Use of herbal medicine composition and preparation thereof in the manufacture of medicine for the prevention and / or treatment of novel coronavirus pneumonia

Abstract

The present invention relates to the use of a herbal composition and its formulation in the manufacture of a medicament for the prevention and / or treatment of novel coronavirus pneumonia.

Description

[Technical field]

[0001] The present invention relates to the pharmaceutical field; specifically, the present invention relates to the use of a herbal composition and its formulation in the manufacture of a medicine for the prevention and / or treatment of novel coronavirus pneumonia. [Background technology]

[0002] The International Committee on Taxonomy of Viruses has named the new coronavirus as Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Meanwhile, the World Health Organization (WHO) announced on the same day that the official name of the disease caused by the virus is covid-19 (Corona virus disease 2019), and that the virus is spreading rapidly.

[0003] According to current epidemiological investigations, the clinical symptoms of COVID-19 patients are mainly fever, lethargy, and dry cough, and a small number of patients also have symptoms such as nasal congestion, runny nose, sore throat, diarrhea, etc. Approximately half of the patients develop respiratory distress and / or hypoxia after one week, and severe cases rapidly progress to acute respiratory distress syndrome (ARDS), pyogenic shock, refractory metabolic acidosis, increased blood viscosity, and bleeding dysfunction. Treatment of COVID-19 hypoxemia is very important, and many of the confirmed severe patients will develop dyspnea and / or hypoxemia one week after onset. Clinically, respiratory support and circulatory support are required, and based on symptomatic treatment, it is necessary to actively treat and prevent complications, treat underlying diseases, and prevent secondary infection. Compared with mild patients, the changes in the interstitium of both lungs of severe patients are obvious, with many glass opacities and infiltrative shadows, and substantial changes in the lungs appear. At the same time, the body's Th1 response is enhanced, the release of pro-inflammatory factors is increased, inflammation invades the alveolar walls and adjacent alveolar spaces, and the alveolar intervals are progressively thickened. At the same time, pulmonary fibrosis occurs, accompanied by pulmonary dysfunction and progressive dyspnea. The alveoli cannot realize the gas exchange process, and the oxygenation function is weakened, which further reduces the amount of oxygen in the blood and causes hypoxemia. Severe patients will quickly progress to acute respiratory distress syndrome (ARDS), pyomelic shock, metabolic acidosis that is difficult to correct, blood condensation dysfunction, and multiple organ failure. It has also been reported that a sustained decline in oxygenation index is one of the warning factors for severe and critical cases. All patients whose condition worsened had an oxygenation index of only 100-150 mmHg for more than 12 hours, and such patients are very likely to induce cytokine storm (CSS) due to lack of oxygen, which causes the release of a large amount of inflammatory factors in the lungs and promotes inflammatory damage such as pulmonary fibrosis. Therefore, in the course of treatment for COVID-19, it is particularly important to pay special attention to changes in related indicators such as the patient's oxygenation index and oxygen saturation, and improve the occurrence and progression of hypoxemia in combination with prevention and treatment to reduce the probability of patients becoming severe or critical.

[0004] The 3rd to 7th versions of the "China's Novel Coronavirus Infection Treatment Plan (Trial)" specifically put forward the treatment principles of traditional Chinese medicine and dialectical treatment plans based on the clinical symptoms of patients. The treatment of COVID-19 pneumonia hypoxemia was first mentioned in the "China's Novel Coronavirus Infection Treatment Plan (Trial) 6th Edition" published on February 18, 2020, as "for patients with progressive deterioration of oxygenation indexes, rapid image diagnosis, and excessive activation of the body's inflammatory response..." Fufang Danshen Microdrop Pills (T89) is a Chinese herbal medicine developed by Tenshiri Co., Ltd., which activates blood, promotes circulation, and relieves pain. It is used for chest dyspnea and angina pectoris. Its main ingredients are Danshen, Panax notoginseng and ice chips. It has the effect of treating acute myocardial infarction and acute myocardial ischemia. T89 is a drug extracted from natural products. It has currently been submitted for clinical research to the US FDA and is numbered T89. This product has a history of use of more than 25 years in China and has good safety. In patients with pneumonia caused by the new coronavirus, the invasion of the covid-19 virus caused an increase in the patient's myocardial enzymes accompanied by a systemic inflammatory reaction, leading to multiple organ failure and central nervous system damage. The causes of this include systemic thrombosis, microcirculatory disorders, inflammatory factor storms, ROS invasion and hypoxic blood oxygen caused by the virus invasion. These diseases increase the mortality rate of patients, especially in patients with underlying diseases such as cardiovascular disease, hypertension and diabetes. To date, no recommended drugs for COVID-19 hypoxemia have been found. Summary of the Invention [Problem to be solved by the invention]

[0005] In order to solve the above technical problems, the present invention relates to the use of a traditional Chinese medicine composition in the manufacture of a medicine for novel coronavirus pneumonia, the traditional Chinese medicine composition being composed of 50.0%-99.9% Danshen and Panax notoginseng extract and 0.1%-50.0% ice chips, by weight percentage, wherein the Danshen and Panax notoginseng extract contain the following components, and the weight ratio of each component is as follows: Danshensu (Danshen substance): Salvianolic acid T: Protocatechuic aldehyde: Salvianolic acid D: Rosmarinic acid: Salvianolic acid B: Salvianolic acid Acid A: Sankinoside R1: Ginsenoside Rg1: Ginsenoside Re: Ginsenoside Rb1: Ginsenoside Rd: Dihydrotanshinone I: Tanshinone I: Cryptotanshinone: Tanshinone IIA = (2-6): (0.5-2): (1-3): (0.2-1): (0.2-1): (0.5-2): (0.5-2): (0.2-1): (1-4): (0.1-0.5): (1-4): (0.1-1): (0.01-0.05): (0.05-0.1): (0.02-0.1): (0.1-0.5)The herbal medicine composition is a dispersive intravascular coagulation inhibitor composition that suppresses dispersive intravascular coagulation (DIC) in patients with novel coronavirus pneumonia and reduces the mortality rate. , provide for use.

[0006] In patients with pneumonia caused by the new coronavirus, the invasion of the covid-19 virus caused an increase in myocardial enzymes accompanied by a systemic inflammatory response, leading to multiple organ failure and central nervous system damage. This is due to symptoms such as systemic thrombosis, microcirculatory disorder, inflammatory factor storm, and ROS invasion caused after viral invasion. The herbal medicine composition of the present invention can effectively improve the clinical symptoms of patients with new coronavirus infection, improve the microcirculatory disorder of patients, reduce the formation of pulmonary thrombus, inhibit dispersed intravascular condensation (DIC), and reduce the mortality rate of patients with moderate to severe new coronavirus infection.

[0007] Furthermore, the herbal medicine composition of the present invention comprises: This is a composition for preventing or treating diffuse pulmonary disease in patients with novel coronavirus pneumonia. In addition, the herbal medicine composition of the present invention comprises It can prevent or reduce the formation of blood clots in patients with COVID-19 infection, and reduce the formation of serous fluid, fibrin exudate and clear membrane in the alveolar cavity. It can reduce alveolar sequestration vascular congestion and edema, and reduce mononuclear and lymphocyte infiltration and the formation of intravascular clear clots. It can suppress platelet aggregation and adhesion, thereby preventing blood clot formation throughout the body.

[0008] Furthermore, the herbal medicine composition of the present invention can change vascular function and improve microcirculatory blood perfusion by regulating the vascular contraction state, improving the exchange of oxygen and nutrients in the heart, lungs, and other organs, thereby improving microcirculatory disorders in patients with novel coronavirus infection.

[0009] Furthermore, the herbal medicine composition of the present invention can suppress dispersed intravascular coagulation (DIC) in patients with novel coronavirus infection and reduce the mortality rate.

[0010] According to the clinical classification symptoms, there are mild (mild clinical symptoms, no pneumonia signs on imaging), normal (fever, respiratory symptoms, etc., pneumonia signs on imaging), severe (respiratory distress, RR≧30 breaths / min, oxygen saturation≦93% at rest, arterial blood oxygen pressure (PaO2) / oxygen inhalation concentration (FiO2)≦300mmHg), and critical (respiratory failure appears, and mechanical ventilation is required. Shock occurs. ICU supervision is required to treat other organ failure.) The herbal medicine composition of the present invention usually treats moderate to severe pneumonia.

[0011] In the herbal medicine composition of the present invention, the herbal medicine composition comprises, by weight percentage, 75.0% to 99.9% of Danshen / Tenchi ginseng extract and 0.1% to 25.0% of ice chips. The herbal composition of the present invention contains, by weight percentage, 90.0% to 99.9% of Danshen / Tenchi ginseng extract and 0.1% to 10.0% of ice chips. In the Chinese herbal medicine composition of the present invention, the Danshen extract contains the following components, and the weight ratio of each component is as follows: Danshensu (Danshensu): Salvianolic acid T: Protocatechuic aldehyde: Salvianolic acid D: Rosmarinic acid: Salvianolic acid B: Salvianolic acid A: Sankinoside R1: Ginsenoside Rg1: Ginsenoside Re: Ginsenoside Rb1: Ginsenoside Rd: Dihydrotanshinone I: Tanshi Non-I: Cryptotanshinone: Tanshinone IIA = (3~4): (0.9~1.2): (1.4~2.0): (0.5~0.7): (0.5~0.9): (1~1.6): (0.7~1.2): (0.5~0.9): (1.8~2.8): (0.2~0.4): (1.7~2.2): (0.2~0.6): (0.03~0.04): (0.07~0.08): (0.05~0.06): (0.26~0.28).

[0012] In a more preferred herbal medicine composition, the Danshen / Tanqi ginseng extract contains the following components, and the weight ratio of each component is Danshensu (Danshensu): Salvianolic acid T: Protocatechualdehyde: Salvianolic acid D: Rosmarinic acid: Salvianolic acid B: Salvianolic acid A: Sankinoside R1: Ginsenoside Rg1: Ginsenoside Re: Ginsenoside Rb1: Ginsenoside Rd: Dihydrotanshinone I: Tanshinone I: Cryptotanshinone: Tanshinone IIA = 3.6:1.1:1.7:0.6:0.7:1.3:0.9:0.7:2.4:0.3:1.8:0.4:0.03:0.07:0.06:0.27.

[0013] In the herbal composition of the present invention, the Danshen / Tenchi ginseng extract is prepared using 75-99 parts by weight of Danshen and 10-25 parts by weight of Tenchi ginseng as raw materials. In the herbal composition of the present invention, the Danshen / Tenchi ginseng extract is prepared using 82-84 parts by weight of Danshen and 16-17 parts by weight of Tenchi ginseng as raw materials. The herbal composition of the present invention can be prepared into various preparations such as injections, tablets, capsules, drip pills / micro drip pills and micro drip pill capsules, preferably micro drip pills. The term "micro drip pills" refers to drip pills with a smaller volume than conventional drip pills. Specifically, it refers to drip pills with a particle size of 0.2mm-4mm, particularly drip pills with a particle size of 0.2mm-2mm, preferably drip pills with a particle size of 1mm-2mm. The micro-droplet pills of the present invention are prepared by mixing the herbal composition and the drop pill matrix in a weight ratio of 1:5 to 5:1.

[0014] The method for producing the micro-droplet pills of the present invention includes the following steps: (1) raw material dissolving step: putting the drug and the drop pill matrix into a homogenizer, mixing uniformly at 1000-5000 rpm for 1-200 minutes, and then dissolving the raw material uniformly at 3000-10000 rpm for 1-100 minutes. In the raw material dissolving process, the temperature is maintained at 60-100°C, and the weight ratio of the drug to the drop pill matrix is ​​1:5-5:1 to obtain a dissolved drug solution; (2) dripping step: dripping the dissolved drug solution. The process includes: conveying the drug to a nozzle, and dripping the drug while vibrating through the dripping nozzle under conditions of a dripping nozzle temperature of 70-300°C, a dripping vibration frequency of 2-2000Hz, a dripping pressure of 0.5-4.0Bar, and an acceleration of 1-20G so that the dripping speed matches the raw material dissolving speed in step (1); and (3) a condensing process: quickly cooling the dripped drug droplets with a cooling gas, and condensing them into solid droplets having a particle size of 0.2mm-4.0mm while the temperature of the cooling gas is below 0°C. In the above step (1), the dropping pill matrix comprises one or more combinations among PEG, sorbitol, xylitol, lactitol, maltose, starch, methylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, gum arabic, alginic acid, dextrin, cyclodextrin, agar, lactose, the preferred dropping pill matrix is ​​solid PEG, such as PEG-1000, PEG-2000, PEG-3000, PEG-4000, PEG-5000, PEG-6000, PEG-7000, PEG-8000, more preferably one or more combinations among PEG-1000, PEG-2000, PEG-3000, PEG-4000, PEG-6000, PEG-8000, most preferably PEG-6000, PEG-4000 or the combination of PEG-4000 and PEG-6000.

[0015] More preferably, the manufacturing method includes: (1) raw material dissolving step: putting the drug and the dropping pill matrix into a homogenizer and mixing them uniformly at 1000-5000 rpm, then dissolving the raw materials uniformly at 3000-10000 rpm for 20-80 minutes, maintaining the temperature at 80-100°C in the raw material dissolving process, and obtaining a dissolved drug solution with a weight ratio of the drug and the dropping pill matrix of 1:3-3:1; (2) dripping step: carrying the dissolved drug solution to a drip nozzle, the dropping speed is adjusted to the dissolution speed of the raw material in step (1) under the conditions of a dropping nozzle temperature of 70-200°C, a dropping vibration frequency of 20-300Hz, a dropping pressure of 0.5-4.0Bar, and an acceleration of 1-15G; and (3) a condensing step: the dropped droplets are quickly cooled with a cooling gas, and condensed into solid droplets having a particle size of 0.2mm-4.0mm while the temperature of the cooling gas is below 0°C.

[0016] In the above step (1), the weight ratio of the drug and the drop pill matrix is ​​1:3-3:1, and the speed is 3000-5000 rpm, and the mixture is uniformly mixed for 10-60 minutes, and then the raw material is uniformly dissolved at 4000-9000 rpm, and the temperature is maintained at 70-90 ℃ during the raw material dissolving process for 5-30 minutes; preferably, the weight ratio of the drug and the drop pill matrix is ​​1:(1-3), and the speed is 3000-4000 rpm, and the mixture is uniformly mixed for 10-30 minutes, and then the raw material is uniformly dissolved at 4000-6000 rpm, and the temperature is maintained at 75-85 ℃ during the raw material dissolving process for 6-30 minutes. In the above step (2), the dropping nozzle temperature is 70 to 100°C, and preferably 75 to 85°C, the dropping vibration frequency is 50 to 300 Hz, and preferably 100 to 200 Hz, and more preferably 90 to 200 Hz, and more preferably 130 to 140 Hz, and most preferably 137 Hz, the acceleration is 3.5 to 4.5 G, and preferably 4.0 G, the dropping pressure is 1.0 to 3.0 Bar, and preferably 1.8 Bar, and the dropping speed is 10 to 40 kg / h, and preferably 12 to 30 kg / h, and more preferably 15 to 25 kg / h. In the above step (3), the gas is air, nitrogen gas or inert gas, the cooling temperature is 0 to -150°C, preferably -60 to -140°C, more preferably -80 to -120°C, and the diameter of the drop pill is 1.0mm to 2.0mm.

[0017] The production method of the present invention further includes a drying step (4) of drying in a fluidized dryer at −20 to 100° C., preferably −20 to 90° C., for 1 to 4 hours to obtain a naked pellet.

[0018] More preferably, the step (4) employs a gradient temperature rise drying method, in which the mixture is brought into a fluidized state at -20 to 30°C, dried at 15 to 35°C for 10 to 120 minutes, dried at 35 to 55°C for 10 to 60 minutes, and dried at 55 to 100°C for 0 to 60 minutes; preferably, the gradient temperature rise drying method is carried out as follows, in which the mixture is brought into a fluidized state at 0 to 20°C, dried at 25°C for 60 minutes, dried at 45°C for 30 minutes, and dried at 55°C for 0 to 30 minutes.

[0019] The production method of the present invention further includes a coating step (5): coating the bare pellets obtained in step (4) in a fluidized state at a temperature of 30 to 65°C, with a coating liquid concentration of 5 to 25 wt%, preferably 18 to 20 wt%, in which the coating material is selected from the group consisting of shellac, cellulose acetate phthalate, methyl acrylate, methyl methacrylate, or Opadry, and the weight ratio of the coating material to the bare pellets is 1:50 to 1:10, preferably 1:50 to 1:25.

[0020] The manufacturing method of the present invention may further include, prior to step (1), a material pre-mixing step: adding the medicinal extract or powder to water and stirring at 30 to 80°C for 10 minutes or more to obtain a medicinal premix. To better demonstrate the beneficial effects of the present invention, the following experiments are provided. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0021] In one embodiment, the present invention provides a Chinese herbal medicine composition, which is composed of 50.0%-99.9% Danshen / Tenchi ginseng extract and 0.1%-50.0% ice chips, by weight, of which the Danshen / Tenchi ginseng extract is composed of Danshensu (Danshensu): Salvianolic acid T: Protocatechuic aldehyde: Salvianolic acid D: Rosmarinic acid: Salvianolic acid B: Salvianolic acid A: Sankinoside R1: Ginsenoside Rg1: Ginsenoside Re: Ginsenoside R b1: Contains ginsenoside Rd: dihydrotanshinone I: tanshinone I: cryptotanshinone: tanshinone IIA = (2~6): (0.5~2): (1~3): (0.2~1): (0.2~1): (0.5~2): (0.5~2): (0.2~1): (1~4): (0.1~0.5): (1~4): (0.1~1): (0.01~0.05): (0.05~0.1): (0.02~0.1): (0.1~0.5).

[0022] A preferred herbal composition of the present invention comprises, by weight percentage, 75.0% to 99.9% of Danshen / Tenchi ginseng extract and 0.1% to 25.0% of ice chips. A more preferred herbal composition of the present invention comprises, by weight percentage, 90.0% to 99.9% of Danshen / Tenchi ginseng extract and 0.1% to 10.0% of ice chips. In the above-mentioned herbal medicine composition, the Danshen / Tanqi ginseng extract is preferably, in parts by weight, Danshensu (Danshensu): Salvianolic Acid T: Protocatechuic Aldehyde: Salvianolic Acid D: Rosmarinic Acid: Salvianolic Acid B: Salvianolic Acid A: Sankinoside R1: Ginsenoside Rg1: Ginsenoside Re: Ginsenoside Rb1: Ginsenoside Rd: Dihydrotanshinone I: Tanshinone I: Crypto Tanshinone: Contains Tanshinone IIA=(3~4):(0.9~1.2):(1.4~2.0):(0.5~0.7):(0.5~0.9):(1~1.6):(0.7~1.2):(0.5~0.9):(1.8~2.8):(0.2~0.4):(1.7~2.2):(0.2~0.6):(0.03~0.04):(0.07~0.08):(0.05~0.06):(0.26~0.28). In the above-mentioned herbal medicine composition, the Danshen / Tenchi ginseng extract more preferably contains, by weight, Danshensu (Danshensu): Salvianolic acid T: Protocatechualdehyde: Salvianolic acid D: Rosmarinic acid: Salvianolic acid B: Salvianolic acid A: Sankinoside R1: Ginsenoside Rg1: Ginsenoside Re: Ginsenoside Rb1: Ginsenoside Rd: Dihydrotanshinone I: Tanshinone I: Cryptotanshinone: Tanshinone IIA = 3.6:1.1:1.7:0.6:0.7:1.3:0.9:0.7:2.4:0.3:1.8:0.4:0.03:0.07:0.06:0.27. The above-mentioned herbal composition is produced by extracting Red Sage and Panax notoginseng to obtain an extract, and then adding and mixing ice chips.

[0023] The herbal composition of the present invention is preferably prepared by the following method. (1) Decant the herbal medicines Danshen and Panax notoginseng with water under alkaline conditions, filter the decoction, concentrate the filtrate and precipitate it with alcohol, remove the supernatant and filter, recover the ethanol to obtain the extract (or further dry the extract) to obtain Danshen and Panax notoginseng extract. (2) Add ice chips to the Danshen / Tenchi ginseng extract and mix evenly. Among them, Danshen and Panax notoginseng can be decoctioned in water under the same alkaline conditions, or in water under the same alkaline conditions.

[0024] Preferably, the Danshen / Tenchi ginseng extract is prepared by the following method. Step (1): Decant Danshen and Panax notoginseng in an aqueous solution with alkali 1-3 times for 1-3 hours each time, and then filter to obtain filtrate I; Step (2): Add water to the residue and boil for 1 to 3 hours each time, then filter to obtain filtrate II; Step (3): Filtrates I and II are combined and concentrated, the concentrate is subjected to alcohol precipitation, allowed to stand, the supernatant is removed, filtered, the ethanol is recovered, and the extract is concentrated or dried to obtain Danshen / Tenchi ginseng extract. Wherein, the alkaline aqueous solution in step (1) includes, but is not limited to, one or more of sodium bicarbonate, sodium carbonate, sodium hydrogen phosphate, sodium dihydrogen phosphate, sodium hydroxide, calcium hydroxide, magnesium hydroxide aqueous solution, pH is 7.5-9.0, and the amount of base added in said alkaline aqueous solution is 1-4.5% by weight, preferably 2.25-3% by weight, of the amount of herb to ensure complete extraction of Danshensu sodium and Salvianolic acid T. In step (3), alcohol precipitation is preferably carried out by adding 50% to 100% ethanol, preferably 95% ethanol, and preferably the alcohol precipitation is carried out so that the ethanol concentration is 60% to 75%.

[0025] More preferably, the Danshen / Tenchi ginseng extract of the present invention is prepared by the following method: Step (1): Cut the Danshen herb into sections of 5 cm or less, preferably 1-2 cm, crush the Panax notoginseng herb into 1 cm granules, weigh out sodium bicarbonate accounting for 2.25-3% by weight of the total herb weight, put the weighed Danshen, Panax notoginseng, and sodium bicarbonate into an extraction tank, add 5 times the amount of process water for each tank, heat to boiling, maintain boiling for 2h±20 minutes, and filter. Step (2): Extract the residue twice, add four times the amount of water, heat to boiling, keep boiling for 1 hour ± 15 minutes, filter, and discard the residue. Step (3): Concentrate the extract under reduced pressure until it has a relative density of 1.16-1.20 (80±5°C) or a corresponding sugar content of 48%-52%, obtain a concentrate, pour the concentrate into an alcohol precipitation tank, add an appropriate amount of ethanol to adjust the alcohol content to 65%-70%, leave to stand for 12-24 hours until complete precipitation, isolate the supernatant, discard the precipitate, concentrate the supernatant to obtain the extract, or dry the extract to obtain Danshen / Tenchi ginseng extract. In particular, the "5 times the amount" in the above step (1) means 5 times the total weight of the crude drugs, and similarly, the "4 times the amount" in the above step (2) means 4 times the total weight of the drug residue.

[0026] The herbal composition of the present invention is prepared from 75-90 parts by weight of Danshen, 10-25 parts of Panax notoginseng, and 0.1-4 parts of ice chips. A preferred herbal composition is prepared by using, by weight, 80-86 parts of Danshen, 15-18 parts of Panax notoginseng, and 0.2-2 parts of ice chips. The most preferred herbal composition is prepared by using, by weight, 82-84 parts of Danshen, 16-17 parts of Panax notoginseng, and 0.4-1.2 parts of ice chips. The herbal composition of the present invention may be in the form of an extract or a powder.

[0027] In one embodiment, the present invention provides a pharmaceutical preparation of a herbal medicine composition, comprising the herbal medicine composition and one or more pharma- ceutically acceptable carriers, the weight percentage of the herbal medicine composition in the preparation may be 0.1%-99.9%, and the rest is the pharma- ceutically acceptable carriers. The pharmaceutical preparation of the present invention is in the form of a unit dose pharmaceutical preparation, where "unit dose" means a unit of preparation such as one tablet, one capsule, one bottle of oral liquid, one bag of granules, etc., and may be prepared by any method well known in the pharmaceutical field. All methods include combining the herbal composition of the present invention with a carrier, which constitutes one or more auxiliary ingredients. In general, the preparation process involves combining the herbal composition of the present invention with a liquid carrier, or a finely divided solid carrier, or a combination of both, uniformly and intimately, and then forming into the required preparation as necessary. The pharmaceutical preparation of the present invention can be generally prepared by standard pharmaceutical techniques such as mixing, granulating, pressing, etc., to prepare the herbal composition of the present invention and the pharmaceutical carrier. As is well known to those skilled in the art, the form and characteristics of the pharmaceutical carrier or diluent depend on the amount of active ingredient to be mixed therewith, the route of administration, and other known factors.

[0028] The dosage forms include tablets, sugar-coated tablets, film-coated tablets, enteric-coated tablets, capsules, hard capsules, soft capsules, oral liquids, buccal tablets, granules, powders, pills, powders, pastes, pills, suspensions, powders, solutions, injections, suppositories, ointments, plasters, creams, sprays, drops, and patches. The formulation of the present invention is preferably in an oral dosage form such as capsules, tablets, oral liquids, granules, pills, powders, pills, pastes, and the like. The oral formulations may contain commonly used excipients such as binders, fillers, diluents, tableting agents, lubricants, disintegrants, colorants, flavoring agents, and wetting agents, and may optionally include tablet coatings.

[0029] The fillers used include cellulose, mannitol, lactose and other similar fillers.Suitable disintegrants include starch, polyvinylpyrrolidone and starch derivatives such as sodium starch hydroxyacetate.Suitable lubricants include, for example, magnesium stearate.Suitable pharma-ceutically acceptable wetting agents include sodium lauryl sulfate. Solid oral compositions can be manufactured by conventional techniques such as blending, filling, tableting, etc. Repeated blending can be used to distribute the active material throughout compositions employing large amounts of filler. The oral liquid preparation may be in the form of, for example, an aqueous or oily suspension, solution, emulsion, syrup or elixir, or a dry product that can be reconstituted in water or other suitable carrier before use. Such liquid preparations may contain suspending agents such as sorbitol, syrup, methylcellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel, hydrogenated edible fats, emulsifying agents such as lecithin, sorbitan monooleate, and gum arabic, non-aqueous carriers such as almond oil, fractionated coconut oil, oily esters such as glycerin, propylene glycol, and ethanol (which may contain edible oils), and preservatives such as methyl parahydroxybenzoate, propyl parahydroxybenzoate, or sorbic acid. Conventional flavors and coloring agents may also be included, if necessary. For injections, the liquid unit dosage form prepared contains the active substance of the present invention and a sterile carrier. Depending on the carrier and concentration, the compound can be suspended or dissolved. The preparation of the solution is usually carried out by dissolving the active substance in the carrier, filtering and sterilizing the solution before being placed in a suitable vial or ampoule, and sealing the solution. Auxiliary agents such as local anesthetics, preservatives, buffers, etc. can also be dissolved in the carrier. To enhance its stability, the composition can be frozen after being placed in a vial, and water can be removed under vacuum.

[0030] Suitable pharma- ceutically acceptable carriers that may be added when preparing a drug are selected from the group consisting of mannitol, sorbitol, sodium pyrosulfite, sodium bisulfite, sodium thiosulfate, cysteine ​​hydrochloride, thioglycolic acid, methionine, vitamin C, disodium EDTA, calcium sodium EDTA, carbonates, acetates, phosphates of monovalent alkali metals, aqueous solutions thereof, hydrochloric acid, acetic acid, sulfuric acid, phosphoric acid, amino acids, sodium chloride, calcium chloride, sodium lactate, xylitol, maltose, glucose, fructose, dextran, glycine, starch, sucrose, lactose, mannitol, silicon derivatives, cellulose, its derivatives, alginates, gelatin, polyvinylpyrrolidone, glycerin, Tween 80, agar, calcium carbonate, calcium bicarbonate, surfactants, polyethylene glycol, cyclodextrin, β-cyclodextrin, phospholipid-based materials, kaolin, talc, calcium stearate, magnesium stearate, and the like.

[0031] In the present invention, the herbal composition is preferably prepared into a dripping pill preparation, more preferably into a micro-dripping pill preparation. In another embodiment, the present invention provides Fufang Danshen micro-drop pills, which are prepared by the weight ratio of the herbal composition and the drop pill matrix of 1:5-5:1.Preferably, the Fufang Danshen micro-drop pills of the present invention are prepared by the weight ratio of the herbal composition and the drop pill matrix of 1:3-3:1.Most preferably, the Fufang Danshen micro-drop pills of the present invention are prepared by the weight ratio of the herbal composition and the drop pill matrix of 1:(1-3).

[0032] The preparation method of Fufang Danshen micro-drop pills of the present invention includes: (1) raw material dissolving process: put the medicine and the drop pill matrix into the homogenizer, mix uniformly at 1000-5000 rpm for 1-200 minutes, then dissolve the raw material uniformly at 3000-10000 rpm for 1-100 minutes, in the raw material dissolving process, maintain the temperature at 60-100°C, and obtain the dissolved drug solution so that the weight ratio of the medicine and the drop pill matrix is ​​1:5-5:1. (2) Dropping step: The above-mentioned dissolving solution is carried to a dropping nozzle, and dropped while vibrating through the dropping nozzle under the conditions of a dropping nozzle temperature of 70-300°C, a dropping vibration frequency of 2-2000Hz, a dropping pressure of 0.5-4.0Bar, and an acceleration of 1-20G so as to match the dropping speed with the raw material dissolving speed in the above step (1). (3) Condensation process: The dropped droplets are quickly cooled with a cooling gas, and condensed into solid droplets having a particle size of 0.2 mm to 4.0 mm while the temperature of the cooling gas is below 0°C.

[0033] Preferably, the preparation method for Fufang Danshen micro-drop pills of the present invention includes: (1) raw material dissolving process: put the medicine and the drop pill matrix into the homogenizer, mix uniformly at 1000-5000 rpm for 1-200 minutes, then dissolve the raw material uniformly at 3000-10000 rpm for 1-100 minutes, in the raw material dissolving process, maintain the temperature at 80-100°C, and obtain the dissolved drug solution so that the weight ratio of the medicine and the drop pill matrix is ​​1:3-3:1. (2) Dropping step: The above-mentioned dissolving solution is carried to a dropping nozzle, and dropped while vibrating through the dropping nozzle under the conditions of a dropping nozzle temperature of 70-200°C, a dropping vibration frequency of 20-300Hz, a dropping pressure of 0.5-4.0Bar, and an acceleration of 1-15G so as to match the dropping speed with the raw material dissolving speed in the above step (1). (3) Condensation process: The dropped droplets are quickly cooled with a cooling gas, and condensed into solid droplets having a particle size of 0.2 mm to 4.0 mm while the temperature of the cooling gas is below 0°C.

[0034] Wherein, in the above step (1), the matrix of the drop pill comprises one or more combinations of PEG, sorbitol, xylitol, lactitol, maltose, starch, methylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, gum arabic, alginic acid, dextrin, cyclodextrin, agar, lactose.Preferred matrix of the drop pill is solid PEG, such as PEG-1000, PEG-2000, PEG-3000, PEG-4000, PEG-5000, PEG-6000, PEG-7000, PEG-8000, more preferably one or more combinations of PEG-1000, PEG-2000, PEG-3000, PEG-4000, PEG-6000, PEG-8000.Most preferred is PEG-6000, PEG-4000, or the combination of PEG-4000 and PEG-6000. The homogenization in the above step (1) can increase the uniformity of the content, and can increase the uniformity of the content from the original RSD=10% to 7%. Preferably, in the above step (1), the weight ratio of the drug and the dropping pill matrix is ​​1:3-3:1, the speed is 3000-5000 rpm, the mixture is mixed uniformly for 10-60 minutes, the mixture is then mixed uniformly for 4000-9000 rpm, and the temperature is maintained at 70-90°C for 5-30 minutes in the process of dissolving the raw material. Most preferably, the weight ratio of the drug and the dropping pill matrix is ​​1:(1-3), the mixture is mixed uniformly for 10-30 minutes, the mixture is then mixed uniformly for 4000-6000 rpm, and the temperature is maintained at 75-85°C for 6-30 minutes in the process of dissolving the raw material. Among these, in the above step (2), preferably, the dropping nozzle temperature is 70 to 100°C, and preferably 75 to 85°C, the dropping vibration frequency is 50 to 300 Hz, and preferably 100 to 200 Hz, and more preferably 90 to 200 Hz, and more preferably 130 to 140 Hz, and most preferably 137 Hz, the acceleration is 3.5 to 4.5 G, and preferably 4.0 G, the dropping pressure is 1.0 to 3.0 Bar, and preferably 1.8 Bar, and the dropping speed is 10 to 40 kg / h, and preferably 12 to 30 kg / h, and more preferably 15 to 25 kg / h. In the above step (3), gas cooling means that the falling droplets are rapidly cooled by a low-temperature cold trap, solidified, and molded. The temperature range of the cooling gas is 0°C or lower, preferably 0 to -150°C, preferably -60°C to -140°C, more preferably -80°C to -120°C, and the cooling gas is preferably air, nitrogen gas, or inert gas. The particle size of the obtained microdroplets is preferably 1.0mm to 2.0mm.

[0035] In addition, the manufacturing method of the micro-drop pills of the present invention further includes a drying step as step (4), preferably drying with a fluidized drying device, drying at -20 to 100°C, preferably -20 to 90°C for 1 to 4 hours to obtain naked pills. Specifically, the low-temperature dripping pills after completing the dripping through the above step (3) are dried in a fluidized bed at a temperature of 40 to 150°C, preferably at a temperature of 40 to 60°C, for 1 to 4 hours, preferably 1 to 3 hours, most preferably 2 hours to obtain naked pills. In the above step (4), the following gradient temperature rising drying method is preferred, which is fluidized at -20 to 30°C, dried at 15 to 35°C for 10 to 120 minutes, dried at 35 to 55°C for 10 to 60 minutes, and dried at 55 to 100°C for 0 to 60 minutes. More preferred is the following gradient temperature rising drying method, which is fluidized at 0 to 20°C, dried at 25°C for 60 minutes, dried at 45°C for 30 minutes, and dried at 55°C for 0 to 30 minutes. This process can keep the dripping pills in a fluidized state, solve the problem of dripping pills adhesion, and improve efficiency, and the production capacity can reach 30kg / h. Furthermore, the method for producing microdroplets of the present invention further includes a coating step as step (5). In this step, the bare pills obtained in step (4) are coated in a fluidized state at a temperature of 30-65°C. The coating liquid concentration is 5-25wt%, preferably 18-20wt%, in which the coating material is selected from the group consisting of shellac, cellulose acetate phthalate, methyl acrylate, methyl methacrylate, or Opadry. The weight ratio of the coating material to the bare pills is 1:50-1:10, preferably 1:50-1:25.

[0036] In order to better carry out the method for producing microdroplets of the present invention, it is also possible to further include a material premixing step before the above step (1), and it is also preferable to add the drug extract or powder to water and then stir at 30-80℃ for more than 10 minutes to obtain a drug premix with uniform moisture content. This step can make up for the shortcomings of adding dry powder. The drop pills prepared by the method of the present invention can be packaged as they are, or can be put into capsule cases to be made into capsules. After the capsules are made, a step of weighing the capsules one by one can be added, so that the filled capsules can be weighed one by one at high speed before packaging, and any defective capsules that may exist can be removed. EXAMPLES

[0037] The process of the present invention will now be described in more detail with reference to the following examples, which are intended to illustrate but not to limit the present invention.

[0038] <Method for measuring the content of each component in Danshen and Panax notoginseng extract> In the following examples, the contents of each component of each herbal medicine composition: Danshensu, salvianolic acid T, protocatechuic aldehyde, salvianolic acid D, rosmarinic acid, salvianolic acid B, salvianolic acid A, dihydrotanshinone I, tanshinone I, cryptotanshinone, tanshinone IIA, sanquinoside R1, ginsenoside Rg1, ginsenoside Re, ginsenoside Rb1, and ginsenoside Rd were measured according to the following methods.

[0039] <Detection of phenolic acid and tanshinone components> Preparation of control and test solution Reference solution: Weigh accurately a certain amount of reference substances Danshensu, Salvianolic acid T, Protocatechualdehyde, Salvianolic acid D, Rosmarinic acid, Salvianolic acid B, Salvianolic acid A, Dihydrotanshinone I, Tanshinone I, Cryptotanshinone, and Tanshinone IIA, place them in a 10-ml volumetric flask, dissolve them with methanol, dilute to the mark, dilute further if necessary, shake well to prepare solutions with the following respective concentrations, filter through a 0.22-μm membrane to obtain the reference solution. Danshensu 0.0315 mg / ml, Salvianolic acid T 0.04596 mg / ml, Protocatechualdehyde 0.07556 mg / ml, Salvianolic acid D 0.04385 mg / ml, Rosmarinic acid 0.04263 mg / ml, Salvianolic acid B 0.04248 mg / ml, Salvianolic acid A 0.1118 mg / ml, Dihydrotanshinone I 0.02098 mg / ml, Tanshinone I 0.02085 mg / ml, Cryptotanshinone 0.02442 mg / ml, Tanshinone IIA 0.01992 mg / ml. Test sample solution: Weigh accurately 0.1 g of the Danshen·Tianqi·Ginseng extract sample, place it in a 10-ml volumetric flask, dissolve it with pure water, dilute to the mark, and then filter through a 0.22-μm membrane to obtain the test sample solution. Measurement method: Pipette 10 μl each of the reference solution and the test sample solution accurately, inject them into an ultra-high performance liquid chromatography apparatus, and measure. Chromatography column: Agilent Zorbax SB C18 (4.6×250 mm, 5 μm) Flow rate: 0.5 mL / min Column temperature: 30 °C Detection wavelength: 281 nm Dissolution conditions: As shown in Table 1 below.

[0040]

Table 1

[0041] <Detection of saponin components> Preparation of control solutions: Appropriate amounts of sankinoside R1 control, ginsenoside Rg1 control, ginsenoside Rb1 control, ginsenoside Re, and ginsenoside Rd control were taken, precisely weighed, and methanol was added to prepare solutions containing 0.5 mg, 2.0 mg, 1.0 mg, 0.5 mg, 0.5 mg, 0.5 mg, and 1.0 mg per ml. Preparation of test sample solution: 0.1g of sample was precisely weighed, dissolved in 10ml of 4% aqueous ammonia solution, and passed through a D101 type large pore adsorption resin column (inner diameter 0.7cm, column height 5cm) to elute with 30ml of water, then 30ml of 30% methanol, and then 10ml of methanol. The methanol solution was collected in a 10ml measuring flask, shaken uniformly, and collected. Chromatography conditions and system applicability test: Octadecylsilane-bonded silica gel was used as the packing material, acetonitrile was used as mobile phase A, and water was used as mobile phase B. Gradient elution was performed according to Table 2 below. The flow rate was 1.0 ml per minute, the detection wavelength was 203 nm, the column temperature was 30°C, and the recording time was 75 minutes.

[0042] [Table 2] Measurement: 10 μl of each of the control solution and test solution was precisely drawn up and injected into the liquid chromatography device.

[0043] <Production of the herbal medicine composition of the present invention> <Example 1> Take 820g of Danshen herb and cut it into 1-2cm small pieces, and crush 160g of Panax notoginseng herb into 0.18cm granules. Measure out sodium bicarbonate with 2.25% of the herb weight. Put the measured Danshen, Panax notoginseng, and sodium bicarbonate into the extraction tank, add 5 times the amount of process water for each tank, heat to boiling, keep boiling for about 2h, filter, and discard the residue for the second extraction, add 4 times the amount of water, heat to boiling, keep boiling for about 1h, filter, and discard the residue. Concentrate the extract under reduced pressure to a relative density of 1.16-1.20 (80±5℃) or the corresponding sugar content of 48-52% to obtain the concentrate. Pour the concentrate into the alcohol precipitation tank, add an appropriate amount of ethanol to adjust the alcohol content to 65%-70%, and leave to stand for 12 hours until complete precipitation, isolate the supernatant, and discard the precipitate. The supernatant was concentrated to obtain the extract, which was then dried to obtain the Danshen and Panax notoginseng extract. The Danshen and Tienqi ginseng extract was measured according to the above method. The Danshen and Tienqi ginseng extract contained Danshensu (Danshensu) 36mg / g, Salvianolic acid T 11mg / g, Protocatechuic aldehyde 17mg / g, Salvianolic acid D 6mg / g, Rosmarinic acid 7mg / g, Salvianolic acid B 13mg / g, Salvianolic acid A 9mg / g, Sankinoside R 17mg / g, Ginsenoside Rg1 24mg / g, Ginsenoside Re 3mg / g, Ginsenoside Rb1 18mg / g, Ginsenoside Rd 4mg / g, Dihydrotanshinone I 0.3mg / g, Tanshinone I 0.7mg / g, Cryptotanshinone 0.6mg / g, and Tanshinone IIA 2.7mg / g. 90 g of Danshen / Tenchi ginseng extract and 9 g of ice chips were mixed uniformly to obtain a Chinese herbal medicine composition.

[0044] <Example 2> 75 g of the Danshen / Panax Notoginseng extract prepared in Example 1 and 25 g of ice chips were mixed uniformly to obtain a herbal medicine composition. <Example 3> 800.0g of Danshen and 150.0g of Panax notoginseng were added to water under alkaline conditions (pH=9) and boiled for 1 hour each time, then filtered to obtain filtrate I. The drug residue was added to water and boiled for 1 hour each time, then filtered to obtain filtrate II. Filtrates I and II were combined and concentrated, and the concentrate was added to ethanol to make the alcohol concentration 70%, allowed to stand, the supernatant was removed, filtered, the ethanol was recovered, concentrated and dried to obtain Danshen-Panax notoginseng extract. The Danshen and Tienqi ginseng extract was measured according to the above method. The Danshen and Tienqi ginseng extract contained Danshensu 40mg / g, Salvianolic acid T 12mg / g, Protocatechuic aldehyde 20mg / g, Salvianolic acid D 7mg / g, Rosmarinic acid 9mg / g, Salvianolic acid B 16mg / g, Salvianolic acid A 12mg / g, Sankinoside R1 9mg / g, Ginsenoside Rg1 28mg / g, Ginsenoside Re 4mg / g, Ginsenoside Rb1 22mg / g, Ginsenoside Rd 6mg / g, Dihydrotanshinone I 0.4mg / g, Tanshinone I 0.8mg / g, Cryptotanshinone 0.6mg / g, and Tanshinone IIA 2.8mg / g. 99.9 g of Danshen / Tenchi ginseng extract and 0.1 g of ice chips were mixed uniformly to obtain a Chinese herbal medicine composition. <Example 4> 90 g of the Danshen / Panax Notoginseng extract prepared in Example 3 and 10 g of ice chips were mixed uniformly to obtain a herbal medicine composition.

[0045] <Example 5> 750g of Danshen and 250g of Panax notoginseng were added to water under alkaline conditions (pH=7.5) and boiled twice for 2 hours each time, then filtered to obtain filtrate I. The drug residue was added to water and boiled twice for 2 hours each time, then filtered to obtain filtrate II. Filtrates I and II were combined and concentrated, and ethanol was added to the concentrate to make the alcohol concentration 70%, allowed to stand, the supernatant was removed, filtered, the ethanol was recovered, concentrated and dried to obtain Danshen-Panax notoginseng extract. The Danshen and Panax notoginseng extracts were assayed according to the above-mentioned method. The Danshen and Panax notoginseng extracts contained 30mg / g, 9mg / g, 14mg / g, 5mg / g, 5mg / g, 10mg / g, 7mg / g, 5mg / g, 18mg / g, 2mg / g, 17mg / g, 2mg / g, 0.3mg / g, 0.7mg / g, 0.5mg / g, and 2.6mg / g of Danshensu, Salvianolic Acid T, Protocatechuic Aldehyde, Salvianolic Acid D, Rosmarinic Acid, Salvianolic Acid B, Salvianolic Acid A, Sankinoside R1, Ginsenoside Rg1, Ginsenoside Re, Ginsenoside Rb1, Ginsenoside Rd, Dihydrotanshinone I, Tanshinone I, Cryptotanshinone, and Tanshinone IIA, respectively. 50 g of Danshen and Panax notoginseng extract and 50 g of ice chips were mixed uniformly to obtain a Chinese herbal medicine composition. <Example 6> 99 g of the Danshen / Panax Notoginseng extract prepared in Example 5 and 1 g of ice chips were mixed uniformly to obtain a herbal medicine composition.

[0046] <Example 7> 83 parts of Danshen and 17 parts of Panax notoginseng were added to water under alkaline conditions (pH=7.5) and boiled twice for 2 hours each time, then filtered to obtain filtrate I. The drug residue was added to water and boiled twice for 2 hours each time, then filtered to obtain filtrate II. Filtrates I and II were combined and concentrated, and the concentrate was added to ethanol to make the alcohol concentration 70%, allowed to stand, the supernatant was removed, filtered, the ethanol was recovered, concentrated and dried to obtain Danshen-Panax notoginseng extract. One piece of ice was added and mixed uniformly to obtain a Chinese herbal medicine composition. The ice was a commercially available product. The measurements were performed according to the above-mentioned method. The contents of Danshensu, Salvianolic Acid T, Protocatechuic Aldehyde, Salvianolic Acid D, Rosmarinic Acid, Salvianolic Acid B, Salvianolic Acid A, Sankinoside R1, Ginsenoside Rg1, Ginsenoside Re, Ginsenoside Rb1, Ginsenoside Rd, Dihydrotanshinone I, Tanshinone I, Cryptotanshinone, and Tanshinone IIA in Danshen and Panax notoginseng extract were 40mg / g, 12mg / g, 20mg / g, 7mg / g, 9mg / g, 16mg / g, 12mg / g, 9mg / g, 28mg / g, 4mg / g, 22mg / g, 6mg / g, 0.4mg / g, 0.8mg / g, 0.6mg / g, and 2.8mg / g, respectively.

[0047] <Example 8> 400g of Danshen herb was taken and cut into 1-2cm pieces, and 80g of Panax notoginseng herb was crushed into granules. Sodium bicarbonate was measured to be 3% of the herb weight, and the measured Danshen, Panax notoginseng, and sodium bicarbonate were put into the extraction tank, and 5 times the amount of process water was added to each tank, heated to boiling, boiling was maintained for about 2 hours ± 20 minutes, filtered, and the residue was extracted for the second time, and 4 times the amount of water was added, heated to boiling, boiling was maintained for about 1 hour ± 15 minutes, filtered, and the residue was discarded. The extract was concentrated under reduced pressure to a relative density of 1.16-1.20 (80 ± 5°C) or the corresponding 50% sugar content to obtain the concentrate. The concentrate was poured into an alcohol precipitation tank, and an appropriate amount of ethanol was added to adjust the alcohol content to 68%, and the mixture was left to stand for 20 hours until complete precipitation, and the supernatant was isolated and the precipitate was discarded. The supernatant was concentrated to obtain the extract, which was then dried to obtain the Danshen and Panax notoginseng extract. The measurements were performed according to the above-mentioned method. The contents of Danshensu, Salvianolic Acid T, Protocatechuic Aldehyde, Salvianolic Acid D, Rosmarinic Acid, Salvianolic Acid B, Salvianolic Acid A, Sankinoside R1, Ginsenoside Rg1, Ginsenoside Re, Ginsenoside Rb1, Ginsenoside Rd, Dihydrotanshinone I, Tanshinone I, Cryptotanshinone, and Tanshinone IIA in Danshen and Panax notoginseng extract were 20mg / g, 5mg / g, 10mg / g, 2mg / g, 0.2mg / g, 5mg / g, 5mg / g, 2mg / g, 1mg / g, 10mg / g, 1mg / g, 0.1mg / g, 0.5mg / g, 0.2mg / g, and 1mg / g, respectively. 90 g of Danshen and Panax notoginseng extract and 10 g of ice chips were mixed uniformly to obtain a Chinese herbal medicine composition.

[0048] <Example 9> 500g of Danshen herb was taken and cut into 1-2cm pieces, 102g of Panax notoginseng herb was crushed into granules, and sodium bicarbonate equivalent to 2.5% of the herb weight was measured. The measured Danshen, Panax notoginseng, and sodium bicarbonate were placed into an extraction tank, and each tank was heated to boiling with 6 times the amount of process water, kept boiling for about 2 hours, and filtered. The residue was extracted for the second time, and 6 times the amount of water was added, heated to boiling, kept boiling for about 1 hour, filtered, and the residue was discarded. The extract was concentrated under reduced pressure to a relative density of 1.16-1.20 (80±5℃) or the corresponding sugar content of 48%, to obtain the concentrate. The concentrate was poured into an alcohol precipitation tank, and an appropriate amount of ethanol was added to adjust the alcohol content to 65%, and the tank was left to stand for 24 hours until complete precipitation, and the supernatant was isolated and the precipitate was discarded. The supernatant was concentrated to obtain the extract, which was then dried to obtain the Danshen and Panax notoginseng extract. The measurements were performed according to the above-mentioned method. The contents of Danshensu, Salvianolic Acid T, Protocatechuic Aldehyde, Salvianolic Acid D, Rosmarinic Acid, Salvianolic Acid B, Salvianolic Acid A, Sankinoside R1, Ginsenoside Rg1, Ginsenoside Re, Ginsenoside Rb1, Ginsenoside Rd, Dihydrotanshinone I, Tanshinone I, Cryptotanshinone, and Tanshinone IIA in Danshen and Panax notoginseng extract were 60mg / g, 20mg / g, 30mg / g, 10mg / g, 10mg / g, 20mg / g, 20mg / g, 10mg / g, 40mg / g, 5mg / g, 40mg / g, 10mg / g, 0.5mg / g, 1mg / g, 1mg / g, and 5mg / g, respectively. 99.9 g of Danshen / Tenchi ginseng extract and 0.1 g of ice chips were mixed uniformly to obtain a Chinese herbal medicine composition.

[0049] <Production of the pharmaceutical preparation of the present invention> <Example 10> 0.5g of the herbal composition described in any one of Examples 1 to 9 and 10.5g of PEG-6000 were taken, mixed uniformly, and dissolved by heating. After the raw materials were dissolved, the mixture was transferred to a dripping tank, and the medicinal liquid was dripped into liquid paraffin at 6 to 8°C to remove the oil, to produce 400 dripping pills.

[0050] <Example 11> 0.5 g of the herbal composition according to any one of Examples 1 to 9, 4.5 g of glucose, 0.9 g of sodium thiosulfate and 1 ml of distilled water were taken, and the above ingredients were mixed uniformly, freeze-dried, and dispensed into 500 bottles to obtain the desired composition. <Example 12> 0.5 g of the herbal composition described in any one of Examples 1 to 9, 5.5 g of mannitol, 0.9 g of calcium sodium edetate and 2 ml of distilled water were taken, and the above ingredients were mixed uniformly, then freeze-dried and dispensed into 300 bottles to obtain the desired composition. <Example 13> 0.5 g of the herbal composition according to any one of Examples 1 to 9, 50 g of starch, and 50 g of sucrose were taken, and the above ingredients were uniformly mixed, then granulated and compressed into tablets. <Example 14> 0.5 g of the herbal composition according to any one of Examples 1 to 9, 50 g of starch, and 50 g of sucrose were taken, and the above ingredients were uniformly mixed, then granulated, and placed in capsules to obtain capsules.

[0051] <Preparation of the Fufang Danshen Micro Drop Pills of the Present Invention> <Example 15> 82.5 g of the herbal composition prepared in Example 1 and 165 g of PEG-6000 were obtained. (1) Pre-mixing step: The herbal medicine composition was added to water and pre-mixed, and stirred in an insulated tank at 40±10°C for 60 minutes or more so that the water content of the herbal medicine composition was 13.0 wt%, thereby obtaining and preparing a herbal medicine composition premix. (2) Raw material dissolving process: First, PEG-6000 is put into the raw material dissolving tank, heated to 90℃, and pre-dissolved, and then the Chinese herbal medicine composition premix is ​​added, and the material is mixed at low speed (3200 rpm). After mixing is completed, the homogenization speed is increased to 5000 rpm, and the raw material is dissolved in 6 minutes. In the raw material dissolving process, the temperature of the material is maintained at 80±5℃. Thus, the dissolved drug solution is obtained. (3) Dropping step: The above-mentioned dissolving solution was carried to a dropping nozzle, the vibration frequency of the dropping nozzle was adjusted to 137 Hz, the dropping nozzle temperature was controlled to 80°C, the solution was made to flow into the dropping nozzle by a pressurized method (dropping pressure 1.8 Bar), and the solution was dropped by vibration from the bottom of the dropping nozzle so that the dropping speed was matched to the raw material dissolving speed in the above step (1). (4) Condensation process: The dripped medicine is dripped into a cooling pipe and cooled with low-temperature inert gas at a cooling temperature of -115±5℃, so that the dripped medicine is cooled into a solid drip pill. (5) Drying process: The above-mentioned drop pills are fluidized and dried. After the material is in a good fluidized state in the bed, the temperature is raised to 25°C, dried for 60 minutes, further raised to 45°C, dried for 30 minutes, then raised to 55°C, dried for 30 minutes, and then cooled to below 30°C and discharged. The moisture content of the drop pills is controlled to 3.0-7.0wt%, and intermediate naked pills are obtained. (6) Coating process: The amount of coating powder used was calculated according to the coating charge and formulation, and 4% of the weight of the bare pills was used to prepare a coating solution with a concentration of 18wt%, which was then stirred for 45 minutes. The set air temperature was set to 25°C, and the qualified bare pills were put into the fluidized bed, after which the set air temperature was raised to 48°C, and coating was started after the material temperature reached 38°C. In the coating process, the material temperature was controlled to 35-45°C, and after coating was completed, the temperature was lowered to below 30°C and discharged, and the dripping pills were sieved to obtain intermediate coated pills. The weight gain of the intermediate coated pills was controlled to 3.3±0.7wt%, and the moisture content was controlled to 3.0-7.0wt%. (7) Capsule manufacturing and packaging process: The produced drop pills with a particle size of 1.0 mm to 2.0 mm were loaded into capsules, and 100% online weight inspection was completed by a capsule weight checker, and then the final products were packaged. During the dripping process, the formation status of the dripping pills can be monitored and adjusted online in real time by stroboscopic irradiation and visual inspection. After the drug-carrier coating, the dripping pills can be screened and sized to improve the uniformity and roundness of the particle size.

[0052] <Example 16> The same procedure as in Example 15 was followed to prepare Fufangdanshen micro-droplet pills, except that the weight ratio of the above herbal composition and PEG-6000 was 1:5. <Example 17> The same procedure as in Example 15 was followed to prepare Fufangdanshen micro-droplet pills, except that the weight ratio of the above herbal composition and PEG-6000 was 5:1. <Example 18> 82.5g of the herbal composition prepared in Example 1 and 165g of a 1:1 mixture of cyclodextrin and agar were taken and made into microdroplets, and the preparation method was as follows: (1) Raw material dissolving process: The herbal medicine composition and a 1:1 mixture of cyclodextrin and agar as a drop pill matrix are put into a homogenizer, and mixed uniformly at 1000 rpm for 1 minute, and then the raw material is dissolved uniformly at 3000 rpm for 1 minute. In the raw material dissolving process, the temperature of the material is maintained at 60°C, and a dissolved medicinal solution is obtained. (2) Dropping step: The above-mentioned dissolving solution was carried to a dropping nozzle, and dropped while vibrating through the dropping nozzle under the conditions of a dropping nozzle temperature of 70°C, a dropping vibration frequency of 50 Hz, and a dropping pressure of 0.5 Bar so that the dropping speed was matched to the dissolving speed of the raw material in the above step (1). (3) Condensation process: The dripped droplets were quickly cooled with a cooling gas, and condensed into round droplets with a particle size of 0.2 mm while the temperature of the cooling gas was 0°C.

[0053] <Example 19> 82.5g of the herbal composition prepared in Example 1 and 165g of a mixture of gum arabic and lactose in a 1:1 ratio were taken and prepared into Fufang Danshen micro-droplet pills, and the preparation method was as follows: (1) Raw material dissolving process: The herbal medicine composition and a 1:1 mixture of gum arabic and lactose as a drop pill matrix were put into a homogenizer, and mixed uniformly at 5000 rpm for 200 minutes, and then uniformly dissolved in the raw materials at 10000 rpm for 100 minutes. In the raw material dissolving process, the temperature of the material was maintained at 100°C, and a dissolved medicinal liquid was obtained. (2) Dropping step: The above-mentioned dissolving solution was carried to a dropping nozzle, and dropped while vibrating through the dropping nozzle under the conditions of a dropping nozzle temperature of 300°C, a dropping vibration frequency of 300 Hz, and a dropping pressure of 4.0 Bar so that the dropping speed was matched to the raw material dissolving speed in the above step (1). (3) Condensation process: The dripped droplets were quickly cooled with a cooling gas, and condensed into round droplets with a particle size of 4.0 mm while the temperature of the cooling gas was -150°C.

[0054] <Example 20> 82.5g of the herbal composition prepared in Example 1 and 165g of lactitol were taken and prepared into Fufang Danshen micro-droplet pills, and the preparation method was as follows: (1) Raw material dissolving process: put the Chinese herbal medicine composition and lactitol as the matrix of the drop pill into the homogenizer, mix uniformly at 2500 rpm for 100 minutes, then dissolve the raw material uniformly at 6000 rpm for 50 minutes. In the raw material dissolving process, the temperature of the material is kept at 80°C, and thus a dissolved medicinal liquid is obtained. (2) Dropping step: The above-mentioned dissolving solution was carried to a dropping nozzle, and dropped while vibrating through the dropping nozzle under the conditions of a dropping nozzle temperature of 150°C, a dropping vibration frequency of 150Hz, and a dropping pressure of 2Bar so that the dropping speed was matched to the dissolving speed of the raw material in the above step (1). (3) Condensation process: The dripped droplets were quickly cooled with a cooling gas, and condensed into round droplets with a particle size of 2 mm, even though the temperature of the cooling gas was -100°C. (4) Drying process: The above drop pills were fluidized and dried in a fluidized drying device at 50°C for 2 hours to obtain dried drop pills and naked pills. (5) Coating process: the above-mentioned dried drop pills and bare pills were coated in a fluidized bed, the weight ratio of the coating material to the bare pills was 1:25, the coating liquid concentration was 10 wt%, and the coating was performed at a temperature of 40°C to obtain coated drop pills, and the coating material was Opadry.

[0055] <Example 21> 82.5g of the herbal composition prepared in Example 1 and 165g of PEG8000 were taken and prepared into Fufang Danshen micro-droplet pills, and the preparation method was as follows: The above herbal medicine composition powder was added to water, and then stirred at 60° C. for 10 minutes or more to obtain a herbal medicine composition premix. (1) Raw material dissolving process: the above-mentioned herbal medicine composition premix and PEG-8000 were put into a homogenizer and mixed uniformly at 2500 rpm for 100 minutes, and then the raw materials were dissolved uniformly at 6000 rpm for 50 minutes. During the raw material dissolving process, the temperature of the material was maintained at 80°C to obtain a dissolved medicinal solution. (2) Dropping step: The above-mentioned dissolving solution was carried to a dropping nozzle, and dropped while vibrating through the dropping nozzle under the conditions of a dropping nozzle temperature of 150°C, a dropping vibration frequency of 150Hz, and a dropping pressure of 2Bar so that the dropping speed was matched to the dissolving speed of the raw material in the above step (1). (3) Condensation process: The dripped droplets were quickly cooled with a cooling gas, and condensed into round droplets with a particle size of 2 mm, even though the temperature of the cooling gas was -100°C. (4) Drying process: The above drop pills were fluidized and dried in a fluidized drying device at 50°C for 2 hours to obtain dried drop pills and naked pills. (5) Coating process: the above-mentioned dried drop pills and bare pills were coated in a fluidized bed, the weight ratio of the coating material to the bare pills was 1:25, the coating liquid concentration was 10 wt%, and the coating was performed at a temperature of 40°C to obtain coated drop pills, and the coating material was shellac.

[0056] <Example 22> 92g of the herbal composition prepared in Example 1 and 270g of PEG-1000 were used to prepare Fufang Danshen micro-droplet pills, and the preparation method was as follows: The herbal medicine composition powder was added to water and stirred at 30° C. for more than 10 minutes to obtain a pharmaceutical premix. (1) Raw material dissolving process: The above-mentioned herbal medicine composition and PEG-1000 were put into a homogenizer and mixed uniformly at 2500 rpm for 100 minutes, and then the raw materials were dissolved uniformly at 6000 rpm for 20 minutes. During the raw material dissolving process, the temperature of the material was maintained at 100°C, and a dissolved medicinal solution was obtained. (2) Dropping step: The above-mentioned dissolving solution was carried to a dropping nozzle, and dropped while vibrating through the dropping nozzle under the conditions of a dropping nozzle temperature of 70°C, a dropping vibration frequency of 100Hz, a dropping pressure of 1.0Bar, an acceleration of 1G, and a dropping speed of 10Kg / h, so that the dropping speed was matched to the raw material dissolving speed in the above step (1). (3) Condensation process: The dripped droplets were quickly cooled with cooling gas, and condensed into round droplets with a particle size of 2 mm while the temperature of the cooling gas was -80°C. (4) Drying process: the above drop pills are dried by gradient temperature rising drying method, and the pills are fluidized at -20℃, dried at 15℃ for 10 minutes, dried at 35℃ for 10 minutes, and dried at 55℃ for 30 minutes to obtain dried drop pills and naked pills. (5) Coating process: the above-mentioned dried drop pills and bare pills were coated in a fluidized bed, the weight ratio of the coating material to the bare pills was 1:25, the coating liquid concentration was 10 wt%, and the coating was performed at a temperature of 40°C to obtain coated drop pills, and the coating material was cellulose acetate phthalate.

[0057] <Example 23> 105g of the herbal composition prepared in Example 1 and 35g of the 1:1 combination of PEG-4000 and PEG-6000 were taken and prepared into Fufang Danshen micro-droplet pills, and the preparation method was as follows: The herbal medicine composition powder was added to water and stirred at 80° C. for 10 minutes or more to obtain a herbal medicine composition premix. (1) Raw material dissolving process: The herbal medicine composition premix and a 1:1 combination of PEG-4000 and PEG-6000 were put into a homogenizer and mixed uniformly at 2500 rpm for 100 minutes, and then the raw materials were dissolved uniformly at 6000 rpm for 80 minutes. During the raw material dissolving process, the temperature of the material was maintained at 80°C, and a dissolved medicinal solution was obtained. (2) Dropping step: The above-mentioned dissolving solution was carried to a dropping nozzle, and dropped while vibrating through the dropping nozzle under the conditions of a dropping nozzle temperature of 100°C, a dropping vibration frequency of 200Hz, a dropping pressure of 3.0Bar, an acceleration of 20G, and a dropping speed of 40Kg / h, so that the dropping speed was matched to the raw material dissolving speed in the above step (1). (3) Condensation process: The dripped droplets were quickly cooled with cooling gas, and condensed into round droplets with a particle size of 2 mm while the temperature of the cooling gas was -120°C. (4) Drying process: the above drop pills are dried by gradient temperature rising drying method, and the pills are fluidized at 30℃, dried at 35℃ for 120 minutes, dried at 55℃ for 60 minutes, and dried at 100℃ for 60 minutes to obtain dried drop pills and naked pills. (5) Coating process: the above-mentioned dried drop pills and bare pills were coated in a fluidized bed, the weight ratio of the coating material to the bare pills was 1:25, the coating liquid concentration was 10 wt%, and the coating was performed at a temperature of 35°C to obtain coated drop pills, and the coating material was methyl acrylate.

[0058] <Example 24> Obtained were 600g of the herbal composition prepared in Example 1, 5g of ice chips and 600g of xylitol drop pill matrix. (1) Raw material dissolving step: First, xylitol was added to a raw material dissolving tank and heated to 90°C to dissolve in advance, and the herbal medicine composition was further added and uniformly mixed into the dissolving liquid. (2) Dropping process: The above-mentioned solution was conveyed to the dropping nozzle by a pressurized method, and the dropping nozzle was kept warm using a steam jacket. The above-mentioned solution was made to flow into the dropping nozzle under the conditions of a dropping nozzle temperature of 40°C and a dropping vibration frequency of 50 Hz, and then dropped from the bottom of the dropping nozzle. (3) Condensation process: The dripped liquid was cooled with low-temperature inert gas in a cooling pipe, and the dripped liquid was cooled to a cooling temperature of -20°C to form solid droplets. (4) Drying and coating process: After cooling, the solid droplets were subjected to fluidized drying and drug-carrier coating to produce coated micro-droplets with a particle size of 0.2mm to 1.0mm at a drying temperature of 75℃. (5) Packaging process: the coated micro-droplets are loaded into capsules, and 100% online weighing is completed by a capsule weighing machine, and then the final product is packaged. The particle size of the droplets is 0.2-1.0 mm. During the dripping process, the formation status of the dripping pills can be monitored and adjusted online in real time by stroboscopic irradiation and visual inspection. After the drug-carrier coating, the dripping pills can be screened and sized to improve the uniformity and roundness of the particle size.

[0059] <Example 25> Obtained were 600 g of the herbal composition prepared in Example 1, 5 g of ice chips and 3000 g of PEG-6000 and PEG-4000 dropping pill matrix. (1) Raw material dissolving process: First, PEG-6000 and PEG-4000 were added to a raw material dissolving tank and heated to 120°C to dissolve in advance, and then the herbal medicine composition was added and uniformly mixed into the dissolving liquid. (2) Dropping process: The above-mentioned solution was conveyed to the dropping nozzle by a pressurized method, and the dropping nozzle was kept warm using a steam jacket. The above-mentioned solution was made to flow into the dropping nozzle under the conditions of a dropping nozzle temperature of 80°C and a dropping vibration frequency of 20 Hz, and then dropped from the bottom of the dropping nozzle. (3) Condensation process: The dripped liquid was cooled with low-temperature inert gas in a cooling pipe, and the dripped liquid was cooled to a cooling temperature of -80°C to form solid droplets. (4) Drying and coating process: After cooling, the solid droplets were subjected to fluidized drying and drug-carrier coating to produce coated microdroplets with a particle size of 0.5-1.0 mm at a drying temperature of 150°C. (5) Packaging process: the coated microdroplets are loaded into capsules, and 100% online weighing is completed by a capsule weighing machine, and then the final products are packaged. During the dripping process, the formation status of the dripping pills can be monitored and adjusted online in real time by stroboscopic irradiation and visual inspection. After the drug-carrier coating, the dripping pills can be screened and sized to improve the uniformity and roundness of the particle size.

[0060] <Example 26> 600g of the herbal composition prepared in Example 1, 5g of ice chips and 120g of PEG-1000 dropping pill matrix were obtained. (1) Raw material dissolving step: First, PEG-1000 was added to a raw material dissolving tank and heated to 40°C to dissolve in advance, and then the herbal medicine composition was added and uniformly mixed in the dissolving liquid. (2) Dropping process: The above-mentioned solution was conveyed to the dropping nozzle by pressurization, and the dropping nozzle was kept warm using a steam jacket. The above-mentioned solution was made to flow into the dropping nozzle under the conditions of a dropping nozzle temperature of 40 to 60°C and a dropping vibration frequency of 200 Hz, and then dropped from the bottom of the dropping nozzle. (3) Condensation process: The dripped liquid was cooled with low-temperature inert gas in a cooling pipe, and the dripped liquid was cooled to a cooling temperature of -100°C to form solid droplets. (4) Drying and coating process: The cooled solid droplets are fluidized and coated with a drug carrier. They are fluidized at 20°C, dried at 25°C for 60 minutes, dried at 45°C for 30 minutes, and dried at 55°C for 30 minutes to produce coated microdroplets with a particle size of 3.0mm to 4.0mm. (5) Packaging process: the coated microdroplets are loaded into capsules, and 100% online weighing is completed by a capsule weighing machine, and then the final products are packaged. During the dripping process, the formation status of the dripping pills can be monitored and adjusted online in real time by stroboscopic irradiation and visual inspection. After the drug-carrier coating, the dripping pills can be screened and sized to improve the uniformity and roundness of the particle size.

[0061] <Example 27> Obtained were 600g of the herbal composition prepared in Example 1, 5g of ice chips and 3000g of PEG-6000, PEG-4000 dropping pill matrix. (1) Raw material dissolving process: First, PEG-6000 and PEG-4000 are added to the raw material dissolving tank, heated to 120℃, and pre-dissolved. Then, the herbal medicine composition is added and the mixture is put into the homogenizer and uniformly mixed at 1000rpm for 1 minute. Then, the raw material is uniformly dissolved at 3000rpm for 1 minute. In the raw material dissolving process, the temperature of the material is maintained at 60℃, and a dissolved medicinal liquid is obtained. (2) Dropping process: The above-mentioned solution was conveyed to the dropping nozzle by pressurization, and the dropping nozzle was kept warm using a steam jacket. The above-mentioned solution was made to flow into the dropping nozzle under the following conditions: the dropping nozzle temperature was 70°C, the dropping vibration frequency was 50Hz, and the dropping pressure was 0.5Bar, and then the solution was dropped from the bottom of the dropping nozzle. (3) Condensation process: The dripped liquid was cooled with low-temperature inert gas in a cooling pipe, and the dripped liquid was cooled to a solid droplet at a cooling temperature of 0°C. (4) Drying and coating process: After cooling, the solid droplets were subjected to fluidized drying and drug-carrier coating to produce coated microdroplets with a particle size of 0.2 mm at a drying temperature of 150°C. (5) Packaging process: the coated microdroplets are loaded into capsules, and 100% online weighing is completed by a capsule weighing machine, and then the final products are packaged.

[0062] <Example 28> 600g of the herbal composition prepared in Example 1, 5g of ice chips and 1800g of PEG-6000 dropping pill matrix were obtained. (1) Raw material dissolving process: First, PEG-6000 is added to the raw material dissolving tank, heated to 120℃, and pre-dissolved. Then, the herbal medicine composition is added and put into the homogenizer, and mixed uniformly at 5000 rpm for 200 minutes. Then, the raw material is uniformly dissolved at 10000 rpm for 1 minute. In the raw material dissolving process, the temperature of the material is maintained at 100℃, and a dissolved medicinal liquid is obtained. (2) Dropping process: The above-mentioned solution was conveyed to the dropping nozzle by pressurization, and the dropping nozzle was kept warm using a steam jacket. The above-mentioned solution was made to flow into the dropping nozzle under the following conditions: the dropping nozzle temperature was 300°C, the dropping vibration frequency was 300Hz, and the dropping pressure was 4.0Bar, and then the solution was dropped from the bottom of the dropping nozzle. (3) Condensation process: The dripped liquid was cooled with low-temperature inert gas in a cooling pipe, and the dripped liquid was cooled to a cooling temperature of -150°C to form solid droplets. (4) Drying and coating process: After cooling, the solid droplets were subjected to fluidized drying and drug-carrier coating to produce coated micro-droplets with a particle size of 4.0 mm at a drying temperature of 150°C. (5) Packaging process: the coated microdroplets are loaded into capsules, and 100% online weighing is completed by a capsule weighing machine, and then the final products are packaged.

[0063] <Example 29> 600g of the herbal composition prepared in Example 1, 5g of ice chips and 2400g of PEG-4000 dropping pill matrix were obtained. (1) Raw material dissolving process: First, PEG-4000 is added to the raw material dissolving tank, heated to 120℃, and pre-dissolved. Then, the herbal medicine composition is added and mixed uniformly at 3000 rpm for 10 minutes. Then, the raw material is uniformly dissolved at 4000 rpm for 5 minutes. In the raw material dissolving process, the temperature of the material is maintained at 70-90℃, and a dissolved medicinal liquid is obtained. (2) Dropping process: The above-mentioned solution was conveyed to the dropping nozzle by a pressurized method, and the dropping nozzle was kept warm using a steam jacket. The above-mentioned solution was made to flow into the dropping nozzle under the conditions of a dropping nozzle temperature of 70°C, a dropping vibration frequency of 90 Hz, and a dropping pressure of 1.0 Bar, and then the solution was dropped from the bottom of the dropping nozzle. (3) Condensation process: The dripped liquid was cooled with low-temperature inert gas in a cooling pipe, and the dripped liquid was cooled to a cooling temperature of -140°C to form solid droplets. (4) Drying process: After cooling, the solid droplets were subjected to fluidized drying at a drying temperature of 150°C to produce microdroplet rounds with a particle size of 1.0 mm.

[0064] <Example 30> 600g of the herbal composition prepared in Example 1, 5g of ice chips and 2400g of PEG-4000 dropping pill matrix were obtained. (1) Raw material dissolving process: First, PEG-4000 was added to the raw material dissolving tank and heated to 120°C to dissolve in advance, and then the herbal medicine composition was added and mixed uniformly at 4000 rpm for 60 minutes, and then the raw material was dissolved uniformly at 9000 rpm for 30 minutes. In the raw material dissolving process, the temperature of the material was maintained at 90°C, and a dissolved medicinal liquid was obtained. (2) Dropping process: The above-mentioned solution was conveyed to the dropping nozzle by a pressurized method, and the dropping nozzle was kept warm using a steam jacket. The above-mentioned solution was made to flow into the dropping nozzle under the conditions of a dropping nozzle temperature of 100°C, a dropping vibration frequency of 200 Hz, and a dropping pressure of 3.0 Bar, and then the solution was dropped from the bottom of the dropping nozzle. (3) Condensation process: The dripped liquid was cooled with low-temperature inert gas in a cooling pipe, and the dripped liquid was cooled to a cooling temperature of -140°C to form solid droplets. (4) Drying process: After cooling, the solid droplet pellets were subjected to fluidized bed drying at a drying temperature of 150°C to produce microdroplet pellets with a particle size of 2.0 mm.

[0065] <Example 31> 600g of the herbal composition prepared in Example 1, 5g of ice chips and 2000g of PEG-6000 dropping pill matrix were obtained. (1) Raw material dissolving process: First, PEG-6000 was added to a raw material dissolving tank and heated to 90°C to dissolve in advance, and then the herbal medicine composition was added and uniformly mixed into the dissolved medicinal liquid. (2) Dropping process: The above-mentioned solution was conveyed to the dropping nozzle by pressurization, and the dropping nozzle was kept warm using a steam jacket. The dropping nozzle temperature was 80°C, and the dropping vibration frequency was 50Hz. The above-mentioned solution was made to flow into the dropping nozzle, and then dropped from the bottom of the dropping nozzle. (3) Condensation process: The dripped liquid was cooled with low-temperature inert gas in a cooling pipe, and the dripped liquid was cooled to a cooling temperature of -20°C to form solid droplets. (4) Drying and coating process: After cooling, the solid droplets were subjected to fluidized drying and drug-carrier coating to produce coated microdroplets with a particle size of 1.0-2.0 mm at a drying temperature of 75°C. (5) Packaging process: the coated microdroplets are loaded into capsules, and 100% online weighing is completed by a capsule weighing machine, and then the final products are packaged. During the dripping process, the formation status of the dripping pills can be monitored and adjusted online in real time by stroboscopic irradiation and visual inspection. After the drug-carrier coating, the dripping pills can be screened and sized to improve the uniformity and roundness of the particle size.

[0066] <Example 32> 82.5 g of the herbal composition prepared in Example 1 and 165 g of PEG-6000 were obtained. (1) Raw material dissolving process: First, PEG-6000 is added to the raw material dissolving tank, heated to 90℃, and pre-dissolved, then the Chinese herbal medicine composition is added, and the material is mixed by low-speed homogenization (3200rpm). After the mixing is completed, the homogenization speed is increased to 5000rpm, and the raw material is dissolved in 6 minutes. In the raw material dissolving process, the temperature of the material is maintained at 80±5℃. Thus, the dissolved medicinal liquid is obtained. (2) Dropping step: The above-mentioned dissolving solution was carried to a dropping nozzle, the vibration frequency of the dropping nozzle was adjusted to 137 Hz, the dropping nozzle temperature was controlled to 80°C, the solution was made to flow into the dropping nozzle by a pressurized method (dropping pressure 1.8 Bar), and the solution was dropped by vibration from the bottom of the dropping nozzle so that the dropping speed was matched to the raw material dissolving speed in the above step (1). (3) Condensation process: The dripped medicine is dripped into a cooling pipe and cooled with low-temperature inert gas at a cooling temperature of -115±5°C, so that the dripped medicine is cooled into solid drip pills. (4) Drying process: The above-mentioned drop pills are fluidized and dried. After the material is in a good fluidized state in the bed, the temperature is raised to 25°C and dried for 60 minutes, then the temperature is raised to 45°C and dried for 30 minutes, then the temperature is raised to 55°C and dried for 30 minutes, and then the temperature is lowered to below 30°C and discharged. The moisture content of the drop pills is controlled to 3.0-7.0wt%, and the intermediate naked pills are obtained. (5) Coating process: The amount of coating powder used was calculated according to the coating charge and formulation, and 4% of the weight of the bare pills was used to prepare a coating solution with a concentration of 18wt%, which was then stirred for 45 minutes. The set air temperature was set to 25°C, and the qualified bare pills were put into the fluidized bed, after which the set air temperature was raised to 48°C, and coating was started after the material temperature reached 38°C. In the coating process, the material temperature was controlled to 35-45°C, and after coating was completed, the temperature was lowered to below 30°C and discharged, and the dripping pills were sieved to obtain intermediate coated pills. The weight gain of the intermediate coated pills was controlled to 3.3±0.7wt%, and the moisture content was controlled to 3.0-7.0wt%. (6) Capsule manufacturing and packaging process: The produced droplets with a particle size of 1.0 mm to 2.0 mm are loaded into capsules, and 100% online weight inspection is completed by a capsule weight checker, and then the capsules are packaged into final products. During the dripping process, the formation status of the dripping pills can be monitored and adjusted online in real time by stroboscopic irradiation and visual inspection. After the drug-carrier coating, the dripping pills can be screened and sized to improve the uniformity and roundness of the particle size. Through the inventor's research and efficacy tests, it is found that the micro-droplets obtained in Examples 15 to 32 have similar beneficial effects such as better therapeutic effect, higher bioavailability, smaller drug dosage required by patients, and better compliance than the current Fufang Danshen dripping pill products.

[0067] <Examples of efficacy> <Drug Efficacy Example 01: Effect of Example 32 product on mortality rate in LPS-induced DIC model rats> 1. Experimental Materials and Methods 1.1 Experimental animals SD rat, SPF grade, male, 220-250 grams. Animal certificate number: 110011200105605444. 1.2 Test Substance The product obtained according to Example 32 (hereinafter referred to as micro-droplet pills) 1.3 Dose design The dose administered to rats in this experiment was 837 mg micro-pill / kg. 1.4 Experimental Method Drug preparation method: 837mg of microdroplet pills were precisely weighed and placed in a container, and an appropriate amount of pure water was added and ultrasonically dissolved completely, and then the volume was adjusted to 10ml. Experimental method: Referring to the literature and previous experimental studies, 14 rats (n=7) were randomly divided into a model group and a microdroplet group. After weighing the experimental animals in each group, 30mg / kg LPS was injected into the tail vein according to the body weight to replicate the DIC model. In the model group, 30mg / kg LPS was injected into the tail vein, and in the microdroplet group, 20 minutes after the model replication, each rat was forced to receive microdroplet intragastrically according to the body weight. The administration dose was 837mg / kg, and the administration volume was 10ml / kg. The mortality rate of the experimental animals in each group was observed up to 72 hours after the model replication.

[0068] <2. Experimental Results> Effect of microdroplets on mortality in LPS-induced DIC model rats According to the experimental results, after 72 hours of observation from model duplication, the mortality rate of the model group injected with 30 mg / kg LPS via the tail vein was 57.1%, while the mortality rate of the microdroplet group orally administered with 837 mg / kg microdroplet was 14.3%.

[0069] [Table 3]

[0070] <3. Conclusion> Under the present experimental conditions, after model replication, a single oral administration of the microdroplets of the present invention significantly improved the survival rate of LPS-induced SD rats.

[0071] <Drug Efficacy Example 02> Effect of the product of Example 32 on the mortality rate of LPS-induced DIC model mice> 1. Experimental Materials and Methods 1.1 Experimental animals Kunming mouse, SPF grade, male, 18-22 grams. Animal certificate number: 110011200107075313. 1.2 Test substance The product obtained according to Example 32 (hereinafter referred to as micro-droplet pills) 1.3 Dose design The dose administered to mice in this experiment was 1660.5 mg micropills / kg. 1.4 Experimental Method Drug preparation method: Precisely weigh out 1660.5mg of microdroplet pills, place them in a container, add an appropriate amount of pure water, and dissolve completely by ultrasonication, then dilute to a constant volume of 10ml. Experimental method: 16 Kunming mice (n=8) were randomly divided into a model group and a microdroplet group. After weighing the experimental animals in each group, 35mg / kg LPS was intraperitoneally injected according to the body weight to replicate the DIC model. In the model group, 35mg / kg LPS was intraperitoneally injected, and in the microdroplet group, 20 minutes after the model replication, each mouse was forced to intragastrically administer microdroplet according to the body weight. The administration dose was 1660.5mg / kg, and the administration volume was 10ml / kg. The mortality rate of the experimental animals in each group was observed up to 72 hours after the model replication.

[0072] <2. Experimental Results> Effect of microdroplets on mortality in LPS-induced DIC model mice According to the experimental results, after 72 hours of observation after model duplication, the mortality rate of the model group that received 35 mg / kg LPS intraperitoneally was 87.5%, while the mortality rate of the microdroplet group that received 1660.5 mg / kg microdroplet orally was 12.5%.

[0073] [Table 4]

[0074] <3. Conclusion> Under the present experimental conditions, after model replication, a single oral administration of the microdroplets of the present invention significantly improved the survival rate of LPS-induced Kunming mice.

[0075] <Effectiveness Example 03: Effect of the product of Example 32 on prothrombin time (PT) in LPS-induced DIC model rats> 1. Experimental Materials and Methods 1.1 Experimental animals SD rat, SPF grade, male, 220-250 grams. Animal certificate number: 110011200105605444. 1.2 Test substance The product obtained according to Example 32 (hereinafter referred to as micro-droplet pills) 1.3 Dose design The dose administered to rats in this experiment was 837 mg micro-pill / kg. 1.4 Experimental Method Drug preparation method: 837mg of microdroplet pills were precisely weighed and placed in a container, and an appropriate amount of pure water was added and ultrasonically dissolved completely, and then the volume was adjusted to 10ml. Experimental method: Nine rats (n=3) were randomly divided into a normal group, a model group, and a microdroplet group. After weighing the experimental animals in each group, 5mg / kg LPS was injected into the tail vein according to the body weight to replicate the DIC model. In the model group, 5mg / kg LPS was injected into the tail vein, and in the microdroplet group, 20 minutes after the model replication, each rat was forced to receive microdroplet intragastrically according to the body weight. The administration dose was 837mg / kg, and the administration volume was 10ml / kg. Four hours after the model replication, plasma was collected from the experimental animals in each group for PT detection.

[0076] <2. Experimental Results> Effect of microdroplet on prothrombin time (PT) in rats with LPS-induced DIC The experimental results showed that the PT value of the model rat group was longer than that of the normal group 4 hours after injection of 5 mg / kg LPS via the tail vein, and oral administration of 837 mg / kg microdroplets significantly improved the LPS-induced PT time prolongation.

[0077] [Table 5]

[0078] <3. Conclusion> Under these experimental conditions, the PT value in the model rat group was longer than that in the normal group, and the LPS-induced PT time prolongation was significantly improved in the microdroplet group orally administered with 837 mg microdroplet / kg.

[0079] <Drug Efficacy Example 04: Effect of the product of Example 32 on the systemic diffuse coagulation index (D-Dimer) of patients with severe COVID-19 pneumonia> The following efficacy experiment is a clinical experiment conducted in the spirit of humanitarianism under the conditions of clinical approval by the US FDA. The criteria for inclusion in the group were mainly hospitalized patients with severe COVID-19 pneumonia and patients with significant systemic blood circulation disorders and diffuse coagulation. Under the condition that the patients maintained the necessary medical conditions, the product prepared according to Example 32 was administered at 300 mg / dose, three times a day. At the same time, the hospitalization time of hospitalized patients was improved and the systemic diffuse coagulation index D-Dimer was reduced, reflecting the medical value of the present invention for treating COVID-19 pneumonia.

[0080] [Table 6] No patients in this study deteriorated or were admitted to the ICU (normal rate is 4%). No patients died in this study (normal rate is 2%). The average length of stay in this study was 2.1 days (normal was 7 days). From the above, the average hospitalization time of the patients who participated in this experiment, except for one patient who dropped out, was reduced from 7 days in the control treatment group to 2 days at the same time, the biochemical indicator D-Dimer was significantly reduced, and the systemic diffuse coagulation phenomenon was improved. So far, there has been no case of the patient's deterioration, admission to the emergency room, or death, demonstrating the clinical value of the present invention in treating COVID-19 pneumonia.

Claims

1. Use of a herbal medicine composition in the manufacture of a medicament for the prevention and / or treatment of novel coronavirus pneumonia, The herbal composition is composed of 50.0% to 99.9% of Danshen and Panax notoginseng extracts and 0.1% to 50.0% of ice chips, by weight percentage; The above-mentioned Danshen and Panax notoginseng extracts contain the following ingredients: The weight ratio of each component is Danshensu (Danshensu): Salvianolic acid T: Protocatechuic aldehyde: Salvianolic acid D: Rosmarinic acid: Salvianolic acid B: Salvianolic acid A: Sankinoside R1: Ginsenoside Rg1: Ginsenoside Re: Ginsenoside Rb1: Ginsenoside Rd: Dihydrotanshinone I: Tanshinone I: Cryptotanshinone: Tanshinone IIA = (2-6): (0.5-2): (1-3): (0.2-1): (0.2-1): (0.5-2): (0.5-2): (0.2-1): (1-4): (0.1-0.5): (1-4): (0.1-1): (0.01-0.05): (0.05-0.1): (0.02-0.1): (0.1-0.5), and The use, characterized in that the herbal medicine composition is a dispersive intravascular coagulation inhibiting composition that inhibits dispersive intravascular coagulation (DIC) in patients with novel coronavirus pneumonia and reduces the mortality rate.

2. The use of claim 1, wherein the herbal medicine composition is a diffuse pulmonary disease preventive composition or a diffuse pulmonary disease therapeutic composition for preventing or treating diffuse pulmonary disease in patients with novel coronavirus pneumonia.

3. The use according to claim 1, wherein the herbal medicine composition is a thrombus formation prevention composition or a thrombus formation reduction composition for preventing or reducing thrombus formation in patients with novel coronavirus pneumonia.

4. The use according to claim 1, wherein the herbal medicine composition is a composition that improves microcirculatory disorders in patients with novel coronavirus pneumonia.

5. The use according to claim 1, wherein the herbal medicine composition is a dispersible intravascular coagulation inhibitor composition that suppresses dispersible intravascular coagulation in patients with moderate and severe novel coronavirus pneumonia.

6. The use according to claim 1, wherein the herbal composition is composed of 75.0%-99.9% Danshen and Panax notoginseng extracts and 0.1%-25.0% ice chips by weight percentage.

7. The use according to any one of claims 1 to 6, wherein the herbal composition is prepared into a pharma-ceutically acceptable preparation.

8. The medicament is a microdroplet pill, The use according to claim 7, wherein the micro-drop pills are prepared by mixing the herbal composition and the drop pill matrix in a weight ratio of 1:5 to 5:

1.

9. The method for producing the microdroplet pills comprises: (1) raw material dissolving process: put the medicine and the drop pill matrix into the homogenizer, mix uniformly at 1000-5000 rpm for 1-200 minutes, then dissolve the raw material uniformly at 3000-10000 rpm for 1-100 minutes, in the raw material dissolving process, maintain the temperature at 60-100°C, and obtain the dissolved drug solution so that the weight ratio of the medicine and the drop pill matrix is ​​1:5-5:1; (2) Dropping step: carrying the dissolving solution to a dropping nozzle, and dropping the solution through the dropping nozzle while vibrating the solution under the conditions of a dropping nozzle temperature of 70 to 300° C., a dropping vibration frequency of 2 to 2000 Hz, a dropping pressure of 0.5 to 4.0 Bar, and an acceleration of 1 to 20 G so that the dropping speed is matched to the raw material dissolving speed of the step (1); (3) A condensation step: The condensation step includes rapidly cooling the dripped droplets with a cooling gas, and condensing the droplets into solid droplets having a particle size of 0.2 mm to 4.0 mm while the temperature of the cooling gas is 0° C. or less.

10. The use according to claim 9, wherein in step (1), the drop pill matrix is ​​one or a combination of multiple kinds among PEG-based, sorbitol, xylitol, lactitol, maltose, starch, methylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, gum arabic, alginic acid, dextrin, cyclodextrin, agar, and lactose.

11. The method for producing the microdroplet pills comprises: (1) raw material dissolving process: put the medicine and the drop pill matrix into the homogenizer, mix uniformly at 1000-5000 rpm, then dissolve the raw material uniformly at 3000-10000 rpm for 20-80 minutes, maintain the temperature at 80-100°C during the raw material dissolving process, and obtain a dissolved drug solution with the weight ratio of the medicine and the drop pill matrix being 1:3-3:1; (2) Dropping step: carrying the dissolving solution to a dropping nozzle, and dropping the solution through the dropping nozzle while vibrating the nozzle under the conditions of a dropping nozzle temperature of 70 to 200° C., a dropping vibration frequency of 20 to 300 Hz, a dropping pressure of 0.5 to 4.0 Bar, and an acceleration of 1 to 15 G so that the dropping speed is matched to the raw material dissolving speed of the step (1); (3) A condensation step: The condensation step includes rapidly cooling the dripped droplets with a cooling gas, and condensing the droplets into solid droplets having a particle size of 0.2 mm to 4.0 mm while the temperature of the cooling gas is 0° C. or less.

12. The use according to claim 11, wherein the method for producing the microdroplet pills further comprises a drying step (4) in which the pills are dried in a fluidized bed dryer at -20 to 100°C for 1 to 4 hours to obtain naked pills.

13. The use according to claim 12, wherein in the gradient temperature rising drying method in the step (4), the mixture is brought into a fluidized state at -20 to 30°C, dried at 15 to 35°C for 10 to 120 minutes, dried at 35 to 55°C for 10 to 60 minutes, and dried at 55 to 100°C for 0 to 60 minutes.

14. The method for producing the microdroplet pills further comprises a coating step as step (5), The use according to claim 13, wherein in the step (5), the bare pellets obtained in the step (4) are coated in a fluidized state at a temperature of 30-65°C, the coating liquid concentration is 5-25 wt%, the coating material is selected from the group consisting of shellac, cellulose acetate phthalate, methyl acrylate, methyl methacrylate, or Opadry, and the weight ratio of the coating material to the bare pellets is 1:50-1:

10.

15. The use according to any one of claims 10 to 14, further comprising a material pre-mixing step before the step (1), in which the drug extract or powder is added to water, and then stirred at 30-80°C for 10 minutes or more to obtain a drug premix so that the water content is uniform.

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