WO2021219031A1 - 一种中药组合物及其制剂在制备预防和/或治疗新型冠状病毒肺炎药物中的应用 - Google Patents
一种中药组合物及其制剂在制备预防和/或治疗新型冠状病毒肺炎药物中的应用 Download PDFInfo
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Definitions
- the present invention relates to the field of medicine. Specifically, the present invention relates to the application of a traditional Chinese medicine composition and its preparation in the preparation of drugs for the prevention and/or treatment of novel coronavirus pneumonia.
- coronavirus pneumonia the International Virus Classification Committee named this new type of coronavirus as severe acute respiratory syndrome coronavirus 2 (severe acute respiratory syndrome coronavirus 2, SARS-CoV-2).
- SARS-CoV-2 severe acute respiratory syndrome coronavirus 2
- the World Health Organization (WHO) announced on the same day that the official name of the disease caused by this virus is COVID-19 (coronavirus disease 2019), and the virus spreads rapidly.
- COVID-19 patients are mainly fever, fatigue, and dry cough. A few patients have symptoms such as nasal congestion, runny nose, sore throat, and diarrhea. About half of the patients will develop dyspnea and/or hypoxemia after 1 week. In severe cases, they can rapidly progress to acute respiratory distress syndrome (ARDS), septic shock, and difficult to correct metabolic acid Poisoning, increased blood viscosity and coagulation dysfunction.
- ARDS acute respiratory distress syndrome
- septic shock septic shock
- metabolic acid Poisoning increased blood viscosity and coagulation dysfunction.
- the treatment of COVID-19 hypoxemia is very important. Most of the severely ill patients diagnosed with COVID-19 will have difficulty breathing and/or hypoxemia one week after the onset of onset.
- respiratory support and circulatory support are required, and on the basis of symptomatic treatment , Actively prevent and treat complications, treat underlying diseases, and prevent secondary infections.
- symptomatic treatment Actively prevent and treat complications, treat underlying diseases, and prevent secondary infections.
- Compared with mild patients, severely ill patients have obvious changes in the interstitium of both lungs, with multiple ground glass shadows, infiltration shadows, and lung consolidation; at the same time, Th1 response in the body increases, the release of pro-inflammatory factors increases, and inflammation invades alveolar walls and adjacent alveolar cavities.
- Cytokine storm CSS
- CSS will cause the release of a large number of inflammatory factors in the lungs, and promote inflammatory damage such as lung fibrosis. Therefore, in the treatment of COVID-19, we should focus on the changes in the patient’s oxygenation index, blood oxygen saturation and other related indicators. Combine prevention and treatment to improve the occurrence and development of hypoxemia, and reduce the probability of patients becoming severe or even critical. , It is particularly important.
- Compound Danshen Micro-dropping Pill (T89) is a traditional Chinese medicine developed by Tasly to promote blood circulation, remove blood stasis, regulate qi and relieve pain. It is used for chest congestion and angina pectoris. Its main ingredients are Danshen, Panax Notoginseng and Borneol. It has the effect of treating acute myocardial infarction and acute myocardial ischemia.
- T89 is a medicine extracted and prepared from nature. Currently, it is applying for clinical research in the US FDA, and the number is T89. This product has a history of more than 25 years of use in China, and it has good safety. Due to the invasion of the covid-19 virus, patients with new coronary pneumonia have elevated myocardial enzymes accompanied by systemic inflammatory reactions, and even cause multiple organ failure and central nervous system damage. The reason for this is systemic thrombosis, microcirculation disorder, inflammatory factor storm, ROS invasion, hypoxemia and so on after virus invasion. These diseases will increase the mortality of patients, especially for patients with basic diseases such as cardiovascular disease, hypertension and diabetes. As of now, there is no recommended medication for COVID-19 hypoxemia.
- the present invention provides an application of a traditional Chinese medicine composition in the preparation of a new type of coronavirus pneumonia medicine. % ⁇ 50.0%, wherein the Danshen Panax notoginseng extract contains the following components, and the weight ratio of each component is:
- the traditional Chinese medicine composition of the present invention can effectively improve the clinical symptoms of patients with novel coronavirus pneumonia, improve the patient's microcirculation disorder, reduce the formation of pulmonary thrombosis, and inhibit diffuse intravascular coagulation (DIC), thereby reducing moderate to severe novel coronavirus pneumonia The patient's mortality rate.
- the traditional Chinese medicine composition of the present invention can prevent or reduce the formation of thrombus in patients with novel coronavirus pneumonia, and reduce the formation of serous fluid, fibrinous exudate and hyaline membrane in the alveolar cavity.
- Reduce alveolar septal vascular congestion and edema reduce mononuclear and lymphocyte infiltration and the formation of hyaline thrombus in blood vessels. It can inhibit platelet aggregation and adhesion, thus preventing systemic thrombosis.
- the traditional Chinese medicine composition of the present invention can improve the exchange of oxygen and nutrients in the heart, lungs and other organs by adjusting the state of vasomotor and contraction, changing vascular function and improving microcirculation blood perfusion, thereby improving the new type of coronavirus pneumonia.
- the patient s microcirculation disorder.
- the traditional Chinese medicine composition of the present invention can inhibit diffuse intravascular coagulation (DIC) in patients with novel coronavirus pneumonia and reduce mortality.
- DIC diffuse intravascular coagulation
- the traditional Chinese medicine composition of the present invention wherein the traditional Chinese medicine composition is composed of 75.0% to 99.9% of Danshen and Panax notoginseng extract and 0.1% to 25.0% of borneol by weight percentage.
- the traditional Chinese medicine composition of the present invention is composed of 90.0% to 99.9% of Danshen and Panax notoginseng extract and 0.1% to 10.0% of borneol by weight percentage.
- the traditional Chinese medicine composition of the present invention wherein the Danshen Panax notoginseng extract contains the following components, and the weight ratio of each component is:
- the traditional Chinese medicine composition wherein the Danshen Panax notoginseng extract contains the following components, and the weight ratio of each component is:
- the traditional Chinese medicine composition of the present invention wherein the Danshen Panax notoginseng extract is prepared from raw materials in the following parts by weight: 75-90 parts of danshen and 10-25 parts of Panax notoginseng.
- the traditional Chinese medicine composition of the present invention wherein the Danshen Panax notoginseng extract is prepared from raw materials in the following parts by weight: 82-84 parts of Danshen and 16-17 parts of Panax notoginseng.
- the traditional Chinese medicine composition of the present invention can be prepared into various preparations, such as injections, tablets, capsules, dripping pills/microdroplets and microdroplet capsules, etc., preferably microdroplets.
- the "micro-droplet pill” refers to a droplet pill with a smaller volume than the existing dripping pill. Specifically, it refers to a drop pill having a particle size of 0.2 mm to 4 mm, particularly a drop pill having a particle size of 0.2 mm to 2 mm, and preferably a particle size of 1 mm to 2 mm.
- the micro-droplet pill of the present invention is prepared from the traditional Chinese medicine composition and the dropping pill base in a weight ratio of 1:5 to 5:1.
- the preparation method of the micro-droplet pill of the present invention includes the following steps:
- Materializing step Put the medicine and dripping pill matrix into a homogenizer, homogenize and mix at 1000 ⁇ 5000rpm for 1 ⁇ 200min, then homogenize the material at 3000 ⁇ 10000rpm for 1 ⁇ 100min, During the feeding process, the temperature is maintained at 60-100°C to obtain a molten drug solution, and the weight ratio of the drug to the dropping pill base is 1:5-5:1;
- Dripping step transport the above molten liquid to the dripper, under the conditions of dripper temperature 70 ⁇ 300°C, dripping vibration frequency 2 ⁇ 2000Hz, dripping pressure 0.5 ⁇ 4.0Bar, acceleration 1 ⁇ 20G, The dripping system is vibrated by the dripper, and the dripping speed is matched with the speed of step (1).
- the dropping pill base includes PEG, sorbitol, xylitol, lactitol, maltose, starch, methyl cellulose, sodium carboxymethyl cellulose, hydroxypropyl methyl cellulose, One or more combinations of gum arabic, alginic acid, dextrin, cyclodextrin, agar, and lactose;
- the preferred dropping pill base 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 preferably PEG-6000, PEG-4000 or a combination of PEG-4000 and PEG-6000.
- preparation method wherein the method includes the following steps:
- Materializing step Put the medicine and dripping pill matrix into a homogenizer, homogenize and mix at 1000 ⁇ 5000rpm, and then homogenize the material at 3000 ⁇ 10000rpm for 20 ⁇ 80min. In the process of mixing, the temperature Keep it at 80-100°C to obtain a molten drug solution, and the weight ratio of the drug to the dropping pill base is 1:3 to 3:1;
- Dripping step transport the above-mentioned molten liquid to the dripper, under the conditions of dripper temperature 70 ⁇ 200°C, dripping vibration frequency 20 ⁇ 300Hz, dripping pressure 0.5 ⁇ 4.0Bar, acceleration 1 ⁇ 15G, The dripping system is vibrated by the dripper, and the dripping speed is matched with the speed of step (1).
- the weight ratio of the drug to the dropping pill base is 1:3 ⁇ 3:1, homogenized at 3000 ⁇ 5000rpm for 10 ⁇ 60min, then homogenized at 4000 ⁇ 9000rpm
- the material, the time is 5-30min, and the temperature is maintained at 70-90°C during the process; preferably, the weight ratio of the drug to the dripping pill base is 1:(1-3), and the mixture is homogeneously mixed at 3000-4000rpm , Time 10-30min, then, homogenize the material at 4000-6000rpm, time 6-30min, during the materialization process, keep the temperature at 75-85°C.
- the dripper temperature is 70-100°C, preferably 75-85°C;
- the dripping vibration frequency is 50-300Hz, preferably 100-200Hz, more preferably 90-200Hz, more preferably 130-140Hz, most preferably 137 Hz; acceleration 3.5-4.5G, preferably 4.0G;
- dripping pressure is 1.0-3.0 Bar, preferably 1.8 Bar;
- dripping speed is 10-40 kg/h, preferably 12-30 kg/h, more preferably 15-25 kg/h.
- the gas is air, nitrogen, or inert gas;
- the cooling temperature is 0 to -150°C, preferably -60 to -140°C, more preferably -80 to -120°C;
- the diameter of the drop pill It is 1.0mm ⁇ 2.0mm.
- the preparation method of the present invention also includes a drying step as step (4), using fluidized drying equipment to dry, and drying at -20-100°C, preferably -20-90°C for 1 to 4 hours, to obtain vegetarian pellets.
- the step (4) adopts a gradient heating drying method: forming a fluidized state at -20 ⁇ 30°C, drying at 15 ⁇ 35°C for 10 ⁇ 120min, drying at 35 ⁇ 55°C for 10 ⁇ 60min, and drying at 55 ⁇ 100°C. Drying at 0°C for 0-60 minutes; preferably, the gradient heating drying method is performed as follows: forming a fluidized state at 0-20°C, drying at 25°C for 60 minutes, drying at 45°C for 30 minutes, and drying at 55°C for 0-30 minutes.
- the preparation method of the present invention also includes a coating step as step (5).
- the step is to treat the nutrient pellets at a temperature of 30 to 65° C. when the pill obtained in step (4) is in a fluidized state.
- the pellets are coated; the concentration of the coating solution is 5-25% by weight, preferably 18-20% by weight, wherein the coating material is selected from shellac, cellulose acetate phthalate, methyl acrylate, methyl methacrylate, or European Pady; the weight ratio of the coating material to the pill is 1:50 to 1:10, preferably 1:50 to 1:25.
- the preparation method of the present invention may also have a material premixing step before step (1). After adding water to the drug extract or powder, stir at 30-80°C for more than 10 minutes to obtain a drug premix.
- the present invention provides a traditional Chinese medicine composition.
- the traditional Chinese medicine composition is composed of 50.0% to 99.9% of Danshen and Panax notoginseng extract and 0.1% to 50.0% of Borneol in weight percentage, wherein the Danshen and Panax notoginseng extract contains (parts by weight):
- the preferred traditional Chinese medicine composition of the present invention is composed of 75.0% to 99.9% of danshen and Panax notoginseng extract and 0.1% to 25.0% of Borneol in weight percentage.
- a further preferred traditional Chinese medicine composition of the present invention is composed of 90.0% to 99.9% of danshen and Panax notoginseng extract and 0.1% to 10.0% of Borneol in weight percentage.
- the Danshen Panax notoginseng extract preferably contains (parts by weight):
- the Danshen Panax notoginseng extract more preferably contains (parts by weight):
- the above-mentioned traditional Chinese medicine composition can be prepared by extracting and processing Danshen and Panax notoginseng to obtain extracts, and then adding borneol and mixing.
- the traditional Chinese medicine composition of the present invention is preferably prepared by the following method:
- Danshen and Panax notoginseng can be decocted in water under the same alkaline condition; or in water under the same alkaline condition.
- the Danshen Panax notoginseng extract can be prepared by the following method:
- Step (1) decocting Danshen Panax notoginseng in alkaline aqueous solution for 1 to 3 times, each time for 1 to 3 hours, and filtering to obtain filtrate I;
- Step (2) decoct the dregs in water for 1 to 3 times for 1 to 3 hours each time, filter, and filtrate II;
- Step (3) Combine and concentrate the filtrate I and II, precipitate the concentrated solution with alcohol, stand still, take the supernatant, filter, recover ethanol, concentrate to obtain an extract, or dry the extract to obtain an extract of Salvia miltiorrhiza notoginseng.
- 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, potassium hydroxide, and magnesium hydroxide aqueous solution.
- the pH is 7.5 to 9.0
- the amount of alkali added in the above-mentioned alkaline aqueous solution is 1 to 4.5% by weight, preferably 2.25 to 3% by weight of the amount of the medicinal material, so as to ensure complete extraction of Danshensu sodium and salvianolic acid T.
- step (3) it is preferable to add 50%-100% ethanol, preferably 95% ethanol for alcohol precipitation, preferably alcohol precipitation until the concentration of ethanol is 60%-75%.
- the Danshen Panax notoginseng extract of the present invention is prepared by the following method:
- Step (1) Cut Danshen medicinal material into segments of less than 5 cm, preferably 1-2 cm, pulverize Panax notoginseng medicinal material into 1 cm granules, weigh 2.25 to 3% by weight of sodium bicarbonate in the total amount of medicinal materials, and weigh them. Put the salvia, notoginseng and sodium bicarbonate into the extraction tank, add 5 times the amount of process water to each tank, heat and boil, keep boiling for 2h ⁇ 20min, filter,
- Step (2) Extract the medicine residue for the second time, add 4 times the amount of water, heat and boil, keep boiling for 1h ⁇ 15min, filter, and discard the medicine residue;
- Step (3) The extract is concentrated under reduced pressure to a relative density of 1.16 to 1.20 (80 ⁇ 5°C) or a corresponding sugar content of 48% to 52% to obtain a concentrated solution.
- the concentrated solution is poured into an alcohol precipitation tank, and an appropriate amount of ethanol is added to adjust To the alcohol content is 65% to 70%, let stand for 12 to 24 hours, until the precipitation is complete, separate the supernatant, discard the precipitate, concentrate the supernatant to obtain an extract, or dry the extract to obtain Danshen III Seven extracts.
- the 5 times amount in step (1) refers to 5 times the total weight of the medicinal materials
- the 4 times amount in step (2) refers to 4 times the total weight of the medicinal residue
- the traditional Chinese medicine composition of the present invention is prepared from 75 to 90 parts of Salvia miltiorrhiza, 10 to 25 parts of Panax notoginseng and 0.1 to 4 parts of borneol by weight of original medicinal materials.
- the preferred traditional Chinese medicine composition is prepared from the original medicinal materials in parts by weight of 80-86 parts of danshen, 15-18 parts of Panax notoginseng and 0.2-2 parts of Borneol.
- the most preferred traditional Chinese medicine composition is prepared from 82-84 parts by weight of original medicinal materials of Danshen, 16-17 parts of Panax notoginseng and 0.4-1.2 parts of Borneol.
- the traditional Chinese medicine composition of the present invention can be an extract or a powder.
- the present invention provides a pharmaceutical preparation of the traditional Chinese medicine composition.
- the pharmaceutical preparation comprises the traditional Chinese medicine composition of the invention and one or more pharmaceutically acceptable carriers.
- the weight percentage of the traditional Chinese medicine composition of the present invention in its preparation can be 0.1% to 99.9%, and the rest is a pharmaceutically acceptable carrier.
- the pharmaceutical preparations of the present invention are in the form of unit-dose pharmaceutical preparations, and the unit-dose refers to the unit of the preparation, such as each tablet of a tablet, each capsule of a capsule, each bottle of oral liquid, each bag of granules, etc., And it can be prepared by any method well known in the pharmaceutical field. All methods include the step of combining the traditional Chinese medicine composition of the present invention with a carrier, which constitutes one or more auxiliary components. Generally speaking, the preparation process of the preparation is as follows: the combination of the traditional Chinese medicine composition of the present invention and the liquid carrier, or the finely pulverized solid carrier, or the combination of the two is uniformly and tightly combined, and then, if necessary, the product is formed into The necessary preparations.
- standard pharmaceutical techniques can be used to prepare the pharmaceutical preparations of the present invention from the traditional Chinese medicine composition of the present invention and the pharmaceutical carrier, and these methods include mixing, granulation and compression. It is well known to those skilled in the art that the form and characteristics of the pharmaceutically acceptable carrier or diluent depend on the amount of the active ingredient to be mixed with it, the route of administration and other known factors.
- the pharmaceutical preparation form can be any pharmaceutically acceptable dosage form, these dosage forms include: tablets, sugar-coated tablets, film-coated tablets, enteric-coated tablets, capsules, hard capsules, soft capsules, oral liquids, oral liquids Supplements, granules, granules, pills, powders, ointments, pills, suspensions, powders, solutions, injections, suppositories, ointments, plasters, creams, sprays, drops, patches.
- the preparation of the present invention is preferably an oral dosage form, such as capsules, tablets, oral liquids, granules, pills, powders, pills, ointments and the like.
- the preparation for oral administration may contain commonly used excipients, such as binders, fillers, diluents, tableting agents, lubricants, disintegrating agents, coloring agents, flavoring agents and wetting agents, and may be used for tablets if necessary.
- Agent for coating such as binders, fillers, diluents, tableting agents, lubricants, disintegrating agents, coloring agents, flavoring agents and wetting agents, and may be used for tablets if necessary.
- Agent for coating such as binders, fillers, diluents, tableting agents, lubricants, disintegrating agents, coloring agents, flavoring agents and wetting agents, and may be used for tablets if necessary.
- Agent for coating such as binders, fillers, diluents, tableting agents, lubricants, disintegrating agents, coloring agents, flavoring agents and wetting agents, and may be used for tablets if necessary.
- Agent for coating such as binders, fillers, diluents, tableting agents,
- Suitable fillers include cellulose, mannitol, lactose and other similar fillers.
- Suitable disintegrants include starch, polyvinylpyrrolidone and starch derivatives, such as sodium starch glycolate.
- Suitable lubricants include, for example, magnesium stearate.
- Suitable pharmaceutically acceptable wetting agents include sodium lauryl sulfate.
- the solid oral composition can be prepared by common methods such as mixing, filling, and tableting. Repeated mixing allows the active material to be distributed throughout those compositions that use large amounts of fillers.
- Oral liquid preparations can be in the form of aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or can be a dry product that can be reconstituted with water or other suitable carriers before use.
- Such liquid preparations may contain conventional additives, such as suspending agents, such as sorbitol, syrup, methyl cellulose, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminum stearate gel or hydrogenated edible fats, Emulsifiers such as lecithin, sorbitan monooleate or gum arabic; non-aqueous carriers (they may include edible oils) such as almond oil, fractionated coconut oil, oily esters such as esters of glycerol, propylene glycol or ethanol; preservatives Agents such as methyl paraben or propyl paraben or sorbic acid, and if necessary, may contain conventional flavoring agents or coloring agents.
- suspending agents such as sorbitol, syrup,
- the prepared liquid unit dosage form 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. Solutions are usually prepared by dissolving the active substance in a carrier, filtering and sterilizing it before filling it into a suitable vial or ampoule, and then sealing it. Excipients such as a local anesthetic, preservatives and buffers can also be dissolved in this carrier. In order to improve its stability, the composition can be frozen after filling the vial, and the water can be removed under vacuum.
- a suitable pharmaceutically acceptable carrier can be optionally added, and the pharmaceutically acceptable carrier is selected from the group consisting of mannitol, sorbitol, sodium metabisulfite, sodium bisulfite, sodium thiosulfate, and hydrochloric acid.
- the traditional Chinese medicine composition is preferably made into a drop pill preparation, more preferably a micro drop pill preparation.
- the present invention provides a compound Danshen micro-dropping pill
- the compound Danshen micro-dropping pill is made of a traditional Chinese medicine composition and a dripping pill base in a weight ratio of 1:5 to 5:1; preferably Specifically, the compound Danshen micro-dropping pill of the present invention is made of a traditional Chinese medicine composition with a weight ratio of 1:3 to 3:1 and the dripping pill matrix; most preferably, the compound Danshen micro-dropping pill of the present invention is made of a weight ratio of 1: (1 ⁇ 3) Chinese medicinal composition and dripping pill base composition.
- the preparation method of the compound danshen micro-dropping pill of the present invention includes the following steps:
- Materializing step Put the medicine and dripping pill matrix into a homogenizer, homogenize and mix at 1000 ⁇ 5000rpm for 1 ⁇ 200min, then homogenize the material at 3000 ⁇ 10000rpm for 1 ⁇ 100min, During the feeding process, the temperature is maintained at 60-100°C to obtain a molten drug solution, and the weight ratio of the drug to the dropping pill base is 1:5-5:1;
- Dripping step transport the above molten liquid to the dripper, under the conditions of dripper temperature 70 ⁇ 300°C, dripping vibration frequency 2 ⁇ 2000Hz, dripping pressure 0.5 ⁇ 4.0Bar, acceleration 1-20G, The dripping system is vibrated by the dripper, and the dripping speed is matched with the speed of step (1).
- the preparation method of the compound danshen micro-dropping pill of the present invention includes the following steps:
- Materializing step Put the medicine and dripping pill matrix into a homogenizer, homogenize and mix at 1000 ⁇ 5000rpm for 1 ⁇ 200min, then homogenize the material at 3000 ⁇ 10000rpm for 1 ⁇ 100min, During the feeding process, the temperature is maintained at 80-100°C to obtain a molten drug solution, and the weight ratio of the drug to the dropping pill base is 1:3 to 3:1;
- Dripping step deliver the above-mentioned molten liquid to the dripper, under the conditions of dripper temperature 70 ⁇ 200°C, dripping vibration frequency 20 ⁇ 300Hz, dripping pressure 0.5 ⁇ 4.0Bar, acceleration 1-15G, The dripping system is vibrated by the dripper, and the dripping speed is matched with the speed of step (1).
- the dripping pill base includes PEG, sorbitol, xylitol, lactitol, maltose, starch, methyl cellulose, sodium carboxymethyl cellulose, hydroxypropyl methyl cellulose
- the preferred dropping pill base 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 of PEG-1000, PEG-2000, PEG-3000, PEG-4000, PEG-6000, PEG-8000
- a combination of PEG-6000, PEG-4000 or a combination of PEG-4000 and PEG-6000 is most preferred.
- the weight ratio of the drug to the dripping pill base is 1:3 to 3:1, homogenously mixed at 3000 to 5000 rpm for 10 to 60 minutes, and then at 4000 to 9000 rpm Homogenize the material for 5-30 minutes.
- the temperature is maintained at 70-90°C; most preferably, the weight ratio of the drug to the dropping pill base is 1: (1 to 3), Mix homogeneously at 3000 ⁇ 4000rpm for 10-30min. Then, homogenize the material at 4000 ⁇ 6000rpm for 6-30min. During the process, keep the temperature at 75 ⁇ 85°C.
- the dripper temperature is 70-100°C, preferably 75-85°C;
- the dripping vibration frequency is 50-300Hz, preferably 100-200Hz, more preferably 90-200Hz, more preferably 130 ⁇ 140Hz, most preferably 137Hz; acceleration 3.5 ⁇ 4.5G, preferably 4.0G;
- dripping pressure is 1.0 ⁇ 3.0Bar, preferably 1.8Bar;
- dripping speed is 10 ⁇ 40kg/h, preferably 12 ⁇ 30kg/h, more preferably 15 ⁇ 25kg/h.
- gas cooling refers to the use of a low-temperature cold trap to rapidly cool the falling droplets to solidify and shape them.
- the temperature range of the cooling gas is 0°C or less, preferably 0 to -150°C, preferably -60°C to -140°C, more preferably -80°C to -120°C, and preferably the cooling gas is air, nitrogen, or inert gas.
- the particle size of the resulting micro-pill is preferably 1.0 mm to 2.0 mm.
- the preparation method of the micro-droplet pill of the present invention further includes a drying step as step (4), preferably using a fluidized drying device, and drying at -20 to 100°C, preferably -20 to 90°C for 1 to 4 hours, to obtain Vegetarian pills.
- the low-temperature dripping pellets that have been dripped in step (3) are dried in a fluidized bed at a temperature of 40 ⁇ 150°C, preferably at a temperature of 40 ⁇ 60°C, and the drying time is 1 ⁇ 4h, preferably 1 ⁇ 3h, most preferably For 2h, get vegetarian pills.
- the following gradient heating drying method is preferred: forming a fluidized state at -20 ⁇ 30°C, drying at 15 ⁇ 35°C for 10 ⁇ 120min, drying at 35 ⁇ 55°C for 10 ⁇ 60min, and drying at 55 ⁇ 100 Drying at 0°C for 0-60 minutes; further preferred is the following gradient heating drying method: forming a fluidized state at 0-20°C, drying at 25°C for 60 minutes, drying at 45°C for 30 minutes, and drying at 55°C for 0-30 minutes.
- This step keeps the drip pill in a fluidized state, solves the problem of drip pill adhesion, and also improves efficiency, with a production capacity of up to 30 kg/h.
- the preparation method of the microdroplet pill of the present invention further includes a coating step as step (5).
- This step is to coat the vegetarian pills at a temperature of 30 to 65°C when the vegetarian pills obtained in the step (4) are in a fluidized state; the concentration of the coating solution is 5 to 25 wt%, preferably 18 to 20 wt %, wherein the coating material is selected from shellac, cellulose acetate phthalate, methyl acrylate, methyl methacrylate or Opadry.
- the weight ratio of the coating material to the plain pill is 1:50 to 1:10, preferably 1:50 to 1:25.
- step (1) In order to better implement the preparation method of the micro-droplet pill of the present invention, it is preferable to have a material pre-mixing step before step (1). After adding water to the drug extract or powder, stir at 30-80°C for more than 10 minutes to obtain Drug premix to ensure uniform moisture. This step can make up for the shortcomings of dry powder feeding.
- the dripping pill prepared by the method of the present invention can be directly packaged, or it can be filled into a capsule shell and then made into a capsule. After the capsules are made, a step of weighing capsules can be added. The filled capsules are weighed at a high speed before packaging to eliminate possible unqualified capsules.
- each Chinese medicinal composition Danshensu, salvianolic acid T, protocatechuic aldehyde, salvianolic acid D, rosmarinic acid, salvianolic acid B, salvianolic acid A, dihydrogen
- tanshinone I, tanshinone I, cryptotanshinone, tanshinone IIA, notoginsenoside R1, ginsenoside Rg1, ginsenoside Re, ginsenoside Rb1, and ginsenoside Rd were measured according to the following method.
- Reference substance solution accurately weigh a certain amount of reference substance danshensu, salvianolic acid T, protocatechuic aldehyde, salvianolic acid D, rosmarinic acid, salvianolic acid B, salvianolic acid A, dihydrotanshinone I, tanshinone I.
- Cryptotanshinone and Tanshinone IIA are placed in a 10ml volumetric flask, dissolved in methanol and diluted to the mark, diluted and shaken as needed, to prepare solutions of the following concentrations: Danshensu 0.0315mg/ml, Salvianolic acid T 0.04596 mg/ml, protocatechualdehyde 0.07556mg/ml, salvianolic acid D 0.04385mg/ml, rosmarinic acid 0.04263mg/ml, salvianolic acid B 0.04248mg/ml, salvianolic acid A 0.1118mg/ml, two Hydrotanshinone I 0.02098mg/ml, Tanshinone I 0.02085mg/ml, Cryptotanshinone 0.02442mg/ml, Tanshinone IIA 0.01992mg/ml, filtered through a 0.22 ⁇ m membrane to obtain the reference solution.
- Test solution Precisely weigh 0.1g of Danshen Panax notoginseng extract sample and place it in a 10ml volumetric flask, dissolve it with pure water, dilute to the mark, and then filter through a 0.22 ⁇ m membrane to obtain the test solution.
- Determination method accurately draw 10 ⁇ l each of the reference solution and the test solution, and inject them into the ultra-high performance liquid chromatograph for determination.
- Detection wavelength 281nm
- elution conditions are as follows:
- Preparation of reference substance solution Take a proper amount of notoginsenoside R1 reference substance, ginsenoside Rg1 reference substance, ginsenoside Rb1 reference substance, ginsenoside Re, and ginsenoside Rd reference substance, accurately weigh them, and add methanol to make each 1ml each containing 0.5 mg, 2.0mg, 1.0mg, 0.5mg, 0.5mg, 0.5mg, 1.0mg solution, that is.
- test solution accurately weigh 0.1g sample, add 10ml of 4% ammonia solution to dissolve, pass through D101 type macroporous adsorption resin column (inner diameter of 0.7cm, column height of 5cm), eluting with 30ml of water, then Elute with 30ml of 30% methanol and then with 10ml of methanol. Collect the methanol solution into a 10ml measuring flask and shake well to obtain.
- octadecylsilane-bonded silica gel is used as filler; acetonitrile is mobile phase A, water is mobile phase B, and gradient elution is performed according to Table 2 below; flow rate is 1.0ml per minute; The detection wavelength is 203nm; the column temperature is 30°C; and the recording time is 75 minutes.
- Determination Precisely draw 10 ⁇ l each of the reference solution and the test solution and inject them into the liquid chromatograph.
- the extract of Salvia miltiorrhiza notoginseng was determined according to the above determination method. Among them, the extract of Salvia miltiorrhiza notoginseng contains 36 mg/g of Danshensu, 11 mg/g of salvianolic acid, 17 mg/g of protocatechuic aldehyde, and 6 mg/g of salvianolic acid D.
- the extract of Salvia miltiorrhiza notoginseng was determined according to the above-mentioned determination method. Among them, the extract of Salvia miltiorrhiza notoginseng includes 40mg/g of Danshensu, 12mg/g of salvianolic acid, 20mg/g of protocatechuic aldehyde, and 7mg/g of salvianolic acid.
- the extract of Danshen notoginseng was determined according to the above-mentioned determination method.
- the extract of Danshen notoginseng contained danshensu, salvianolic acid T, protocatechuic aldehyde, salvianolic acid D, rosmarinic acid, salvianolic acid B,
- the amounts of salvianolic acid A, notoginsenoside R1, ginsenoside Rg1, ginsenoside Re, ginsenoside Rb1, ginsenoside Rd, dihydrotanshinone I, tanshinone I, cryptotanshinone, and tanshinone IIA are 30 mg/g and 9 mg/g, respectively , 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,
- the contents of notoginsenoside R1, ginsenoside Rg1, ginsenoside Re, ginsenoside Rb1, ginsenoside Rd, dihydrotanshinone I, tanshinone I, cryptotanshinone, and tanshinone IIA are 40mg/g, 12mg/g, 20mg/g, respectively.
- the extract of Danshen notoginseng contains danshensu, salvianolic acid T, protocatechuic aldehyde, salvianolic acid D, rosmarinic acid, salvianolic acid B, salvianolic acid A, three
- heptasaponin R1, ginsenoside Rg1, ginsenoside Re, ginsenoside Rb1, ginsenoside Rd, dihydrotanshinone I, tanshinone I, cryptotanshinone, and tanshinone IIA are respectively 20mg/g, 5mg/g, 10mg/g, 2mg/ g, 0.2mg/g, 5mg/g, 5mg/g, 2mg/g, 1mg/g, 1mg/g, 10mg/g, 1mg/g, 0.1mg/g, 0.5mg/g, 0.2mg/g, 1mg/g.
- the danshensu, salvianolic acid T, protocatechuic aldehyde, salvianolic acid D, rosmarinic acid, salvianolic acid B, salvianolic acid A The contents of notoginsenoside R1, ginsenoside Rg1, ginsenoside Re, ginsenoside Rb1, ginsenoside Rd, dihydrotanshinone I, tanshinone I, cryptotanshinone, and tanshinone IIA are 60mg/g, 20mg/g, 30mg/g, respectively.
- Premixing step premix the traditional Chinese medicine composition with water, and stir in a 40 ⁇ 10°C heat preservation tank for more than 60 minutes to make the water content of the traditional Chinese medicine composition 13.0wt% to obtain the traditional Chinese medicine composition premix for use;
- Materialization step first add PEG-6000 to the chemical material tank, heat to 90°C, melt in advance, then add the premix of the Chinese medicine composition, use a low-speed homogeneous (3200rpm) mixture, and after the mixing is completed, increase The homogenization speed is 5000rpm for 6min. During the process, the temperature of the material is kept at 80 ⁇ 5°C. Thus, a molten chemical solution is obtained.
- Dropping step transport the above-mentioned molten liquid to the dripper, adjust the vibration frequency of the dripper to 137Hz, control the dripper temperature at 80°C, and flow the liquid into the dripper through a pressurized method (drip pressure 1.8Bar) , And vibrate to drip out from the bottom of the dripper, and the dripping speed is matched with step (1) chemical material speed;
- Drying step fluidize and dry the dropping pills, after the material forms a good fluid state in the bed, heat up to 25°C for 60min, then heat up to 45°C for 30min, and continue to heat up to 55°C for drying After 30 minutes, the temperature is lowered to below 30°C and the material is discharged. Controlling the water content of the dripping pill at 3.0-7.0wt% to obtain an intermediate pill;
- Coating step calculate the coating powder dosage according to the coating dosage and the prescription, take 4% Opadry of the weight of the vegetarian pill to prepare a coating solution with a concentration of 18 wt%, and stir for 45 minutes.
- Set the inlet air temperature to 25°C put the qualified pellets into the fluidized bed, increase the set inlet air temperature to 48°C, and start coating after the material temperature reaches 38°C.
- the temperature of the material is controlled at 35-45°C, and after the coating is completed, the temperature is lowered to below 30°C and the material is discharged, and the pellets are screened to obtain intermediate coated pellets.
- the weight gain of the intermediate coated pellets is controlled at 3.3 ⁇ 0.7wt%, and the moisture content is controlled at 3.0 ⁇ 7.0wt%;
- Capsule making and packaging steps capsules are filled with droplets with a particle size of 1.0mm ⁇ 2.0mm, and 100% on-line checkweighing is completed by a capsule checkweigher, and then the final product is packaged.
- the shape of the dripping pill can be monitored and adjusted by stroboscopic irradiation and visual inspection; after the drug is loaded and coated, in order to improve the particle size uniformity and roundness of the dripping pill, a sieve can also be added Pill whole grain steps.
- Materialization step Put the 1:1 mixture of the traditional Chinese medicine composition and the cyclodextrin and agar as the base of the dripping pill into the homogenizer, homogenize and mix at 1000 rpm for 1 min, and then homogenize at 3000 rpm The temperature of the material is maintained at 60°C during the process of dissolving the material, and the molten chemical liquid is obtained;
- Materializing step Put the 1:1 mixture of the Chinese medicine composition and gum arabic and lactose as the base of the dripping pill into the homogenizer, homogenize and mix at 5000 rpm for 200 minutes, and then homogenize the material at 10000 rpm , The time is 100min, and the temperature of the material is kept at 100°C during the process of dissolving the material, thereby obtaining the molten liquid medicine;
- Materializing step Put the traditional Chinese medicine composition and lactitol as the base of the dripping pill into a homogenizer, homogenize and mix at 2500rpm for 100min, and then homogenize the material at 6000rpm for 50min. During the process, the temperature of the material is maintained at 80°C, thereby obtaining a molten liquid;
- Drying step The dripping pills are fluidized and dried using a fluidized drying device, and dried at 50° C. for 2 hours to obtain dry dripping pills.
- Coating step the dry dripping pills are coated in a fluidized bed, the weight ratio of the coating material to the plain pills is 1:25, the concentration of the coating solution is 10wt%, and the coating is carried out at a temperature of 40°C , Get coated dripping pills, the coating material is Opadry.
- Materialization step Put the above-mentioned Chinese medicine composition premix and PEG-8000 into a homogenizer, homogenize and mix at 2500rpm for 100min, then homogenize the material at 6000rpm for 50min, During the process, the temperature of the material is maintained at 80°C to obtain a molten liquid;
- Drying step The dripping pills are fluidized and dried using a fluidized drying device, and dried at 50° C. for 2 hours to obtain dry dripping pills.
- Coating step the dry dripping pills are coated in a fluidized bed, the weight ratio of the coating material to the plain pills is 1:25, the concentration of the coating solution is 10wt%, and the coating is carried out at a temperature of 40°C , Get coated drop pills, coating material shellac.
- the mixture After adding water to the powder of the traditional Chinese medicine composition, the mixture is stirred at 30°C for more than 10 minutes to obtain a medicine premix.
- Materializing step Put the above-mentioned Chinese medicine composition and PEG-1000 into a homogenizer, homogenize and mix at 2500rpm for 100min, then homogenize the material at 6000rpm for 20min, in the process of chemically, Keep the temperature of the material at 100°C to obtain a molten liquid;
- the dripping pills are dried by a gradient heating drying method to form a fluidized state at -20°C, dried at 15°C for 10 minutes, dried at 35°C for 10 minutes, and dried at 55°C for 30 minutes to obtain dry dripping pills. .
- Coating step the dry dripping pills are coated in a fluidized bed, the weight ratio of the coating material to the plain pills is 1:25, the concentration of the coating solution is 10wt%, and the coating is carried out at a temperature of 40°C , The coated dropping pills are obtained, and the coating material is cellulose acetate phthalate.
- the mixture After adding water to the powder of the traditional Chinese medicine composition, the mixture is stirred at 80°C for more than 10 minutes to obtain the premix of the traditional Chinese medicine composition.
- Materialization step Put the combination of Chinese medicine composition premix and PEG-4000 and PEG-6000 1:1 into the homogenizer, homogenize and mix at 2500rpm for 100min, then homogenize at 6000rpm Material, time 80min, in the process of material, the temperature of the material is maintained at 80 °C, to obtain molten liquid;
- Drying step drying the dripping pills using a gradient heating drying method to form a fluidized state at 30°C, drying at 35°C for 120 minutes, drying at 55°C for 60 minutes, and drying at 100°C for 60 minutes to obtain dry dripping pills.
- Coating step the dry dripping pill is coated in a fluidized bed, the weight ratio of the coating material to the pill is 1:25, the concentration of the coating solution is 10wt%, and the coating is carried out at a temperature of 35°C , Get coated dripping pills, the coating material is methyl acrylate.
- Compounding step first add xylitol into the chemical compounding tank, heat to 90°C, melt in advance, then add the traditional Chinese medicine composition, and mix uniformly to form a molten medicinal solution;
- the dripping step the above-mentioned molten liquid is delivered to the dripper by pressure, and the dripper is insulated by a steam jacket. Under the conditions of a dripper temperature of 40°C and a dripping vibration frequency of 50Hz, the dripper The molten liquid flows into the dripper and drips out from the bottom of the dripper;
- Drying and coating steps fluidize and dry the cooled solid droplets and coat them with a drug at a drying temperature of 75°C to prepare coated microdroplets with a particle size of 0.2mm to 1.0mm;
- Packaging step capsule filling of the coated micro-droplets, and 100% on-line checkweighing through a capsule checkweigher, and then package into a final product with a droplet particle size of 0.2-1.0 mm.
- the shape of the dripping pill can be monitored and adjusted by stroboscopic irradiation and visual inspection; after the drug is loaded and coated, in order to improve the particle size uniformity and roundness of the dripping pill, it can also be Add the step of sieve pellets.
- Chemical compounding step first add PEG-6000 and PEG-4000 to the chemical compounding tank, heat to 120°C, melt in advance, then add the traditional Chinese medicine composition, and mix uniformly to form a molten medicinal solution;
- the dripping step the above-mentioned molten liquid is delivered to the dripper by pressure, and the dripper is insulated by a steam jacket. Under the conditions of a dripper temperature of 80°C and a dripping vibration frequency of 20Hz, the dripper The molten liquid flows into the dripper and drips out from the bottom of the dripper;
- Drying and coating steps fluidize and dry the cooled solid droplets and coat them with a drug at a drying temperature of 150°C to prepare coated microdroplets with a particle size of 0.5mm to 1.0mm;
- Packaging step capsule filling of the coated micro-droplets, and 100% on-line check weighing through a capsule check weighing machine, and then packaging into a final product.
- the shape of the dripping pill can be monitored and adjusted by stroboscopic irradiation and visual inspection; after the drug is loaded and coated, in order to improve the particle size uniformity and roundness of the dripping pill, it can also be Add the step of sieve pellets.
- Materialization step first add PEG-1000 to the materialization tank, heat to 40°C, melt in advance, then add the traditional Chinese medicine composition, and mix uniformly to form a molten liquid;
- the dripping step the above-mentioned molten liquid is delivered to the dripper by pressurization, and the dripper is insulated by a steam jacket. Under the condition that the dripper temperature is 40-60°C and the dripping vibration frequency is 200Hz, The molten liquid flows into the dripper and drips out from the bottom of the dripper;
- Drying and coating steps fluidized drying and drug-loading coating of the cooled solid drop pellets, forming a fluidized state at 20°C, drying at 25°C for 60 minutes, drying at 45°C for 30 minutes, and drying at 55°C for 30 minutes.
- Packaging step capsule filling of the coated micro-droplets, and 100% on-line check weighing through a capsule check weighing machine, and then packaging into a final product.
- the shape of the dripping pill can be monitored and adjusted by stroboscopic irradiation and visual inspection; after the drug is loaded and coated, in order to improve the particle size uniformity and roundness of the dripping pill, it can also be Add the step of sieve pellets.
- Materialization step first add PEG-6000 and PEG-4000 to the chemical material tank, heat to 120°C, melt in advance, then add the Chinese medicine composition, put it into the homogenizer, homogenize and mix at 1000rpm, time 1min , Then, homogenize the material at 3000rpm for 1min. During the process, keep the temperature of the material at 60°C to obtain the molten liquid;
- Drying and coating steps fluidize and dry the cooled solid droplets and coat them with a drug, at a drying temperature of 150°C, to prepare coated microdroplets with a particle size of 0.2mm;
- Packaging step capsule filling of the coated micro-droplets, and 100% on-line check weighing through a capsule check weighing machine, and then packaging into a final product.
- Materialization step first add PEG-6000 to the chemical material tank, heat to 120°C, melt in advance, then add the Chinese medicine composition, put it into the homogenizer, homogenize and mix at 5000rpm for 200min, and then Homogenize the material at 10000rpm for 1min. During the process, keep the temperature of the material at 100°C to obtain a molten liquid;
- Drying and coating steps fluidize and dry the cooled solid droplets and coat them with a drug at a drying temperature of 150°C to prepare coated microdroplets with a particle size of 4.0 mm;
- Packaging step capsule filling of the coated micro-droplets, and 100% on-line check weighing through a capsule check weighing machine, and then packaging into a final product.
- Materialization step first add PEG-4000 to the chemical material tank, heat to 120°C, melt in advance, then add the Chinese medicine composition, homogenize and mix at 3000rpm for 10min, then homogenize the material at 4000rpm, The time is 5 minutes, and the temperature of the material is maintained at 70-90°C during the process of dissolving the material, and the molten chemical liquid is obtained;
- the dripping step the above-mentioned molten liquid is delivered to the dripper by pressure, and the dripper is insulated by a steam jacket.
- the dripper temperature is 70°C
- the dripping vibration frequency is 90Hz
- the dripping pressure is 1.0Bar. Under the condition of, make the molten liquid flow into the dripper and drip out from the bottom of the dripper;
- Drying step fluidize and dry the cooled solid drop pellets at a drying temperature of 150° C. to prepare micro drop pellets with a particle size of 1.0 mm.
- Materialization step first add PEG-4000 to the chemical material tank, heat to 120°C, melt in advance, then add the Chinese medicine composition, homogenize and mix at 4000rpm for 60min, then homogenize the material at 9000rpm, The time is 30min. During the process of chemical material, the temperature of the material is kept at 90°C, and the molten chemical liquid is obtained;
- the dripping step the above-mentioned molten liquid is delivered to the dripper by pressure, and the dripper is insulated by a steam jacket.
- the dripper temperature is 100°C
- the dripping vibration frequency is 200Hz
- the dripping pressure is 3.0Bar. Under the condition of, make the molten liquid flow into the dripper and drip out from the bottom of the dripper;
- Drying step fluidize and dry the cooled solid drop pellets at a drying temperature of 150° C. to prepare micro drop pellets with a particle size of 2.0 mm.
- Materialization step first add PEG-6000 to the chemical material tank, heat to 90°C, melt in advance, then add the traditional Chinese medicine composition, and mix uniformly to form a molten medicinal solution;
- the dripping step the above-mentioned molten liquid is delivered to the dripper by pressure, and the dripper is insulated by a steam jacket.
- the dripper temperature is 80°C
- the dripping vibration frequency is 50Hz, so that the molten liquid Flow into the dripper and drip out from the bottom of the dripper;
- Drying and coating steps fluidize and dry the cooled solid droplets and coat them with a drug at a drying temperature of 75°C to prepare coated microdroplets with a particle size of 1.0 to 2.0 mm;
- Packaging step capsule filling of the coated micro-droplets, and 100% on-line check weighing through a capsule check weighing machine, and then packaging into a final product.
- the shape of the dripping pill can be monitored and adjusted by stroboscopic irradiation and visual inspection; after the drug is loaded and coated, in order to improve the particle size uniformity and roundness of the dripping pill, it can also be Add the step of sieve pellets.
- Materialization step first add PEG-6000 to the chemical material tank, heat to 90°C, pre-melt, then add the Chinese medicine composition, use low-speed homogenization (3200rpm) mixture material, after mixing, increase the homogenization speed The material is melted up to 5000rpm for 6min. During the process, the temperature of the material is kept at 80 ⁇ 5°C. Thus, a molten chemical solution is obtained.
- step 2 transport the above molten liquid to the dripper, adjust the vibration frequency of the dripper to 137Hz, control the dripper temperature at 80°C, and flow the liquid into the dripper through a pressurized method (drip pressure 1.8Bar) , And vibrate to drip out from the bottom of the dripper, and the dripping speed is matched with step (1) chemical material speed;
- Drying step fluidize and dry the dropping pill, after the material forms a good fluid state in the bed, heat up to 25°C for 60min, then heat up to 45°C for 30min, and continue to heat up to 55°C for drying After 30 minutes, the temperature is lowered to below 30°C and the material is discharged. Controlling the water content of the dripping pill at 3.0-7.0wt% to obtain an intermediate pill;
- Coating step Calculate the coating powder dosage according to the coating dosage and the prescription, take 4% Opadry of the weight of the vegetarian pill to prepare a coating solution with a concentration of 18% by weight, and stir for 45 minutes. Set the inlet air temperature to 25°C, put the qualified pellets into the fluidized bed, increase the set inlet air temperature to 48°C, and start coating after the material temperature reaches 38°C. During the coating process, the temperature of the material is controlled at 35-45°C, and after the coating is completed, the temperature is lowered to below 30°C and the material is discharged, and the pellets are screened to obtain intermediate coated pellets. The weight gain of the intermediate coated pellets is controlled at 3.3 ⁇ 0.7wt%, and the moisture content is controlled at 3.0 ⁇ 7.0wt%;
- Capsule making and packaging steps capsules are filled with droplets with a particle size of 1.0mm ⁇ 2.0mm, and 100% on-line checkweighing is completed by a capsule checkweigher, and then the final product is packaged.
- the shape of the dripping pill can be monitored and adjusted by stroboscopic irradiation and visual inspection; after the drug is loaded and coated, in order to improve the particle size uniformity and roundness of the dripping pill, a sieve can also be added Pill whole grain steps.
- the micro dripping pill obtained in Examples 15-32 also has good curative effect, high bioavailability, small drug dosage for patients, and compliance. Good and similar beneficial effects.
- Example 01 The effect of the product of Example 32 on the mortality of LPS-induced DIC model rats
- microdrop pill The product obtained in accordance with Example 32 (hereinafter referred to as microdrop pill)
- the dose administered to rats in this experiment is 837 mg micro-drip pill/kg
- Drug preparation method accurately weigh 837 mg of micro-droplet pill, place it in a container, add an appropriate amount of pure water and sonicate until it is completely dissolved, and dilute to 10 ml. .
- the experimental results showed that 72 hours after the observation of the model, the tail vein 30mg/kg LPS, the mortality rate of the model group was 57.1%, and the oral administration of microdroplets 837mg microdroplets/kg, the mortality rate was 14.3%.
- a single oral administration of the micro-dropping pill of the present invention after copying the model can significantly improve the survival rate of SD rats induced by LPS.
- Example 02 The effect of the product of Example 32 on the mortality of DIC model mice induced by LPS
- microdrop pill The product obtained in accordance with Example 32 (hereinafter referred to as microdrop pill)
- mice in this experiment is 1660.5mg micro-droplet pill/kg
- Drug preparation method accurately weigh 1660.5 mg of micro-droplet pill, place it in a container, add an appropriate amount of pure water and sonicate until it is completely dissolved, and dilute to 10ml.
- a single oral administration of the micro-dropping pill of the present invention after copying the model can significantly improve the survival rate of Kunming mice induced by LPS.
- Example 03 The effect of the product of Example 32 on the prothrombin time (PT) of LPS-induced DIC model rats
- microdrop pill The product prepared in accordance with Example 32 (hereinafter referred to as microdrop pill)
- the dose administered to rats in this experiment is 837 mg micro-drip pill/kg
- Medicine preparation method accurately weigh 837 mg of micro-droplet pill, place it in a container, add an appropriate amount of pure water and sonicate until it is completely dissolved, and dilute to 10 ml.
- the PT value of model rats was longer than that of the normal group, and oral administration of 837 mg micro-droplet pill/kg of the micro-droplet pill of the present invention can significantly improve the prolongation of PT time caused by LPS.
- Example 04 The effect of the product of Example 32 on the systemic diffuse coagulation index (D-Dimer) of patients with severe new coronary pneumonia
- the following drug efficacy trials are clinical trials carried out in a humanitarian spirit under the conditions of the clinical approval of the US FDA.
- the entry criteria are mainly hospitalized patients with severe new coronary pneumonia, and patients with significant systemic blood circulation disorders and diffuse coagulation status.
- Add the product prepared according to Example 32, 300 mg/time, 3 times a day, while observing the improvement of the hospital stay and the decrease of the systemic diffuse coagulation index D-Dimer To reflect the medical value of the present invention in the treatment of new coronary pneumonia.
- the average hospital stay in this experiment was 2.1 days (usually 7 days).
- the average length of stay of the patients in this experiment has dropped from 7 days in the control treatment group to 2 days, except for one patient who fell off in this experiment.
- the biochemical index D-Dimer has decreased significantly, and the whole body is diffuse.
- the coagulation phenomenon is improved. So far, no patient has deteriorated, entered an emergency treatment ward, or died, which shows the clinical value of the present invention in the treatment of new coronary pneumonia.
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Abstract
Description
对象 | 1 | 2 | 3 | 4 | 5 |
第1天 | - | 1.4 | 0.93 | 1.21 | 1.36 |
第2天 | 0.79 | 1.02 | 0.97 | 0.56 | 1.15 |
第3天 | 0.79 | 停药 | 0.81 | 0.59 | * |
第4天 | 0.52 | 0.52 | * | ||
第5天 | * | ||||
第6天 |
Claims (15)
- 一种中药组合物在制备预防和/或治疗新型冠状病毒肺炎药物中的应用,其特征在于:所述中药组合物是由以重量百分比计的丹参三七提取物50.0%~99.9%和冰片0.1%~50.0%组成的,其中,所述丹参三七提取物含有以下组分,各组分的重量比为:丹参素:丹酚酸T:原儿茶醛:丹酚酸D:迷迭香酸:丹酚酸B:丹酚酸A:三七皂苷R1:人参皂苷Rg1:人参皂苷Re:人参皂苷Rb1:人参皂苷Rd:二氢丹参酮I:丹参酮I:隐丹参酮:丹参酮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)。
- 如权利要求1所述的应用,其特征在于,能够预防或减少新型冠状病毒肺炎患者血栓的形成。
- 如权利要求1所述的应用,其特征在于,能够改善新型冠状病毒肺炎患者的微循环障碍。
- 如权利要求1所述的应用,其特征在于,能够抑制新型冠状病毒肺炎患者的弥散性血管内凝血状态,降低死亡率。
- 如权利要求1所述的应用,其特征在于,所述新型冠状病毒肺炎为普通、中重度肺炎。
- 如权利要求1所述的应用,其中,所述中药组合物是由以重量百分比计的丹参三七提取物75.0%~99.9%和冰片0.1%~25.0%组成的。
- 如权利要求1-6任意一项所述的应用,其中药组合物制成药学可接受的制剂。
- 如权利要求7所述的应用,其中,所述药物制剂为滴丸剂或微滴丸剂,优选微滴丸剂,所述微滴丸剂是由中药组合物与滴丸基质按照重量比1:5~5:1制成的。
- 如权利要求8所述的应用,其中所述微滴丸剂的制备方法包括以下步骤:(1)化料步骤:将药物与滴丸基质投入均质机中,以1000~5000rpm均质混合,时间1~200min,然后,以3000~10000rpm均质化料,时间1~100min,在化料过程中,温度保持在60~100℃,得熔融药液,所述药物与所述滴丸基质的重量比为1:5~5:1;(2)滴制步骤:将上述熔融药液输送至滴头,在滴头温度70~300℃、滴制振动频率2~2000Hz、滴制压力0.5~4.0Bar、加速度1~20G的条件下,经滴头振动滴制,滴制速度与步骤(1)化料速度匹配;(3)冷凝步骤:滴出的药滴在冷却气体中快速冷却,凝固成粒径为0.2mm~4.0mm固态滴丸,所述冷却气体的温度为0℃以下。
- 如权利要求9所述的应用,其中,上述步骤(1)中,所述滴丸基质包括PEG类、山梨醇、木糖醇、乳糖醇、麦芽糖、淀粉、甲基纤维素、羧甲基纤维素钠、羟丙基甲基纤维素、阿拉伯胶、海藻酸、糊精、环糊精、琼脂、乳糖中的一种或多种组合;优选的滴丸基质为固体PEG, 例如PEG-1000、PEG-2000、PEG-3000、PEG-4000、PEG-5000、PEG-6000、PEG-7000、PEG-8000,进一步优选PEG-1000、PEG-2000、PEG-3000、PEG-4000、PEG-6000、PEG-8000中的一种或多种组合,最优选为PEG-6000、PEG-4000或PEG-4000和PEG-6000的组合。
- 如权利要求9所述的应用,其中,所述微滴丸剂的制备方法包括如下步骤:(1)化料步骤:将药物与滴丸基质投入均质机中,以1000~5000rpm均质混合,然后,以3000~10000rpm均质化料,时间20~80min,在化料过程中,温度保持在80~100℃,得熔融药液,所述药物与所述滴丸基质的重量比为1:3~3:1;(2)滴制步骤:将上述熔融药液输送至滴头,在滴头温度70~200℃、滴制振动频率20~300Hz、滴制压力0.5~4.0Bar、加速度1~15G的条件下,经滴头振动滴制,滴制速度与步骤(1)化料速度匹配;(3)冷凝步骤:滴出的药滴在冷却气体中快速冷却,凝固成粒径为0.2mm~4.0mm固态滴丸,所述冷却气体的温度为0℃以下。
- 如权利要求11所述的应用,其中,所述制备方法还包括作为步骤(4)的干燥步骤,采用流化干燥设备干燥,在-20~100℃、优选-20~90℃干燥1~4h,得素丸。
- 如权利要求12所述的应用,其中,所述步骤(4)采用梯度升温干燥法:于-20~30℃形成流化态,于15~35℃干燥10~120min,于35~55℃干燥10~60min,于55~100℃干燥0~60min;优选地,所述梯度升温干燥法如下进行:于0~20℃形成流化态,于25℃干燥60min,于45℃干燥30min,于55℃干燥0~30min。
- 如权利要求13所述的应用,其中,所述制备方法还包括作为步骤(5)的包衣步骤,所述步骤是在所述步骤(4)得到的素丸处于流化状态下,在30~65℃温度下对所述素丸进行包衣;包衣液浓度为5~25wt%,优选18~20wt%,其中,包衣材料选自:虫胶、苯二甲酸醋酸纤维素、丙烯酸甲酯、甲基丙烯酸甲酯或欧巴代;所述包衣材料与素丸的重量比为1:50~1:10、优选1:50~1:25。
- 如权利要求10~14任一项所述的应用,其中,所述制备方法在步骤(1)前,还可以具有物料预混步骤,将所述药物浸膏或粉末加水后,于30~80℃搅拌10min以上,得到药物预混料。
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EP21797887.3A EP4144357A4 (en) | 2020-04-29 | 2021-04-28 | TRADITIONAL CHINESE MEDICINE COMPOSITION, AND APPLICATION OF PREPARATION OF TRADITIONAL CHINESE MEDICINE COMPOSITION IN THE PREPARATION OF MEDICINE FOR THE PREVENTION AND/OR TREATMENT OF CORONAVIRUS DISEASE 2019 |
AU2021264907A AU2021264907A1 (en) | 2020-04-29 | 2021-04-28 | Traditional Chinese medicine composition, and application of preparation of traditional chinese medicine composition in preparing medicine for preventing and/or treating coronavirus disease 2019 |
JP2022554407A JP2023525627A (ja) | 2020-04-29 | 2021-04-28 | 新型コロナウィルス肺炎の予防および/または治療のための医薬の製造における漢方薬組成物およびその製剤の使用 |
CA3167884A CA3167884A1 (en) | 2020-04-29 | 2021-04-28 | Application of a traditional chinese medicine composition and formulation thereof in the preparation of medicaments for preventing and/or treating novel coronavirus pneumonia |
KR1020227032587A KR20230002324A (ko) | 2020-04-29 | 2021-04-28 | 신종 코로나바이러스 폐렴의 예방 및/또는 치료용 약제의 제조에 있어서의 한약 조성물 및 그 제제의 용도 |
US17/920,888 US20230201293A1 (en) | 2020-04-29 | 2021-04-28 | Application of a traditional chinese medicine composition and formulation thereof in the preparation of medicaments for preventing and/or treating novel coronavirus pneumonia |
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CN115054581B (zh) * | 2022-08-04 | 2022-11-01 | 北京绿源求证科技发展有限责任公司 | 一种治疗脑血管疾病的药物及其制备工艺 |
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CN104274520A (zh) * | 2013-07-11 | 2015-01-14 | 天士力制药集团股份有限公司 | 一种中药组合物及其制剂 |
CN104274518A (zh) * | 2013-07-11 | 2015-01-14 | 天士力制药集团股份有限公司 | 一种中药组合物及制剂 |
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US20050037094A1 (en) * | 2003-07-31 | 2005-02-17 | Xijun Yan | Composition for heart disease, its active ingredients, method to prepare same and uses thereof |
CN100339085C (zh) * | 2003-09-23 | 2007-09-26 | 天津天士力制药股份有限公司 | 治疗心脑血管疾病的中药组合物 |
CN1919239B (zh) * | 2005-08-24 | 2010-09-29 | 天津天士力制药股份有限公司 | 一种治疗心脑血管疾病的中药组合物 |
CN101085018B (zh) * | 2006-06-08 | 2012-01-04 | 天津天士力制药股份有限公司 | 含丹参、三七、黄芪和苏合香的中药组合物及制剂 |
CN103536610B (zh) * | 2013-01-09 | 2015-03-11 | 上海中医药大学 | 三七皂苷Fc的医药用途 |
CN103655910B (zh) * | 2013-12-23 | 2015-07-15 | 广东众生药业股份有限公司 | 复方血栓通胶囊在保护肝脏方面的用途 |
CN204170103U (zh) * | 2014-07-11 | 2015-02-25 | 天士力制药集团股份有限公司 | 气冷滴丸生产线 |
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CN104274518A (zh) * | 2013-07-11 | 2015-01-14 | 天士力制药集团股份有限公司 | 一种中药组合物及制剂 |
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DIAGNOSIS AND TREATMENT PROTOCOL FOR NOVEL CORONAVIRUS PNEUMONIA (TRIAL VERSION 6, 18 February 2020 (2020-02-18) |
See also references of EP4144357A4 |
ZHANG YIQIAN, JIA-WEN SHI, YUAN-HUA LIU, HAO ZHOU, XIAO-QING CAI, JIN WEN, YUAN-XUE LIU, HONG-WEI REN, YU WANG, ZHAO-HUI SONG, YI : "Exploration of Potential Clinical Application Value and Mechanism of Chinese Materia Medica for Tonifying Qi and Activating Blood in COVID-19 With Hypoxemia", CHINESE TRADITIONAL AND HERBAL DRUGS, TAINJIN ZHONGCAOYAO ZAZAHISHE, CN, vol. 51, no. 6, 9 March 2020 (2020-03-09), CN , pages 1435 - 1442, XP055863068, ISSN: 0253-2670, DOI: 10.7501/j.issn.0253-2670.2020.06.008 * |
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