CN114732853A - Application of Chinese medicinal composition in preparing medicine for resisting coronavirus, protecting viscera and enhancing immunity - Google Patents
Application of Chinese medicinal composition in preparing medicine for resisting coronavirus, protecting viscera and enhancing immunity Download PDFInfo
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- CN114732853A CN114732853A CN202110018510.1A CN202110018510A CN114732853A CN 114732853 A CN114732853 A CN 114732853A CN 202110018510 A CN202110018510 A CN 202110018510A CN 114732853 A CN114732853 A CN 114732853A
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Abstract
The invention discloses an application of a traditional Chinese medicine composition in preparing a medicine for preventing and treating pneumonia infected by a novel coronavirus, wherein the traditional Chinese medicine composition mainly comprises weeping forsythia, honeysuckle, isatis root, rhubarb, patchouli, male fern rhizome, rhodiola rosea and the like, the overall regulation advantage of a compound traditional Chinese medicine is exerted, the organic combination of removing disease evil, relieving symptoms and regulating immunity is realized, multi-target treatment is realized, and clinical experiments prove that the traditional Chinese medicine composition has obvious inhibition effect on wild type and S protein D614G mutant type new coronavirus in prevention and treatment, and has protection effect on heart and lung.
Description
Technical Field
The invention relates to application of a traditional Chinese medicine composition in medicines for resisting new corona virus, protecting organs and improving immunity, and belongs to the field of traditional Chinese medicines.
Background
The coronavirus variation is mainly determined by the biological characteristics and the genetic characteristics of the coronavirus, and the coronavirus is found to be a nucleic acid virus synthesized by RNA through the current genetic measurement and the protein measurement, the RNA virus is characterized in that a single-stranded nucleic acid forms a gene chain which is particularly easy to mutate, the protein phenotype of the coronavirus changes after the mutation, and the mutation is better than that of a plurality of animals, the coronavirus has a plurality of different subtypes such as influenza, H5N1, H5N7, H7N9 and the like, and the coronavirus has the mutation now because the protein phenotype also changes after the nucleic acid mutation, so that the coronavirus can be far enough to prevent and control new coronavirus in the future and provide great difficulty. The novel coronavirus pneumonia (Corona Virus Disease 2019, COVID-19) is called new coronavirus pneumonia for short, patients have fever, hypodynamia and dry cough as main clinical manifestations, symptoms of upper respiratory tracts such as nasal obstruction and watery nasal discharge are rare, an anoxic hypoxia state can appear, about half of patients have dyspnea after one week, severe patients rapidly progress to acute respiratory distress syndrome, septic shock, metabolic acidosis which is difficult to correct and blood coagulation dysfunction, and the novel coronavirus pneumonia (Corona Virus Disease 2019, COVID-19) is noteworthy of low-grade fever and even no obvious fever in the course of severe and severe patients, part of patients have slight illness symptoms and can not have fever, the patients recover after 1 week mostly, most of patients have good illness, and few patients are critical in prognosis and even die. Since 2019, 900 more than ten thousand confirmed cases are accumulated in the world, 40 more than ten thousand death cases are accumulated, and the method poses huge threats to the life health and economic development of human beings.
Coronavirus is one of the main pathogens of common cold of adults, can cause upper respiratory tract infection in children, and generally rarely reaches the lower respiratory tract. The incubation period for coronavirus infection is typically 2 to 5 days, with an average of 3 days. Typical coronavirus infections present with cold symptoms such as runny nose, malaise, etc. A total of 7 kinds of coronaviruses are known to infect humans, four of which are more common in the human population (HCoV-229E, HCoV-OC43, HCoV-NL63, HCoV-HKU 1), and the other three are MERS virus (middle east respiratory syndrome virus MERS-CoV), SARS virus (severe acute respiratory syndrome virus SARS-CoV), and 2019 novel coronaviruses (2019-nCoV). HCoV-229E virus is a coronavirus, and in 1965, a virus strain named B814 virus was isolated from the nasal discharge of a patient with common cold by a human embryo tracheal culture method for medical professionals. Subsequently, the researcher isolated a similar virus using human embryonic kidney cells and the representative strain was designated 229E virus. Infection with CoV-229E is globally distributed and is universally susceptible to the population, and multiple studies have shown that almost all children are infected with HCoV-229E in early childhood, a virus that causes common cold and upper respiratory tract infections.
The symptoms after coronavirus infection are different from one type to another, common signs comprise respiratory symptoms, fever, cough, shortness of breath, dyspnea and the like, and in more serious cases, the infection can cause pneumonia, severe acute respiratory syndrome, renal failure and even death, and certain damage is caused to the heart and the lung.
The disease belongs to the category of pestilence in traditional Chinese medicine, the pathogenic factors of epidemic toxin are main pathogenic factors, the invasion of the pathogenic factors into the interior and the transformation of heat are important pathogenesis and prognosis, and the disease is consistent with the clinical characteristics of pneumonia infected by novel coronavirus which is mainly manifested by fever. The traditional Chinese medicine composition mainly comprises fructus forsythiae, honeysuckle, isatis root, rhubarb, patchouli, male fern rhizome, rhodiola rosea and the like. Is an innovative traditional Chinese medicine composition which is developed by applying the Chinese medicine collateral disease theory to reveal the transmission rule of the respiratory infectious disease caused by virus and taking 'antipyretic detoxification, lung diffusing and heat discharging' as a treatment method. The prescription takes the Yinqiao powder from Shangzhongjing Han Lun of Han Dynasty and Wujutong of Qingdai Jutong of Wen Bing tiao as a basic prescription, draws the experiences of Wu of Ming Dynasty and Wu Jutong of Wen Yi Lun of Wen Yi, combines rhodiola rosea with the experiences of clearing lung-heat and removing blood stasis and regulating immunity, embodies the medicine using experience of preventing and treating the epidemic diseases of the Chinese medicine for two thousand years, and particularly adjusts the prescription and the preparation method aiming at the pathogenesis and the expression symptoms of the pneumonia infected by the novel coronavirus, thereby being clinically applicable to infectious diseases of respiratory system accompanied with fever, chilliness, cough, muscle soreness and the like. The invention is an improved invention based on the patent ZL03143211, the content of which is cited in the patent document. The above patent does not disclose the application of the Chinese medicinal composition in preparing the medicine for resisting new coronavirus, protecting organs and improving immunity.
Disclosure of Invention
The invention provides an application of a traditional Chinese medicine composition in preparing a medicine for preventing or treating coronavirus, wherein the coronavirus is wild type new coronavirus and/or S protein mutant type new coronavirus, and the traditional Chinese medicine composition is prepared from the following raw material medicines in parts by weight:
30-55 parts of forsythia fruit 150-
Patchouli 50-90 rhizoma dryopteris crassirhizomae 150-260 rhodiola rosea 50-90 menthol 5-8
50-90 fried Chinese ephedra, 50-90 fried bitter apricot seed, 50-90 cordate houttuynia, 150-
Licorice root 50-90 gypsum 150-260.
The traditional Chinese medicine composition disclosed by the invention preferably comprises the following raw material medicines in parts by weight:
Rhizoma Dryopteris Crassirhizomatis 260 radix Rhodiolae 50 Mentholum 8 processed herba Ephedrae 50
Parched semen Armeniacae amarum 90, herba Houttuyniae 150, Glycyrrhrizae radix 90 and Gypsum Fibrosum 150.
The traditional Chinese medicine composition disclosed by the invention also preferably comprises the following raw material medicines in parts by weight:
forsythia fruit 260 honeysuckle 150 isatis root 260 rhubarb 30 patchouli 90
Rhizoma Dryopteris Crassirhizomatis 150 radix Rhodiolae 90 Mentholum 5 herba Ephedrae 90
Parched semen Armeniacae amarum 50 herba Houttuyniae 260 Glycyrrhrizae radix 50 Gypsum Fibrosum 260.
The traditional Chinese medicine composition disclosed by the invention also preferably comprises the following raw material medicines in parts by weight:
forsythia fruit 170 honeysuckle 170 isatis root 170 rhubarb 34 patchouli 57
Rhizoma dryopteris crassirhizomae 170 rhodiola rosea 57 menthol crystal 5 mix-fried ephedra 57
Parched semen Armeniacae amarum 57, herba Houttuyniae 170, Glycyrrhrizae radix 57, and Gypsum Fibrosum 170.
The traditional Chinese medicine composition disclosed by the invention also preferably comprises the following raw material medicines in parts by weight:
255 portions of forsythia, 255 portions of honeysuckle, 255 portions of isatis root, 255 portions of rhubarb, 51 portions of patchouli, 85
Rhizoma dryopteris crassirhizomae 255 rhodiola rosea 85 menthol crystal 7.5 mix-fried ephedra 85
Parched semen Armeniacae amarum 85 herba Houttuyniae 255 Glycyrrhrizae radix 85 Gypsum Fibrosum 255.
The traditional Chinese medicine can be replaced by traditional Chinese medicines with the same or similar effects, and the medicines can be processed according to the national traditional Chinese medicine processing standard or the traditional Chinese medicine dictionary.
The active ingredients of the traditional Chinese medicine composition are prepared by the following steps:
(1) weighing the traditional Chinese medicinal materials according to the weight proportion of the raw materials, and cleaning and selecting;
(2) crushing herba Agastaches, extracting volatile oil with 5-8 times of water for 4 hr, and collecting volatile oil; filtering the extractive solution, discarding residue, and collecting filtrate;
(3) extracting fructus forsythiae, herba Ephedrae preparata, herba Houttuyniae, and radix et rhizoma Rhei with 6-10 times of 50-90% ethanol for 2 times, each for 1-3 hr, mixing extractive solutions, filtering, recovering ethanol, and collecting filtrate;
(4) adding 7-11 times of water into honeysuckle, gypsum, isatis root, male fern rhizome, liquorice and rhodiola rosea, decocting until boiling, adding fried bitter apricot seed, decocting for 2 times, 0.5-2.5 hours each time, combining the extracting solutions, filtering, combining the obtained filtrate with the filtrate obtained after the oil extraction of the pogostemon cablin in the step (2), concentrating into clear paste with the relative density of 1.10-1.15 measured at the temperature of 60 ℃, adding ethanol, adjusting the alcohol concentration to 70%, refrigerating, standing, filtering, and recovering the ethanol until no alcohol smell exists, thus obtaining the clear paste for later use;
(5) mixing the fluid extract obtained in step (4) with the ethanol extract obtained in step (3), concentrating to obtain fluid extract with relative density of 1.15-1.20 at 60 deg.C, and drying to obtain dry extract powder;
the dry paste powder obtained in the step (5), the volatile oil obtained in the step (2) and menthol jointly form the active ingredients of the traditional Chinese medicine composition.
The medicament of the invention is in the form of capsules, tablets, powders, granules, oral liquid, soft capsules, pills, tinctures, syrups, suppositories, gels, sprays or injections.
In order to make the above dosage forms possible, pharmaceutically acceptable excipients, such as: fillers, disintegrants, lubricants, suspending agents, binders, sweeteners, flavoring agents, preservatives, bases, and the like. The filler comprises: starch, pregelatinized starch, lactose, mannitol, chitin, microcrystalline cellulose, sucrose, etc.; the disintegrating agent comprises: starch, pregelatinized starch, microcrystalline cellulose, sodium carboxymethyl starch, crospolyvinylpyrrolidone, low-substituted hydroxypropylcellulose, croscarmellose sodium, etc.; the lubricant comprises: magnesium stearate, sodium lauryl sulfate, talc, silica, and the like; the suspending agent comprises: polyvinylpyrrolidone, microcrystalline cellulose, sucrose, agar, hydroxypropyl methylcellulose, and the like; the adhesive comprises starch slurry, polyvinylpyrrolidone, hydroxypropyl methylcellulose, etc.; the sweetener comprises: saccharin sodium, aspartame, sucrose, sodium cyclamate, glycyrrhetinic acid, and the like; the flavoring agent comprises: sweeteners and various essences; the preservative comprises: parabens, benzoic acid, sodium benzoate, sorbic acid and its salts, benzalkonium bromide, chloroacetidine acetate, eucalyptus oil, etc.; the matrix comprises: PEG6000, PEG4000, insect wax, etc.
The capsule is prepared by the following steps:
(1) weighing the traditional Chinese medicinal materials according to the weight proportion of the raw materials, and cleaning and selecting;
(2) crushing herba Agastaches, extracting volatile oil with 5-8 times of water for 4 hr, and collecting volatile oil; filtering the extractive solution, discarding residue, and collecting filtrate;
(3) extracting fructus forsythiae, herba Ephedrae preparata, herba Houttuyniae, and radix et rhizoma Rhei with 6-10 times of 50-90% ethanol for 2 times, each for 1-3 hr, mixing extractive solutions, filtering, and recovering ethanol to obtain filtrate;
(4) adding 7-11 times of water into honeysuckle, gypsum, isatis root, male fern rhizome, liquorice and rhodiola rosea, decocting until boiling, adding fried bitter apricot seed, decocting for 2 times, 0.5-2.5 hours each time, combining the extracting solutions, filtering, combining the obtained filtrate with the filtrate obtained after the oil extraction of the pogostemon cablin in the step (2), concentrating into clear paste with the relative density of 1.10-1.15 measured at the temperature of 60 ℃, adding ethanol, adjusting the alcohol concentration to 70%, refrigerating, standing, filtering, and recovering the ethanol until no alcohol smell exists, thus obtaining the clear paste for later use;
(5) mixing the fluid extract obtained in step (4) and the ethanol extract obtained in step (3), concentrating to obtain fluid extract with relative density of 1.15-1.20 at 60 deg.C, and drying to obtain dry extract powder;
(6) adding a proper amount of pharmaceutically acceptable auxiliary materials into the dry paste powder obtained in the step (5) for granulation;
(7) and (3) dissolving the menthol and the volatile oil obtained in the step (2) in ethanol, spraying the particles obtained in the step (6), sealing, uniformly mixing, and encapsulating to obtain the capsule.
The preparation method of the granules comprises the following steps:
(1) weighing the traditional Chinese medicinal materials according to the weight proportion of the raw materials, cleaning, and cutting off the traditional Chinese medicinal materials as appropriate;
(2) crushing herba Agastaches, extracting volatile oil with 5-8 times of water for 4 hr, and collecting volatile oil; filtering the extractive solution, discarding residue, and collecting filtrate;
(3) extracting fructus forsythiae, herba Ephedrae preparata, herba Houttuyniae, and radix et rhizoma Rhei with 6-10 times of 50-90% ethanol for 2 times, each for 1-3 hr, mixing extractive solutions, filtering, and recovering ethanol to obtain filtrate;
(4) adding 7-11 times of water into honeysuckle, gypsum, isatis root, male fern rhizome, liquorice and rhodiola rosea, decocting until boiling, adding fried bitter apricot kernel, decocting for 2 times, 0.5-2.5 hours each time, combining the extracting solutions, filtering, combining the obtained filtrate with the filtrate obtained after oil extraction of the pogostemon cablin in the step (2), concentrating into clear paste with the relative density of 1.10-1.15 measured at the temperature of 60 ℃, adding ethanol, adjusting the alcohol concentration to be 70%, refrigerating, standing, filtering, and recovering the ethanol until no alcohol smell exists, thus obtaining the clear paste for later use;
(5) mixing the fluid extract obtained in step (4) with the ethanol extract obtained in step (3), and concentrating to obtain soft extract with relative density of 1.25-1.35 at 60 deg.C;
(6) adding appropriate pharmaceutically acceptable adjuvants into the soft extract obtained in step (5), and granulating;
(7) and (3) dissolving the menthol and the volatile oil obtained in the step (2) in ethanol, spraying the granules obtained in the step (6), sealing, uniformly mixing and bagging to obtain the menthol-containing capsule.
The preparation method of the preferred granules comprises the following steps:
(1) weighing the traditional Chinese medicinal materials according to the weight proportion of the raw materials, cleaning, and cutting off the traditional Chinese medicinal materials as appropriate;
(2) crushing herba Agastaches, extracting volatile oil with 6 times of water for 4 hr, and collecting volatile oil; filtering the extractive solution, discarding residue, and collecting filtrate;
(3) extracting fructus forsythiae, herba Ephedrae preparata, herba Houttuyniae, and radix et rhizoma Rhei with 8 times of 70% ethanol for 2 times, 2 hr for the first time, and 1.5 hr for the second time, mixing extractive solutions, filtering, and recovering ethanol to obtain filtrate;
(4) adding 9 times of water into honeysuckle, gypsum, isatis root, male fern rhizome, liquorice and rhodiola rosea, decocting until boiling, adding fried bitter apricot seed, decocting for 2 times, wherein the first time is 1.5 hours, and the second time is 1 hour, combining extracting solutions, filtering, combining obtained filtrate with water filtrate obtained after oil extraction of pogostemon cablin in the step (2), concentrating into clear paste with the relative density of 1.10-1.15 measured at the temperature of 60 ℃, adding 95% ethanol, adjusting the alcohol concentration to be 70%, refrigerating, standing, filtering, and recovering ethanol until no alcohol smell exists, so as to obtain clear paste filtrate;
(5) mixing the fluid extract obtained in step (4) and the ethanol extract obtained in step (3), and concentrating to obtain soft extract with relative density of 1.25-1.35 at 60 deg.C;
(6) adding a proper amount of pharmaceutically acceptable auxiliary materials into the thick paste obtained in the step (5), granulating, and finishing granules for later use;
(7) and (3) screening out fine powder from the granules obtained in the step (6), adding ethanol into the menthol and the volatile oil obtained in the step (2) for dissolving, spraying the fine powder, uniformly mixing with the granules obtained in the step (6), sealing for half an hour, and bagging to obtain the menthol crystal.
The preparation method of other dosage forms of the medicine comprises the following steps: the raw materials are weighed according to the proportion and prepared by a conventional preparation method, for example, a preparation process recorded in Vanbitsin traditional Chinese medicine pharmacy (1 st 12 months in 1997 of Shanghai scientific Press) to prepare a conventional dosage form acceptable in pharmacy.
The invention also provides application of the traditional Chinese medicine composition in medicines for preventing or treating respiratory diseases, wherein the respiratory diseases comprise pneumonia, bronchitis, fever, cough, cold and the like.
The invention also provides application of the traditional Chinese medicine composition in a medicine for protecting heart injury, preferably heart injury caused by viruses, wherein the viruses are preferably coronavirus, and more preferably HCoV-229E coronavirus.
The invention also provides application of the traditional Chinese medicine composition in a medicine for protecting lung injury, more preferably lung injury caused by viruses, wherein the viruses are preferably coronavirus, and more preferably HCoV-229E coronavirus.
The invention also provides application of the traditional Chinese medicine composition in medicines for improving human immunity.
Detailed Description
The following examples are intended to illustrate the preparation of the medicaments according to the invention, but they are not intended to limit the scope of the invention in any way.
Example 1
Prescription:
255 g of forsythia, 255 g of honeysuckle, 255 g of isatis root, 255 g of rhubarb, 51 g
Pogostemon cablin 85 g male fern rhizome 255 g rhodiola rosea 85 g menthol crystal 7.5 g
85 g of mix-fried ephedra herb, 85 g of fried bitter apricot seed, 85 g of heartleaf houttuynia herb and 255 g of heartleaf houttuynia herb
Licorice root, gypsum, and gypsum, 255 g.
The preparation method comprises the following steps:
(1) weighing the traditional Chinese medicinal materials according to the prescription, and cleaning;
(2) crushing herba Agastaches, extracting volatile oil with 6 times of water for 4 hr, and collecting volatile oil; filtering the extractive solution, discarding residue, and collecting filtrate;
(3) extracting fructus forsythiae, herba Ephedrae preparata, herba Houttuyniae, and radix et rhizoma Rhei with 8 times of 70% ethanol for 2 times, 2 hr for the first time, and 1.5 hr for the second time, mixing extractive solutions, filtering, and recovering ethanol to obtain filtrate;
(4) adding 9 times of water into honeysuckle, gypsum, isatis root, male fern rhizome, liquorice and rhodiola rosea, decocting until boiling, adding fried bitter apricot seed, decocting for 2 times, wherein the first time is 1.5 hours, and the second time is 1 hour, combining the extracting solutions, filtering, combining the obtained filtrate with the filtrate obtained after the oil extraction of the pogostemon cablin in the step (2), concentrating into clear paste with the relative density of 1.10-1.15 measured at the temperature of 60 ℃, adding ethanol, adjusting the alcohol concentration to 70%, refrigerating and standing for 24 hours, filtering, and recovering the ethanol until no alcohol smell exists, thereby obtaining the clear paste for later use;
(5) mixing the fluid extract obtained in step (4) and the ethanol extract obtained in step (3), concentrating to obtain fluid extract with relative density of 1.15-1.20 at 60 deg.C, and spray drying to obtain dry extract powder;
(6) adding 142 g of starch into the dry paste powder obtained in the step (5), and granulating by using 85% ethanol;
(7) and (3) dissolving the menthol and the volatile oil obtained in the step (2) in ethanol, spraying the particles obtained in the step (6), sealing, uniformly mixing, and filling into 1000 capsules to obtain the capsule.
Example 2
Prescription:
260 g of forsythia, 150 g of honeysuckle, 260 g of isatis root, 260 g of rhubarb and 30 g of rhubarb
Patchouli 90 g male fern rhizome 150 g rhodiola root 90 g menthol 5g
Mix-fried ephedra 90 g, bitter apricot seed 50 g, cordate houttuynia 260 g
Licorice root 50 g plaster 260 g.
The preparation method comprises the following steps:
(1) weighing the traditional Chinese medicinal materials according to the prescription, and cleaning;
(2) crushing herba Agastaches, extracting volatile oil with 5 times of water for 4 hr, and collecting volatile oil; filtering the extractive solution, discarding residue, and collecting filtrate;
(3) extracting fructus forsythiae, herba Ephedrae preparata, herba Houttuyniae, and radix et rhizoma Rhei with 6 times of 50% ethanol for 2 times, 1 hr for the first time, and 2.5 hr for the second time, mixing extractive solutions, filtering, and recovering ethanol to obtain filtrate;
(4) adding 7 times of water into honeysuckle, gypsum, isatis root, male fern rhizome, liquorice and rhodiola rosea, decocting until boiling, adding fried bitter apricot seed, decocting for 2 times, wherein the first time is 1.5 hours, and the second time is 1 hour, combining the extracting solutions, filtering, combining the obtained filtrate with the filtrate obtained after the oil extraction of the pogostemon cablin in the step (2), concentrating into clear paste with the relative density of 1.10-1.15 measured at the temperature of 60 ℃, adding ethanol, adjusting the alcohol concentration to 70%, refrigerating and standing for 24 hours, filtering, and recovering the ethanol until no alcohol smell exists, thereby obtaining the clear paste for later use;
(5) mixing the fluid extract obtained in step (4) with the ethanol extract obtained in step (3), concentrating to obtain fluid extract with relative density of 1.15-1.20 at 60 deg.C, and spray drying to obtain dry extract powder;
(6) adding 151 g of starch into the dry paste powder obtained in the step (5), and granulating by using 85% ethanol;
(7) and (3) adding menthol and the volatile oil obtained in the step (2) into ethanol for dissolving, spraying the granules obtained in the step (6), sealing, uniformly mixing, and pressing into tablets to obtain 935 tablets.
Example 3
Prescription:
fructus forsythiae 185 g, honeysuckle 179 g, radix isatidis 190 g, rhubarb 36 g
Patchouli 60 g male fern rhizome 170 g rhodiola root 57 g menthol 5g
Chinese ephedra 60 g, bitter apricot kernel 60 g, cordate houttuynia 170 g
Licorice root 60 g plaster 170 g.
The preparation method comprises the following steps:
(1) weighing the traditional Chinese medicinal materials according to the prescription, and cleaning;
(2) crushing herba Agastaches, adding 6 times of water to extract volatile oil for 4 hr, and collecting volatile oil with oil yield of 0.33; filtering the extract, discarding the residue, and collecting the water extract;
(3) extracting fructus forsythiae, herba Ephedrae preparata, herba Houttuyniae, and radix et rhizoma Rhei with 8 times of 70% ethanol for 2 times, 2 hr for the first time, and 1.5 hr for the second time, mixing extractive solutions, filtering, and recovering ethanol to obtain filtrate;
(4) adding 9 times of water into honeysuckle, gypsum, isatis root, male fern rhizome, liquorice and rhodiola rosea, decocting until boiling, adding fried bitter apricot seed, decocting for 2 times, wherein the first time is 1.5 hours, and the second time is 1 hour, combining the extracting solutions, filtering, combining the obtained filtrate with the water extract obtained after the oil extraction of the pogostemon cablin in the step (2), concentrating into clear paste with the relative density of 1.10-1.15 measured at the temperature of 60 ℃, adding 95% ethanol, adjusting the alcohol concentration to 70%, refrigerating for 24 hours, filtering, and recovering the ethanol until no alcohol smell exists, thereby obtaining the clear paste for later use;
(5) mixing the fluid extract obtained in step (4) and the ethanol extract obtained in step (3), concentrating to obtain soft extract with relative density of 1.25-1.30 at 60 deg.C, and spray drying to obtain dry extract powder;
(6) and (3) preparing the dry paste powder obtained in the step (5), the volatile oil obtained in the step (2) and the menthol into pills according to a conventional method to obtain pills 905.
Example 4:
the formula of the raw material medicine is as follows:
weeping forsythia 170 g honeysuckle flower 170 g mix-fried Chinese ephedra 57 g stir-fried bitter apricot kernel 57 g
170 g of gypsum, 170 g of isatis root, 170 g of male fern rhizome, 170 g of cordate houttuynia
Patchouli 57 g rhubarb 34g rhodiola 57 g menthol 5.0 g
Licorice root, radix Glycyrrhizae 57 g
The preparation method comprises the following steps:
the extraction process comprises the following steps:
(1) weighing the traditional Chinese medicinal materials according to the prescription, cleaning, and cutting according to the requirement;
(2) extracting herba Agastaches with 6 times of water for 4 hr, collecting volatile oil with oil yield of 0.33%, filtering the extractive solution, removing residue, and collecting water extractive solution;
(3) extracting fructus forsythiae, herba Ephedrae preparata, herba Houttuyniae, and radix et rhizoma Rhei with 8 times of 70% ethanol for 2 times, 2 hr for the first time, and 1.5 hr for the second time, filtering the extractive solutions, mixing the filtrates, and recovering ethanol until no ethanol smell exists;
(4) adding 9 times of water into honeysuckle, fried bitter almond, gypsum, isatis root, male fern rhizome, liquorice and rhodiola rosea, decocting until boiling, adding the fried bitter almond, decocting for 2 times, wherein the first time is 1.5 hours, and the second time is 1 hour, filtering an extracting solution, combining filtrates, simultaneously adding an aqueous solution obtained after oil extraction of the pogostemon cablin in the step (2), concentrating into clear paste with the relative density of 1.10-1.15 determined at 60 ℃, adding 95% ethanol, stirring while adding until the alcohol concentration is 70%, refrigerating and standing for 24 hours, filtering, recovering ethanol from the filtrate until no alcohol taste exists, combining with an alcohol extracting solution, concentrating into thick paste with the relative density of 1.25-1.35 determined at 60 ℃ for later use;
(II) preparation process:
(5) the formula of the preparation is as follows: 335.5g of thick paste obtained in step (4) and 5g of menthol
0.2ml of patchouli oil obtained in the step (2) and 342.5g of powdered sugar 514.0g of dextrin
(6) And (3) granulating: mixing sugar powder and dextrin, making soft mass with soft extract as binder, granulating with 14 mesh screen, oven drying at 60-65 deg.C, and grading with 10 mesh screen;
(7) subpackaging: sieving to obtain fine powder, adding appropriate amount of ethanol into Mentholum and herba Agastaches volatile oil, dissolving, spraying into the fine powder, mixing with the granule, sealing for half an hour, and packaging to obtain 1000g granule.
Description of the drawings:
FIG. 1. EC50The results were calculated where A. is the EC of the drugs of the invention against Wt virus on Vero E6 cells50(ii) a B. EC of the inventive drugs on D61G virus on Vero E6 cells50
FIG. 2: lung histology effects (48 h post dose) (× 100), where a is normal control; b is a model control group; c is the drug group of the invention
FIG. 3: effect on lung pathology (next day after last dose) (× 100), where a is normal control; b is a model control group; c is the medicine group of the invention.
Examples of the experiments
In order to confirm the curative effects of the Chinese medicinal composition of the invention on preventing and treating new corona virus, protecting organs and improving immunity, the following clinical trial research is carried out on the particles (hereinafter referred to as the medicament of the invention) prepared by the method of the embodiment 4:
the first test example: research on in-vitro inhibition of new coronavirus by using medicine of the invention
1. Test materials
1.1 medicaments
The drug of the present invention (batch No. 1804001), the concentration of the drug solution of the present invention: 12 mg/mL (1 mL DMSO dissolves 120 mg of drug, then 9mL DMEM medium (containing 100U/mL double antibody (cyan, streptomycin) and 2% FBS, vortex for 5min, place in a refrigerator at 4 ℃ for 12 h, vortex again for 5min, filter with a 0.22 μ M filter);
1.2 cells: VERO-E6 cell
1.3. Virus
(1) Wild-type neocoronaviruses [ 2019-nCoV, Wild-type (wt) ];
(2) s protein mutant neocoronaviruses [ 2019-nCoV, D614G ]
1.4 reagents
Virus diluent: DMEM medium containing 100U/mL double antibody (penicillin, streptomycin) at final concentration and no serum;
medicine diluent: DMEM medium containing 100U/mL double antibody (penicillin, streptomycin) at final concentration and no serum;
cell culture solution: DMEM medium containing 100U/mL double antibody (cyan, streptomycin) and 10% FBS at final concentration;
fetal Bovine Serum (FBS) (cat No. 10270-044, brand: GIBCO);
DMEM medium (cat # C11995500BT, brand: GIBCO);
1 XPBS (pH7.4) (cat # C10010500BT, brand: GIBCO);
0.25% Trypsin-EDTA (Trypsin Trypsin 2.5g (cat # 0458-;
DMSO (cat number D2650-100 ML:, brand: sigma);
1.5 consumables
96-well flat-bottomed cell culture plates (cat # 3599, brand: costar); 15mL centrifuge tube (stock number: CFT-011 and 150, brand: BIOFIL); 50mL centrifuge tube (stock number: CFT-011 and 150, brand: BIOFIL); a pipette tip (goods number: T-200-Y-R-S, brand: AXYGEN); a 10mL pipette (cat # 4488, brand: costar);
1.6 instruments
A cell incubator; -80 ℃ refrigerator; a centrifuge; inverting the microscope; a biological safety cabinet; an electric pipette; a liquid transferring gun; 8 gun rows; a water bath kettle; oscillator
2. Experimental method
2.1 cell: VERO-E6 cells, after confluent monolayers, were subjected to the drug antiviral assay of the invention.
Virus: new coronaviruses (Wt and D614G), 100 TCID50Perpore Virus inoculated cells.
Medicine preparation: the test concentrations of the drug are 75, 37.5, 18.75, 9.375, 4.69, 2.34, 1.17, 0.59, 0.29 and 0.15 mug/ml for 10 concentrations. The virus and the drug are incubated for 1 h at 37 ℃ and then inoculated with cells, and a normal cell control and a positive virus control are set at the same time.
And (4) observation: after 72h of viral infection, CPE was observed
3. Results
3.1 CPE Observation: after 72h of virus infection, the normal cell control group had no CPE; the CPE is obvious in a virus control group; different drug concentrations showed different inhibitory effects on CPE, as shown in tables 1 and 2.
Median inhibitory concentration (EC)50) And Therapeutic Index (TI) calculation: half maximal inhibitory concentrations (EC) were calculated from the results in Table 150) As shown in FIG. 1, the EC of the inventive drug against Wt virus on Vero E6 cell5017.77 μ g/ml; EC of the drug of the invention against D614G virus5035.85. mu.g/ml.
Based on the results of the toxicity Test (TD) of the same batch of the drug to cells50264.8 μ g/ml), the therapeutic index (TI = TD) was calculated50/EC50). The results show that the therapeutic index of the drug of the invention is 14.90 for the Wt virus and 7.39 for the D614G virus.
Conclusion
The drug of the invention at a certain concentration can inhibit 2019 new coronaviruses (Wt and D614G mutant strains) from forming CPE on Vero E6 cells.
Test example two
1. The test name is: research on coronavirus HCoV-229E test by using medicine of the invention
2. Test materials
2.1 test article
The invention has the following medicine batch numbers: b2001013, specification: 0.35 g/pellet, effective period up to: in 2022, 06 months, produced by Shijiazhuang, Ling pharmaceuticals, Inc.
2.2 Experimental animals
BALB/c mice, SPF grade, 120 mice, half male and half female, 10.0-14.0 g weight, animal quality qualification certificate number: no.1107272011001651, purchased from slai kholda laboratory animals ltd, Hunan, laboratory animals production license no: SCXK (Xiang) 2019-; the pathogenic microorganism safety animal laboratory (ABSL-II) raised in the Hunan province pharmaceutical safety evaluation research center barrier environment C area is recorded and numbered: long wei counter stock (2019) number B001, laboratory animal use license number: SYXK (xiang) 2015-.
2.4 strains: coronavirus HCoV-229E, accession number: ATCC-VR-740, given by the center for disease prevention and control in Hunan province, was cultured and amplified in the Central microorganism laboratory (BSL-II, laboratory docket number: Changbai Shuitai (2019) No. B001).
2.5 cell lines: human lung fibroblast cells (MRC-5) were purchased from Wuhan Punuoise Life technologies, Inc. and subcultured in the cell compartment of the Hunan province center for drug safety evaluation research.
2.6 Primary reagents
DMEM medium (batch No. AD22315267, Hyclone); fetal bovine serum (batch No. M009-6, Sciencell, USA); interleukin-6 (IL-6), interleukin-8 (IL-8), tumor necrosis factor (TNF-alpha), Brain Natriuretic Peptide (BNP), interleukin-2 (IL-2), interleukin-12 (IL-12), T cell immunoregulatory factor (TCITRG), Interferon Regulatory Factor (IRF) enzyme linked immunosorbent assay kit, the above-mentioned kits are provided by Jiangsu enzyme immunoassay company; IL-4 flow antibody (batch: 2031934), CD4 flow antibody (batch: 2115770), INF-gamma flow antibody (batch: 2161229), IL-17A flow antibody (batch: 1995433), CD25 flow antibody (batch: 2018381), FoxP3 flow antibody (batch: 2105941), all of which were purchased from Saimer Feishel technologies, Inc. (China).
2.7 Main Instrument
BCR-MI02-72-C11-PPSU type mouse independent ventilation cage box system (manufactured by Shandong Xinhua medical instruments, Ltd., the number of the center: 578),BSC 1300-II-B2 type biosafety cabinets (manufacturer: Sanhua medical instruments Co., Ltd., number 588 in the present center), CJ-1F type medical purification benches (manufacturer: Suzhou von Experimental animals Equipment Co., Ltd., number 176 in the present center), BSCIIB2-1101 type biosafety cabinets (manufacturer: Shanghai Ruizian purification Equipment Co., Ltd., number 019 in the present center), and 3111 type CO2An incubator (manufacturer: Thermo Fisher company, USA, the number of the center: 147), a DMIL inverted microscope (manufacturer: Leica company, Germany, the number of the center: 027), a YXQ-50A type vertical pressure sterilizer (manufacturer: Shanghai Bonews medical biological instruments, Inc., the number of the center: 584), and a TD4 type desk-top low-speed centrifuge (manufacturer: Kaida practical development Co., Hunan province, the number of the center: 101).
3 Experimental methods
3.1 amplification of viruses
Inoculating MRC-5 cells into a culture bottle, removing part of the culture medium when the cell density reaches 70-80%, covering the rest cells, respectively adding appropriate amount of HCoV-229E virus, slightly shaking the culture plate every 30min after the virus is adsorbed on the cell surface (about 3h to make the virus adsorbed uniformly), replacing fresh medium without FBS, placing at 37 deg.C and 5% CO2Culturing in a humidified constant-temperature incubator. After 96h (prolonged culture time without cell lesion), repeated freezing and thawing method is adopted, centrifugation is carried out at 3000rpm for 10min to remove cell debris, supernatant is collected, virus titer is determined by cytopathogenic method (CPE method), and 50% of tissue cell infection amount (TCID method) is used50) And (4) showing. And then filtering the mixture by using a filter of 0.22 mu m, subpackaging the filtered mixture into freezing storage tubes, and performing labeling and then performing short-medium storage or long-medium storage in liquid nitrogen at minus 80 ℃ for later use. Before infecting animals, the hemagglutination titer of the virus is detected by a hemagglutination method and is adjusted to a proper titer.
TCID50= Log (dilution of virus with CPE less than 50%) + distance ratio × dilution spacing
Wherein the distance ratio = (percentage higher than 50% -50)/(percentage higher than 50% -percentage lower than 50%)
3.2 modeling, grouping and administration
The mice are divided into 6 groups according to sex and weight at random, wherein the 6 groups are respectively a normal control group, a model control group and a drug group, and each group comprises 20 animals. The mice of each group were lightly anesthetized with ether and inoculated nasally with HCoV-229E coronavirus solution (hemagglutination assay for 6Log2, precooling at 4 ℃), 60 μ L/mouse, continuously inoculated for 2 days, normal control group was inoculated nasally with an equal volume of a blank medium, and each group was first administered 2h after the 2 nd molding. The medicine is prepared into liquid medicine with the concentration of 0.156g crude drug/mL by pure water every day, the liquid medicine with the corresponding concentration is given to the medicine according to 20mL/kg through oral gavage, and the pure water with the same volume is given to a normal control group and a model control group for 1 time/day for 7 days continuously.
3.3 dose design
The clinical dosage of the drug is 24g crude drug/day, the average adult weight is 60kg, the mouse equivalent dosage is about 3.12g crude drug/kg according to the body surface area method, and the mouse equivalent dosage of the drug is taken as the administration dosage in the mouse test in the test, namely 3.12g crude drug/kg. Specific dosage design details are shown in table 3.
3.4 Observation index
3.4.1 general physiological observations
Each group of animals was weighed daily and observed for physiological status, and the change in animal body weight over the course of the test was compared.
3.4.2 determination of cytokine content in lung tissue
Respectively randomly selecting 8 animals from each group at 48h after administration and the next day after the last administration, respectively, carrying out euthanasia by dislocation of cervical vertebrae, dissecting and taking lung, then placing into a homogenizer, and according to the lung mass (g): 0.9% sodium chloride injection (mL) = 1: 9 adding 0.9% sodium chloride injection, grinding and homogenizing to prepare mouse lung suspension, centrifuging at 4 ℃ for 15min at 3000rpm, and taking the supernatant for later use. The ELISA kit detects the contents of IL-2, IL-6, IL-8, IL-12 and TNF-alpha in the lung of the mouse.
3.4.3 detection of cytokines in peripheral blood
At 48h after administration and the next day after the last administration, 8 animals, half of the males and females, were randomly selected from each group, blood was collected from the orbit, centrifuged at 3000rpm at 4 ℃ for 15min, and the supernatant was collected for use. The ELISA kit detects the contents of BNP, CK-MB, Tn-I, TCITRG and IRF in mouse serum.
3.4.4 detection of immune cells in Lung tissue
Respectively randomly selecting 8 animals from each group in 48h after administration and the next day after the last administration, carrying out eutrophy by dislocation of cervical vertebrae and eutrophy by dissection, then placing the animals into a homogenizer according to the lung mass (g): 0.9% sodium chloride injection (mL) = 1: 9 adding 0.9% sodium chloride injection, and grinding to obtain homogenate to obtain mouse lung suspension. And (3) detecting the T cell subset (Th 0/Th1/Th 2) and the regulatory/helper T cell (Th 17/Treg) in the lung of the mouse by using a flow cytometer.
3.4.5 Lung tissue Virus Titer assay
Respectively randomly selecting 10 animals from each group at 48h after administration and the next day after the last administration, respectively, carrying out euthanasia by taking out the male and female animals from each group, carrying out cervical vertebra dislocation, carrying out euthanasia, dissecting, taking the lung, then placing in a homogenizer, and carrying out mass (g) of the lung: 0.9% sodium chloride injection (mL) = 1: 9 adding 0.9% sodium chloride injection, and grinding to obtain homogenate to obtain mouse lung suspension. Viral titers were detected in lung tissue by hemagglutination.
3.4.6 pathological examination of Lung tissue
The mice in each group are dislocated and euthanized after being administrated for 48 hours and the next day after the last administration, the lung is dissected and taken, after formalin perfusion and fixation, paraffin embedding, slicing and HE staining are carried out, pathological changes are observed by a light mirror, and the evaluation is carried out on 4 aspects of inflammatory and bloody exudation degrees, alveolar epithelium destruction degrees, pulmonary scaffold collapse alveolar epithelium hyperplasia degrees and macrophage infiltration degrees of chronic inflammatory cells around small blood vessels.
3.5 statistical methods
The test data significant figure rounding was done by rounding and statistical analysis was done as specified by SOP. The software used for statistics was SPSS. The measurement data is averaged + -SD: () Showing that the method of Leven's test is used for checking the normality and the homogeneity of variance. If it has no statistical significance (P)>0.05), statistical analysis was performed using one-way analysis of variance (ANOVA). If ANOVA is statistically significant (P.ltoreq.0.05), a comparative analysis is carried out using LSD test (parametric method). If the variance is not uniform (P.ltoreq.0.05), the test is carried out by Kruskal-Wallis. If the Kruskal-Wallis Test is statistically significant (P.ltoreq.0.05), a comparative analysis is performed using Dunnett's Test (nonparametric method). Statistical results are tested with a =0.05, where P.ltoreq.0.05 indicates statistical significance and P.ltoreq.0.01 indicates that the differences tested are of very significant significance.
4 results of the experiment
4.1 amount of HCoV-229E infected with half of the virus of MRC-5 cells
As shown in Table 4, HCoV-229E stock solution was diluted in a 10-fold gradient and co-cultured with MRC-5 cells to obtain half the viral infection amount (TCID) of MRC-5 cells with HCoV-229E50) Is 10-4.62/0.1mL。
4.2 Effect on animal body weight
As shown in Table 5 and FIG. 1, the body weight of the model control groups D1-D8 was significantly reduced (P.ltoreq.0.01) compared with that of the normal control group, indicating that human coronavirus (HCoV-229E) can cause the weight loss of mice. Compared with a model control group, the weight of the drug group is obviously increased (P is less than or equal to 0.05 or P is less than or equal to 0.01) after the drug is administered for D2-D6 days. It was suggested that the infection of mice with coronavirus (HCoV-229E) caused a sustained weight loss, and that oral gavage of the present invention alleviated the weight loss in infected mice.
4.3 Effect on IL-6, TNF-alpha, IL-2, IL-8, IL-12 content in Lung tissue
As shown in Table 6, after 48h administration, IL-6, TNF-alpha, IL-2, IL-8 and IL-12 in the model control group were all significantly increased compared with the normal control group (P Less than or equal to 0.01). IL-6 in the drug group of the present invention was significantly decreased as compared with the model control group (P Less than or equal to 0.05 orP Less than or equal to 0.01); the drug groups of the invention have significant reduction of TNF-alpha and IL-8 (P Less than or equal to 0.05 orP Less than or equal to 0.01); the IL-2 in the drug group of the invention is remarkably reduced (P Less than or equal to 0.05 orP Less than or equal to 0.01); the drug group of the present invention showed a significant increase in IL-12 (P Less than or equal to 0.05). On the next day after the last administration (D8), compared with normal control group, IL-6, TNF-alpha, IL-2, IL-8 and IL-12 in model control group were all increased significantly (P is less than or equal to 0.01). Compared with the model control group, the IL-6, TNF-alpha, IL-2 and IL-8 of the drug group are all obviously reduced (P Less than or equal to 0.05 orP Less than or equal to 0.01); the IL-12 in the drug group of the present invention showed a decrease but no statistical difference. The fact that the content of inflammatory factors and immune factors in the lung of the infected mouse can be adjusted by orally intragastrically administering the medicine disclosed by the invention is suggested that the infection of the mouse with coronavirus (HCoV-229E) can cause the content of the inflammatory factors and the immune factors in the lung to be increased and abnormal changes of the immune factors.
Influence on BNP, CK-MB and Tn-I in peripheral blood
As shown in Table 7, 48h administration showed that the levels of BNP, creatine phosphokinase-isozyme MB (CK-MB), and troponin (Tn-I) were significantly increased in the model control group compared with the normal control group: (BNP), creatine phosphokinase-isozyme MB (CK-MB), and troponin (Tn-I)P Less than or equal to 0.05 orP Less than or equal to 0.01). Compared with the model control group, the BNP and Tn-I of the drug group are both obviously reducedP Less than or equal to 0.05 orP Less than or equal to 0.01); the CK-MB of the medicine of the invention is obviously reducedP Less than or equal to 0.05 orP Less than or equal to 0.01). The day after the last administration (D8), BNP and CK-MB in the model control group were both significantly increased compared with those in the normal control group (P Less than or equal to 0.05 orP Less than or equal to 0.01), Tn-I shows a rising trend, but no statistical difference exists. Is paired with the modelCompared with the group, the BNP of the drug group of the invention is obviously reducedP Less than or equal to 0.05 orP Less than or equal to 0.01); the CK-MB of the inventive drug group is significantly reducedP Less than or equal to 0.05 orP Less than or equal to 0.01); the Tn-I group of the drug of the invention shows a decreasing trend, but has no statistical difference. The mouse is infected with coronavirus (HCoV-229E) to cause the increase of heart-related functional enzymes in peripheral blood, and the content of the heart-related functional enzymes in the peripheral blood can be obviously reduced by orally intragastrically administering the medicine.
Effects on IRF and TCITRG in peripheral blood
As shown in Table 8, 48h of the administration, the Interferon Regulatory Factor (IRF) and the cellular immune regulatory factor (TCITRG) in the model control group were significantly increased compared with the normal control group (P Less than or equal to 0.05 orP Less than or equal to 0.01). The TCITRG of the drug group of the invention is obviously reduced compared with the model control group (P Less than or equal to 0.01); the drug group of the invention obviously reduces IRF (P Less than or equal to 0.05). On the next day after the last administration (D8), Interferon Regulatory Factor (IRF) and cellular immune regulatory factor (TCITRG) were significantly increased in the model control group compared with the normal control group (D8) ((II))P Less than or equal to 0.05). Compared with the model control group, the IRF of the drug group of the invention is reduced, but has no statistical difference. The drug group of the present invention exhibited a decreasing trend in TCITRG compared to the model control group, but no statistical difference.
Has effects on Th0, Th1/Th2, and Treg/Th17 in peripheral blood
As shown in Table 9, the proportion of Th1/Th2 and Treg/Th17 in the model control group were significantly increased and decreased compared with the normal control group (P ≦ 0.05), Th0 decreased, but there was no statistical difference. Compared with the model control group, the drug group of the invention has obviously reduced Th1/Th2 ratio (P Less than or equal to 0.05) and obviously increased proportion of Treg/Th17 (P Less than or equal to 0.05); compared with the model control group, the drug group Th0 of the invention has no obvious difference.
4.7 Effect on Corona Virus HCoV-229E hemagglutination Titer in Lung
As shown in Table 10, the hemagglutination titers of the normal control groups were significantly increased 48 hours after the administration and the day after the last administration (P Less than or equal to 0.01). Compared with the model control group, the hemagglutination titer of the drug group is obviously reduced 48 hours after the drug is administered (P Less than or equal to 0.05 orP Less than or equal to 0.01); the blood coagulation potency of the medicine composition is obviously reduced (P is less than or equal to 0.01) the next day after the last administration. The medicine of the present invention can lower the blood coagulation titer of coronavirus HCoV-229E in mouse lung.
Influence on pulmonary index and Lung tissue pathology
As shown in Table 11, the lung index of the infected mice was significantly increased 48 hours after the administration of the model control group and the following day after the last administration, compared with that of the normal control group (P Less than or equal to 0.01). Compared with a model control group, the lung index of the drug group is obviously reduced 48 hours after the drug is administrated: (P Less than or equal to 0.05); the lung index of the drug group is obviously reduced the next day after the last administration (P ≤ 0.01)。
As shown in table 12, fig. 2 and 3, the results of HE staining and microscopic examination showed that 48h after administration, no significant abnormal change was observed in lung tissue of the normal control group, and pathological changes such as inflammatory, bloody exudation, alveolar epithelial destruction, lung scaffold collapse, alveolar epithelial hyperplasia, macrophage infiltration and chronic inflammatory cell infiltration around small blood vessels were observed in the model control group animals. Compared with a model control group, the medicine group has the advantages that the number of pathological change animals is reduced, and the pathological change degree is reduced. The following day after the last administration, the lungs of model control animals were seen to have inflammatory exudation, alveolar destruction, and chronic inflammatory cell infiltration around small blood vessels. Compared with a model control group, the number of the pathological change animals in the medicine group is obviously reduced, and the pathological change degree is obviously relieved.
5. Small knot
In the research, a BALB/c mouse model infected by coronavirus HCoV-229E is adopted, and the therapeutic action of the medicament is evaluated by observing the physiological state of the mouse, the inflammatory condition of lung tissues, the virus titer, the level of inflammatory factors, and the proportion of heart-related functional enzymes, immunoregulatory factors and peripheral immune cells in peripheral blood. The experimental result shows that compared with the normal control group, the body weight of the mouse of the model control group is obviously reduced after the mouse is infected with the virus, the lung index is obviously increased, the pathological change in the lung tissue is serious, and the inflammatory factors in the lung tissue are greatly increased, thereby prompting the success of model building. Compared with a model group, the weight average of the body weight of the infected mouse of the medicine (3.12 g crude drug/kg) group is reduced firstly, but the weight of the infected mouse is quickly increased, which indicates that the medicine can inhibit the weight reduction of the infected mouse; 48 hours after administration and the last day after administration, the lung index of mice infected by the medicament (3.12 g crude drug/kg) group is obviously reduced, lung tissue lesion is improved, and virus hemagglutination titer in lungs is obviously reduced, which indicates that the medicament has the effects of relieving lung inflammation injury of infected mice and inhibiting virus damage to lungs.
The proportion of peripheral blood lymphocyte subpopulations of mice in the research shows that compared with a normal control group, the proportion of Th1/Th2 cells in the model control group is obviously increased, and the proportion of Treg/Th17 cells is obviously reduced, which indicates that the proportion of T lymphocytes in the mice infected by coronavirus is unbalanced, and serious immune disorder occurs. Compared with a model control group, the medicine group has obviously reduced proportion of Th1/Th2 cells and obviously increased proportion of Treg/Th17 cells, and the medicine has the function of regulating immune T lymphocytes of mice.
After pathogenic microorganisms infect organisms, a phenomenon that a large amount of various cytokines (TNF-alpha, IL-1, IL-6, IL-12, IFN-alpha, IFN-beta, IFN-gamma, IL-8 and the like) are generated is known as cytokine storm, and can cause acute respiratory distress syndrome and multi-organ failure. The research result shows that after the coronavirus HCoV-229E is infected, the contents of lung tissue inflammatory factors IL-6, TNF-alpha, IL-2, IL-8 and IL-12 in a mouse of a model control group are obviously increased compared with those in a normal control group; compared with a model control group, the medicament can obviously reduce the generation of IL-6, TNF-alpha, IL-2, IL-8 and IL-12, and the result shows that the medicament can effectively relieve the cytokine storm, which is consistent with the pathological observation result of lung tissues.
In addition, compared with the normal control group, BNP, CK-MB and Tn-I in peripheral blood of the mice infected by the model control group are obviously increased, which indicates that the heart of the mice infected by the coronavirus HCoV-229E is also damaged. Compared with a model control group, the peripheral blood BNP, CK-MB and Tn-I contents of the mice in the drug group are in a descending trend, which shows that the drug has the effect of protecting the hearts of the mice infected by the coronavirus.
In conclusion, the medicine (3.12 g crude drug/kg) can obviously inhibit the increase of the lung index of a mouse infected with the coronavirus HCoV-229E, relieve the pathological change of lung tissues, inhibit the replication of the coronavirus HCoV-229E in the lung of the infected mouse, regulate the ratio of peripheral blood lymphocyte subsets of the infected mouse, improve the immune function and reduce the generation of inflammatory factors in the lung. Meanwhile, the protective agent has a certain protective effect on the heart of a mouse infected by the coronavirus HCoV-229E.
Claims (17)
1. The application of a traditional Chinese medicine composition in preparing a medicine for preventing or treating coronavirus is characterized in that the coronavirus is wild type new coronavirus and/or S protein mutant type new coronavirus, and the traditional Chinese medicine composition is prepared from the following raw material medicines in parts by weight:
30-55 parts of forsythia fruit 150-
Patchouli 50-90 rhizoma dryopteris crassirhizomae 150-260 rhodiola rosea 50-90 menthol 5-8
50-90 fried Chinese ephedra, 50-90 fried bitter apricot seed, 50-90 cordate houttuynia, 150-
Licorice root 50-90 gypsum 150-260.
2. The application of the traditional Chinese medicine composition according to claim 1 is characterized by being prepared from the following raw material medicines in parts by weight:
forsythia fruit 150 honeysuckle 260 isatis root 150 rhubarb 55 patchouli 50
Rhizoma dryopteris crassirhizomae 260 rhodiola rosea 50 menthol crystal and ephedra herb 50 roasted with 8
Parched semen Armeniacae amarum 90, herba Houttuyniae 150, Glycyrrhrizae radix 90 and Gypsum Fibrosum 150.
3. The application of the traditional Chinese medicine composition according to claim 1 is characterized by being prepared from the following raw material medicines in parts by weight:
forsythia fruit 260 honeysuckle 150 isatis root 260 rhubarb 30 patchouli 90
Rhizoma Dryopteris Crassirhizomatis 150 radix Rhodiolae 90 Mentholum 5 processed herba Ephedrae 90
Parched semen Armeniacae amarum 50 herba Houttuyniae 260 Glycyrrhrizae radix 50 Gypsum Fibrosum 260.
4. The application of the traditional Chinese medicine composition according to claim 1 is characterized by being prepared from the following raw material medicines in parts by weight:
forsythia fruit 170 honeysuckle 170 isatis root 170 rhubarb 34 patchouli 57
Rhizoma dryopteris crassirhizomae 170 rhodiola rosea 57 menthol crystal 5 fried ephedra 57
Parched semen Armeniacae amarum 57, herba Houttuyniae 170, Glycyrrhrizae radix 57, and Gypsum Fibrosum 170.
5. The application of the traditional Chinese medicine composition according to claim 1 is characterized by being prepared from the following raw material medicines in parts by weight:
255 portions of forsythia, 255 portions of honeysuckle, 255 portions of isatis root, 255 portions of rhubarb, 51 portions of patchouli, 85
Rhizoma dryopteris crassirhizomae 255 rhodiola rosea 85 menthol crystal 7.5 mix-fried ephedra 85
Parched semen Armeniacae amarum 85 herba Houttuyniae 255 Glycyrrhrizae radix 85 Gypsum Fibrosum 255.
6. The use according to any one of claims 1 to 5, characterized in that the active ingredients of the Chinese medicinal composition are prepared by the following steps:
(1) weighing the traditional Chinese medicinal materials according to the weight proportion of the raw materials, and cleaning;
(2) crushing herba Agastaches, extracting volatile oil with 5-8 times of water for 4 hr, and collecting volatile oil; filtering the extractive solution, discarding residue, and collecting filtrate;
(3) extracting fructus forsythiae, herba Ephedrae preparata, herba Houttuyniae, and radix et rhizoma Rhei with 6-10 times of 50-90% ethanol for 2 times, each for 1-3 hr, mixing extractive solutions, filtering, and recovering ethanol to obtain ethanol extractive solution;
(4) adding 7-11 times of water into honeysuckle, gypsum, isatis root, male fern rhizome, liquorice and rhodiola rosea, decocting until boiling, adding fried bitter apricot seed, decocting for 2 times, 0.5-2.5 hours each time, combining the extracting solutions, filtering, combining the obtained filtrate with the filtrate obtained after the oil extraction of the pogostemon cablin in the step (2), concentrating into clear paste with the relative density of 1.10-1.15 measured at the temperature of 60 ℃, adding ethanol, adjusting the alcohol concentration to 70%, refrigerating, standing, filtering, and recovering the ethanol until no alcohol smell exists, thus obtaining the clear paste for later use;
(5) mixing the fluid extract obtained in step (4) and the ethanol extract obtained in step (3), concentrating to obtain fluid extract with relative density of 1.15-1.20 at 60 deg.C, and drying to obtain dry extract powder;
the dry paste powder obtained in the step (5), the volatile oil obtained in the step (2) and the menthol jointly form the active ingredients of the traditional Chinese medicine composition.
7. Use according to any one of claims 1 to 5, characterized in that the pharmaceutical dosage form is a capsule, tablet, powder, granule, oral liquid, pill, tincture, syrup, suppository, gel, spray or injection.
8. Use according to claim 7, characterized in that the capsules are prepared by the following steps:
(1) weighing the traditional Chinese medicinal materials according to the weight proportion of the raw materials, and cleaning;
(2) crushing herba Agastaches, extracting volatile oil with 5-8 times of water for 4 hr, and collecting volatile oil; filtering the extractive solution, discarding residue, and collecting filtrate;
(3) extracting fructus forsythiae, herba Ephedrae preparata, herba Houttuyniae, and radix et rhizoma Rhei with 6-10 times of 50-90% ethanol for 2 times, each for 1-3 hr, mixing extractive solutions, filtering, and recovering ethanol to obtain filtrate;
(4) adding 7-11 times of water into honeysuckle, gypsum, isatis root, male fern rhizome, liquorice and rhodiola rosea, decocting until boiling, adding fried bitter apricot seed, decocting for 2 times, 0.5-2.5 hours each time, combining the extracting solutions, filtering, combining the obtained filtrate with the filtrate obtained after the oil extraction of the pogostemon cablin in the step (2), concentrating into clear paste with the relative density of 1.10-1.15 measured at the temperature of 60 ℃, adding ethanol, adjusting the alcohol concentration to 70%, refrigerating, standing, filtering, and recovering the ethanol until no alcohol smell exists, thus obtaining the clear paste for later use;
(5) mixing the fluid extract obtained in step (4) and the ethanol extract obtained in step (3), concentrating to obtain fluid extract with relative density of 1.15-1.20 at 60 deg.C, and drying to obtain dry extract powder;
(6) adding a proper amount of pharmaceutically acceptable auxiliary materials into the dry paste powder obtained in the step (5) for granulation;
(7) and (3) dissolving the menthol and the volatile oil obtained in the step (2) in ethanol, spraying the particles obtained in the step (6), sealing, uniformly mixing, and encapsulating to obtain the capsule.
9. Use according to claim 7, characterized in that the granules are made by the following steps:
(1) weighing the traditional Chinese medicinal materials according to the weight proportion of the raw materials, cleaning, and cutting according to the condition;
(2) crushing herba Agastaches, extracting volatile oil with 5-8 times of water for 4 hr, and collecting volatile oil; filtering the extractive solution, discarding residue, and collecting filtrate;
(3) extracting fructus forsythiae, herba Ephedrae preparata, herba Houttuyniae, and radix et rhizoma Rhei with 6-10 times of 50-90% ethanol for 2 times, each for 1-3 hr, mixing extractive solutions, filtering, and recovering ethanol to obtain filtrate;
(4) adding 7-11 times of water into honeysuckle, gypsum, isatis root, male fern rhizome, liquorice and rhodiola rosea, decocting until boiling, adding fried bitter apricot kernel, decocting for 2 times, 0.5-2.5 hours each time, combining the extracting solutions, filtering, combining the obtained filtrate with the filtrate obtained after oil extraction of the pogostemon cablin in the step (2), concentrating into clear paste with the relative density of 1.10-1.15 measured at the temperature of 60 ℃, adding ethanol, adjusting the alcohol concentration to be 70%, refrigerating, standing, filtering, and recovering the ethanol until no alcohol smell exists, thus obtaining the clear paste for later use;
(5) mixing the fluid extract obtained in step (4) with the ethanol extract obtained in step (3), concentrating to obtain fluid extract with relative density of 1.15-1.20 at 60 deg.C, and drying to obtain dry extract powder;
(6) adding a proper amount of pharmaceutically acceptable auxiliary materials into the dry paste powder obtained in the step (5) for granulation;
(7) and (3) dissolving the menthol and the volatile oil obtained in the step (2) in ethanol, spraying the granules obtained in the step (6), sealing, uniformly mixing and bagging to obtain the menthol-containing capsule.
10. The use according to claim 9, wherein the granules are prepared by a process comprising the steps of:
(1) weighing the traditional Chinese medicinal materials according to the weight proportion of the raw materials, cleaning, and cutting off the traditional Chinese medicinal materials as appropriate;
(2) crushing herba Agastaches, extracting volatile oil with 6 times of water for 4 hr, and collecting volatile oil with oil yield of 0.33 + -0.05%; filtering the extractive solution, discarding residue, and collecting water extractive solution;
(3) extracting fructus forsythiae, herba Ephedrae preparata, herba Houttuyniae, and radix et rhizoma Rhei with 8 times of 70% ethanol for 2 times, 2 hr for the first time, and 1.5 hr for the second time, mixing extractive solutions, filtering, and recovering ethanol to obtain filtrate;
(4) adding 9 times of water into honeysuckle, gypsum, isatis root, male fern rhizome, liquorice and rhodiola rosea, decocting until boiling, adding fried bitter apricot seed, decocting for 2 times, wherein the first time is 1.5 hours, and the second time is 1 hour, combining the extracting solutions, filtering, combining the obtained filtrate with the water extract obtained after the oil extraction of the pogostemon cablin in the step (2), concentrating into clear paste with the relative density of 1.10-1.15 measured at the temperature of 60 ℃, adding 95% ethanol, adjusting the alcohol concentration to 70%, refrigerating, standing, filtering, and recovering the ethanol until no alcohol smell exists, thus obtaining the clear paste;
(5) mixing the fluid extract obtained in step (4) and the ethanol extract obtained in step (3), and concentrating to obtain soft extract with relative density of 1.25-1.35 at 60 deg.C;
(6) adding a proper amount of pharmaceutically acceptable auxiliary materials into the thick paste obtained in the step (5), granulating, and finishing granules for later use;
(7) and (3) screening out fine powder from the granules obtained in the step (6), adding ethanol into the menthol and the volatile oil obtained in the step (2) for dissolving, spraying the fine powder, uniformly mixing with the granules obtained in the step (6), sealing for half an hour, and bagging to obtain the menthol crystal.
11. The use of any one of claims 1-5, wherein the use of the composition is for the preparation of a medicament for the prevention or treatment of a respiratory disorder.
12. Use according to claim 11, wherein the respiratory diseases are pneumonia, bronchitis, fever, cough, cold.
13. The use of the Chinese medicinal composition according to any one of claims 1 to 5 in the preparation of a medicament for protecting heart from injury.
14. The use according to claim 11, wherein the cardiac injury is viral-induced cardiac injury.
15. The use of the Chinese medicinal composition according to any one of claims 1 to 5 in the preparation of a medicament for protecting lung injury.
16. The use according to claim 13, wherein the lung injury is viral-induced lung injury.
17. The use of the Chinese medicinal composition according to any one of claims 1 to 5 in the preparation of a medicament for enhancing immunity in humans.
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