WO2022036779A1

WO2022036779A1 - Huashibaidu granule, preparation method therefor and anti-viral drug

Info

Publication number: WO2022036779A1
Application number: PCT/CN2020/114893
Authority: WO
Inventors: 魏梅; 程学仁; 刘燎原; 孙冬梅; 梁志毅; 张志鹏; 曾昭君; 钟霞; 徐东婷; 黄梦婷; 陈丹燕; 潘玲; 方朝缵; 伍俊祥; 彭劲源; 毛福林
Original assignee: 广东一方制药有限公司
Priority date: 2020-08-19
Filing date: 2020-09-11
Publication date: 2022-02-24
Also published as: CN112043804A

Abstract

Disclosed is a huashibaidu granule, mainly prepared from the following raw materials in parts by weight: Ephedrae herba, fried armeniacae kernel, raw gypsum, Glycyrrhiza radix, Pogostemon cablin, Magnoliae officinalis cortex, bran-fried Atractylodis Rhizoma, fried Amomum tsaoko kernel, Pinelliae rhizoma praeparatum, Poria, Rheum palmatum, Astragali Radix, Descurainiae Semen/Lepidii Semen, Paeoniae radix rubra and auxiliary materials. Correspondingly, disclosed in the present invention are a method for preparing the huashibaidu granule and an anti-viral drug comprising same. The present invention has the effects of detoxification, removing dampness, ventilating the lungs and releasing heat, and is suitable for patients with mild, common and severe COVID-19.

Description

Huashibaidu granules, preparation method and antiviral drug

technical field

The invention relates to the technical field of traditional Chinese medicines, in particular to a Huashibaidu granule, a preparation method and an antiviral drug.

Background technique

Novel coronavirus pneumonia (Corona Virus Disease 2019, COVID-19), referred to as "new coronary pneumonia". The new coronavirus has the characteristics of strong infectivity, long incubation period and high lethality. The common signs of infection with the new coronavirus are respiratory symptoms such as fever, cough, shortness of breath, and difficulty breathing. Most patients have a good prognosis, and a few patients are in critical condition or even die. About half of the patients developed dyspnea after one week, and the severe cases rapidly progressed to acute respiratory distress syndrome, septic shock, metabolic acidosis that is difficult to correct, and coagulation dysfunction, which has a great impact on people's health, economic development and social stability. huge impact.

According to the current clinical characteristics and epidemiological status of the patients, TCM experts believe that it belongs to the category of TCM epidemics. Chizheng deficiency, its pathological nature mainly involves poison, dampness, cold, heat, dryness, blood stasis, and deficiency, and the symptoms of patients are mainly fever, cough, asthma, wheezing, dyspnea, etc. It is highly contagious and pathogenic, and has now been included in Class B infectious diseases. The National Health Commission and the State Administration of Traditional Chinese Medicine have successively issued the first to seventh editions of the "New Coronary Virus Pneumonia Diagnosis and Treatment Program (Trial)", and Chinese medicine treatment has been recommended since the third edition.

The prescription of Huashibaidu Granules is based on the drug clinical trial approval document 2020L00009 of the State Drug Administration. The applicant uses its leading production technology experience in the field of traditional Chinese medicine formula granules to accelerate the transformation of scientific and technological achievements, organizes the completion of the registration certificate application under the technical guidance of the Chinese Academy of Chinese Medical Sciences, and arranges the production and preparation of Huashibaidu granules after obtaining the registration certificate .

SUMMARY OF THE INVENTION

The technical problem to be solved by the present invention is to provide a Huashi Baidu granule, which has the functions of eliminating dampness and detoxification, dispelling lung heat and expelling heat, and is suitable for mild, common and severe patients with novel coronavirus pneumonia.

The technical problem to be solved by the present invention is also to provide a preparation method of Huashi Baidu granules, which can be prepared into Huashi Baidu granules with unified specifications, unified dosages and unified quality standards, and the Huashi Baidu granules are easy to carry. , It can be used directly, and the quality is stable and controllable.

The technical problem to be solved by the present invention is also to provide a kind of antiviral medicine, which can have obvious curative effect on novel coronavirus.

In order to solve the above-mentioned technical problems, the present invention provides a kind of Huashibaidu granules, which is mainly made of the following raw materials in parts by weight:

Ephedra, fried bitter almond, raw gypsum, licorice, patchouli, Magnolia, bran fried Atractylodes, fried grass nuts, Pinellia, Poria, Rhubarb, Astragalus, Tinglizi, red peony, accessories.

The Huashibaidu granules of the present invention are based on Maxing Shigan Decoction, Xuanbai Chengqi Decoction, Dayuanyin, Huoxiangzhengqi Powder, Taoren Chengqi Decoction, Tingli Dazao Xiefei Decoction, Huangqi Chifeng Decoction and Yupingfeng Powder Ephedra, patchouli, raw gypsum, fried bitter almond, French pinellia, Magnolia, bran fried Atractylodes, fried grass nuts, Poria, Astragalus, Red Peony, Tinglizi, It is composed of fourteen herbs of rhubarb and licorice. It has the functions of detoxification and dampness, clearing heat and relieving asthma. It is used for internal stagnation of heat, external cold and dampness caused by closed lung disease, and for the treatment of new coronary pneumonia. , cough, asthma, chest tightness, epistaxis, nausea, fatigue, fat and pale tongue or red edge, white greasy coating, white and slippery edges, etc. have obvious curative effect.

Preferably, Huashibaidu granules are mainly made from the following raw materials in parts by weight:

3-60 servings of ephedra, 4.5-90 servings of fried bitter almonds, 7.5-150 servings of raw gypsum, 1.5-30 servings of licorice, 5-100 servings of patchouli, 5-100 servings of Magnolia officinalis, 7.5-150 servings of bran fried Atractylodes, stir-fried 5-100 parts of grass nuts, 4.5-90 parts of Pinellia, 7.5-150 parts of Poria, 2.5-50 parts of rhubarb, 5-100 parts of Astragalus, 5-100 parts of Tinglizi, 5-100 parts of red peony root, accessories Moderate amount.

More preferably, Huashibaidu granules are mainly made from the following raw materials in parts by weight:

12-36 servings of ephedra, 18-54 servings of fried bitter almonds, 30-90 servings of raw gypsum, 6-18 servings of licorice, 20-60 servings of patchouli, 20-60 servings of Magnolia officinalis, 30-90 servings of fried Atractylodes Rhizoma bran, stir-fried 20-60 parts of grass nuts, 18-54 parts of Pinellia, 30-90 parts of Poria, 10-30 parts of Rhubarb, 20-60 parts of Astragalus, 20-60 parts of Tinglizi, 20-60 parts of Red Peony, accessories Moderate amount.

The best, Huashibaidu granules are mainly made from the following raw materials in parts by weight:

15-25 servings of ephedra, 26-48 servings of fried bitter almonds, 40-80 servings of raw gypsum, 7-15 servings of licorice, 25-50 servings of patchouli, 25-50 servings of Magnolia officinalis, 25-70 servings of bran fried Atractylodes, stir-fried 25-50 parts of grass nuts, 25-40 parts of Pinellia, 40-80 parts of Poria, 15-25 parts of rhubarb, 25-50 parts of Astragalus, 25-50 parts of Tinglizi, 25-50 parts of red peony root, accessories Moderate amount.

Further, described fried bitter almond is obtained by the following method:

Take the bitter almonds, put them in a hot pot, and fry them with a slow fire until the surface is yellow or brown, with slight scorch spots and aroma.

Described bran fried Atractylodes is prepared by the following method:

Heat the hot pot until the bran is sprinkled into the hot pot, put the Atractylodes Rhizoma slices into the hot pot, stir quickly, fry until the surface is dark yellow, take out of the pot, sieve off the bran, and let it cool. Per 100kg Atractylodes tablets, with bran

Described fried grass nuts are obtained by the following method:

Take the strawberry fruit, remove the impurities, put it in a hot pot, fry it with a slow fire until the surface is browned and slightly bulging, take it out, remove the shell, and take the kernel;

Take the grass nuts, put them in a hot pot, fry them on a slow fire until the surface bulges and the aroma escapes, take them out and let them cool.

The adjuvant is a pharmaceutically acceptable adjuvant, including one or more of dextrin and steviol.

Correspondingly, the present invention provides a preparation method of Huashibaidu granules, which sequentially includes:

(1) take raw gypsum according to the formula, add water to decoct;

(2) Add ephedra, stir-fried bitter almond, licorice, Magnolia officinalis, bran stir-fry Atractylodes, stir-fried grass nuts, Pinellia, Poria, Astragalus, Tinglizi and Chishao according to the recipe, add water and cook;

(3) add patchouli and rhubarb according to the formula, add water to decoct, filter, and obtain the first decoction and medicinal residue;

(4) medicinal dregs add water to decoct again, filter to obtain the second decoction;

(5) the first decoction and the second decoction are concentrated to obtain clear paste;

(6) Mixing the clear paste and auxiliary materials, drying, granulating and packaging to obtain Huashibaidu granules.

Wherein, the formula of described Huashibaidu granules in parts by weight is as follows:

Specifically, in step (1), the decocting time of raw gypsum is 20 to 40 minutes, and the amount of water added is ephedra, fried bitter almonds, raw gypsum, licorice, Magnolia, bran fried Atractylodes, fried grass nuts, Pinellia fragrans, Poria, Astragalus, Tinglizi, Chishao are 1 to 6 times the amount of water.

In step (2), the time of adding water for decocting is 40 to 60 minutes, and the amount of water added is ephedra, fried bitter almonds, raw gypsum, licorice, Magnolia, bran fried Atractylodes, fried grass nuts, French pinellia, Poria, Astragalus , Tinglizi, red peony root 2 to 7 times the amount of water.

In step (3), add patchouli and rhubarb, add water for 5 to 15 minutes, and add water for 6 to 10 times that of patchouli and rhubarb. Preferably, in step (3), patchouli and rhubarb are added, and the boiling time is 8 to 12 minutes, and the amount of water added is 8 times that of the two herbs, patchouli and rhubarb.

In step (4), the medicinal dregs are added with water for decocting for 40-80min, and the amount of water added is ephedra, fried bitter almond, raw gypsum, licorice, patchouli, magnolia, bran fried Atractylodes, fried grass nuts, Pinellia fragrans, Poria, Rhubarb, Astragalus, Tinglizi, Chishao are 6 to 10 times the amount of water for the fourteen herbs. Preferably, in step (4), the medicinal residues are boiled with water for 50 to 60 minutes, and the amount of water added is ephedra, fried bitter almonds, raw gypsum, licorice, patchouli, Magnolia, bran fried Atractylodes, fried grass nuts, method Pinellia, Poria, Rhubarb, Astragalus, Tinglizi, Chishao are 8 times the amount of water for the fourteen herbs.

Step (5) includes:

The first decoction and the second decoction are respectively concentrated under reduced pressure to a clear paste with a relative density of 1.01-1.05, and then combined under reduced pressure and concentrated to a clear paste with a relative density of 1.06-1.20. Preferably, the temperature of the vacuum concentration is 45°C to 85°C, and the pressure is 0.00 to -0.095MPa. Preferably, the drying is at least one of spray drying, belt drying or freeze drying; and the granulation is at least one of boiling granulation, wet granulation and dry granulation.

As a further improvement scheme of the present invention, before step (1), comprising:

Stir-frying bitter almonds, Atractylodes Rhizoma and/or grass nuts to obtain fried bitter almonds, bran fried Atractylodes and/or fried grass nuts;

Wherein, the fried bitter almond is obtained by the following method: take the bitter almond, put it in a hot pot, and fry it with slow fire until the surface is yellow or brownish yellow, with scorched spots and fragrant;

The bran fried Atractylodes is prepared by the following method: heating a hot pot until the bran is sprinkled into the bran and smoking immediately, putting the Atractylodes Rhizoma tablets into the hot pot, stirring quickly, frying until the surface is dark yellow, out of the pot, and sieving the bran , let cool. Per 100kg Atractylodes tablets, with bran

The fried grass nuts are prepared by the following method: take the grass fruits, remove impurities, put them in a hot pot, fry them with low heat until the surface is burnt yellow and slightly swelled, take out, remove the shells, and take the kernels; take the grass nuts, Put it in a hot pot, fry it with a simmer until the surface bulges and the aroma escapes, take it out and let it cool.

Correspondingly, the present invention discloses an antiviral drug, which comprises Huashibaidu granules composed of the above formula. The antiviral drugs include drugs for the treatment of 2019 novel coronavirus, but are not limited thereto.

Correspondingly, the present invention discloses an antiviral drug, which comprises the Huashibaidu granules prepared by the above preparation method. The antiviral drugs include drugs for the treatment of 2019 novel coronavirus, but are not limited thereto.

Implement the present invention, have the following beneficial effects:

(1) The present invention provides a kind of Huashibaidu granules, which is composed of ephedra, fried bitter almond, gypsum, licorice, patchouli, Magnolia, bran fried Atractylodes, fried grass nuts, Pinellia, Poria, Rhubarb, Astragalus, Tinglizi and red peony root fourteen herbs, among them, fried bitter almond contains a higher content of amygdalin, which has obvious effect of relieving cough and asthma, bran fried Atractylodes can improve the effect of Atractylodes on treating phlegm dampness and spleen. It can effectively restore the content of AQP2 and AQP3 in the digestive tract, as well as the content of ADH in the serum. Fried grass nuts can relieve dryness and avoid gastrointestinal discomfort;

Ephedra, fried bitter almond, raw gypsum, patchouli, Tinglizi, and rhubarb have a good synergistic effect, play the role of relieving the exterior, clearing heat and detoxifying, and can effectively improve the symptoms of fever and cough of patients;

Patchouli, Magnolia, bran fried Atractylodes, fried grass nuts, and Pinellia have good synergistic effects. Fatigue and shortness of breath.

Therefore, the Huashi Baidu granules have the functions of removing dampness and detoxification, dispelling heat from the lungs, and are useful for treating new coronary pneumonia symptoms such as fever, cough, fatigue, chest tightness, nausea, muscle soreness, dry throat, sore throat, loss of appetite, and stickiness in the mouth. It has obvious curative effect and is suitable for the treatment of mild, ordinary and severe patients with new coronavirus pneumonia.

(2) the present invention provides a kind of preparation method of Huashibaidu granules, the above-mentioned fourteen herbs are prepared into uniform specifications, uniform dosages and uniform quality standards in strict accordance with the unified preparation method and unified production process, and using modern production equipment Huashibaidu Granules. It has the advantages of easy portability, direct consumption, stable and controllable quality, etc. This form of medication is more suitable for modern clinical urgent needs, and can be directly applied to the clinical treatment of traditional Chinese medicine. The decoction process of the decoction is complicated, the decoction time is long, and the traditional decoction is inconvenient to store, carry and transport, and it is extremely inconvenient when a large amount of medication is urgently needed in clinical practice.

Moreover, the Huashibaidu granules of the present invention have good medicinal effects, and can keep the consistency with traditional decoctions, and the content of paeoniflorin, the total amount of ephedrine hydrochloride and pseudoephedrine hydrochloride can be stably controlled within a certain range, which is consistent with traditional decoctions. There was basically no significant difference in the index content of the decoction.

Description of drawings

Fig. 1 is the thin layer chromatogram of ephedra in Huashi Baidu Granules of the present invention, wherein, 1. Huashi Baidu Granules (J2004006) 3 μl; 2. Huashi Baidu Granules (J2004007) 3 μl; 3. Huashi Baidu Granules (J2004007) Granule (J2004008) 3μl; 4. Ephedrine hydrochloride reference substance 3μl;

Figure 2 is a thin-layer chromatogram of Magnolia officinalis in the Huashi Baidu Granules of the present invention, wherein, 1. Huashi Baidu Granules (J2004006) 4 μl; 2. Huashi Baidu Granules (J2004007) 4 μl; 3. Huashi Baidu Granules (J2004007) 4 μl Poison granules (J2004008) 4 μl; 4. Magnolol reference substance 4 μl; 5. Honokiol reference substance 4 μl;

Fig. 3 is the thin layer chromatogram of red peony in the Huashibaidu granules of the present invention, wherein, 1. Huashibaidu granules (J2004006) 3 μl; 2. Huashibaidu granules (J2004007) 3 μl; 3. Huashibaidu granules (J2004007) Poison granules (J2004008) 3μl; 4. Paeoniflorin reference substance 3μl;

Fig. 4 is the thin layer chromatogram of rhubarb in Huashi Baidu granules of the present invention, wherein, 1. Huashi Baidu granules (J2004006) 2 μl; 2. Huashi Baidu granules (J2004007) 2 μl; 3. Huashi Baidu granules (J2004007) 2 μl Granule (J2004008) 2μl; 4. Rhubarb control material 2μl;

5 is a thin-layer chromatogram of licorice in the Huashi Baidu granules of the present invention, wherein, 1. Huashi Baidu granules (J2004006) 4 μl; 2. Huashi Baidu granules (J2004007) 4 μl; 3. Huashi Baidu granules (J2004007) 4 μl Granule (J2004008) 4μl; 4. Licorice reference medicinal material 4μl;

Fig. 6 is the thin-layer chromatogram of Astragalus in Huashi Baidu granules of the present invention, wherein, 1. Huashi Baidu granules (J2004006) 2 μl; 2. Huashi Baidu granules (J2004007) 2 μl; 3. Huashi Baidu granules (J2004007) 2 μl Granule (J2004008) 2μl; 4. Astragaloside IV reference substance 2μl;

7 is a thin layer chromatogram of Tinglizi in the Huashi Baidu granules of the present invention, wherein 1. Huashi Baidu granules (J2004006) 2 μl; 2. Huashi Baidu granules (J2004007) 2 μl; 3. Huashi Baidu granules (J2004007) 2 μl Baidu Granules (J2004008) 2 μl; 4. Quercetin-3-O-β-D-glucose-7-O-β-D-gentiobiglycoside reference substance 2 μl;

Fig. 8 is the HE staining photo of the lung tissue of the Huashi Baidu granule group of the present invention;

Fig. 9 is a HE-stained photograph of lung tissue of mice in the model group.

detailed description

In order to make the objectives, technical solutions and advantages of the present invention clearer, the present invention will be further described in detail below with reference to the accompanying drawings.

The present invention provides Huashibaidu granules, which are mainly prepared from the following raw materials in parts by weight: ephedra, fried bitter almond, gypsum, licorice, patchouli, Magnolia, bran fried Atractylodes, fried grass fruit Ren, Pinellia, Poria, Rhubarb, Astragalus, Tinglizi, Red Peony, accessories.

Among them, Ephedra is the dry herbaceous stem of Ephedra sinica Stapf, Ephedra intermedia Schrenk et C.A.Mey. or Ephedra equisetina Bge. Green grassy stems are harvested in autumn and sun-dried.

Fried bitter almonds are processed products of dried and mature seeds of Rosaceae plants Prunus armeniaca L.var.ansu Maxim., Siberian apricot Prunus sibirica L., Northeast apricot Prunus mandshurica (Maxim.) Koehne or apricot Prunus armeniaca L.. Harvest the ripe fruit in summer, remove the pulp and core shell, take out the seeds, and dry them in the sun. Mainly produced in Liaoning, Hebei, Inner Mongolia, Shandong and other provinces. This product is shaped like a bitter almond, the surface is yellow to brownish yellow with slight focal spots. Aroma, bitter taste. Specifically, the fried bitter almonds are prepared by the following method: take the bitter almonds, put them in a hot pot, and fry them with slow fire until the surface is yellow or brownish yellow, with slightly scorched spots and aroma.

The main component of bitter almond is amygdalin, which has the pharmacological effect of relieving cough and asthma by decomposing into hydrocyanic acid. Pharmacodynamic studies found that the four test solutions of bitter almonds (fried bitter almond, postnatal bitter almond, dried bitter almond and raw bitter almond) all had obvious effects of relieving cough and relieving asthma. The present invention selects fried bitter almonds, and the content of amygdalin is appropriate, and can play an obvious role in relieving cough and relieving asthma when treating the 2019 novel coronavirus.

Raw gypsum is a sulfate mineral anhydrite gypsum, mainly containing calcium sulfate (CaSO ₄ ·2H ₂ O). After excavation, debris and sediment are removed.

Licorice, the dried root and rhizome of the legume Glycyrrhiza uralensis Fisch., Glycyrrhiza inflata Bat. or Glycyrrhiza glabra L. Excavated in spring and autumn, removed fibrous roots, and sun-dried.

Patchouli is the dry aerial part of the Lamiaceae plant, Pogostemon cablin (Blanco) Benth. Harvest when the branches and leaves are lush, dry in the sun and night, and repeat until dry. Shipai is mainly produced in Guangzhou City, Guangdong Province, and is also cultivated in Hainan, Taiwan, Guangxi, Yunnan and other provinces.

Magnolia officinalis is the dried bark, root bark and branch bark of Magnolia officinalis Rehd.et Wils. or Magnolia officinalis Rehd.et Wils.var.biloba Rehd.et Wils. Peel off from April to June, dry the root bark and branch bark directly in the shade; boil the dried bark in boiling water, stack it in a damp place, "sweating" until the inner surface turns purple-brown or tan, steam until soft, take it out, and roll it into a Cylindrical, dry.

Bran fried Atractylodes is a processed product of the dried rhizomes of Atractylodes lancea (Thunb.) DC. or Atractylodes chinensis (DC.) Koidz. Excavation in spring and autumn, removing sediment, drying, and knocking off fibrous roots. Specifically, the bran fried Atractylodes is prepared by the following method: heating a hot pot until the bran is sprinkled into the bran to smoke immediately, putting the Atractylodes Atractylodis into the hot pot, stirring quickly, frying until the surface is dark yellow, out of the pot, sieving Remove bran and let cool. Per 100kg Atractylodes tablets, with bran

Both the raw and bran-fried Atractylodes Rhizoma reduced the water content of the large intestine of the model rats, and the serum GAS content and AMS increased. However, adding the bran-fried Atractylodes Atractylodis in the present invention, in addition to the above effects, it can also restore the contents of AQP2 and AQP3 in the digestive tract, as well as the serum GAS content and AMS. The content of ADH enhances the effect of Atractylodes Rhizoma in treating phlegm-dampness and trapping the spleen.

Stir-fried grass nuts are dried and ripe fruits of Amomum tsao-ko Crevost et Lemaire, a ginger plant. Harvest when the fruit is ripe in autumn, remove impurities, and dry in the sun or at low temperature. Specifically, the fried grass nuts are prepared by the following method: take the grass fruit, remove impurities, put it in a hot pot, fry it with slow heat until the surface is browned and slightly bulged, take out, remove the shell, and take the kernel; take the grass Put the nuts in a hot pot, fry them with a simmer until the surface swells and the aroma escapes, take them out and let them cool.

The warm-dry properties of strawberries are obvious, and the use of fried strawberries in the present invention can alleviate the dryness and avoid gastrointestinal discomfort.

Pinellia ternata is the dry tuber of Pinellia ternata (Thunb.) Breit. Excavated in summer and autumn, washed, removed the outer skin and fibrous roots, and sun-dried. Mainly produced in Sichuan, Hubei, Henan, Guizhou and other provinces. This product is a processed product of Pinellia. Take Pinellia, separate the size, soak it in water until there is no dry core, take it out; take another appropriate amount of licorice, add water to decoct twice, combine the decoction, pour it into the lime liquid made of an appropriate amount of water, stir well, add the above soaked Soak it, stir it 1-2 times a day, and keep the pH value of the infusion solution above 12, until the section is yellow and uniform, and when the taste is slightly numb, take it out, wash it, dry it in the shade or dry it. For every 100kg of net Pinellia, use 15kg of licorice and 10kg of quicklime.

Poria cocos is the dried sclerotia of Poria cocos (Schw.) Wolf of the Poria family fungus. More than July to September excavation, remove the sediment after excavation, pile up "sweat", spread it out to dry the surface, then "sweat", repeat several times until wrinkles appear and most of the internal water is lost, then dry in the shade , called "Poria"; or cut fresh Poria according to different parts, dried in the shade, called "Poria block" and "Poria tablet" respectively.

Rhubarb is the dried root and rhizome of Rheum palmatum L., Rheum tanguticum Maxim.ex Balf. or Rheum officinale Baill. When the stems and leaves are withered in the late autumn or before germination in the next spring, the fine roots are removed, the outer skin is scraped, the petals or segments are cut, and the ropes are threaded into strings to dry or directly dry.

Astragalus, the dried root of the legume Astragalus membranaceus (Fisch.) Bge.var. mongolicus (Bge.) Hsiao or Astragalus membranaceus (Fisch.) Bge. Excavated in spring and autumn, removed fibrous roots and root heads, and sun-dried.

Tinglizi is the dry mature seeds of Cruciferous plant Descurainia sophia(L.)Webb.ex Prantl. or Lepidium apetalum Willd. The plants are harvested when the fruit is ripe in summer, dried in the sun, and the seeds are rubbed out to remove impurities.

Paeonia lactiflora is the dry root of Paeonia lactiflora Pall. or Paeonia veitchii Lynch of the Ranunculaceae plant. Harvest and control in spring and autumn, remove rhizomes, whiskers and sediment, and dry in the sun.

The adjuvant is a pharmaceutically acceptable adjuvant, including one or more of dextrin and steviol, but not limited to this.

The Huashibaidu granules of the present invention take ephedra, patchouli and gypsum as the king medicine in the prescription, ephedra and patchouli are acrid, bitter, warm and have a fragrant smell, soothe skin and relieve asthma, dispel dampness and neutralize the middle; gypsum, acrid, , sweet, cold, clearing the lung and stomach stagnation heat and promoting body fluid, the three medicines complement each other to achieve the effects of relieving the exterior and dispelling cold, aromatizing dampness, clearing heat and relieving asthma. Stir-fried bitter almond, French pinellia, Magnolia, bran fried Atractylodes, stir-fried grass nut, Poria as minister medicine, fried bitter almond, French pinellia, Magnolia, pungent, bitter, warm, promoting Qi and reducing inversion, opening knot Relieve asthma; bran fried Atractylodes, fried grass nuts, pungent, bitter and warm, enter the spleen and stomach meridian, dry dampness and strengthen the spleen, break the knot of suffocation; Poria, light infiltration, dehumidification and invigorating the spleen; six herbs are used together to help dry the monarch. Dampness strengthens the spleen, circulates qi and unclogs the orifices, dredges the bowels, and helps the evil to go out. With astragalus, red peony root, tincture seed, rhubarb as adjuvant, astragalus, sweet, warm and invigorating the lung and spleen, red peony root, bitter, slightly cold, cooling blood and dissipating blood stasis, used for the treatment of blood stasis caused by damage to the right qi in the later stage of the epidemic and qi stagnation. Blood stasis, etc.; Tinglizi is acrid and cold, assists the monarch medicine gypsum to clear lung heat, and also benefits water, preventing or treating "damp lung (pulmonary edema) lesions"; rhubarb, bitter cold enters the large intestine meridian and clears the fu-organs, and the lungs and the large intestine are related to each other. In addition, the monarch medicine gypsum plaster is used as an adjuvant to clear the lung heat, and the red peony root is used to cool the blood and activate the blood. Using licorice as the medicine, licorice ganping, reconciling various medicines, with red peony root and shaoyao licorice decoction to relieve emergency. The whole recipe has the functions of clearing away dampness, clearing away heat and relieving asthma, nourishing qi and dissipating blood stasis.

It is clinically found that patients with severe new coronary pneumonia have the following characteristics: (1) Fever is the main manifestation, which is mostly low body heat, which is difficult to heal, but it can also be moderate to low fever, or even no fever; (2) wheezing and fatigue are the main symptoms; Digestive system symptoms such as anorexia, loose stools, and diarrhea are often combined; ④ Most of the patients have thick and greasy tongue coating. Judging from the above characteristics, it is in line with the pathogenic characteristics of dampness: heavy turbidity, hindering qi and injuring yang, sticking, and descending. Dampness pathogens can cause disease alone, and can also be cold and hot, manifesting as cold-dampness, dampness-heat, of which heat can be caused by dryness, or it can be transformed by dampness for a long time. Damp pathogens, cold-dampness, and damp-heat can be combined with epidemic toxins to cause disease, which can be seen in mild cold-damp stagnation of the lung, damp-heat accumulation in the lung, or common damp-toxin stagnation in the lung, and cold-dampness in the lung. The disease develops, injures the blood, reverses the pericardium, and evolves into severe new coronary pneumonia. Therefore, it is believed that the prominent manifestation of new coronary pneumonia is "damp toxin epidemic", the disease is located in the lung, and is closely related to the spleen. Epidemic toxin is the fundamental, and the core pathogenesis is the combination of epidemic toxin and damp pathogens, which can simultaneously invade the body with cold and heat, block the chest and lungs, abnormal up and down of Qi, blood stasis, and qi and yin consumption. The pathological nature of COVID-19 is complex and involves multiple pathological factors.

The main disease site is in the lungs, followed by the spleen and stomach. The core pathogenesis is dampness and toxin stagnation. It can be divided into four stages: the initial stage, the middle stage, the critical stage and the recovery stage. The lungs resolve phlegm, promote blood circulation and remove blood stasis, clear the internal organs, and nourish the righteousness. Therefore, the compatibility of the Huashi Baidu granules of the present invention is based on the core pathogenesis. The combination of epidemic toxin and cold-dampness, aversion to cold and fever, the treatment is appropriate to relieve the exterior and remove dampness and toxin; the combination of epidemic toxin and dampness and heat can cause loose stools, fatigue and fatigue, and it is suitable for clearing away heat, removing dampness and eliminating toxin, and simultaneously nourishing qi and nourishing yin; Chest and lung, wheezing, chest tightness, shortness of breath.

The Huashibaidu granule formula of the present invention integrates the core pathogenesis of traditional Chinese medicine treatment in the "Diagnosis and Treatment Scheme for Pneumonia Infected by Novel Coronavirus (Trial Version 5)". ", with damp turbidity and heat stagnation of the lung as the main, highlighting the effect of dampening and promoting qi, dispelling lung and relieving asthma, clearing heat and resolving phlegm, benefiting qi and promoting blood circulation. Early clinical observation shows that the present invention can improve the clinical symptoms of severe novel coronavirus infection pneumonia. Symptoms, for severe patients, can significantly relieve the main symptoms such as cough, fatigue, dry mouth or vomiting. After the treatment of integrated traditional Chinese and Western medicine, the healing time is shortened. The respiratory function of the patient is obviously improved, and the time to get out of oxygen is shortened. For ordinary patients, the The symptoms of fever are significantly relieved, and the symptoms of loss of appetite and chest tightness can also be improved. The clinical symptoms such as cough, fatigue, dry mouth or vomiting of severe and common novel coronavirus pneumonia have been significantly improved, supplementing the severe and common types of pneumonia urgently needed by the current epidemic situation. Drugs for the treatment of novel coronavirus pneumonia.

The amount of ephedra, patchouli, raw gypsum, fried bitter almonds, Pinellia fragrans, Magnolia officinalis, bran fried Atractylodes, fried grass nuts, Poria, Astragalus, red peony, Tinglizi, rhubarb and licorice of the present invention has a wide range , 3-60 servings of ephedra, 4.5-90 servings of fried bitter almonds, 7.5-150 servings of raw gypsum, 1.5-30 servings of licorice, 5-100 servings of patchouli, 5 servings of Magnolia officinalis -100 servings, 7.5-150 servings of bran fried Atractylodes, 5-100 servings of fried grass nuts, 4.5-90 servings of Pinellia, 7.5-150 servings of Poria, 2.5-50 servings of rhubarb , 5-100 copies of Astragalus, 5-100 copies of Tinglizi, and 5-100 copies of Chishao, suitable for mass production.

During the research process, the inventors used molecular docking technology to identify the key targets of the invasion, replication, assembly, shedding and transfer of COVID-19, as well as the key roles of various traditional Chinese medicines in the formulation of Huashibaidu composition, as well as the key role of lung damage and inflammatory response in the host. target for analysis. The results showed that ephedra inhibited the viral invasion and shedding targets TMPRSS2, TACE, AAK1 (viral invasion, endocytosis regulation), and the key targets of tissue damage after the virus invaded the host. VEGFR2 (vascular permeability) and ALK5 (vascular permeability, lung fibrosis) respond. Rhubarb responds to TMPRSS2, a target that inhibits virus entry and shedding, and AMPK, VEGFR2, and ALK5, which are key targets of tissue damage after virus invasion into the host. Paeonia lactiflora responds to targets Mpro and ACE2.

For the ephedra in the composition for eliminating dampness and baidu, it mainly plays the role of dispersing lung qi, resolving phlegm and relieving cough. According to the principle of traditional Chinese medicine formula, it belongs to the monarch medicine and plays an important role in the prescription. At the same time, the ephedrine introduced by ephedra is volatile and easily lost in the process of mass production. Therefore, the present invention controls the content of ephedrine hydrochloride and pseudoephedrine hydrochloride, and the content of described ephedrine hydrochloride and pseudoephedrine hydrochloride is 0.7～2.7mg/g, and then guarantees the curative effect of dampness and sepsis composition.

For the rhubarb in the composition for eliminating dampness and baidu, its main function is to clear lung heat, activate blood and cool blood. phenol, emodin methyl ether). However, the combined anthraquinone is easily decomposed into free anthraquinone when heated, resulting in a weakened drug effect. Therefore, the present invention needs to control the content of the combined anthraquinone, and the content of the combined anthraquinone should not be less than 0.016%, thereby ensuring the curative effect of the composition for eliminating dampness and sepsis.

It should be noted that bound anthraquinone content = total anthraquinone content - free anthraquinone content. In a specific implementation, the total anthraquinone content and the free anthraquinone content in the Huashibaidu composition can be determined by high performance liquid chromatography, and then the bound anthraquinone content can be calculated.

It should be noted that the adjuvant is a pharmaceutically acceptable adjuvant, including one or more of dextrin and steviol, and the amount of the adjuvant can be determined according to the actual situation, generally 1-200 parts, preferably 10-100 servings, but not limited to this. The auxiliary materials may also include common auxiliary materials such as maltodextrin, beta cyclodextrin, silicon dioxide, magnesium stearate, etc., and are not limited thereto.

The formula for eliminating dampness and baidu is composed of ephedra, patchouli, raw gypsum, fried bitter almond, French pinellia, Magnolia, bran fried Atractylodes, fried grass nuts, Poria, Astragalus, red peony, Tinglizi, rhubarb and licorice fourteen The composition of herbal medicines is generally made of traditional Chinese medicine decoctions for consumption. However, the decoction of Huashibaidu decoction is complicated in the decoction process, the decoction takes a long time, and the traditional decoction is inconvenient to store, carry and transport. extremely inconvenient.

To this end, the present invention provides a preparation method of Huashibaidu Granules. The above-mentioned fourteen herbs are prepared into uniform specifications, uniform dosages, and uniform quality standards by using modern production equipment in strict accordance with the unified preparation method and unified production process. Huashibaidu Granules. Specifically, the preparation method includes:

(1) take raw gypsum according to the formula, add water to decoct;

In order to ensure the expected curative effect of clinical medication, gypsum in the prescription is a mineral medicine, and the active ingredients are not easy to be decocted. It needs to be decocted first, that is, it should be decocted for about 30 minutes, and then add other drugs to decoct at the same time; patchouli is effective. The ingredients are easy to evaporate and disperse after decoction, and it should be put into boiling for a few minutes when it is ready to be fried. If the rhubarb is fried for a long time, the diarrhea force will be slowed down, and it is also suitable to be placed after the decoction.

The Huashi Baidu granules prepared by this method have the advantages of easy portability, direct consumption, stable and controllable quality. The clinical application solves the problems that the decoction of Huashibaidu decoction is complicated, the decoction time is long, the traditional decoction is inconvenient to store, carry and transport, and it is extremely inconvenient when a large amount of medication is urgently needed in clinical practice.

In the above preparation method, the order of addition of the fourteen herbs, the amount of water added, the decocting time, the number of times of decocting, the concentration method and the relative density of the clear paste are all key points in the decocting process, which affect the curative effect of Huashibaidu Granules. , and affected the paeoniflorin content, the total amount of ephedrine hydrochloride and pseudoephedrine hydrochloride. The present invention is further elaborated below in conjunction with the technical details of each step:

In step (1), the raw gypsum is decocted first, and the decoction time of the raw gypsum is 20-40 minutes, which conforms to the characteristics of gypsum and is beneficial to the decoction of the active ingredients. Preferably, the decoction time of the raw gypsum is about 30 minutes.

The amount of water added in step (1) is ephedra, fried bitter almonds, raw gypsum, licorice, Magnolia, bran fried Atractylodes, fried grass nuts, Pinellia, Poria, Astragalus, Tinglizi, Chishao these twelve herbs. 1 to 6 times the amount of water, which is the amount of water added in combination with the production conditions of large production equipment, which is conducive to the decoction of gypsum and subsequent active ingredients of medicine, and is suitable for mass production.

In step (2), the time of adding water for decocting is 40-60 minutes. In the present invention, after decoction of raw gypsum, ephedra, fried bitter almonds, licorice, Magnolia, bran fried Atractylodes, fried grass nuts, Pinellia, Poria, Astragalus, Tinglizi and red peony are added for 40-60 minutes. , is conducive to the frying of the active ingredients of ephedra, fried bitter almonds, licorice, magnolia, bran fried Atractylodes, fried grass nuts, Pinellia, Poria, Astragalus, Tinglizi and red peony. Preferably, the time of adding water for decocting in step (2) is 50 minutes.

The amount of water added in step (2) is ephedra, fried bitter almonds, raw gypsum, licorice, Magnolia officinalis, bran fried Atractylodes, fried grass nuts, Pinellia, Poria, Astragalus, Tinglizi, Chishao these twelve herbs 2 to 7 times the amount of water. This is the amount of water added in combination with the production conditions of large production equipment, which is beneficial to ephedra, fried bitter almonds, raw gypsum, licorice, magnolia, bran fried Atractylodes, fried grass nuts, Pinellia, Poria, Astragalus, Tingli The active ingredient of red peony root is fried out, and it is suitable for mass production at the same time.

In step (3), add patchouli and rhubarb, add water and cook for 5 to 15 minutes. Patchouli and rhubarb are added in step (3) to avoid the volatilization or weakening of active ingredients due to decoction, and the decoction time of patchouli and rhubarb is 5 to 15 minutes, which can also avoid active ingredients. Dissipate or weaken.

The amount of water added in step (3) is 6 to 10 times that of the two herbs, patchouli and rhubarb. This is the amount of water added in combination with the production conditions of large production equipment, which is beneficial to ephedra, fried bitter almonds, raw gypsum, licorice, magnolia, bran fried Atractylodes, fried grass nuts, Pinellia, Poria, Astragalus, Tingli Zi, the active ingredients of red peony root are continuously decocted, and the active ingredients of patchouli and rhubarb are decocted, which are suitable for mass production at the same time.

More preferably, in step (3), add patchouli and rhubarb, add water and cook for 8-12 minutes, and the amount of water added is 8 times that of patchouli and rhubarb.

In step (4), the medicinal dregs are added with water for decocting for 40-80min, and the amount of water added is ephedra, fried bitter almond, raw gypsum, licorice, patchouli, magnolia, bran fried Atractylodes, fried grass nuts, Pinellia fragrans, Poria, Rhubarb, Astragalus, Tinglizi, Chishao are 6 to 10 times the amount of water for the fourteen herbs. In the invention, the medicinal residues are decocted again, which is beneficial to fully decocting the effective components and improves the medicinal effect of the Huashibaidu granules.

Preferably, in step (4), the medicinal residues are boiled with water for 50 to 60 minutes, and the amount of water added is ephedra, fried bitter almonds, raw gypsum, licorice, patchouli, Magnolia, bran fried Atractylodes, fried grass nuts, method Pinellia, Poria, Rhubarb, Astragalus, Tinglizi, Chishao are 8 times the amount of water for the fourteen herbs.

Step (5) includes:

The first decoction and the second decoction are respectively concentrated under reduced pressure to a clear paste with a relative density of 1.01-1.05, and then combined under reduced pressure and concentrated to a clear paste with a relative density of 1.06-1.20. Under the relative density, the clear paste has good fluidity and suitable paste amount, which is matched with the current large-scale production drying equipment.

Preferably, the temperature of the vacuum concentration is 45°C to 85°C, and the pressure is 0.00 to -0.095MPa. The reduced-pressure concentration conditions can ensure the stability of the ingredients to the greatest extent during the mass production of Huashibaidu Granules.

Preferably, the drying is at least one of spray drying, belt drying or freeze drying, but is not limited thereto. The granulation is at least one of boiling granulation, wet granulation, and dry granulation, but is not limited thereto.

Those skilled in the art can choose the appropriate drying method and granulation method according to the actual production conditions.

As a further improvement scheme of the present invention, before step (1), comprise:

Wherein, the fried bitter almonds are prepared by the following method: take the bitter almonds, put them in a hot pot, and fry them with slow fire until the surface is yellow or brownish yellow, with slightly scorched spots and aroma.

The bran fried Atractylodes is prepared by the following method: heating a hot pot until the bran is sprinkled into the bran to smoke immediately, putting the Atractylodes Rhizoma tablets into the hot pot, stirring quickly, frying until the surface is dark yellow, out of the pot, and sieving out the bran , let cool. Per 100kg Atractylodes tablets, with bran

The Huashibaidu particles of the present invention can be applied to the treatment of various viral diseases, such as 2019 novel coronavirus, or others. As long as the pathogenesis of the viral disease is dampness and stagnation, the Huashibaidu granules can be reasonably used as the main treatment method or as an auxiliary treatment method.

It should be noted that the Huashibaidu granules of the present invention are especially suitable for treating patients with 2019 novel coronavirus. Preliminary clinical observation shows that the present invention can improve the clinical symptoms of severe novel coronavirus infection pneumonia, and for severe patients, it can significantly relieve the main symptoms such as cough, fatigue, dry mouth or vomiting, and after the treatment of integrated traditional Chinese and Western medicine, the healing time is shortened, and the improvement is obvious. The patient's respiratory function, and the time away from oxygen inhalation is shortened. For ordinary patients, the symptoms of fever are significantly relieved, and the symptoms of loss of appetite and chest tightness can also be improved. The clinical symptoms such as cough, fatigue, dry mouth or vomiting for severe and common new coronavirus infection pneumonia have been significantly improved, and it has supplemented the current epidemic situation urgently needed drugs for severe and common new coronavirus infection pneumonia.

The present invention is further described below with specific examples

Example 1

The preparation steps of the Huashibaidu granules of the present embodiment are as follows:

(1) The preparation raw materials include: 24 pieces of Ephedra, 40 pieces of Patchouli, 60 pieces of raw gypsum, 36 pieces of fried bitter almond, 36 pieces of Pinellia, 40 pieces of Magnolia, 60 pieces of fried Atractylodes , 40 pieces of fried grass nuts, 60 pieces of Poria, 40 pieces of Astragalus, 40 pieces of red peony, 40 pieces of Tinglizi, 20 pieces of rhubarb, 12 pieces of licorice, 50 pieces of dextrin, 0.6 stevia share.

(2) Preparation of Huashibaidu Granules: take the total crude drug amount of Huashibaidu prescription decoction pieces to be 548kg, add 2440L of raw gypsum water to decoct for 30 minutes, add the other eleven flavors except patchouli and rhubarb, add 1464L of water After decocting for 50 minutes, add patchouli and rhubarb, add 480L of water and decocted for 10 minutes, filter to obtain the first decoction and medicinal residues; add 4384L of medicinal residues to decoct for 1 hour, filter to obtain The second decoction; the first decoction and the second decoction are respectively concentrated under reduced pressure to a clear paste with a relative density of 1.01 to 1.05 under the condition of temperature 45 ℃～85 ℃, merge, reduce under the condition of temperature 45 ℃～85 ℃ Pressing and concentrating to a clear paste with a relative density of 1.06-1.20; adding dextrin and steviol and mixing, spray drying, adding dextrin and mixing, dry granulation and packaging to obtain Huashibaidu granules.

Example 2

(2) Preparation of Huashibaidu Granules: take the total crude drug amount of Huashibaidu prescription decoction pieces to be 548kg, add 2440L of raw gypsum water to decoct for 30 minutes, add the other eleven flavors except patchouli and rhubarb, add 1464L of water After decocting for 50 minutes, add patchouli and rhubarb, add 480L of water and decocted for 10 minutes, filter to obtain the first decoction and medicinal residues; add 4384L of medicinal residues to decoct for 1 hour, filter to obtain The second decoction; the first decoction and the second decoction are respectively concentrated under reduced pressure to a clear paste with a relative density of 1.01 to 1.05 under the condition of temperature 45 ℃～85 ℃, merge, reduce under the condition of temperature 45 ℃～85 ℃ Pressing and concentrating to a clear paste with a relative density of 1.06-1.20; adding dextrin and steviol and mixing, boiling for granulation, drying, and packaging to obtain Huashibaidu granules.

Example 3

(2) Preparation of Huashibaidu Granules: take the total crude drug amount of Huashibaidu prescription decoction pieces to be 548kg, add 2440L of raw gypsum water to decoct for 30 minutes, add the other eleven flavors except patchouli and rhubarb, add 1464L of water After decocting for 50 minutes, add patchouli and rhubarb, add 480L of water and decocted for 10 minutes, filter to obtain the first decoction and medicinal residues; add 4384L of medicinal residues to decoct for 1 hour, filter to obtain The second decoction; the first decoction and the second decoction are respectively concentrated under reduced pressure to a clear paste with a relative density of 1.01 to 1.05 under the condition of temperature 45 ℃～85 ℃, merge, reduce under the condition of temperature 45 ℃～85 ℃ Pressing and concentrating to a clear paste with a relative density of 1.06-1.20; adding dextrin and steviol and mixing, belt drying, wet granulation, drying and packaging to obtain Huashibaidu granules.

Example 4

(2) Preparation of Huashibaidu Granules: take the total crude drug amount of Huashibaidu prescription decoction pieces to be 548kg, add 488L of raw gypsum water to decoct for 30 minutes, add the other eleven flavors except patchouli and rhubarb, add 3416L of water After decocting for 50 minutes, add patchouli and rhubarb, add 480L of water and decocted for 10 minutes, filter to obtain the first decoction and medicinal residues; add 4384L of medicinal residues to decoct for 1 hour, filter to obtain The second decoction; the first decoction and the second decoction are respectively concentrated under reduced pressure to a clear paste with a relative density of 1.01 to 1.05 under the condition of temperature 45 ℃～85 ℃, merge, reduce under the condition of temperature 45 ℃～85 ℃ Pressing and concentrating to a clear paste with a relative density of 1.06-1.20; adding dextrin and steviol and mixing, spray drying, adding dextrin and mixing, dry granulation and packaging to obtain Huashibaidu granules.

Example 5

(1) The preparation materials include: 12 pieces of Ephedra, 20 pieces of Patchouli, 30 pieces of raw gypsum, 18 pieces of fried bitter almond, 18 pieces of Pinellia, 20 pieces of Magnolia, and 30 pieces of fried Atractylodes , 20 pieces of fried grass nuts, 30 pieces of Poria, 20 pieces of Astragalus, 20 pieces of red peony, 20 pieces of Tinglizi, 10 pieces of rhubarb, 6 pieces of licorice, 25 pieces of dextrin, 0.3 stevia share.

(2) Preparation of Huashibaidu Granules: take the total crude drug amount of Huashibaidu decoction pieces to be 274kg, add 1464L of raw gypsum water to decoct for 30 minutes, add the other eleven flavors except patchouli and rhubarb, add 488L of water After decocting for 50 minutes, add patchouli and rhubarb, add 240L of water and decocted for 10 minutes, filter to obtain the first decoction and medicinal residues; add 2192L of medicinal residues to decoct for 1 hour, filter to obtain The second decoction; the first decoction and the second decoction are respectively concentrated under reduced pressure to a clear paste with a relative density of 1.01 to 1.05 under the condition of temperature 45 ℃～85 ℃, merge, reduce under the condition of temperature 45 ℃～85 ℃ Pressing and concentrating to a clear paste with a relative density of 1.06-1.20; adding dextrin and steviol and mixing, spray drying, adding dextrin and mixing, dry granulation and packaging to obtain Huashibaidu granules.

Example 6

(1) The preparation materials include: 36 pieces of Ephedra, 60 pieces of Patchouli, 90 pieces of raw gypsum, 54 pieces of fried bitter almond, 54 pieces of Pinellia, 60 pieces of Magnolia, 90 pieces of fried Atractylodes , 60 pieces of fried grass nuts, 90 pieces of Poria, 60 pieces of Astragalus, 60 pieces of red peony, 60 pieces of Tinglizi, 30 pieces of rhubarb, 18 pieces of licorice, 99 pieces of dextrin, 1 piece of stevia share.

(2) Preparation of Huashibaidu Granules: take the total crude drug amount of Huashibaidu decoction pieces to be 822kg, add 2196L of raw gypsum water to decoct for 30 minutes, add the other eleven flavors except patchouli and rhubarb, add 3660L of water After decocting for 50 minutes, add patchouli and rhubarb, add 720L of water and decocted for 10 minutes, filter to obtain the first decoction and medicinal residues; add 6576L of medicinal residues to decoct for 1 hour, filter to obtain The second decoction; the first decoction and the second decoction are respectively concentrated under reduced pressure to a clear paste with a relative density of 1.01 to 1.05 under the condition of temperature 45 ℃～85 ℃, merge, reduce under the condition of temperature 45 ℃～85 ℃ Pressing and concentrating to a clear paste with a relative density of 1.06-1.20; adding dextrin and steviol and mixing, spray drying, adding dextrin and mixing, dry granulation and packaging to obtain Huashibaidu granules.

Example 7

(1) The raw materials for preparation include: 3 pieces of Ephedra, 5 pieces of Patchouli, 7.5 pieces of raw gypsum, 4.5 pieces of fried bitter almond pieces, 4.5 pieces of Pinellia, 5.0 pieces of Magnolia, and 7.5 pieces of fried Atractylodes. , 5.0 pieces of fried grass nuts, 7.5 pieces of Poria, 5.0 pieces of Astragalus, 5.0 pieces of red peony, 5.0 pieces of Tinglizi, 2.5 pieces of rhubarb, 1.5 pieces of licorice, 5.5 pieces of dextrin, 0.05 of stevia share.

(2) Preparation of Huashibaidu Granules: take the total crude drug amount of Huashibaidu prescription decoction pieces to be 68.5kg, add 305L of raw gypsum and decoct for 30 minutes, add the other eleven flavors except patchouli and rhubarb, add 183L After decocting in water for 50 minutes, add patchouli and rhubarb, add 60L of water and decoct for 10 minutes, filter to obtain the first decoction and medicinal residue; add 548L of medicinal residue to decoct for 1 hour, filter, Obtain the second decoction; the first decoction and the second decoction are respectively concentrated under reduced pressure to a clear paste with a relative density of 1.01 to 1.05 under the condition of temperature 45 ℃～85 ℃, merge, under the condition of temperature 45 ℃～85 ℃ Concentrate under reduced pressure to a clear paste with a relative density of 1.06-1.20; add dextrin and steviol and mix, spray-dry, add dextrin and mix, dry granulate, and package to obtain Huashibaidu granules.

Example 8

(1) The preparation raw materials include: 60 pieces of Ephedra, 100 pieces of Patchouli, 150 pieces of gypsum, 90 pieces of fried bitter almond, 90 pieces of Pinellia, 100 pieces of Magnolia, 150 pieces of fried Atractylodes , 100 pieces of fried grass nuts, 150 pieces of Poria, 100 pieces of Astragalus, 100 pieces of red peony, 100 pieces of Tinglizi, 50 pieces of rhubarb, 30 pieces of licorice, 179 pieces of dextrin, 2 stevia share.

(2) Preparation of Huashibaidu Granules: take the total crude drug amount of Huashibaidu prescription decoction pieces to be 1370kg, add 6100L of raw gypsum water to decoct for 30 minutes, add the other eleven flavors except patchouli and rhubarb, add 3660L of water After decocting for 50 minutes, add patchouli and rhubarb, add 1200L of water and decocted for 10 minutes, filter to obtain the first decoction liquid and medicinal residue; add 10960L of medicinal residue to decoct for 1 hour, filter to obtain The second decoction; the first decoction and the second decoction are respectively concentrated under reduced pressure to a clear paste with a relative density of 1.01 to 1.05 at a temperature of 45°C to 85°C. Pressing and concentrating to a clear paste with a relative density of 1.06-1.20; adding dextrin and steviol and mixing, spray drying, adding dextrin and mixing, dry granulation and packaging to obtain Huashibaidu granules.

Comparative Example 1

The traditional decoction preparation steps of the Huashi Baidu granules of this comparative example are as follows:

(1) The preparation materials include: 3 pieces of Ephedra, 5 pieces of Patchouli, 7.5 pieces of raw gypsum, 4.5 pieces of fried bitter almond pieces, 4.5 pieces of Pinellia, 5 pieces of Magnolia, and 7.5 pieces of fried Atractylodes. , 5 pieces of fried grass nuts, 7.5 pieces of Poria, 5 pieces of Astragalus, 5 pieces of red peony, 5 pieces of Tinglizi, 2.5 pieces of rhubarb, 1.5 pieces of licorice.

(2) Preparation of Huashibaidu Granules: The total crude drug amount of Huashibaidu prescription decoction pieces is 68.5g. Add water to decoct for 30 minutes, add the other eleven flavors except patchouli and rhubarb, add water to decoct for 50 minutes, add patchouli and rhubarb, add water to decoct for 10 minutes, filter, and concentrate the filtrate to an appropriate amount; The residue is boiled with water for 1 hour, filtered, and the filtrate is concentrated to an appropriate amount, combined with the above-mentioned medicinal liquid, and then concentrated to an appropriate amount to obtain the traditional decoction of Huashibaidu granules.

Comparative Example 2

The preparation steps of the Huashibaidu granules of this comparative example are as follows:

(1) The preparation raw materials include: 24 pieces of Ephedra, 40 pieces of Patchouli, 60 pieces of raw gypsum, 36 pieces of fried bitter almond, 36 pieces of Pinellia, 40 pieces of Magnolia, 60 pieces of fried Atractylodes , 40 pieces of fried grass nuts, 60 pieces of Poria, 40 pieces of Astragalus, 40 pieces of red peony, 40 pieces of Tinglizi, 20 pieces of rhubarb, 12 pieces of licorice, maltodextrin, beta cyclodextrin Essence, Steviolin, Silicon Dioxide, Magnesium Stearate.

(2) Preparation of Huashibaidu Granules: take the total crude drug amount of Huashibaidu prescription decoction pieces to be 548kg, add 2440L of raw gypsum water to decoct for 30 minutes, add the other eleven flavors except patchouli and rhubarb, add 1464L of water After decocting for 50 minutes, add patchouli and rhubarb, add 480L of water and decocted for 10 minutes, filter to obtain the first decoction and medicinal residues; add 4384L of medicinal residues to decoct for 1 hour, filter to obtain The second decoction; the first decoction and the second decoction are respectively concentrated under reduced pressure to a clear paste with a relative density of 1.01 to 1.05 under the condition of temperature 45 ℃～85 ℃, merge, reduce under the condition of temperature 45 ℃～85 ℃ Press and concentrate to a clear paste with a relative density of 1.06-1.20; add maltodextrin, betacyclodextrin and steviol, mix well, spray dry, add silicon dioxide, magnesium stearate and mix well, dry granulation, packaging, Obtain Huashibaidu granules.

Example 1-8 and comparative example 1-2 are done index component content measurement, and the results are as follows:

(1) Determination method of index component content

Paeoniflorin: Determination according to high performance liquid chromatography ("Chinese Pharmacopoeia" 2015 edition four general rules 0512).

Chromatographic conditions and system suitability test: use octadecylsilane-bonded silica gel as the filler; use methanol-0.05mol/L potassium dihydrogen phosphate solution (35:65) as the mobile phase; the detection wavelength is 230 nm; 1 ml per minute; the column temperature is 30 °C. The theoretical plate number should not be less than 3000 according to the paeoniflorin peak.

Preparation of reference substance solution: take an appropriate amount of paeoniflorin reference substance, accurately weigh it, and add methanol to make a reference substance solution containing 0.13 mg per 1ml.

Preparation of the test solution: take an appropriate amount of this product, grind it finely, take about 1.0 g, accurately weigh it, place it in a conical flask with a stopper, add 25 ml of methanol precisely, weigh it, heat under reflux for 30 minutes, let it cool, and then Weigh the weight, make up the lost weight with methanol, shake well, filter, and take the filtrate.

Determination method: Precisely draw 10 μl of the reference solution and the test solution, respectively, inject them into a liquid chromatograph, and measure.

Ephedrine hydrochloride and pseudoephedrine hydrochloride: according to high performance liquid chromatography (Chinese Pharmacopoeia 2015 edition four general rules 0512).

Chromatographic conditions and system suitability test: use polar ether to connect phenyl-bonded silica gel as filler; use methanol-0.092% phosphoric acid solution (containing 0.04% triethylamine and 0.02% diethylamine) (1.5:98.5) as flow phase; detection wavelength is 210 nm; column temperature is 35°C; flow rate is 0.8 ml per minute. The number of theoretical plates should not be less than 3000 calculated according to the peak of ephedrine hydrochloride.

Preparation of reference substance solution: take appropriate amount of ephedrine hydrochloride reference substance and pseudoephedrine hydrochloride reference substance, accurately weigh, add methanol to make a mixed solution containing 10μg per 1ml, that is, get.

Preparation of the test solution: take an appropriate amount of this product, grind it finely, take about 0.5g, accurately weigh it, put it in a stoppered conical flask, accurately add 50ml of 0.1mol/L hydrochloric acid solution, weigh it, and ultrasonically treat it (power 250W, frequency 40kHz) for 30 minutes, let cool, weigh again, make up the lost weight with 0.1mol/L hydrochloric acid solution, shake well, centrifuge (4000 rpm) for 5 minutes, take the supernatant, filter Pass, accurately measure 25ml of subsequent filtrate, add it on the solid-phase extraction column (with mixed-type cation exchange reversed-phase adsorbent as filler, 150mg, 6ml, pre-wash with 6ml of methanol and water), use 0.1mol/ L hydrochloric acid solution and 6 ml of methanol each were eluted, the eluate was discarded, followed by eluting with 10 ml of a freshly prepared acetonitrile-concentrated ammonia test solution (95:5) mixed solution, the eluate was collected and placed in a 10-ml measuring flask, and the above mixed solution was added. Dilute the solution to the mark, shake well, and get it.

(2) Index measurement results

The content of paeoniflorin, the total amount of ephedrine hydrochloride and pseudoephedrine hydrochloride in the samples of Examples 1 to 8, Comparative Example 1 and Comparative Example 2 were measured, and the measurement results were shown in Table 1.

Table 1 Preparation example of Huashibaidu granules and content of index components in comparative examples

Note: Huashibaidu Granules are 5g per bag.

It can be seen from the index component contents of Examples 1 to 8 and Comparative Example 1 in Table 1 that the Huashibaidu Granules prepared in different process parameter ranges, different drying methods, different granulation methods, and different batches in each embodiment of the present invention, its peony The glycoside content, the total amount of ephedrine hydrochloride and pseudoephedrine hydrochloride can be stably controlled within a certain range, and there is basically no obvious difference with the index content of traditional decoction, indicating that the Huashi Baidu granules prepared by the present invention can be better than traditional decoction. of maintaining consistency.

From Table 1, it can be seen from the index component content of Example 1 and Comparative Example 2 that the quality of Huashi Baidu granules prepared by adding different pharmaceutical excipients in Comparative Example 2 is basically the same as that prepared by adding only dextrin and steviol in Example 1. .

From the comparison of the results of Examples 1 to 8, it can be seen that the effects of the present invention can also be achieved by adjusting various parameters, and various technical features can be combined arbitrarily. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the protection scope of the present invention.

Further, the Huashi Baidu granules of the present invention are detected and tested for efficacy, as follows:

1. Select the Huashibaidu granules of three batches of the present invention (batch numbers are J2004006, J2004007, J2004008) for relevant detection, as follows:

(1) The test results of the product batch number J2004006 are shown in Table 2 below:

(2) The test results of the product batch number J2004007 are shown in Table 3 below:

(3) The test results of the product batch number J2004008 are shown in Table 4 below:

It should be noted that the packaging specification of the above-mentioned Huashibaidu granules is: 5g per bag.

2. Carry out the pharmacodynamics experiment of the prescription of Huashibaidu Granules of the present invention, namely the observation of anti-SARS-CoV-2 infection, and the results are as follows:

(1) Materials and methods

1. Test drug

Test substance name: Huashibaidu Granules

Test substance provider: Chinese Academy of Chinese Medical Sciences

Test substance batch number: 20200202

Preparation of the test substance: take 2.25g of medicinal powder, add water in stages to dissolve or mix, dilute to 10ml, and shake to obtain, each 0.1ml contains 0.0225g of medicinal powder, 0.2ml/10g.

Storage conditions of the test substance: 4°C protected from light

2. Challenge strains

Strain name: SARS-CoV-2

Route of infection: nasal drip

Infectious dose: 10 ⁵ TCID ₅₀ /piece

Infection volume: 50 µl

3. Experimental animals

Animal name: hACE2 transgenic mice

Animal grade: SPF grade

Animal age: 10-12 weeks old

Animal weight: body weight 20-24g

Animal source: Institute of Medical Laboratory Animals, Chinese Academy of Medical Sciences

4. Experimental method:

Animal grouping: divided into Huashibaidu granule group and model group

Number of animals per group: 6

Dosage: according to the volume of 0.2ml/10g body weight (provided by the entrusting party)

Route of administration: gavage

Dosing time: 1 hour after challenge, once a day for 5 consecutive days, the model group was given an equal volume of normal saline

5. Observation indicators

Mice were observed for 5 consecutive days after challenge, and the body weight changes were recorded. On the 5th day after infection, all mice were euthanized to detect tissue virus energy, and lung weight was measured to calculate lung index. One mouse was routinely taken left lung tissue for pathology. an examination

6. Data Statistical Processing Method

The quantitative data generated in this experiment were analyzed by variance analysis using the statistical processing software SPSS Version 170.

(2) Experimental results

1. Animal clinical manifestations:

The mice in the model group showed weight loss after infection, and the average weight loss percentage was the highest of 5.75%. Compared with the model group, the mice in the Huashibaidu granule group continued to lose weight after infection, and the percentage of weight loss on the fifth day was 13.33%. The results showed that the weight loss rate of mice in the Huashibaidu Granules group was significantly higher than that in the model group.

The average lung index of the mice in the model group was 1.16. Compared with the model group, the average lung index of the mice in the Huashibaidu granules group was 1.14, which was not significantly different from the model. See Table 5. It shows that the mice in the Huashibaidu granules group were given There was no significant improvement in lung index after infection.

Compared with the model group, there is a significant difference in the lung tissue load of the test mice in each group, *p<0.05

Lung tissue weight/mouse weight*100=lung index

2. Viral load:

The hACE2 transgenic mouse model was infected with SARS-CoV-2 to observe the virus-inhibiting effect in vivo. The viral load in the lung tissue of mice in the model group was 10 ^5.58 copies/ml 5 days after infection. The viral load in the lung tissue of mice in the Huashibaidu granule group was 10 ^3.94 copies/ml 5 days after infection, which was significantly lower than that in the model group. It was shown that the Huashibaidu granule group had a significant inhibitory effect on the virus. See Table 6:

3. Pathological diagnosis:

The mice in the hACE2 transgenic model group infected with SARS-CoV-2 for 5 days showed diffuse moderate interstitial pneumonia, with widened alveolar septa, inflammatory cell infiltration, a small amount of inflammatory cell infiltration around blood vessels, interstitial vasodilation and congestion, and alveolar infiltration. A small amount of inflammatory cells and serous exudate in the cavity.

The lung tissue of the mice in the Huashibaidu granule group showed mild interstitial pneumonia, with mild alveolar septum widening, a small amount of inflammatory cell infiltration, a small amount of inflammatory cell infiltration around blood vessels, and interstitial vasodilation and congestion; focal pulmonary edema , Serum and a small amount of inflammatory cell exudation can be seen in the alveolar cavity.

The results showed that compared with the model group, the widening of alveolar septum in the Huashibaidu granule group was reduced to a certain extent, but focal pulmonary edema occurred, and the changes in lung tissue cases did not improve significantly, as shown in Figures 8 and 9 and Table 7:

Note: +, mild disease; ++, moderate disease; +++, severe disease; ++++, very severe disease.

Pulmonary disease grading standard:

Widening of alveolar septum: +, mild lesions, mild widening of alveolar septum. ++, moderate lesions, the alveolar septum was significantly widened, and the lesion range was greater than 1/4. +++, severe disease, the alveolar septum is obviously widened, and the alveolar septum is widened, merged, and the alveolar cavity is obviously narrowed, and the lesion range is more than 2/4. ++++, very severe disease, alveolar septum widening, fusion, alveolar cavity obviously narrowing and disappearing, local lung tissue consolidation, the lesion area is more than 3/4.

Other lesions (f Intraalveolar exudation, inflammatory cell infiltration, vasodilation and congestion, hemorrhage, etc.); +, mild lesions, the scope of lesions is less than 1/4 of the lung tissue section. ++, moderate disease, the extent of the disease accounts for about 1/4 to 2/4 of the lung tissue section. +++, severe disease, the extent of the disease is about 2/4 to 3/4 of the lung tissue section.

(3) Experimental conclusion:

According to the virus replication, clinical manifestations and pathological examinations in mice, it is suggested that the 0.2ml/10g/d Huashibaidu granules can significantly inhibit the virus in hACE2 transgenic mice infected with SARS-CoV-2. The viral load in lung tissue decreased by 10 ^3.94 copies. Huashibaidu granules did not significantly improve clinical symptoms and pulmonary inflammation.

3. For the treatment of 2019 novel coronavirus patients, the results are as follows:

On January 28, 2020, Wuhan Jinyintan Hospital set up an integrated traditional Chinese and Western medicine ward with 43 beds. The medical team of the Chinese Academy of Chinese Medical Sciences was responsible for treating 121 patients with integrated traditional Chinese and Western medicine, and 80 patients were discharged, including traditional Chinese medicine. Thirty-two cases were treated with Huashi Baidu granules, supplemented by traditional Chinese medicine injections according to the condition. The treatment conditions are summarized as follows

(1) Research methods

1. Research purpose

To evaluate the efficacy and safety of Huashi Baidu Granules in the treatment of new coronary pneumonia.

2. Study population

Hospitalized patients who took Huashibaidu Granules from January 28, 2020 to March 4, 2020.

3. Study Design

Non-randomized, prospective, observational study.

4. Data sources and collection methods

Data sources: Obtain information such as patient medical records, laboratory examinations, doctor's orders, and CT reports through the HIS system; observe and record TCM syndromes of patients through front-line doctors.

(2) Selection and withdrawal of subjects

1. Diagnostic criteria:

Suspected cases have one of the following etiological, serological or chest imaging evidences:

(1). Real-time fluorescent RT-PCR detection of new coronavirus nucleic acid positive;

(2). Virus gene sequencing, highly homologous to known new coronaviruses;

(3) The serum 2019-nCoV-specific IgM antibody and IgG antibody are positive; the serum 2019-nCoV-specific IgG antibody is changed from negative to positive or the recovery period is 4 times or more higher than that in the acute period.

(4) Early chest CT showed multiple small patchy shadows and interstitial changes, especially in the extrapulmonary zone. It then develops into multiple ground-glass opacities and infiltration shadows in both lungs. In severe cases, pulmonary consolidation may occur, and pleural effusion is rare.

2. Inclusion criteria:

Patients must meet all of the following inclusion criteria to be eligible for this study

(1). Age 18-80 years old;

(2) Meet the diagnostic criteria for COVID-19;

(3) The patients are able and willing to sign the informed consent and follow the research protocol.

3. Exclusion criteria

Patients who met any of the following exclusion criteria were excluded from this study:

(1) Combined with serious primary diseases such as severe cardiopulmonary, cerebrovascular, hematopoietic system and endocrine system;

(2). Pregnant and lactating women;

(3) Patients who are participating in other clinical trials;

(4). Poorly controlled mentally ill patients.

4. Exit Criteria

(1) For whatever reason, the patient is unwilling or impossible to continue the clinical trial, and the investigator is suspended by requesting the doctor in charge to withdraw from the study;

(2) Although the subjects did not explicitly propose to withdraw from the study, but those who no longer receive medication and testing and are lost to follow-up are also "withdrawn" (or "dropped out"). Where possible, the reasons for their withdrawal should be understood and documented. Such as:

Consciously feel intolerable to some adverse reactions; unable to continue clinical trials for other reasons; or lost to follow-up without explaining the reasons, etc.

5. Elimination standard

(1). Significant program deviation. Subjects found not to meet the inclusion criteria of the study protocol and continued participation in the study may pose an unacceptable risk to the subject's health.

(2) Patients whose condition deteriorates during the research process and should stop the clinical trial according to the judgment of the doctor;

(3). Lack of effectiveness. The investigator determines that the subject will not benefit from the study treatment and that continued participation in the study would pose unacceptable risks to the subject;

(4). Unintended pregnancy.

(3) Research plan

1. Research drugs

Name: Hua Shi Bai Du Fang

Manufacturer: Sinopharm Group Traditional Chinese Medicine Holding Subsidiary: Guangdong Yifang Pharmaceutical Co., Ltd.

Dosage form: compound granules

How to use: A set of two small boxes. Ordinary patients, one box in the morning and one in the evening; for the seriously ill, follow the doctor's advice.

2. General treatment

(1) Rest in bed, strengthen supportive treatment, and ensure sufficient heat; pay attention to water and electrolyte balance to maintain a stable internal environment; closely monitor vital signs, oxygen saturation, etc.

(2) Monitor blood routine, urine routine, CRP, biochemical indicators (liver enzymes, myocardial enzymes, renal function, etc.), coagulation function, arterial blood gas analysis, chest imaging, etc. according to the condition. Cytokine detection can be performed in those with conditions.

(3) Give effective oxygen therapy measures in a timely manner, including nasal cannula, mask oxygen delivery and nasal high-flow oxygen therapy.

(4). Antiviral treatment: use α-interferon (5 million U or equivalent dose for adults, add 2 mL of sterile water for injection, nebulized inhalation twice a day), lopinavir/ritonavir ( 200mg/50mg/capsule for adults, 2 capsules each time, twice a day, the course of treatment does not exceed 10 days), ribavirin (recommended to be used in combination with interferon or lopinavir/ritonavir, 500mg/time for adults , intravenous infusion 2 to 3 times a day, the course of treatment does not exceed 10 days), Arbidol (200mg for adults, 3 times a day, the course of treatment does not exceed 10 days).

(4) Statistical methods

Statistical methods: continuous variables list mean and standard deviation or median and upper and lower quartiles, and perform normality test and homogeneity of variance test. Under the condition of normal distribution and homogeneity of variance, use t test Comparisons between groups were performed, otherwise, Wilcoxon rank-sum test was used for comparison between groups; categorical variables were listed as frequencies and percentages, and compared by chi-square test or Fisher's exact test. Before and after comparison within groups, paired t test/signed rank test was used for continuous variables, and McNemar test or McNemar-Bowker test was used for categorical variables. Survival analysis was performed using log-rank test or Breslow test.

(5) Analysis of the results

1. Baseline analysis

Among the 32 patients, 17 were male and 15 were female, with an average age of 55.34 years (55.34±12.08), including 6 patients with cardiovascular and cerebrovascular diseases, 2 with respiratory system diseases, 4 with malignant tumors, 1 with digestive system diseases, and endocrine system diseases. 3 cases. The number of days in hospital was (11.56±4.70) days, the time for nucleic acid to turn negative after diagnosis was (10.41±5.75) days, the time for nucleic acid to turn negative after admission was (5.82±5.24) days, and the time for nucleic acid to turn negative after traditional Chinese medicine treatment was (5.09±5.13) days, The clinical remission time was (8.16±4.55) days.

Table 8 Basic information of included patients

2. Analysis of curative effect

(1). Comparison of basic vital signs before and after treatment

Body temperature decreased significantly after treatment (from 36.96±0.73 to 36.65±0.20) (P<0.05),

Systolic blood pressure (129.9±14.57 decreased to 122.61 ± 14.36), diastolic blood pressure (82.74 ± 10.41 decreased to 74.35 ± 9.69) were significantly decreased after treatment (P<0.05). There was no significant difference between the patients' respiration and heart rate before and after treatment.

Table 9 Comparison of basic vital signs before and after treatment

(2). Comparison of laboratory indexes before and after treatment

2.1 Blood routine

The percentage of lymphocytes did not change before and after treatment, but the absolute value of lymphocytes increased significantly after treatment (1.32±0.47 to 1.55±0.5) (P<0.05); the absolute value of neutrophils/absolute lymphocytes increased significantly after treatment decreased (2.92±1.42 to 2.34±0.66) (P<0.05); both the absolute value and percentage of eosinophils increased (P<0.001); the hemoglobin concentration decreased after treatment (128.38±12.91 to 123.72±11.1)( P<0.05), but the average value was within the normal range; platelets were significantly increased after treatment (226.84±72.45 to 262.41±87.79) (P<0.05); there was no statistical difference in neutrophil count and percentage before and after treatment (P<0.05). P>0.05).

2.2 Inflammatory factors

C-reactive protein decreased from (28.12±38.46) to (4.88±8.77), and there was a statistically significant difference before and after treatment (P<0.001); after ferritin treatment, it decreased significantly (523.55±404.61 to 323.18±196.23) (P<0.001) ); after treatment with amyloid A, it decreased significantly (102.29±112.73 to 51.53±106.32) (P<0.001); after treatment, ESR decreased significantly (43.8±23.32 to 37.59±24.9) (P<0.05). Other indicators such as procalcitonin, IL-6 did not change significantly.

2.3 Myocardial enzymes

Creatine kinase decreased significantly after treatment (from 107.78±98.92 to 54.53±17.08) (P<0.001); myoglobin decreased significantly after treatment (from 53.65±47.29 to 34.38±14.05) (P<0.05); Acid dehydrogenase decreased significantly after treatment (from 199.91±76.62 to 148.47±38.57) (P<0.001); lactate dehydrogenase decreased significantly after treatment (from 256.53±84.67 to 212.84±43.4) (P<0.05); After protein treatment, it decreased significantly (from 4.55±3.92 to 3.78±3.45) (P<0.05); other cardiac indexes such as creatine kinase isoenzyme and BNP did not change significantly.

2.4 Liver and kidney function

Serum albumin was significantly increased after treatment (34.12±3.36 to 36.91±4.18) (P<0.001), and total protein was also significantly increased (65.12±5.74 to 68.44±4.84) (P<0.05); decreased (74.02±25.11 to 69.58±22.14) (P<0.05); significantly decreased after aspartate aminotransferase treatment (33.03±16.91 to 23.34±8.02) (P<0.05); significantly decreased after r-glutamyl transpeptidase treatment decreased (40.38±26.46 to 35.84±26.98) (P<0.05). Alanine aminotransferase and urea did not change significantly.

2.5 Blood oxygen saturation, coagulation index

There was no significant change in blood oxygen saturation and D-dimer (P>0.05).

Table 10 Comparison of laboratory indicators before and after treatment

(3). Comparison of clinical symptoms-outcome with baseline

The clinical symptoms of fever, cough, fatigue and dry mouth were significantly relieved after treatment (P<0.05), and other symptoms did not change significantly before and after treatment.

Table 11 Comparison of laboratory indicators before and after treatment

(6) Conclusion

The above shows that 32 hospitalized patients with COVID-19 have been treated with Huashibaidu Granules, and the effect is very significant in terms of clinical symptoms, physical and chemical examinations, including the time when nucleic acid detection turned negative. The average time for nucleic acid to turn negative was 5.09 days, the average clinical remission time was 8.16 days, and the average hospital stay was 11.56 days. Fever, cough, fatigue and dry mouth symptoms improved significantly. From the physical and chemical examination, the inflammatory indexes such as erythrocyte sedimentation rate, C-reactive protein, ferritin, and amyloid A decreased significantly, while the absolute value of lymphocytes increased significantly after treatment; while the indexes reflecting body function such as albumin increased significantly after treatment High, five indicators of myocardial enzymes, liver and kidney function were recovered well. It shows that Huashibaidu granules can not only have good antiviral and anti-inflammatory effects, but also have good safety and restore human physiological functions, which is in line with the treatment concept of traditional Chinese medicine for strengthening the body and eliminating pathogens. Typical cases more intuitively reflect the good curative effect of Huashibaidu Granules, which have played an important role in the treatment of COVID-19.

The above are the preferred embodiments of the present invention. It should be pointed out that for those skilled in the art, without departing from the principles of the present invention, several improvements and modifications can also be made, and these improvements and modifications may also be regarded as It is the protection scope of the present invention.

Claims

A kind of Huashibaidu granule, is characterized in that, it is mainly made by following raw material by weight:

Ephedra, fried bitter almond, raw gypsum, licorice, patchouli, Magnolia, bran fried Atractylodes, fried grass nuts, Pinellia, Poria, Rhubarb, Astragalus, Tinglizi, red peony, accessories.
The Huashibaidu granules as claimed in claim 1, characterized in that, they are mainly made from the following raw materials in parts by weight:

3-60 servings of ephedra, 4.5-90 servings of fried bitter almonds, 7.5-150 servings of raw gypsum, 1.5-30 servings of licorice, 5-100 servings of patchouli, 5-100 servings of Magnolia officinalis, 7.5-150 servings of bran fried Atractylodes, stir-fried 5-100 parts of grass nuts, 4.5-90 parts of Pinellia, 7.5-150 parts of Poria, 2.5-50 parts of rhubarb, 5-100 parts of Astragalus, 5-100 parts of Tinglizi, 5-100 parts of red peony root, accessories Moderate amount.
The Huashibaidu granules as claimed in claim 2, characterized in that, they are mainly made from the following raw materials in parts by weight:

12-36 servings of ephedra, 18-54 servings of fried bitter almonds, 30-90 servings of raw gypsum, 6-18 servings of licorice, 20-60 servings of patchouli, 20-60 servings of Magnolia officinalis, 30-90 servings of fried Atractylodes Rhizoma bran, stir-fried 20-60 parts of grass nuts, 18-54 parts of Pinellia, 30-90 parts of Poria, 10-30 parts of Rhubarb, 20-60 parts of Astragalus, 20-60 parts of Tinglizi, 20-60 parts of Red Peony, accessories Moderate amount.
The Huashibaidu granules as claimed in claim 3, characterized in that, they are mainly made from the following raw materials in parts by weight:

15-25 servings of ephedra, 26-48 servings of fried bitter almonds, 40-80 servings of raw gypsum, 7-15 servings of licorice, 25-50 servings of patchouli, 25-50 servings of Magnolia officinalis, 25-70 servings of bran fried Atractylodes, stir-fried 25-50 parts of grass nuts, 25-40 parts of Pinellia, 40-80 parts of Poria, 15-25 parts of rhubarb, 25-50 parts of Astragalus, 25-50 parts of Tinglizi, 25-50 parts of red peony root, accessories Moderate amount.
Huashibaidu granules as claimed in claim 1, wherein the fried bitter almond is obtained by the following method:

Take the bitter almonds, put them in a hot pot, and fry them with a slow fire until the surface is yellow or brown, with slight scorch spots and aroma.
The Huashi Baidu granules as claimed in claim 1, wherein the bran fried Atractylodes Rhizoma is prepared by the following method:

Heat the hot pot until the bran is sprinkled in and smoke immediately, put the Atractylodes Rhizoma slices into the hot pot, stir quickly, fry until the surface is dark yellow, take out of the pot, sieve off the bran, and let cool; per 100kg of Atractylodes Rhizoma slices, use bran
The Huashibaidu granules as claimed in claim 1, wherein the fried grass nuts are prepared by the following method:

Take the strawberry fruit, remove the impurities, put it in a hot pot, fry it with a slow fire until the surface is browned and slightly bulging, take it out, remove the shell, and take the kernel;

Take the grass nuts, put them in a hot pot, fry them on a slow fire until the surface bulges and the aroma escapes, take them out and let them cool.
The Huashi Baidu granules according to claim 1, wherein the adjuvant is a pharmaceutically acceptable adjuvant, including one or more of dextrin and steviol.
A preparation method of Huashibaidu granules, characterized in that, sequentially comprising:

(1) take raw gypsum according to the formula, add water to decoct;

(2) Add ephedra, stir-fried bitter almond, licorice, Magnolia officinalis, bran stir-fry Atractylodes, stir-fried grass nut, Pinellia, Poria, Astragalus, Tinglizi and red peony root according to the recipe, add water and decocted;

(3) add patchouli and rhubarb according to the formula, add water to decoct, filter, and obtain the first decoction and medicinal residue;

(4) medicinal dregs add water to decoct again, filter to obtain the second decoction;

(5) the first decoction and the second decoction are concentrated to obtain clear paste;

(6) Mixing the clear paste and auxiliary materials, drying, granulating and packaging to obtain Huashibaidu granules.
The preparation method of Huashi Baidu granule as claimed in claim 9, is characterized in that, the formula of described Huashi Baidu granule in parts by weight is as follows:

3-60 servings of ephedra, 4.5-90 servings of fried bitter almonds, 7.5-150 servings of raw gypsum, 1.5-30 servings of licorice, 5-100 servings of patchouli, 5-100 servings of Magnolia officinalis, 7.5-150 servings of bran fried Atractylodes, stir-fried 5-100 parts of grass nuts, 4.5-90 parts of Pinellia, 7.5-150 parts of Poria, 2.5-50 parts of rhubarb, 5-100 parts of Astragalus, 5-100 parts of Tinglizi, 5-100 parts of red peony root, accessories Moderate amount.
The preparation method of Huashibaidu granules as claimed in claim 10, characterized in that, in step (1), the decoction time of raw gypsum is 20 to 40 minutes, and the amount of water added is ephedra, fried bitter almond, raw gypsum, licorice , Magnolia, bran fried Atractylodes, fried grass nuts, Pinellia, Poria, Astragalus, Tinglizi, Chishao these twelve herbs 1 to 6 times the amount of water.
The preparation method of Huashibaidu granules as claimed in claim 10, characterized in that, in step (2), the time for decocting with water is 40 to 60 minutes, and the amount of water added is ephedra, fried bitter almond, gypsum, licorice , Magnolia, bran fried Atractylodes, fried grass nuts, Pinellia, Poria, Astragalus, Tinglizi, Chishao these twelve herbs 2 to 7 times the amount of water.
The preparation method of Huashibaidu granules as claimed in claim 10, characterized in that, in step (3), patchouli and rhubarb are added, and the time for adding water for decocting is 5 to 15 minutes, and the amount of water added is patchouli Incense, rhubarb these two herbs 6 to 10 times the amount of water.
The preparation method of Huashibaidu granules as claimed in claim 13, characterized in that, in step (3), patchouli and rhubarb are added, and the time for adding water for decocting is 8 to 12 minutes, and the amount of water added is patchouli Incense, rhubarb these two herbs 8 times the amount of water.
The preparation method of Huashibaidu granules as claimed in claim 10, characterized in that, in step (4), the medicinal residues are added with water for decocting for 40-80min, and the amount of water added is ephedra, fried bitter almonds, raw gypsum, licorice, Patchouli, Magnolia, bran fried Atractylodes, fried grass nuts, Pinellia, Poria, Rhubarb, Astragalus, Tinglizi, Red Peony are 6 to 10 times the amount of water.
The preparation method of Huashibaidu granules as claimed in claim 15, characterized in that, in step (4), the medicinal residues are added with water for decocting for 50-60min, and the amount of water added is ephedra, fried bitter almond, raw gypsum, licorice, Patchouli, Magnolia, bran fried Atractylodes, fried grass nuts, Pinellia, Poria, Rhubarb, Astragalus, Tinglizi, Red Peony are 8 times the amount of water.
The preparation method of Huashibaidu granules as claimed in claim 9 or 10, wherein step (5) comprises:

The first decoction and the second decoction are respectively concentrated under reduced pressure to a clear paste with a relative density of 1.01-1.05, and then combined under reduced pressure and concentrated to a clear paste with a relative density of 1.06-1.20.
The method for preparing Huashibaidu granules according to claim 17, wherein the temperature of the decompression concentration is 45°C to 85°C, and the pressure is 0.00 to -0.095MPa.
The preparation method of Huashibaidu granules as claimed in claim 9 or 10, wherein in step (5), the drying is at least one of spray drying, belt drying or freeze drying;

The granulation is at least one of boiling granulation, wet granulation and dry granulation.
The preparation method of Huashibaidu granules as claimed in claim 9, is characterized in that, before step (1), comprises:

Stir-frying bitter almonds, Atractylodes Rhizoma and/or grass nuts to obtain fried bitter almonds, bran fried Atractylodes and/or fried grass nuts;

Wherein, described fried bitter almond is obtained by the following method: take the bitter almond, put in a hot pot, fry it with slow fire until the surface is yellow or brownish yellow, with microstriped scorch spots and aroma;

The bran fried Atractylodes is prepared by the following method: heating a hot pot until the bran is sprinkled into the bran and smoking immediately, putting the Atractylodes Rhizoma tablets into the hot pot, stirring quickly, frying until the surface is dark yellow, out of the pot, and sieving the bran , let cool; per 100kg of atractylodes tablets, use bran

The fried grass nuts are prepared by the following method: take the grass fruits, remove impurities, put them in a hot pot, fry them with low heat until the surface is burnt yellow and slightly swelled, take out, remove the shells, and take the kernels; take the grass nuts, Put it in a hot pot, fry it with a simmer until the surface bulges and the aroma escapes, take it out and let it cool.
An antiviral drug, characterized in that it comprises the Huashibaidu granules as claimed in any one of claims 1-8.
The antiviral drug of claim 21, wherein the antiviral drug is a drug for the treatment of 2019 novel coronavirus.
An antiviral drug, characterized in that it comprises the Huashibaidu granules prepared by the preparation method according to any one of claims 9-20.
The antiviral drug of claim 23, wherein the antiviral drug is a drug for the treatment of 2019 novel coronavirus.