Application of Jingfang preparation in the preparation of drugs for treating sequelae of COVID-19 and its preparation method

Abstract

The present invention discloses the application of a Jingfang preparation in the preparation of a drug for treating the sequelae of the new crown and its preparation method, and belongs to the field of medicine. The Jingfang preparation is made of eleven raw medicinal materials such as Schizonepeta tenuifolia, Saposhnikovia divaricata, Notopterygium wilfordii, Angelica dahurica, Bupleurum chinense, Peucedanum chinense, Chuanxiong, Fructus Aurantii Immaturus, Poria cocos, Platycodon grandiflorum, and Licorice, and has the effects of diaphoresis, dispelling wind and removing dampness. The Jingfang preparation of the present invention is an effective prescription for treating the sequelae of the new crown, which can effectively treat viral myocarditis in the recovery period of new crown patients, reduce the serum concentrations of liver function markers ALT and AST and kidney function markers Cre and BUN, thereby effectively protecting liver and kidney function, effectively inhibiting the inflammatory response of acute respiratory distress syndrome, and effectively treating diarrhea at the same time, treating both the symptoms and the root cause, and having a definite therapeutic effect on the sequelae of the new crown.

Description

Technical Field

[0001] The present invention relates to the application of a Jingfang preparation and a preparation method thereof, and specifically to the application of a Jingfang preparation in the preparation of drugs for treating sequelae of COVID-19 and a preparation method thereof, belonging to the field of medicine. Background Art

[0002] Novel coronavirus pneumonia (COVID-19) refers to acute infectious pneumonia caused by the 2019 novel coronavirus. The most common clinical symptoms in infected patients are fever, fatigue, and dry cough, with a small number of patients experiencing upper respiratory and gastrointestinal symptoms such as nasal congestion, runny nose, and diarrhea. Severe cases often develop dyspnea after one week, and severe cases may further develop acute respiratory distress syndrome, septic shock, difficult-to-correct metabolic acidosis, and coagulation disorders. COVID-19 is a multisystem disease that affects more than just the lungs, causing varying degrees of damage to the kidneys, liver, heart, brain, and nervous system. It is reported that the majority of critically ill patients suffer from organ dysfunction, most commonly heart damage, acute kidney injury, liver dysfunction, and pneumothorax. To date, there are no effective targeted medications for COVID-19, and isolation and symptomatic supportive care are the mainstays of treatment.

[0003] With the intensification of epidemic prevention and control efforts, a large number of patients have recovered and been discharged from hospitals. However, some discharged patients, despite testing negative for nucleic acid, experiencing reduced or significantly resolved pneumonia, and maintaining a normal body temperature, may still experience symptoms such as fatigue, shortness of breath, decreased appetite, diarrhea, and anxiety. Some patients may also develop pulmonary fibrosis due to poor absorption of lung inflammation, which can affect their quality of life. The prognosis is particularly poor for the elderly and those with chronic health conditions. Furthermore, recovered patients may suffer from various organ damage sequelae caused by COVID-19, including heart damage, acute kidney injury, liver dysfunction, and damage to the nervous system and digestive system. A recent study released by the University Hospital of Frankfurt shows that the majority of people who recover from COVID-19 experience heart damage. Even those who tested negative for COVID-19 still experienced heart problems in 78% of participants, with myocarditis being the most common cause of long-term damage. Therefore, the treatment of these post-COVID-19 sequelae warrants greater attention and priority.

[0004] Traditional Chinese Medicine (TCM) has played a significant role in the diagnosis and treatment of this epidemic. Among them, the Chinese medicine preparation Jingfang Granule has been recommended in many provinces' COVID-19 prevention plans for the treatment of COVID-19 with cold-dampness stagnation in the lungs. The Jingfang preparation, derived from the ancient formula Jingfang Baidu San, is made from eleven raw medicinal materials: Schizonepeta tenuifolia, Saposhnikovia divaricata, Notopterygium wilfordii, Angelica dahurica, Bupleurum chinense, Peucedanum chinense, Chuanxiong rhizome, Citrus aurantium, Poria cocos, Platycodon grandiflorum, and Licorice root. It has the effects of inducing sweating, dispelling wind and dampness, and is clinically used to treat symptoms such as colds, headaches and body aches, aversion to cold and no sweating, nasal congestion and runny nose, and cough with white sputum. The main herbs in the formula, Schizonepeta tenuifolia and Saposhnikovia divaricata, are pungent, warm, and dispersing, inducing sweating, dispelling wind pathogens, and eliminating the root of all diseases. The auxiliary herbs, Notopterygium wilfordii and Angelica dahurica, are pungent, warm, and dispersing, treating wind, cold, and dampness throughout the body. Chuanxiong promotes blood circulation and dispels wind, while Bupleurum chinense disperses muscles and assists Notopterygium wilfordii, while Angelica dahurica dispels external pathogens and relieves pain. Citrus aurantium (Fructus Aurantii) lowers qi, Platycodon grandiflorum (Pueraria lobata) invigorates the lungs, Peucedanum chinense (Phellodendron chinense) dispels phlegm, and Poria cocos (Poria cocos) dissipates dampness and serves as an adjuvant. Licorice root (Glycyrrhiza uralensis) harmonizes the herbs and serves as a guiding agent. Combined use of these herbs induces sweating, reduces fever, circulates blood, alleviates wind and relieves pain, promotes lung qi, eliminates phlegm and dampness, and relieves coughs, eliminating cold symptoms and leading to recovery. In recent years, with the in-depth development of research into traditional Chinese medicine preparations, more and more benefits of Jingfang preparations have been discovered.

[0005] During the process of upgrading the process of Jingfang preparation, the inventors discovered that Jingfang preparation has a significant effect on the treatment of COVID-19 sequelae. Pharmacodynamic tests have shown that Jingfang preparation is an effective formula for treating COVID-19 sequelae: it can effectively treat viral myocarditis, reduce serum concentrations of liver function markers ALT and AST, and renal function markers Cre and BUN, thereby effectively protecting liver and kidney function, effectively inhibit the inflammatory response of acute respiratory distress syndrome, and effectively treat diarrhea, treating both the symptoms and the root cause, and has a definite and significant therapeutic effect on COVID-19 sequelae. Summary of the Invention

[0006] The purpose of the present invention is to provide a Jingfang preparation for the preparation of a drug for treating COVID-19 sequelae. The Jingfang preparation of the present invention is derived from the ancient prescription Jingfang Baidu San, and relies on existing technology to prepare a series of Jingfang preparations such as Jingfang granules and Jingfang tablets. The use described in the present invention was discovered during the clinical application of the company's drugs and was subsequently verified by relevant pharmacodynamic tests to have great commercial value.

[0007] The use of a Jingfang preparation in the preparation of a drug for treating sequelae of COVID-19, wherein the Jingfang preparation is made from the following traditional Chinese medicine components:

[0008]

[0009] Preferably:

[0010]

[0011] The experimental results show that Jingfang preparations can effectively treat viral myocarditis, reduce the serum concentrations of liver function markers ALT and AST and renal function markers Cre and BUN, thereby effectively protecting liver and kidney function, effectively inhibiting the inflammatory response of acute respiratory distress syndrome, and at the same time effectively treating diarrhea, treating both the symptoms and the root cause, and have a definite and significant therapeutic effect on the sequelae of COVID-19.

[0012] Another object of the present invention is to provide a Chinese medicine oral preparation containing the above-mentioned Chinese medicine composition and a preparation method thereof, wherein the Chinese medicine oral preparation is one of granules, tablets, capsules and microcapsules.

[0013] The preparation method of the oral Chinese medicine preparation comprises the following steps:

[0014] A. Extract volatile oils from seven medicinal herbs: Schizonepeta tenuifolia, Saposhnikovia divaricata, Notopterygium wilfordii, Angelica dahurica, Peucedanum chinense, Chuanxiong rhizome, and Fructus Aurantii Immaturus. The volatile oils from these seven herbs are then distilled, followed by the distilled residues and the aqueous solutions of Chuanxiong rhizome and Fructus Aurantii Immaturus for later use.

[0015] B. Take the volatile oil obtained in step A and add β-cyclodextrin to prepare inclusion complexes;

[0016] C. The distilled aqueous solution of Chuanxiong and Fructus Aurantii obtained in step A is prepared into a 20-30% ethanol solution as a solvent, and the residue of Chuanxiong and Fructus Aurantii obtained in step A and Poria cocos are percolated to obtain a percolate for later use;

[0017] D. decoct the residues of Schizonepeta tenuifolia, Saposhnikovia divaricata, Notopterygium incisum, Angelica pubescens, and Peucedanum chinense obtained in step A with the remaining three herbs: Bupleurum chinense, Platycodon grandiflorum, and Licorice root 2-3 times for 1.5-2.5 hours each time, combine the decoctions, filter, and concentrate the filtrate to an extract having a relative density of 1.18-1.25 at 60-70°C;

[0018] E. Combine the filtrate obtained in step C and the extract obtained in step D, mix well, let stand, filter, and concentrate the filtrate to an extract with a relative density of 1.22-1.28 at 50-60°C;

[0019] F. The extract obtained in step E and the β-cyclodextrin inclusion compound obtained in step B are prepared into oral pharmaceutical preparations directly or by adding pharmaceutically acceptable excipients through conventional procedures.

[0020] The preferred dosage form of the present invention is a granule, and the preparation method of the granule comprises the following steps:

[0021] A. Extract volatile oils from seven medicinal herbs: Schizonepeta tenuifolia, Saposhnikovia divaricata, Notopterygium wilfordii, Angelica dahurica, Peucedanum chinense, Chuanxiong rhizome, and Fructus Aurantii Immaturus. The volatile oils from these seven herbs are then distilled, followed by the distilled residues and the aqueous solutions of Chuanxiong rhizome and Fructus Aurantii Immaturus for later use.

[0022] B. Take the volatile oil obtained in step A and add β-cyclodextrin to prepare inclusion complexes;

[0023] C. The distilled aqueous solution of Chuanxiong and Fructus Aurantii obtained in step A is prepared into a 25% ethanol solution as a solvent, and the residue of Chuanxiong and Fructus Aurantii obtained in step A and Poria cocos are percolated to obtain a percolate for later use;

[0024] D. decoct the residues of Schizonepeta tenuifolia, Saposhnikovia divaricata, Notopterygium incisum, Angelica pubescens, and Peucedanum chinense obtained in step A with the remaining three herbs: Bupleurum chinense, Platycodon grandiflorum, and Licorice root in water three times for 2 hours each time. Combine the decoctions, filter, and concentrate the filtrate to an extract having a relative density of 1.23 at 60-70°C.

[0025] E. Combine the filtrate obtained in step C and the extract obtained in step D, mix well, let stand, filter, and concentrate the filtrate to an extract with a relative density of 1.26 at 50-60°C;

[0026] F. Take the extract obtained in step E, dry it in a belt vacuum dryer under vacuum conditions of -0.08MPa--0.10MPa and a drying temperature of 63°C, grind it into fine powder, sieve it, add the β-cyclodextrin inclusion compound obtained in step B, mix well to obtain fine powder of the schisandra chinensis extract, add excipients in a weight ratio of sucrose powder: hydroxypropyl starch: mannitol = 3:2:0.5, mix well, make granules, dry, and granulate to obtain the product.

[0027] Another preferred dosage form of the present invention is a micropellet preparation, and the preparation method of the microcapsule preparation comprises the following steps:

[0028] A. Extract volatile oils from seven medicinal herbs: Schizonepeta tenuifolia, Saposhnikovia divaricata, Notopterygium wilfordii, Angelica dahurica, Peucedanum chinense, Chuanxiong rhizome, and Fructus Aurantii Immaturus. The volatile oils from these seven herbs are then distilled, followed by the distilled residues and the aqueous solutions of Chuanxiong rhizome and Fructus Aurantii Immaturus for later use.

[0029] B. Take the volatile oil obtained in step A and add β-cyclodextrin to prepare inclusion complexes;

[0030] C. The distilled aqueous solution of Chuanxiong and Fructus Aurantii obtained in step A is prepared into a 28% ethanol solution as a solvent, and the residue of Chuanxiong and Fructus Aurantii obtained in step A and Poria cocos are percolated to obtain a percolate for later use;

[0031] D. decoct the residues of Schizonepeta tenuifolia, Saposhnikovia divaricata, Notopterygium wilfordii, Angelica pubescens, and Peucedanum chinense obtained in step A with the remaining three herbs, namely, Bupleurum chinense, Platycodon grandiflorum, and Licorice root, twice in water for 2.5 hours each time. Combine the decoctions, filter, and concentrate the filtrate to an extract having a relative density of 1.22 at 60-70°C.

[0032] E. Combine the filtrate obtained in step C and the extract obtained in step D, mix well, let stand, filter, and concentrate the filtrate to an extract with a relative density of 1.25 at 50-60°C;

[0033] F. Take the extract obtained in step E, add the cyclodextrin inclusion compound obtained in step B, mix well, make granules, belt vacuum dry, and grind to obtain a fine powder of the Jingfang extract for later use;

[0034] G. Weigh the fine powder of the schisandra extract from step F, the capsule material, the anti-adherent agent, and the plasticizer according to the formula, add the capsule material, anti-adherent agent, and plasticizer to purified water, heat and stir at 54°C to dissolve, and prepare a 33% by mass capsule material solution. Cool to room temperature, add the fine powder of the schisandra extract and the emulsifier while stirring, homogenize and emulsify to obtain an emulsion, and set aside;

[0035] H. The emulsion in step G is spray-dried under the conditions of an inlet air temperature of 165° C., a spray pressure of 0.40 MPa, and a feed rate of 21.5 ml / min, and the microcapsules are collected and cooled to obtain the microcapsules.

[0036] Preferably, the belt vacuum drying conditions in step F are a vacuum degree of -0.08 MPa to 0.10 MPa and a drying temperature of 56°C.

[0037] Preferably, the capsule material in step G is sodium chorate: maltodextrin = 3:2, the anti-adhesive agent is octadecyl alcohol: titanium dioxide = 3:1, and the plasticizer is polyethylene glycol: citric acid = 3:1.

[0038] Preferably, the emulsifier in step C is a composite emulsifier of sucrose fatty acid ester: soybean lecithin = 8:5 by weight, and the amount used is 1.18% by mass of the total formulation.

[0039] To verify the efficacy of the Jingfang preparation of the present invention in treating sequelae of COVID-19, the inventors conducted corresponding animal experiments. It should be noted that the animal experiments were conducted on samples obtained from representative formulations and preparation methods of the present invention. Due to space limitations, the experiments and results of other formulations and preparation methods included in the present invention are not exhaustively listed here.

[0040] Experimental Example 1 Effect of Jingfang Preparation on Myocarditis in Mice

[0041] 1. Materials

[0042] 1.1 Experimental Animals and Diet: Sixty SPF-grade Balb / c male mice, 6-8 weeks old, weighing 16-18 g, were provided by Lunan Pharmaceutical Group Co., Ltd., Laboratory Animal License No. SYXK(Lu)2018-0008. Mice were acclimatized for one week in a clean animal laboratory, separated by sex, at room temperature of 20-25°C, relative humidity of 40%-60%, under natural light, and with free access to food and water.

[0043] 1.2 Instruments, reagents and drugs AG285 electronic analytical balance (Mettler-Toledo, Switzerland), SE-LECTRA-E fully automatic biochemical analyzer (Rittal Scientific, The Netherlands), Thermo Scientific Medifuge small desktop centrifuge (Thermo Fisher Scientific, USA); Eagle culture medium (Vicente Biotechnology Co., Ltd.), mouse TNF-α and cTnI enzyme-linked immunosorbent assay kit (Nanjing Jiancheng Biological Research Institute); the test drug was Jingfang Granules in Example 5 (produced by Lunan Houpu Pharmaceutical Co., Ltd.), and the positive control drug was ribavirin granules (batch number 20190701, Chenxin Pharmaceutical Co., Ltd.).

[0044] 2 Methods

[0045] 2.1 Grouping and Modeling Sixty healthy Balb / c male mice were randomly divided into six groups, with 10 mice in each group, namely the normal control group, the model control group, the ribavirin positive control group (referred to as the "positive control group"), the Jingfang granule high-dose group (referred to as the "experimental high-dose group"), the Jingfang granule medium-dose group (referred to as the "experimental medium-dose group"), and the Jingfang granule low-dose group (referred to as the "experimental low-dose group"). CVB3 virus was cultured in Eagle's culture medium. Except for the normal control group, mice in the other groups were intraperitoneally injected with 1×10 4 The mice were injected with 0.2 ml of CVB3 diluent / ml, and the normal control group was injected intraperitoneally with 0.2 ml of Eagle culture medium.

[0046] 2.2 Administration Two hours after virus inoculation, each group was gavaged and the dose was converted according to the dose conversion coefficients for different animals in the appendix of the "Guidelines for Clinical Research of New Chinese Medicines". The positive control group was gavaged with ribavirin 0.10 g / kg, the high-dose group, the medium-dose group and the low-dose group were gavaged with Jingfang Granules 9 g / kg, 4.5 g / kg and 2.25 g / kg, respectively, which were equivalent to 2 times, 1 times and 0.5 times the human equivalent dose, with a dosing volume of 10 ml / kg. The normal control group and the model control group were given an equal volume of normal saline orally, once a day, for 7 consecutive days.

[0047] 2.3 Detection indicators and methods After 7 days of administration, the eyeballs of the mice were removed and blood was collected. The blood was centrifuged at 4000 r / min for 10 min, and the serum was separated. The levels of cTnI (cardiac troponin I) and TNF-α (tumor necrosis factor α) in the serum were determined using ELISA kits.

[0048] 2.4 Statistical analysis SPSS 19.0 statistical software was used for analysis, and the experimental data were expressed as “mean ± standard deviation”. ". One-way analysis of variance was used to compare multiple groups, and P < 0.05 indicated statistically significant differences.

[0049] 3 Results

[0050] Compared with the normal control group, the serum levels of cTnI and TNF-α in the model control group were significantly elevated, with statistically significant differences (P < 0.05), indicating that the model was successfully established. Compared with the model control group, the serum levels of cTnI and TNF-α in the positive control group and the high-, medium-, and low-dose experimental groups were significantly decreased, with statistically significant differences (P < 0.05). These results suggest that Jingfang Granule is effective in treating viral myocarditis. The results are shown in Table 1.

[0051] Table 1 Effects of Jingfang Granules on Viral Myocarditis in Mice ( n=10)

[0052]

[0053] Note: Compared with the normal control group, if P<0.05, “ Δ " " indicates; compared with the model control group: P < 0.05 is indicated by "*".

[0054] Experimental Example 2 Effects of Jingfang Preparation on Acute Liver Injury in Mice

[0055] 1. Materials

[0056] 1.1 Experimental Animals and Diet: 60 healthy KM mice, half male and half female, weighing (20 ± 2) g, were provided by Lunan Pharmaceutical Group Co., Ltd., Laboratory Animal License No.: SYXK(Lu)2018-0008. Before the experiment, the mice were acclimatized for 1 week in a clean animal laboratory, separated by sex, at room temperature of 20–25°C, relative humidity of 40%–60%, under natural light, and with free access to food and water.

[0057] 1.2 Instruments, reagents, and drugs Thermo Scientific Medifuge small desktop centrifuge (Thermo Fisher Scientific, USA), AG285 electronic analytical balance (Mettler-Toledo, Switzerland); mouse ALT, AST enzyme-linked immunosorbent assay kit (Sigma, USA), carbon tetrachloride (Shanghai Aladdin Biochemical Technology Co., Ltd.); the test drug was Jingfang Granules in Example 5 (produced by Lunan Houpu Pharmaceutical Co., Ltd.), and the positive control drug was bifendate (batch number: 19058003, Shandong Health Pharmaceutical Co., Ltd.).

[0058] 2 Methods

[0059] 2.1 Grouping and Modeling 60 healthy KM mice were randomly divided into 6 groups, namely normal control group, model control group, bifendate positive control group (referred to as "positive control group"), Jingfang granule high-dose group (referred to as "experimental high-dose group"), Jingfang granule medium-dose group (referred to as "experimental medium-dose group") and Jingfang granule low-dose group (referred to as "experimental low-dose group"), with 10 mice in each group, half male and half female. Except for the normal control group, the mice in the other groups were intraperitoneally injected with 0.2% carbon tetrachloride at 0.1ml / 10g. After 24 hours, an acute liver injury model was formed. The normal control group was given an equal dose of peanut oil for intraperitoneal injection. 0.5mL of blood samples were collected (5 mice were randomly selected from each group and blood was collected from the eye sockets). ALT (alanine aminotransferase) and AST (aspartate aminotransferase) in the serum were measured. The levels of each modeling group were significantly higher than those in the normal control group, indicating that the modeling was successful.

[0060] 2.2 On the third day after successful modeling, all groups were gavaged with the drug. The dose conversion was performed according to the dose conversion coefficients for different animals in the appendix of the "Guidelines for Clinical Research of New Chinese Medicines". The positive control group was gavaged with 0.15g / kg of bifendate, and the high-dose group, medium-dose group and low-dose group were gavaged with 9g / kg, 4.5g / kg and 2.25g / kg of Jingfang Granules, respectively, which were equivalent to 2 times, 1 times and 0.5 times the human equivalent dose. The administration volume was 10ml / kg. The model control group was given an equal volume of normal saline orally, once a day, for 8 consecutive days.

[0061] 2.3 Detection Indicators and Methods: One hour after dosing on day 8, blood was collected from the mice via the eye socket. 1.5 mL of blood was collected in a centrifuge tube. The tube was allowed to stand for 30 minutes and then centrifuged at 10,000 rpm for 20 minutes to separate the serum. ALT and AST levels were measured according to the ELISA kit instructions.

[0062] 2.4 Statistical analysis SPSS 19.0 statistical software was used for analysis, and the experimental data were expressed as “mean ± standard deviation”. ". One-way analysis of variance was used to compare multiple groups, and P < 0.05 indicated statistically significant differences.

[0063] 3 Results

[0064] Compared with the normal control group, the serum ALT and AST levels of mice in the model control group were significantly elevated, with the differences being statistically significant (P < 0.05), indicating that the model was successfully established. Compared with the model control group, the serum ALT and AST levels of mice in the positive control group and the high-, medium-, and low-dose experimental groups were significantly decreased, with the differences being statistically significant (P < 0.05). These results suggest that Jingfang Granule has a protective effect against CCl4-induced liver injury. The results are shown in Table 2.

[0065] Table 2 Effects of Jingfang Granules on Liver Injury in Mice ( n=10)

[0066]

[0067] Note: Compared with the normal control group, if P<0.05, “ Δ " " indicates; compared with the model control group: P < 0.05 is indicated by "*".

[0068] Experimental Example 3 Effects of Drugs on Acute Kidney Injury in Mice

[0069] 1. Materials

[0070] 1.1 Experimental Animals and Diet: 60 healthy KM mice, half male and half female, weighing (20 ± 2) g, were provided by Lunan Pharmaceutical Group Co., Ltd., Laboratory Animal License No.: SYXK(Lu)2018-0008. Before the experiment, the mice were acclimatized for 1 week in a clean animal laboratory, separated by sex, at room temperature of 20–25°C, relative humidity of 40%–60%, under natural light, and with free access to food and water.

[0071] 1.2 Instruments, reagents and drugs AG285 electronic analytical balance (Mettler-Toledo, Switzerland), SE-LECTRA-E fully automatic biochemical analyzer (Rittal Scientific, The Netherlands), Thermo Scientific Medifuge small desktop centrifuge (Thermo Fisher Scientific, USA); cisplatin (Sigma, USA), sodium pentobarbital (Jinan Hongbo Chemical Co., Ltd.), creatinine determination kit (Sigma, USA), urinary nitrogen kit (Quanzhou Ruixin Biotechnology Co., Ltd.); the test drug was Jingfang Granules in Example 5 (produced by Lunan Houpu Pharmaceutical Co., Ltd.), and the positive control drug was resveratrol (batch number: 19067002, Guangdong Bide Biotechnology Co., Ltd.).

[0072] 2 Methods

[0073] 2.1 Grouping and Modeling Sixty healthy KM mice were randomly divided into 6 groups, namely normal control group, model control group, resveratrol positive control group (referred to as "positive control group"), Jingfang granule high-dose group (referred to as "experimental high-dose group"), Jingfang granule medium-dose group (referred to as "experimental medium-dose group") and Jingfang granule low-dose group (referred to as "experimental low-dose group"), with 10 mice in each group, half male and half female. Except for the normal control group, mice in the other groups were intraperitoneally injected with 20 mg / kg cisplatin on the first day of the experiment to create an acute kidney injury model in mice. The normal control group was intraperitoneally injected with an equal amount of normal saline. 0.5 mL of blood samples were collected (5 mice were randomly selected from each group and blood was collected from the eye sockets) to measure Cre (creatinine) and BUN (urea nitrogen) in the serum. The levels of Cre (creatinine) and BUN (urea nitrogen) in the modeling groups were significantly higher than those in the normal control group, indicating that the modeling was successful.

[0074] 2.2 On the second day after successful modeling, all groups were gavaged with the drug. The dose conversion was performed according to the dose conversion coefficients for different animals in the appendix of the "Guidelines for Clinical Research of New Chinese Medicines". The positive control group was gavaged with 0.20g / kg of resveratrol, and the high-dose group, medium-dose group and low-dose group were gavaged with 9g / kg, 4.5g / kg and 2.25g / kg of Jingfang Granules, respectively, which were equivalent to 2 times, 1 times and 0.5 times the human equivalent dose. The administration volume was 10ml / kg. The model control group was given an equal volume of normal saline orally, once a day, for 7 consecutive days.

[0075] 2.3 Detection indicators and methods The mice in each group were fasted for 12 hours before the last oral administration. One hour after the last oral administration, the mice were anesthetized by intraperitoneal injection of sodium pentobarbital (60 mg / kg). The eyeballs were removed to collect blood, and the blood was centrifuged at 3000 r / min for 10 min to separate the serum. The serum creatinine (Cre) and urea nitrogen (BUN) levels were determined by an automatic biochemical analyzer.

[0076] 2.4 Statistical analysis SPSS 19.0 statistical software was used for analysis, and the experimental data were expressed as “mean ± standard deviation”. ". One-way analysis of variance was used to compare multiple groups, and P < 0.05 indicated statistically significant differences.

[0077] 3 Results

[0078] Compared with the normal control group, the serum levels of Cre and BUN in the model control group were significantly increased, with statistically significant differences (P < 0.05), indicating that the model was successfully established. Compared with the model control group, the serum levels of Cre and BUN in the positive control group and the high-, medium-, and low-dose experimental groups were significantly decreased, with statistically significant differences (P < 0.05). These results suggest that Jingfang Granule has a protective effect against cisplatin-induced renal injury. The results are shown in Table 3.

[0079] Table 3 Effects of Jingfang Granules on renal injury in mice ( n=10)

[0080]

[0081] Note: Compared with the normal control group, if P<0.05, “ Δ " " indicates; compared with the model control group: P < 0.05 is indicated by "*".

[0082] Experimental Example 4 Effect of Drugs on Acute Respiratory Distress Syndrome (ARDS) in Rats

[0083] 1. Materials

[0084] 1.1 Experimental Animals and Diet Sixty healthy male Sprague-Dawley rats, weighing (200 ± 20) g, were provided by Lunan Pharmaceutical Group Co., Ltd. (Experimental Animal License No.: SYXK(Lu)2018-0008). Before the experiment, rats were acclimatized in a clean animal laboratory for one week, with sexes separated and maintained at room temperature of 20–25°C, relative humidity of 40%–60%, and natural light. They had free access to food and water.

[0085] 1.2 Instruments, reagents, and drugs Thermo Scientific Medifuge small desktop centrifuge (Thermo Fisher Scientific, USA), -80°C low-temperature refrigerator (Qingdao Haier Special Electric Co., Ltd.), AG285 electronic analytical balance (Mettler-Toledo, Switzerland); rat TNF-α and IL-1β enzyme-linked immunosorbent assay kit (R&D Company, USA), lipopolysaccharide LPS (Sigma, USA), pentobarbital sodium (Jinan Hongbo Chemical Co., Ltd.); the test drug was Jingfang Granules in Example 5 (produced by Lunan Houpu Pharmaceutical Co., Ltd.), and the positive control drug was ambroxol hydrochloride (batch number: 19049001, Shanghai Boehringer Ingelheim Pharmaceutical Co., Ltd.).

[0086] 2 Methods

[0087] 2.1 Grouping and Modeling Sixty healthy male SD rats were randomly divided into 6 groups, with 10 rats in each group, namely the normal control group, the model control group, the ambroxol hydrochloride positive control group (referred to as the "positive control group"), the Jingfang granule high-dose group (referred to as the "experimental high-dose group"), the Jingfang granule medium-dose group (referred to as the "experimental medium-dose group"), and the Jingfang granule low-dose group (referred to as the "experimental low-dose group"). Except for the normal control group, the rats in the other groups were instilled with 7.5 mg / kg of LPS (prepared with sterile saline) through the trachea, and then the rats were turned over to evenly distribute the drug solution in both lungs of the rats to establish the ARDS model. The rats in the normal control group were instilled with the same amount of sterile saline through the trachea. If the rats showed symptoms such as mental depression, lack of activity, loss of appetite, rapid breathing, and diarrhea, the model was successfully established.

[0088] 2.2 Six hours after drug administration and modeling, the dose conversion was performed according to the dose conversion coefficients for different animals in the appendix of the "Guiding Principles for Clinical Research of New Chinese Medicines". The rats in the positive control group were intraperitoneally injected with 0.04g / kg of ambroxol hydrochloride injection, and the rats in the high-dose group, medium-dose group and low-dose group were orally administered with 9g / kg, 4.5g / kg and 2.25g / kg of Jingfang Granules, respectively, which are equivalent to 2 times, 1 times and 0.5 times the human equivalent dose, with a dosing volume of 10ml / kg. The normal control group and the model control group were orally administered with an equal volume of normal saline once a day for 21 consecutive days.

[0089] 2.3 Detection indicators and methods After the last dose of the drug, rats were intraperitoneally injected with 30 mg / kg of sodium pentobarbital. After anesthesia, rats underwent tracheotomy, a hollow catheter was inserted, the right bronchus was ligated, and the left lung was lavaged into the left bronchus with 5 ml of cold saline. This was repeated three times with a recovery rate of more than 90%. The collected BALF (bronchoalveolar lavage fluid) was centrifuged at 3000 r / min for 10 minutes at 4°C, and the supernatant was stored in an ultra-low temperature refrigerator at -80°C. The levels of TNF-α and IL-1β were detected using TNF-α and IL-1β ELISA kits, and the operation was carried out strictly according to the instructions of the kit.

[0090] 2.4 Statistical analysis SPSS 19.0 statistical software was used for analysis, and the experimental data were expressed as “mean ± standard deviation”. ". One-way analysis of variance was used to compare multiple groups, and P < 0.05 indicated statistically significant differences.

[0091] 3 Results

[0092] Compared with the normal control group, the BALF levels of TNF-α and IL-1β in the model control group were significantly increased, with statistically significant differences (P < 0.05), indicating that the model was successfully established. Compared with the model control group, the serum levels of TNF-α and IL-1β in the positive control group and the high-, medium-, and low-dose experimental groups were significantly decreased, with statistically significant differences (P < 0.05). These results suggest that Jingfang Granule has a certain inhibitory effect on the inflammatory response of ARDS. The results are shown in Table 4.

[0093] Table 4 Effects of Jingfang Granules on Acute Respiratory Distress Syndrome in Rats ( n=10)

[0094]

[0095] Note: Compared with the normal control group, if P<0.05, “ Δ " " indicates; compared with the model control group: P < 0.05 is indicated by "*".

[0096] Experimental Example 5 Effects of Drugs on Diarrhea in Mice

[0097] 1. Materials

[0098] 1.1 Experimental Animals and Diets Sixty SPF-grade KM mice, half male and half female, weighing (20 ± 2) g, were provided by Lunan Pharmaceutical Group Co., Ltd., Laboratory Animal License No. SYXK(Lu)2018 0008. Before the experiment, the mice were acclimatized in a clean animal laboratory for one week, separated by sex, at room temperature of 20–25°C, relative humidity of 40%–60%, under natural light, and with free access to food and water.

[0099] 1.2 Instruments, reagents and drugs Automatic colony counter (Shanghai Haiheng Electromechanical Instrument Co., Ltd.), AG285 electronic analytical balance (Mettler-Toledo, Switzerland), Thermo Scientific Medifuge small desktop centrifuge (Thermo Fisher Scientific, USA), -80°C low-temperature refrigerator (Qingdao Haier Special Electrical Appliance Co., Ltd.), bacterial incubator (Shanghai Jinghong Experimental Equipment Co., Ltd.), anaerobic incubator (Shanghai Xinyi Instrument Co., Ltd.), selective culture medium (Qingdao Haibo Biological Company); mouse diamine oxidase (DAO) ELISA kit (Xiamen Huijia Biotechnology Co., Ltd.), D-lactic acid detection and analysis kit (colorimetric method) (Wuhan Aimejie Technology Co., Ltd.), SIgA kit (Institute of Isotopes, China Institute of Atomic Energy), lincomycin (Shandong Ruiyang Pharmaceutical Co., Ltd.), PBS (Thermo Fisher Scientific, USA); the test drug was Jingfang Granules in Example 5 (produced by Lunan Houpu Pharmaceutical Co., Ltd.), and the positive control drug was Bifidobacterium Triple Live Bacteria Tablets (trade name Bificon, batch number: 19075002, Shanghai Xinyi Pharmaceutical Co., Ltd.).

[0100] 2 Methods

[0101] 2.1 Grouping and Modeling Sixty SPF KM mice were selected, of which 50 were gavaged with lincomycin hydrochloride 0.4 mL / time twice daily for 4 consecutive days. The mice were observed for lethargy, decreased activity, weight loss, redness around the anus, and diarrhea. The defecation of the mice was also observed. The presence of yellow-brown, loose, and unformed feces and a decrease in the number of bifidobacteria and lactobacilli cultured from fresh feces indicated successful modeling. The 50 mice with successful modeling were randomly divided into a model control group, a bifidobacteria triple live bacteria tablet control group (referred to as the "positive control group"), a Jingfang granule high-dose group (referred to as the "experimental high-dose group"), a Jingfang granule medium-dose group (referred to as the "experimental medium-dose group"), and a Jingfang granule low-dose group (referred to as the "experimental low-dose group"), with 10 mice in each group, half male and half female. The remaining 10 mice were gavaged with an equal amount of normal saline and set as the normal control group.

[0102] 2.2 Starting from the 5th day of administration, all groups were gavaged with the drug. The dose conversion was performed according to the dose conversion coefficients for different animals in the appendix of the "Guidelines for Clinical Research of New Chinese Medicines". The positive control group was gavaged with 0.2g / kg of Bifidobacterium Triple Live Bacteria Tablets, and the high-dose group, medium-dose group and low-dose group were gavaged with 9g / kg, 4.5g / kg and 2.25g / kg of Jingfang Granules, respectively, which were equivalent to 2 times, 1 times and 0.5 times the human equivalent dose. The administration volume was 10ml / kg. The normal control group and the model control group were given an equal volume of normal saline by gavage, once a day, for 14 consecutive days.

[0103] 2.3 Detection indicators and methods

[0104] 2.3.1 Intestinal flora detection After 14 days of continuous administration, the mice were killed by cervical dislocation. 100 μg of cecal contents of each group of mice were collected aseptically, added to 800 μL of diluent, mixed thoroughly, and diluted again. 1×10 -3 -1×10 -8 The diluted suspension was inoculated into selective culture medium and cultured in a 37°C incubator and an anaerobic incubator for 24 hours. Enterobacteriaceae, enterococci, bifidobacteria, and lactobacilli were identified by colony morphology, biochemical reactions, and Gram staining. Identified bacteria were counted, and the logarithm value was used to represent the number of viable dominant bacteria (1g CFU / g).

[0105] 2.3.2 Determination of diamine oxidase and D-lactic acid content After 14 days of continuous administration, the mice were killed by cervical dislocation, 5 mL of blood was collected from the heart, and serum was collected after centrifugation at 3000 rpm for 10 min to detect serum diamine oxidase (DAO) and D-lactic acid levels.

[0106] 2.3.3 Intestinal Mucosal SIgA (Secretory Immunoglobulin A) Assay: A 15 cm intestinal segment, starting 10 cm below the pylorus and extending toward the ileocecal region, was laid flat on filter paper and cut longitudinally. The intestinal mucosal surface was rinsed with sterile PBS buffer. Finally, a portion of the mucus was gently scraped from the intestinal mucosal surface using a glass slide. The mucus was placed in a 1.5 mL sterile EP tube and frozen for testing. Intestinal mucosal SIgA levels were analyzed using a biotin-anti-biotin enzyme-linked immunosorbent assay according to the kit instructions.

[0107] 2.4 Statistical analysis SPSS 19.0 statistical software was used for analysis, and the experimental data were expressed as “mean ± standard deviation”. ". One-way analysis of variance was used to compare multiple groups, and P < 0.05 indicated statistically significant differences.

[0108] 3 Results

[0109] 3.1 Comparison of Intestinal Microbiota Compared with the normal control group, the model control group showed a decrease in the number of Lactobacilli and Bifidobacteria, while an increase in the number of Enterobacteriaceae and Enterococci; the differences were statistically significant (P < 0.05). Compared with the model control group, the positive control group and the high-, medium-, and low-dose experimental groups showed an increase in the number of Lactobacilli and Bifidobacteria, while a decrease in the number of Enterobacteriaceae and Enterococci; the differences were statistically significant (P < 0.05). The results are shown in Table 5. These results suggest that Jingfang Granules have a protective and repairing effect on the intestinal biofilm barrier of mice with antibiotic-associated diarrhea.

[0110] 3.2 Determination of Serum DAO and D-Lactic Acid Contents Compared with the normal control group, the serum DAO and D-lactic acid levels of mice in the model control group were significantly increased, with the differences being statistically significant (P < 0.05). Compared with the model control group, the serum DAO and D-lactic acid levels of mice in the positive control group and the high-, medium-, and low-dose experimental groups were significantly decreased, with the differences being statistically significant (P < 0.05). These results suggest that Jingfang Granules can effectively improve the intestinal barrier function of mice with antibiotic-associated diarrhea.

[0111] 3.3 Determination of SIgA Content in Intestinal Mucus Compared with the normal control group, the SIgA content in the intestinal mucosa of mice in the model control group was significantly reduced, with a statistically significant difference (P < 0.05). Compared with the model control group, the SIgA content in the intestinal mucosa of mice in the positive control group and the high-, medium-, and low-dose experimental groups was significantly increased, with a statistically significant difference (P < 0.05). These results suggest that Jingfang Granule has a positive effect on improving intestinal immune function in mice with antibiotic-associated diarrhea. The results are shown in Table 6.

[0112] In summary, Jingfang Granules can effectively treat antibiotic-associated diarrhea.

[0113] Table 5 Effects of Jingfang Granules on the number of intestinal flora in mice ( n=10)

[0114]

[0115]

[0116] Note: Compared with the normal control group, if P<0.05, “ Δ " " indicates; compared with the model control group: P < 0.05 is indicated by "*".

[0117] Table 6 Effects of Jingfang Granules on serum DAO, D-lactic acid and intestinal mucosal SIgA levels in mice ( n=10)

[0118]

[0119] Note: Compared with the normal control group, if P<0.05, “ Δ " " indicates; compared with the model control group: P < 0.05 is indicated by "*".

[0120] The above experimental results show that Jingfang Granules can effectively treat viral myocarditis, reduce the serum concentrations of liver function markers ALT and AST and renal function markers Cre and BUN, thereby effectively protecting liver and kidney function, effectively inhibiting the inflammatory response of acute respiratory distress syndrome, and effectively treating diarrhea at the same time, treating both the symptoms and the root cause, and have a definite and significant therapeutic effect on the sequelae of COVID-19. DETAILED DESCRIPTION

[0121] The present invention is further described below by way of specific examples. However, those skilled in the art should be aware that the examples do not limit the present invention in any way.

[0122] Example 1 Preparation of Jingfang Granules

[0123]

[0124]

[0125] A. Extract volatile oils from seven medicinal herbs: Schizonepeta tenuifolia, Saposhnikovia divaricata, Notopterygium wilfordii, Angelica dahurica, Peucedanum chinense, Chuanxiong rhizome, and Fructus Aurantii Immaturus. The volatile oils from these seven herbs are then distilled, followed by the distilled residues and the aqueous solutions of Chuanxiong rhizome and Fructus Aurantii Immaturus for later use.

[0126] B. Take the volatile oil obtained in step A and add β-cyclodextrin to prepare inclusion complexes;

[0127] C. The distilled aqueous solution of Chuanxiong and Fructus Aurantii obtained in step A is prepared into a 27% ethanol solution as a solvent, and the residues of Chuanxiong and Fructus Aurantii obtained in step A and Poria cocos are percolated to obtain a percolate for later use;

[0128] D. decoct the residues of Schizonepeta tenuifolia, Saposhnikovia divaricata, Notopterygium incisum, Angelica pubescens, and Peucedanum chinense obtained in step A with the remaining three herbs, namely, Bupleurum chinense, Platycodon grandiflorum, and Licorice root, three times for 2 hours each time. Combine the decoctions, filter, and concentrate the filtrate to an extract having a relative density of 1.24 at 60-70°C.

[0129] E. Combine the filtrate obtained in step C and the extract obtained in step D, mix well, let stand, filter, and concentrate the filtrate to an extract with a relative density of 1.24 at 50-60°C;

[0130] F. Take the extract obtained in step E, dry it in a belt vacuum dryer under the conditions of vacuum degree -0.08MPa--0.10MPa and drying temperature 63°C, grind it into fine powder, sieve it, add the β-cyclodextrin inclusion compound obtained in step B, mix well to obtain fine powder of schisandra chinensis extract, add the formulated amount of sucrose powder, hydroxypropyl starch, and mannitol (weight ratio 4:2:1), mix well, make into granules, dry, and granulate into 10 kg.

[0131] Example 2 Preparation of Jingfang Tablets

[0132]

[0133] A. Extract volatile oils from seven medicinal herbs: Schizonepeta tenuifolia, Saposhnikovia divaricata, Notopterygium wilfordii, Angelica dahurica, Peucedanum chinense, Chuanxiong rhizome, and Fructus Aurantii Immaturus. The volatile oils from these seven herbs are then distilled, followed by the distilled residues and the aqueous solutions of Chuanxiong rhizome and Fructus Aurantii Immaturus for later use.

[0134] B. Take the volatile oil obtained in step A and add β-cyclodextrin to prepare inclusion complexes;

[0135] C. The distilled aqueous solution of Chuanxiong and Fructus Aurantii obtained in step A is prepared into a 24% ethanol solution as a solvent, and the residues of Chuanxiong and Fructus Aurantii obtained in step A and Poria cocos are percolated to obtain a percolate for later use;

[0136] D. decoct the residues of Schizonepeta tenuifolia, Saposhnikovia divaricata, Notopterygium wilfordii, Angelica pubescens, and Peucedanum chinense obtained in step A with the remaining three herbs, namely, Bupleurum chinense, Platycodon grandiflorum, and Licorice root, twice in water, each time for 1.5 hours. Combine the decoctions, filter, and concentrate the filtrate to an extract having a relative density of 1.25 at 60-70°C;

[0137] E. Combine the filtrate obtained in step C and the extract obtained in step D, mix well, let stand, filter, and concentrate the filtrate to an extract with a relative density of 1.28 at 50-60°C;

[0138] F. Take the extract obtained in step E, dry it in a belt vacuum dryer under vacuum conditions of -0.08MPa--0.10MPa and a drying temperature of 63°C, grind it into fine powder, sieve it, add the β-cyclodextrin inclusion compound obtained in step B, mix well to obtain fine powder of the schisandra chinensis extract, add the formulated amount of microcrystalline cellulose, low-substituted hydroxypropyl cellulose, and mannitol (weight ratio of 4:3:1), mix well, prepare coarse granules, dry, grind, sieve, prepare granules, dry at low temperature, granulate, add 0.2% magnesium stearate and 0.1% talc, mix well, and press into 10,000 tablets.

[0139] Example 3 Preparation of Jingfang Microcapsules

[0140]

[0141] A. Extract volatile oils from seven medicinal herbs: Schizonepeta tenuifolia, Saposhnikovia divaricata, Notopterygium wilfordii, Angelica dahurica, Peucedanum chinense, Chuanxiong rhizome, and Fructus Aurantii Immaturus. The volatile oils from these seven herbs are then distilled, followed by the distilled residues and the aqueous solutions of Chuanxiong rhizome and Fructus Aurantii Immaturus for later use.

[0142] B. Take the volatile oil obtained in step A and add β-cyclodextrin to prepare inclusion complexes;

[0143] C. The distilled aqueous solution of Chuanxiong and Fructus Aurantii obtained in step A is prepared into a 29% ethanol solution as a solvent, and the residue of Chuanxiong and Fructus Aurantii obtained in step A and Poria cocos are percolated to obtain a percolate for later use;

[0144] D. decoct the residues of Schizonepeta tenuifolia, Saposhnikovia divaricata, Notopterygium wilfordii, Angelica pubescens, and Peucedanum chinense obtained in step A with the remaining three herbs, namely, Bupleurum chinense, Platycodon grandiflorum, and Licorice root, twice in water for 2.5 hours each time. Combine the decoctions, filter, and concentrate the filtrate to an extract having a relative density of 1.23 at 60-70°C.

[0145] E. Combine the filtrate obtained in step C and the extract obtained in step D, mix well, let stand, filter, and concentrate the filtrate to an extract with a relative density of 1.27 at 50-60°C;

[0146] F. Take the extract obtained in step E, add the cyclodextrin inclusion compound obtained in step B, mix well, make granules, vacuum dry under a belt vacuum condition of -0.08MPa--0.10MPa and a drying temperature of 55°C, grind to obtain a fine powder of the Jingfang extract, set aside;

[0147] G. Weigh the fine powder of the schizonepeta extract from step F according to the formula, a mixture of sodium chelate:maltodextrin = 5:3 as the capsule material, octadecanol:titanium dioxide = 2:1 as the anti-adherent agent, and polyethylene glycol:citric acid = 4:1 as the plasticizer. Add the above capsule material, anti-adherent agent, and plasticizer to purified water, heat and stir at 52°C to dissolve, and prepare a capsule material solution with a mass fraction of 33.5%. Cool to room temperature, add the fine powder of the schizonepeta extract while stirring, and add 1.17% of the total formulation of sucrose fatty acid ester:soybean lecithin = 8:5 composite emulsifier, homogenize and emulsify to obtain an emulsion, which is set aside.

[0148] H. The emulsion in step G is spray-dried under the conditions of an inlet air temperature of 166° C., a spray pressure of 0.40 MPa, and a feed rate of 22.5 ml / min. The microcapsules are collected and cooled to obtain the microcapsules.

[0149] Example 4 Preparation of Jingfang Capsules

[0150]

[0151] A. Extract volatile oils from seven medicinal herbs: Schizonepeta tenuifolia, Saposhnikovia divaricata, Notopterygium wilfordii, Angelica dahurica, Peucedanum chinense, Chuanxiong rhizome, and Fructus Aurantii Immaturus. The volatile oils from these seven herbs are then distilled, followed by the distilled residues and the aqueous solutions of Chuanxiong rhizome and Fructus Aurantii Immaturus for later use.

[0152] B. Take the volatile oil obtained in step A and add β-cyclodextrin to prepare inclusion complexes;

[0153] C. The distilled aqueous solution of Chuanxiong and Fructus Aurantii obtained in step A is prepared into a 29% ethanol solution as a solvent, and the residue of Chuanxiong and Fructus Aurantii obtained in step A and Poria cocos are percolated to obtain a percolate for later use;

[0154] D. decoct the residues of Schizonepeta tenuifolia, Saposhnikovia divaricata, Notopterygium wilfordii, Angelica pubescens, and Peucedanum chinense obtained in step A with the remaining three herbs, namely, Bupleurum chinense, Platycodon grandiflorum, and Licorice root, three times for 1.5 hours each time. Combine the decoctions, filter, and concentrate the filtrate to an extract having a relative density of 1.20 at 60-70°C;

[0155] E. Combine the filtrate obtained in step C and the extract obtained in step D, mix well, let stand, filter, and concentrate the filtrate to an extract with a relative density of 1.24 at 50-60°C;

[0156] F. Take the extract obtained in step E, dry it in a belt vacuum dryer under the conditions of vacuum degree -0.08MPa--0.10MPa and drying temperature 63℃, grind it into fine powder, sieve it, add the β-cyclodextrin inclusion compound obtained in step B, mix well to obtain fine powder of Schizonepeta tenuifolia extract, add the formulated amount of starch and microcrystalline cellulose (weight ratio 6:1), mix well, granulate, dry, granulate, fill, polish in a grinder, and remove damaged capsules to obtain the product.

[0157] Example 5 Preparation of Jingfang Granules

[0158]

[0159] A. Extract volatile oils from seven medicinal herbs: Schizonepeta tenuifolia, Saposhnikovia divaricata, Notopterygium wilfordii, Angelica dahurica, Peucedanum chinense, Chuanxiong rhizome, and Fructus Aurantii Immaturus. The volatile oils from these seven herbs are then distilled, followed by the distilled residues and the aqueous solutions of Chuanxiong rhizome and Fructus Aurantii Immaturus for later use.

[0160] B. Take the volatile oil obtained in step A and add β-cyclodextrin to prepare inclusion complexes;

[0161] C. The distilled aqueous solution of Chuanxiong and Fructus Aurantii obtained in step A is prepared into a 25% ethanol solution as a solvent, and the residue of Chuanxiong and Fructus Aurantii obtained in step A and Poria cocos are percolated to obtain a percolate for later use;

[0162] D. decoct the residues of Schizonepeta tenuifolia, Saposhnikovia divaricata, Notopterygium incisum, Angelica pubescens, and Peucedanum chinense obtained in step A with the remaining three herbs, namely, Bupleurum chinense, Platycodon grandiflorum, and Licorice root, three times for 2 hours each time. Combine the decoctions, filter, and concentrate the filtrate to an extract having a relative density of 1.23 at 60-70°C.

[0163] E. Combine the filtrate obtained in step C and the extract obtained in step D, mix well, let stand, filter, and concentrate the filtrate to an extract with a relative density of 1.26 at 50-60°C;

[0164] F. Take the extract obtained in step E, dry it in a belt vacuum dryer under vacuum conditions of -0.08MPa-0.10MPa and a drying temperature of 63°C, grind it into fine powder, sieve it, add the β-cyclodextrin inclusion compound obtained in step B, mix well to obtain fine powder of the schisandra chinensis extract, add excipients in a weight ratio of sucrose powder: hydroxypropyl starch: mannitol = 3:1:0.5, mix well, make granules, dry, and granulate to obtain the product.

[0165] Example 6 Preparation of Jingfang Capsules

[0166]

[0167] A. Extract volatile oils from seven medicinal herbs: Schizonepeta tenuifolia, Saposhnikovia divaricata, Notopterygium wilfordii, Angelica dahurica, Peucedanum chinense, Chuanxiong rhizome, and Fructus Aurantii Immaturus. The volatile oils from these seven herbs are then distilled, followed by the distilled residues and the aqueous solutions of Chuanxiong rhizome and Fructus Aurantii Immaturus for later use.

[0168] B. Take the volatile oil obtained in step A and add β-cyclodextrin to prepare inclusion complexes;

[0169] C. The distilled aqueous solution of Chuanxiong and Fructus Aurantii obtained in step A is prepared into a 26% ethanol solution as a solvent, and the residues of Chuanxiong and Fructus Aurantii obtained in step A and Poria cocos are percolated to obtain a percolate for later use;

[0170] D. decoct the residues of Schizonepeta tenuifolia, Saposhnikovia divaricata, Notopterygium wilfordii, Angelica pubescens, and Peucedanum chinense obtained in step A with the remaining three herbs, namely, Bupleurum chinense, Platycodon grandiflorum, and Licorice root, twice for 2 hours each time, combine the decoctions, filter, and concentrate the filtrate to an extract having a relative density of 1.19 at 60-70°C;

[0171] E. Combine the filtrate obtained in step C and the extract obtained in step D, mix well, let stand, filter, and concentrate the filtrate to an extract with a relative density of 1.23 at 50-60°C;

[0172] F. Take the extract obtained in step E, dry it in a belt vacuum dryer under the conditions of vacuum degree -0.08MPa--0.10MPa and drying temperature 63°C, grind it into fine powder, sieve it, add the β-cyclodextrin inclusion compound obtained in step B, mix well to obtain fine powder of schisandrae rhizome extract, add the formulated amount of starch, micropowder silica gel, and low-substituted hydroxypropyl cellulose (weight ratio of 5:2:2), mix well, granulate, dry, granulate, fill, polish in a grinder, and remove damaged capsules to obtain the product.

[0173] Example 7 Preparation of Jingfang Capsules

[0174]

[0175]

[0176] A. Extract volatile oils from seven medicinal herbs: Schizonepeta tenuifolia, Saposhnikovia divaricata, Notopterygium wilfordii, Angelica dahurica, Peucedanum chinense, Chuanxiong rhizome, and Fructus Aurantii Immaturus. The volatile oils from these seven herbs are then distilled, followed by the distilled residues and the aqueous solutions of Chuanxiong rhizome and Fructus Aurantii Immaturus for later use.

[0177] B. Take the volatile oil obtained in step A and add β-cyclodextrin to prepare inclusion complexes;

[0178] C. The distilled aqueous solution of Chuanxiong and Fructus Aurantii obtained in step A is prepared into a 30% ethanol solution as a solvent, and the residue of Chuanxiong and Fructus Aurantii obtained in step A and Poria cocos are percolated to obtain a percolate for later use;

[0179] D. decoct the residues of Schizonepeta tenuifolia, Saposhnikovia divaricata, Notopterygium wilfordii, Angelica pubescens, and Peucedanum chinense obtained in step A with the remaining three herbs, namely, Bupleurum chinense, Platycodon grandiflorum, and Licorice root, twice in water, each time for 1.5 hours. Combine the decoctions, filter, and concentrate the filtrate to an extract having a relative density of 1.19 at 60-70°C;

[0180] E. Combine the filtrate obtained in step C and the extract obtained in step D, mix well, let stand, filter, and concentrate the filtrate to an extract with a relative density of 1.25 at 50-60°C;

[0181] F. Take the extract obtained in step E, dry it in a belt vacuum dryer under the conditions of vacuum degree -0.08MPa--0.10MPa and drying temperature 63℃, grind it into fine powder, sieve it, add the β-cyclodextrin inclusion compound obtained in step B, mix well to obtain fine powder of Schizonepeta tentacis extract, add the formulated amount of starch and micro-powdered silica gel (weight ratio 4:1), mix well, granulate, dry, granulate, fill, polish in a grinder, and remove damaged capsules to obtain the product.

[0182] Example 8 Preparation of Jingfang Tablets

[0183]

[0184] A. Extract volatile oils from seven medicinal herbs: Schizonepeta tenuifolia, Saposhnikovia divaricata, Notopterygium wilfordii, Angelica dahurica, Peucedanum chinense, Chuanxiong rhizome, and Fructus Aurantii Immaturus. The volatile oils from these seven herbs are then distilled, followed by the distilled residues and the aqueous solutions of Chuanxiong rhizome and Fructus Aurantii Immaturus for later use.

[0185] B. Take the volatile oil obtained in step A and add β-cyclodextrin to prepare inclusion complexes;

[0186] C. The distilled aqueous solution of Chuanxiong and Fructus Aurantii obtained in step A is prepared into a 22% ethanol solution as a solvent, and the residue of Chuanxiong and Fructus Aurantii obtained in step A and Poria cocos are percolated to obtain a percolate for later use;

[0187] D. decoct the residues of Schizonepeta tenuifolia, Saposhnikovia divaricata, Notopterygium wilfordii, Angelica pubescens, and Peucedanum chinense obtained in step A with the remaining three herbs, namely, Bupleurum chinense, Platycodon grandiflorum, and Licorice root, twice in water for 2.5 hours each time. Combine the decoctions, filter, and concentrate the filtrate to an extract having a relative density of 1.24 at 60-70°C.

[0188] E. Combine the filtrate obtained in step C and the extract obtained in step D, mix well, let stand, filter, and concentrate the filtrate to an extract with a relative density of 1.22 at 50-60°C;

[0189] F. Take the extract obtained in step E, dry it in a belt vacuum dryer under vacuum conditions of -0.08MPa--0.10MPa and a drying temperature of 63°C, grind it into fine powder, sieve it, add the β-cyclodextrin inclusion compound obtained in step B, mix well to obtain fine powder of the schizonepeta exigua extract, add the formulated amount of starch, dextrin and sucrose (weight ratio of 3:2:1), mix well, make coarse granules, dry, grind, sieve, make granules, dry at low temperature, granulate, add 0.3% magnesium stearate, mix well, and press into 10,000 tablets.

[0190] Example 9 Preparation of Jingfang Granules

[0191]

[0192] A. Extract volatile oils from seven medicinal herbs: Schizonepeta tenuifolia, Saposhnikovia divaricata, Notopterygium wilfordii, Angelica dahurica, Peucedanum chinense, Chuanxiong rhizome, and Fructus Aurantii Immaturus. The volatile oils from these seven herbs are then distilled, followed by the distilled residues and the aqueous solutions of Chuanxiong rhizome and Fructus Aurantii Immaturus for later use.

[0193] B. Take the volatile oil obtained in step A and add β-cyclodextrin to prepare inclusion complexes;

[0194] C. The distilled aqueous solution of Chuanxiong and Fructus Aurantii obtained in step A is prepared into a 20% ethanol solution as a solvent, and the residue of Chuanxiong and Fructus Aurantii obtained in step A and Poria cocos are percolated to obtain a percolate for later use;

[0195] D. decoct the residues of Schizonepeta tenuifolia, Saposhnikovia divaricata, Notopterygium wilfordii, Angelica pubescens, and Peucedanum chinense obtained in step A with the remaining three herbs, namely, Bupleurum chinense, Platycodon grandiflorum, and Licorice root, three times for 1.5 hours each time. Combine the decoctions, filter, and concentrate the filtrate to an extract having a relative density of 1.18 at 60-70°C.

[0196] E. Combine the filtrate obtained in step C and the extract obtained in step D, mix well, let stand, filter, and concentrate the filtrate to an extract with a relative density of 1.26 at 50-60°C;

[0197] F. Take the extract obtained in step E, dry it in a belt vacuum dryer under the conditions of vacuum degree -0.08MPa--0.10MPa and drying temperature 63℃, grind it into fine powder, sieve it, add the β-cyclodextrin inclusion compound obtained in step B, mix well to obtain fine powder of Schizonepeta tenuifolia extract, add the formulated amount of sucrose powder and dextrin (weight ratio 5:2), mix well, make it into granules, dry it, and make it into 10kg.

Claims

1. The use of a Jingfang preparation in the preparation of a drug for treating sequelae of COVID-19, characterized in that: The sequelae of the novel coronavirus is acute respiratory distress syndrome; the Jingfang preparation is made of the following traditional Chinese medicine components: 97 parts by weight of Schizonepeta tenuifolia, 97 parts by weight of Saposhnikovia divaricata, 97 parts by weight of Notopterygium incisum 97 weight parts of Angelica dahurica, 97 weight parts of Bupleurum chinense, 97 weight parts of Peucedanum chinense 97 parts by weight of Chuanxiong, 97 parts by weight of Citrus aurantium, 97 parts by weight of Poria cocos 97 parts by weight of Platycodon grandiflorum and 32.4 parts by weight of Licorice.

2. The use according to claim 1, characterized in that The Jingfang preparation is one of granules, tablets, capsules and microcapsules.

3. The use according to claim 1 or 2, characterized in that The preparation method of the Jingfang preparation comprises the following steps: A. Extract volatile oils from seven medicinal herbs: Schizonepeta tenuifolia, Saposhnikovia divaricata, Notopterygium wilfordii, Angelica dahurica, Peucedanum chinense, Chuanxiong rhizome, and Fructus Aurantii Immaturus. The volatile oils from these seven herbs are then distilled, followed by the distilled residues and the aqueous solutions of Chuanxiong rhizome and Fructus Aurantii Immaturus for later use. B. Take the volatile oil obtained in step A and add β-cyclodextrin to prepare inclusion complexes; C. The aqueous solution of the distilled Chuanxiong and Fructus Aurantii obtained in step A is prepared into a 20-30% ethanol solution as a solvent, and the residue of the Chuanxiong and Fructus Aurantii obtained in step A and Poria cocos are percolated to obtain a percolate for later use; D. decoct the residues of Schizonepeta tenuifolia, Saposhnikovia divaricata, Notopterygium incisum, Angelica pubescens, and Peucedanum chinense obtained in step A with the remaining three herbs: Bupleurum chinense, Platycodon grandiflorum, and Licorice root 2-3 times for 1.5-2.5 hours each time, combine the decoctions, filter, and concentrate the filtrate to an extract having a relative density of 1.18-1.25 at 60-70°C; E. Combine the filtrate obtained in step C and the extract obtained in step D, mix well, let stand, filter, and concentrate the filtrate to an extract with a relative density of 1.22-1.28 at 50-60°C; F. The extract obtained in step E and the β-cyclodextrin inclusion compound obtained in step B are prepared into granules, tablets, capsules or microcapsules directly or by adding pharmaceutically acceptable excipients through conventional procedures.

4. The use according to claim 3, characterized in that The preparation method of the granules comprises the following steps: A. Extract volatile oils from seven medicinal herbs: Schizonepeta tenuifolia, Saposhnikovia divaricata, Notopterygium wilfordii, Angelica dahurica, Peucedanum chinense, Chuanxiong rhizome, and Fructus Aurantii Immaturus. The volatile oils from these seven herbs are then distilled, followed by the distilled residues and the aqueous solutions of Chuanxiong rhizome and Fructus Aurantii Immaturus for later use. B. Take the volatile oil obtained in step A and add β-cyclodextrin to prepare inclusion complexes; C. The distilled aqueous solution of Chuanxiong and Fructus Aurantii obtained in step A is prepared into a 25% ethanol solution as a solvent, and the residues of Chuanxiong and Fructus Aurantii obtained in step A and Poria cocos are percolated to obtain a percolate for later use; D. decoct the residues of Schizonepeta tenuifolia, Saposhnikovia divaricata, Notopterygium incisum, Angelica pubescens, and Peucedanum chinense obtained in step A with the remaining three herbs: Bupleurum chinense, Platycodon grandiflorum, and Licorice root in water three times for 2 hours each time. Combine the decoctions, filter, and concentrate the filtrate to an extract having a relative density of 1.23 at 60-70°C. E. Combine the filtrate obtained in step C and the extract obtained in step D, mix well, let stand, filter, and concentrate the filtrate to an extract with a relative density of 1.26 at 50-60°C; F. Take the extract obtained in step E, dry it in a belt vacuum dryer under vacuum conditions of -0.08MPa--0.10MPa and drying temperature of 63°C, grind it into fine powder, sieve it, add the β-cyclodextrin inclusion compound obtained in step B, mix well to obtain fine powder of the schisandra chinensis extract, add excipients in a weight ratio of sucrose powder: hydroxypropyl starch: mannitol = 3:2:0.5, mix well, make into granules, dry, and granulate to obtain the product.

5. The use according to claim 3, characterized in that The preparation method of the microcapsule comprises the following steps: A. Extract volatile oils from seven medicinal herbs: Schizonepeta tenuifolia, Saposhnikovia divaricata, Notopterygium wilfordii, Angelica dahurica, Peucedanum chinense, Chuanxiong rhizome, and Fructus Aurantii Immaturus. The volatile oils from these seven herbs are then distilled, followed by the distilled residues and the aqueous solutions of Chuanxiong rhizome and Fructus Aurantii Immaturus for later use. B. Take the volatile oil obtained in step A and add β-cyclodextrin to prepare inclusion complexes; C. The distilled aqueous solution of Chuanxiong and Fructus Aurantii obtained in step A is prepared into a 28% ethanol solution as a solvent, and the residues of Chuanxiong and Fructus Aurantii obtained in step A and Poria cocos are percolated to obtain a percolate for later use; D. decoct the residues of Schizonepeta tenuifolia, Saposhnikovia divaricata, Notopterygium wilfordii, Angelica pubescens, and Peucedanum chinense obtained in step A with the remaining three herbs, namely, Bupleurum chinense, Platycodon grandiflorum, and Licorice root, twice in water for 2.5 hours each time. Combine the decoctions, filter, and concentrate the filtrate to an extract having a relative density of 1.22 at 60-70°C. E. Combine the filtrate obtained in step C and the extract obtained in step D, mix well, let stand, filter, and concentrate the filtrate to an extract with a relative density of 1.25 at 50-60°C; F. Take the extract obtained in step E, add the cyclodextrin inclusion compound obtained in step B, mix well, make granules, belt vacuum dry, and grind to obtain a fine powder of the Jingfang extract for later use; G. Weigh the fine powder of the schisandra extract from step F, the capsule material, the anti-adherent agent, and the plasticizer according to the formula, add the capsule material, the anti-adherent agent, and the plasticizer to purified water, heat and stir at 54°C to dissolve, and prepare a 33% by mass capsule material solution. Cool to room temperature, add the fine powder of the schisandra extract and the emulsifier while stirring, homogenize and emulsify to obtain an emulsion, and set aside; H. The emulsion in step G is spray-dried under the conditions of an inlet air temperature of 165° C., a spray pressure of 0.40 MPa, and a feed rate of 21.5 ml / min, and the microcapsules are collected and cooled to obtain the microcapsules.

6. The use according to claim 5, characterized in that The belt vacuum drying conditions in step F are vacuum degree -0.08MPa--0.10MPa and drying temperature 56°C.

7. The use according to claim 5, characterized in that In step G, the capsule material is sodium chelate: maltodextrin = 3:2, the anti-adhesive agent is octadecyl alcohol: titanium dioxide = 3:1, and the plasticizer is polyethylene glycol: citric acid = 3:

1.

8. The use according to claim 5, characterized in that The emulsifier in step G is a composite emulsifier of sucrose fatty acid ester: soybean lecithin = 8:5 by weight, and the amount used is 1.18% by mass of the total formulation.

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