliovirus
Figure BDA0002637631360000131
TABLE 2 in vitro inhibitory Activity results (titer lg PFU/mL) of oral liquids against Japanese encephalitis virus, dengue virus, rabies virus and hepatitis A virus
Group of Encephalitis B virus Dengue fever virus Rabies virus
Blank control group 12.50±0.09 12.35±0.05 12.56±0.06
Example 1 9.99±0.05 10.40±0.02 9.96±0.02
Example 2 10.31±0.09 10.25±0.05 10.38±0.06
Oral liquid 1(1.56ug/mL) 8.38±0.05 8.98±0.05 8.94±0.05
Oral liquid 1(6.25ug/mL) 7.28±0.06 8.57±0.02 7.57±0.03
Oral liquid 1(25ug/mL) 6.18±0.02 6.30±0.05 6.78±0.07
IC50(ug/mL) 17.01±0.02 16.71±0.01 17.85±0.01
Therapeutic index (TC)50/IC50) 7.60 7.74 7.25
Oral liquid 2(1.56ug/mL) 8.91±0.01 9.15±0.08 9.15±0.05
Oral liquid 2(6.25ug/mL) 8.54±0.02 8.50±0.03 8.69±0.01
Oral liquid 2(25ug/mL) 6.88±0.03 7.59±0.01 6.98±0.10
IC50(ug/mL) 23.75±0.11 22.88±0.01 20.85±0.06
Therapeutic index (TC)50/IC50) 5.48 5.69 6.25
Oral liquid 3(1.56ug/mL) 8.98±0.01 9.02±0.02 8.98±0.07
Oral liquid 3(6.25ug/mL) 8.77±0.08 8.32±0.01 9.38±0.05
Oral liquid 3(25ug/mL) 7.87±0.03 8.69±0.02 8.38±0.10
IC50(ug/mL) 27.65±0.05 25.68±0.01 27.68±0.10
Therapeutic index (TC)50/IC50) 5.01 5.39 5.00
TABLE 3 results of in vitro inhibitory Activity of oral liquids against hepatitis A Virus, hepatitis B Virus and herpes simplex Virus type 1 Virus (titer lg PFU/mL)
Figure BDA0002637631360000141
Figure BDA0002637631360000151
Experimental example 3 in vivo antiviral Performance test of oral liquid
1. Experimental methods
This experimental example was conducted to examine the in vivo antiviral activity of the oral liquids prepared in examples 4 to 6 of the present invention and comparative examples 1 to 5 (coronavirus family viruses: 2019-nCoV and MERS-CoV; orthomyxoviridae virus: influenza A H1N1 virus; Enterovirus: poliovirus; hepadnavirus: hepatitis A virus and hepatitis B virus; rabies virus: rabies virus; herpesviridae virus: herpes simplex virus type 1; flaviviridae virus: encephalitis B virus and dengue virus), and the following steps were specifically conducted:
(1) mixing 2.5X 108PFU hCD 26-expressing recombinant adenovirus vector was nasally transfected into BALB/c mice (purchased from Guangdong province laboratory animal monitoring institute);
(2) hCD26 mice were expressed by nasal drip infection with 2019-nCoV, MERS-CoV, H1N1 influenza A virus, poliovirus, encephalitis B virus, dengue virus, rabies virus, hepatitis A virus, hepatitis B virus and herpes simplex virus 1 virus on day 4 after transfection, and were randomly grouped into placebo, example 4 [90 mg/(kg. d) ], example 5 [90 mg/(kg. d) ], example 6 [90 mg/(kg. d) ], comparative examples 1-5, 6 mice per group, all of which were female, and were administered by gavage, and the placebo was administered with an equivalent amount of 0.1% DMSO solution;
(3) 3 mice per group were randomly selected to be anesthetized CO 5 days post infection2Killing, taking heart, liver, lung and brain tissues of the mouse, transferring into PBS, homogenizing on ice by using a manual homogenizer, centrifuging for 5min at 4 ℃ at 12000r/min, and collecting supernatant;
(14) virus titer test was performed, test method in vitro antiviral test of experimental example 2.
2. Results of the experiment
The results are shown in tables 4-6, and it can be seen that the antiviral oral liquid prepared in the embodiments 4-6 of the present invention has significant inhibitory effect on the viruses; the inhibition effect of the oral liquid prepared in the comparative examples 1-5 on the 10 viruses is not obviously different from that of a blank control group.
The above results illustrate that: the antiviral oral liquid prepared by the invention can effectively and obviously inhibit the replication of 10 viruses in mice.
TABLE 4 in vivo inhibition results (titer lg PFU/mL) of oral liquids against 2019-nCoV, MERS-CoV, influenza A H1N1, and poliovirus
Figure BDA0002637631360000161
TABLE 5 results of in vivo inhibition of Japanese encephalitis virus, dengue virus, rabies virus and hepatitis A virus by oral liquid (titer lg PFU/mL)
Figure BDA0002637631360000162
Figure BDA0002637631360000171
TABLE 6 in vivo inhibition results (titer lg PFU/mL) of the oral liquids against hepatitis A virus, hepatitis B virus and herpes simplex virus 1 virus
Group of Hepatitis A virus Hepatitis B virus Herpes simplex virus type 1
Blank control group 8.52±0.01 8.90±0.01 8.97±0.09
Comparative example 1 8.76±0.03 8.86±0.07 8.56±0.02
Comparative example 2 8.92±0.01 8.69±0.02 8.89±0.07
Comparative example 3 8.98±0.05 8.87±0.09 8.19±0.07
Comparative example 4 8.83±0.08 8.53±0.01 8.87±0.05
Comparative example 5 8.98±0.02 8.36±0.06 8.70±0.02
Example 4 5.72±0.02 5.52±0.07 5.87±0.07
Example 5 5.98±0.08 6.05±0.05 6.05±0.07
Example 6 7.86±0.03 7.78±0.06 7.30±0.08
Experimental example 4 spray cytotoxicity test
1. Experimental methods
In the experimental example, an MTT method is used for testing the toxicity of the antiviral spray prepared in the embodiments 10 to 12 of the invention on cells, and the specific experimental steps are as follows:
(1) by 1 × 105Concentration per well, human embryonic kidney cells 293(HEK293 cells) were seeded into 96-well plates and 100. mu.L DMEM medium was added thereto at 37 ℃ with 5% CO2Culturing until a monolayer of cells is formed;
(2) discarding culture solution, washing with PBS for 2 times, diluting the antiviral spray prepared by the embodiment of the invention with DMEM in gradient, inoculating on cells at 100 μ L/well with each concentration of more than 4 multiple wells, setting the same concentration control group, and adding 5% CO at 37 deg.C2Culturing for 48 h;
(3) mu.L of MTT solution (2.5mg/mL) was added to each well at 37 ℃ with 5% CO2Incubating for 4 h; discarding the supernatant, adding 120 μ L DMSO/well, and shaking for 20 min;
(4) the absorbance (OD) at 490nm of each well was measured on a multifunctional reader and the 50% toxic concentration was calculated as the drug median Toxic Concentration (TC) by the Reed-Muench method50)。
2. Results of the experiment
The TC of the HEK293 cell by the antiviral spray prepared in the embodiment 10-12 is measured by using an MTT method50The values were 134.25. mu.g/mL, 131.36. mu.g/mL, 138.52. mu.g/mL, respectively; the antiviral spray prepared by the invention has no cytotoxicity (low toxicity)Ignore).
Experimental example 5 in vitro antiviral Performance test of spray
1. Experimental methods
In this experimental example, the in vitro antiviral (coronavirus, 2019-nCoV, MERS-CoV; orthomyxoviridae, H1N1 influenza a virus, enterovirus, poliovirus, hepacivirus, hepatitis a virus, hepatitis b virus, rabies virus, herpesviridae, herpes simplex virus 1, flaviviridae, encephalitis b virus and dengue virus) experiments of the antiviral spray prepared in examples 10 to 12 of the present invention were tested, and the specific experimental steps were as follows:
(1) HEK293 cells were plated at 4.5X 104The individual cells/well concentration were added to a 96 well plate in DMEM with 1% fetal bovine serum at 37 ℃ with 5% CO2Culturing for 24 h;
(2) discard the supernatant and add 100TCID to each well separately502019-nCoV, MERS-CoV, influenza A H1N1, poliovirus, Japanese encephalitis virus, dengue fever virus, rabies virus, hepatitis A virus, hepatitis B virus and herpes simplex virus type 1 virus liquid, 5% CO at 37 DEG C2Adsorbing for 2 h;
(3) discarding supernatant, washing cells with PBS, performing gradient dilution on the spray prepared in the embodiment of the invention with DMEM, respectively adding into each well, setting as experimental group, adding DMEM with the same amount into blank control group, and adding 5% CO at 37 deg.C2Incubating for 72h, and collecting virus supernatant;
(4) HEK293 cells were plated at 2X 106One cell/well, seeded in 12-well plates, 5% CO at 37 ℃2Culturing for 24 h;
(5) diluting the virus supernatant collected in step (3) by 10 times gradient, inoculating to HEK293 cells, and culturing at 37 deg.C with 5% CO2Adsorbing for 2 h;
(6) the supernatant was discarded and the cells were washed with PBS, 2mL of 1% (w/v) methylcellulose-DMEM overlay was added, 5% CO at 37 deg.C2Culturing for 72 h;
(7) removing the methylcellulose-DMEM covering, washing the cells 2 times with PBS, and fixing the cells with 10% formaldehyde at room temperature for 30 min;
(8) discarding the supernatant, washing the cells with PBS for 2 times, adding 0.5% crystal violet, staining for 5min at room temperature, washing with deionized water for 2 times, drying, counting plaques, and calculating the half Inhibitory Concentration (IC) of 50% virus-inhibited drug by Reed-Muench method50)。
2. Results of the experiment
The results of the in vitro inhibitory activity of the antiviral spray prepared by the embodiment of the invention on viruses are shown in tables 7-9. As can be seen from the table, the antiviral spray prepared by the invention has obvious in-vitro antiviral activity.
TABLE 7 in vitro inhibitory Activity results (titer lg PFU/mL) for sprays on 2019-nCoV, MERS-CoV, influenza A H1N1, and poliovirus
Figure BDA0002637631360000191
TABLE 8 in vitro inhibitory Activity results (titer lg PFU/mL) of sprays on Japanese encephalitis virus, dengue virus, rabies virus and hepatitis A virus
Figure BDA0002637631360000192
Figure BDA0002637631360000201
TABLE 9 in vitro inhibitory Activity results (titer lg PFU/mL) of sprays against hepatitis A, hepatitis B and herpes simplex virus 1 viruses
Figure BDA0002637631360000202
Figure BDA0002637631360000211
Experimental example 6 in vivo antiviral Performance test of spray
1. Experimental methods
In this experimental example, the in vivo antiviral tests (coronavirus family viruses: 2019-nCoV and MERS-CoV; orthomyxoviridae viruses: influenza A H1N1, Enterovirus: poliovirus, hepacivirus: hepatitis A virus and hepatitis B virus; rabies virus: rabies virus; herpesviridae viruses: herpes simplex virus type 1; flavivirus viruses: encephalitis B virus and dengue virus) of the sprays prepared in examples 10 to 12 and comparative examples 6 to 8 of the present invention were carried out by the following specific experimental steps:
(1) mixing 2.5X 108PFU hCD 26-expressing recombinant adenovirus vector was nasally transfected into BALB/c mice (purchased from Guangdong province laboratory animal monitoring institute);
(2) hCD26 mice were expressed by nasal drip infection with 2019-nCoV, MERS-CoV, H1N1 influenza A virus, poliovirus, encephalitis B virus, dengue virus, rabies virus, hepatitis A virus, hepatitis B virus and herpes simplex virus 1 virus on day 4 after transfection, and were randomly grouped into placebo, example 10 [90 mg/(kg. d) ], example 11 [90 mg/(kg. d) ], example 12 [90 mg/(kg. d) ], comparative examples 6-8, 6 mice per group, all of which were female, and were administered by gavage, and the placebo was administered with an equivalent amount of 0.1% DMSO solution;
(3) 3 mice per group were randomly selected to be anesthetized CO 5 days post infection2Killing, taking heart, liver, lung and brain tissues of the mouse, transferring into PBS, homogenizing on ice by using a manual homogenizer, centrifuging for 5min at 4 ℃ at 12000r/min, and collecting supernatant;
(14) virus titer test was performed, test method in vitro antiviral test of experimental example 2.
2. Results of the experiment
The results are shown in tables 10 to 12, and it can be seen that the antiviral sprays prepared in the embodiments 10 to 12 of the present invention all have significant inhibitory effects on these viruses; the inhibiting effect of the spray prepared in comparative examples 6-8 on the 10 viruses is not obviously different from that of a blank control group.
The above results illustrate that: the antiviral spray prepared by the invention can effectively and obviously inhibit the replication of the 10 viruses in mice.
TABLE 10 in vivo inhibition results (titer lg PFU/mL) of sprays on 2019-nCoV, MERS-CoV, influenza A H1N1, and poliovirus
Figure BDA0002637631360000221
TABLE 11 in vivo inhibition results of sprays for Japanese encephalitis virus, dengue virus, rabies virus and hepatitis A virus (titer lg PFU/mL)
Group of Encephalitis B virus Dengue fever virus Rabies virus
Blank control group 9.35±0.08 9.69±0.01 9.97±0.09
Comparative example 6 9.76±0.03 9.98±0.07 9.28±0.07
Comparative example 7 9.59±0.01 9.85±0.07 9.35±0.07
Comparative example 8 9.98±0.05 9.75±0.08 9.85±0.07
Example 10 7.62±0.02 6.80±0.07 6.80±0.07
Example 11 6.35±0.08 7.09±0.05 7.10±0.01
Example 12 8.32±0.03 8.08±0.06 8.02±0.02
TABLE 12 in vivo inhibition results (titer lg PFU/mL) of the sprays on hepatitis A, hepatitis B and herpes simplex virus 1 viruses
Figure BDA0002637631360000222
Figure BDA0002637631360000231
Experimental example 7 antiviral ophthalmic agent Performance test
1. Stability test
The ophthalmic preparation prepared in example 16 was used as an example.
An appropriate amount of the antiviral ophthalmic drug sample prepared in example 16 was placed at a high temperature (65 ℃), a low temperature (3 ℃) and a high light (4500Lx) for 15 days, and samples were taken for 0, 8 and 15 days to examine the stability of the sample, and the results are shown in Table 13.
TABLE 13 stability test results for antiviral ophthalmic agents
Time of day Visible foreign body pH value
Day 0 Compliance with regulations 6.23
Low temperature for 8 days Compliance with regulations 6.20
High temperature for 8 days Compliance with regulations 6.22
Illuminating for 8 days Compliance with regulations 6.26
Low temperature for 15 days Compliance with regulations 6.28
High temperature for 15 days Compliance with regulations 6.21
Illuminating for 15 days Compliance with regulations 6.23
From the results in table 13, it can be seen that the antiviral ophthalmic preparation prepared by the present invention still meets the standards in terms of each index and has good stability after being placed under the conditions of high temperature, low temperature and light for 15 days.
2. Rabbit eye irritation test
The ophthalmic preparation prepared in example 16 was used as an example, and the control drug was physiological saline.
Experimental animals: new Zealand rabbits 1.0-1.5Kg (purchased from laboratory animal monitoring institute in Guangdong province), male and female half, before experiment, animals were raised for 7 days, and animal behavior, activity, diet, mental state and eye health were observed and recorded.
The experimental method comprises the following steps:
dividing rabbits into 2 groups at random, each group comprises 5 rabbits, and dividing the groups into a control group and an experimental group; the control group was dropped with 1.0ml of physiological saline, and the experimental group was dropped with 1.0ml of the ophthalmic preparation prepared in example 16.
The rabbit eye conjunctiva changes were observed 3 times a day (8:00, 13:00, 17:00) for 20 consecutive days, 4 hours after the last administration, 1% fluorescein sodium solution was added 10 hours later, and the results were examined 11 hours later with a slit lamp biomicroscope and recorded. After stopping the drug, the animals were observed for irritation, conjunctival congestion, secretion and corneal staining at 1, 8, 15 and 20 days, and scored as shown in Table 14.
TABLE 14 evaluation criteria for ocular irritation
Degree of irritation Scoring
Has no irritation 0～3
Mild irritation 4～8
Moderate irritation 9～12
Stimulation of intensity 13～16
The total integral of the stimulus responses of the tested animal such as conjunctiva, cornea and iris is obtained by adding the stimulus response scores of the cornea, iris and conjunctiva of each rabbit, and the total of the integral of one group is divided by the number of animals to obtain the stimulus score of the antiviral combination for the rabbit eye, wherein the higher the score is, the stronger the stimulus is, and the results are shown in table 15.
TABLE 15 Rabbit eye irritation evaluation score
Eye irritation response Condition Score value
Cornea 0
Iris (iris) 1
Conjunctiva (conjunctiva) 0
As can be seen from Table 15, the cornea, iris and conjunctiva of the eye were normal with scores of 0 to 1, indicating that the ophthalmic preparation of the present invention had no irritating effects on the eyes.
Experimental example 8 ophthalmic Agents cytotoxicity test
1. Experimental methods
In this experimental example, an MTT method is used to test the toxicity of the antiviral ophthalmic agent prepared in embodiments 16 to 18 of the present invention to cells, and the specific experimental steps are as follows:
(1) by 1 × 105Concentration per well, human embryonic kidney cells 293(HEK293 cells) were seeded into 96-well plates and 100. mu.L DMEM medium was added thereto at 37 ℃ with 5% CO2Culturing until a monolayer of cells is formed;
(2) discarding the culture solution, washing with PBS for 2 times, diluting the antiviral eye medicine prepared in the embodiment of the invention with DMEM in gradient, inoculating on cells, 100 μ L/well, setting multiple wells with each concentration of more than 4, setting the same concentration control group, and setting 5% CO at 37 deg.C2Culturing for 48 h;
(3) mu.L of MTT solution (2.5mg/mL) was added to each well at 37 ℃ with 5% CO2Incubating for 4 h; discarding the supernatant, adding 120 μ L DMSO/well, and shaking for 20 min;
(4) the absorbance (OD) at 490nm of each well was measured on a multifunctional reader and the 50% toxic concentration was calculated as the drug median Toxic Concentration (TC) by the Reed-Muench method50)。
2. Results of the experiment
The TC of the antiviral eye medicament prepared in the embodiments 16-18 of the invention on HEK293 cells is measured by using an MTT method50The values were 136.23. mu.g/mL, 138.69. mu.g/mL, 142.25. mu.g/mL, respectively; the antiviral ophthalmic agent prepared by the invention has no cytotoxicity (the toxicity is low and can be ignored).
Experimental example 9 in vitro antiviral Performance test of ophthalmic preparation
1. Experimental methods
This experimental example tested in vitro antiviral (coronavirus family: 2019-nCoV, MERS-CoV; orthomyxoviridae: H1N1 influenza A virus; Enterovirus: poliovirus; hepacivirus: hepatitis A virus, hepatitis B virus; rabies virus: rabies virus; herpesviridae: herpes simplex virus type 1; flaviviridae: encephalitis B virus, dengue virus) experiments of the ophthalmic preparations prepared in examples 16 to 18 and comparative examples 9 to 10 of the present invention, and the specific experimental steps were as follows:
(1) HEK293 cells were plated at 4.5X 104The individual cells/well concentration were added to a 96 well plate in DMEM with 1% fetal bovine serum at 37 ℃ with 5% CO2Culturing for 24 h;
(2) discard the supernatant and add 100TCID to each well separately502019-nCoV, MERS-CoV, influenza A H1N1, poliovirus, Japanese encephalitis virus, dengue fever virus, rabies virus, hepatitis A virus, hepatitis B virus and herpes simplex virus type 1 virus liquid, 5% CO at 37 DEG C2Adsorbing for 2 h;
(3) discarding the supernatant, washing the cells with PBS, performing gradient dilution on the eye medicament prepared by the invention with DMEM, respectively adding into each well to set as an experimental group, adding equivalent DMEM into a blank control group, and adding 5% CO at 37 DEG C2Incubating for 72h, and collecting virus supernatant;
(4) HEK293 cells were plated at 2X 106One cell/well, seeded in 12-well plates, 5% CO at 37 ℃2Culturing for 24 h;
(5) performing 10-fold gradient dilution on the virus supernatant collected in the step (3)Inoculated into HEK293 cells at 37 ℃ with 5% CO2Adsorbing for 2 h;
(6) the supernatant was discarded and the cells were washed with PBS, 2mL of 1% (w/v) methylcellulose-DMEM overlay was added, 5% CO at 37 deg.C2Culturing for 72 h;
(7) removing the methylcellulose-DMEM covering, washing the cells 2 times with PBS, and fixing the cells with 10% formaldehyde at room temperature for 30 min;
(8) discarding the supernatant, washing the cells with PBS for 2 times, adding 0.5% crystal violet, staining for 5min at room temperature, washing with deionized water for 2 times, drying, counting plaques, and calculating the half Inhibitory Concentration (IC) of 50% virus-inhibited drug by Reed-Muench method50)。
2. Results of the experiment
The results of the in vitro inhibitory activity of the antiviral ophthalmic drug prepared by the invention on viruses are shown in tables 16-18. As can be seen from the table, the antiviral ophthalmic agents prepared in the embodiments 16 to 18 of the present invention have significant in vitro antiviral activity, which is similar to that of the blank control group in the data of the comparative examples 9 to 10, and no significant antiviral activity is observed.
TABLE 16 in vitro inhibitory Activity results (titer lg PFU/mL) of ophthalmic agents against 2019-nCoV, MERS-CoV, influenza A H1N1, and poliovirus
Figure BDA0002637631360000261
Figure BDA0002637631360000271
TABLE 17 in vitro inhibitory Activity results (titer lg PFU/mL) of ophthalmic agents against Japanese encephalitis virus, dengue virus, rabies virus and hepatitis A virus
Figure BDA0002637631360000272
TABLE 18 results of in vitro inhibitory Activity of ophthalmic Agents against hepatitis A Virus, hepatitis B Virus and herpes simplex Virus type 1 (titer lg PFU/mL)
Figure BDA0002637631360000273
Figure BDA0002637631360000281
The above embodiments are preferred embodiments of the present invention, but the present invention is not limited to the above embodiments, and any other changes, modifications, substitutions, combinations, and simplifications which do not depart from the spirit and principle of the present invention should be construed as equivalents thereof, and all such changes, modifications, substitutions, and simplifications are intended to be included in the scope of the present invention.

Claims (10)

1. An antiviral composition comprising a Rosa roxburghii extract.
2. The composition as claimed in claim 1, wherein the extract of Rosa roxburghii Tratt is aqueous extract and/or alcoholic extract of Rosa roxburghii Tratt.
3. The composition of claim 1 or 2, further comprising a metal salt and/or sialic acid.
4. Use of a composition as claimed in any one of claims 1 to 3 in the preparation of an antiviral medicament.
5. An antiviral oral liquid comprising the composition according to any one of claims 1 to 3.
6. The antiviral oral liquid of claim 5, comprising the following components in parts by weight: 10-25 parts of roxburgh rose extract, 5-20 parts of metal salt, 8-20 parts of sialic acid, 8-25 parts of antioxidant and 5-25 parts of sweetener.
7. An antiviral spray comprising the composition according to any one of claims 1 to 3.
8. The antiviral spray as claimed in claim 7, which is characterized by comprising the following components in parts by weight: 5-20 parts of rosa roxburghii tratt extract, 3-18 parts of metal salt, 5-18 parts of sialic acid, 1-12 parts of solvent, 6-16 parts of glycerol and 1-10 parts of essence.
9. An antiviral ophthalmic agent comprising the composition according to any one of claims 1 to 3.
10. The antiviral ophthalmic agent as claimed in claim 9, which comprises the following components in parts by weight: 6-18 parts of rosa roxburghii tratt extract, 2-18 parts of metal salt, 2-5 parts of osmotic pressure regulator, 0.2-5 parts of antioxidant, 1-10 parts of solubilizer, 0.1-0.5 part of bacteriostatic agent, 0.1-5 parts of tackifier, 0.1-0.5 part of borneol and the balance of water for injection.
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Application publication date: 20201110