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 PDF

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Publication number
WO2021219031A1
WO2021219031A1 PCT/CN2021/090690 CN2021090690W WO2021219031A1 WO 2021219031 A1 WO2021219031 A1 WO 2021219031A1 CN 2021090690 W CN2021090690 W CN 2021090690W WO 2021219031 A1 WO2021219031 A1 WO 2021219031A1
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WIPO (PCT)
Prior art keywords
dripping
peg
pill
chinese medicine
traditional chinese
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Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
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PCT/CN2021/090690
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English (en)
French (fr)
Inventor
孙鹤
苏雪峰
钟志永
李安妮
闫希军
吴迺峰
闫凯境
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Tasly Pharmaceutical Group Co Ltd
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Tasly Pharmaceutical Group Co Ltd
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Priority to KR1020227032587A priority Critical patent/KR20230002324A/ko
Priority to CA3167884A priority patent/CA3167884A1/en
Priority to AU2021264907A priority patent/AU2021264907A1/en
Priority to US17/920,888 priority patent/US20230201293A1/en
Priority to EP21797887.3A priority patent/EP4144357A4/en
Priority to JP2022554407A priority patent/JP7657819B2/ja
Publication of WO2021219031A1 publication Critical patent/WO2021219031A1/zh
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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

一种由丹参三七提取物和冰片制备的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的药物中的应用。

Description

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 技术领域
本发明涉及一种医药领域，具体而言，本发明涉及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。
背景技术
新型冠状病毒肺炎，国际病毒分类委员会将这种新型冠状病毒命名为严重急性呼吸综合征冠状病毒2(severe acute respiratory syndrome coronavirus 2，SARS-CoV-2)。而世界卫生组织(WHO)同日宣布，由这一病毒导致的疾病的正式名称为COVID-19(coronavirus disease 2019)，该病毒传播迅速。
基于目前的流行病学调查，COVID-19患者临床症状以发热、乏力、干咳为主，少数患者伴有鼻塞、流涕、咽痛和腹泻等症状。约半数患者在1周后会出现呼吸困难和/或低血氧症，严重者可快速进展为急性呼吸窘迫综合征(acute respiratory distress syndrome，ARDS)、脓毒症休克、难以纠正的代谢性酸中毒、血黏度上升和出凝血功能障碍。COVID-19低氧血症的治疗十分关键，确诊的重症患者多在发病一周后岀现呼吸困难和/或低氧血症，临床上需要给予呼吸支持和循环支持，并在对症治疗的基础上，积极防治并发症，治疗基础疾病，预防继发感染。相比于轻症患者，重症患者双肺间质改变明显，多发磨玻璃影、浸润影，出现肺实变；同时体内Th1反应增强、促炎因子释放增多，炎症侵犯肺泡壁和临近的肺泡腔，进行性造成肺泡间隔增厚和肺纤维化，伴有肺功能障碍和进行性呼吸困难，肺泡不能实现气体交换过程，氧合功能减弱进一步导致血液中的氧含量下降出现低氧血症，严重者可快速进展为急性呼吸窘迫综合征(ARDS)、脓毒症休克、难以纠正的代谢性酸中毒和出凝血功能障碍及多器官功能衰竭等。此外，据报道，持续的氧合指数下降可作为重型和危重型预警因素之一，病情加重的患者都曾有超过12h氧合指标只有100～150mmHg，这类患者因为缺氧极有可能会诱发细胞因子风暴(CSS)，CSS将导致肺部大量炎性因子释放，促进肺部纤维化等炎症损伤。因此，在COVID-19的治疗过程中，应重点关注患者氧合指数、血氧饱和度等相关指标的变化，防治结合改善低氧血症的发生发展，降低患者转为重型甚至危重型的几率，显得尤为重要。
3～7版《新型冠状病毒肺炎诊疗方案(试行)》根据患者临床表现特别提出了中医治疗原则和辨证论治方案。针对新冠肺炎低氧血症的治疗，在2020年2月18日发布的《新型冠状病毒肺炎诊疗方案(试行第六版)》中首次提及“对于氧合指标进行性恶化、影像学进展迅速、机体炎症反应过度激活状态的患者……”。
复方丹参微滴丸(T89)为天士力公司开发的活血化瘀、理气止痛的中药，用于胸中憋闷、心绞痛，其主要成分为丹参、三七和冰片。具有治疗急性心肌梗塞和急性心肌缺血作用。
T89是从天然中提取制备的药物。目前在美国FDA申报临床研究，编号为T89。该产品在中国国 内具有25年以上的使用历史，具有很好的安全性。新冠肺炎的患者由于covid-19病毒的入侵，患者的心肌酶升高伴有全身炎性反应，甚至引起多器官的衰竭和中枢神经损伤。造成这样的原因是病毒侵袭后的引起的系统性血栓、微循环障碍、炎性因子风暴、ROS侵袭和低血氧等等。这些疾病会导致患者死亡率升高，特别是针对患有心血管疾病、高血压和糖尿病等基础疾病的患者尤甚。截至目前，未见COVID-19低氧血症的推荐用药。
发明内容
为了解决上述技术问题，本发明提供一种中药组合物在制备新型冠状病毒肺炎药物中的应用，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)。
新冠肺炎的患者由于covid-19病毒的入侵，患者的心肌酶升高伴有全身炎性反应，甚至引起多器官的衰竭和中枢神经损伤。造成这样的原因是病毒侵袭后的引起的系统性血栓、微循环障碍、炎性因子风暴、ROS侵袭等症状。本发明的中药组合物可以有效改善新型冠状病毒肺炎患者的临床症状，改善患者的微循环障碍，降低肺血栓的形成，抑制弥散性血管内凝血(DIC)，从而降低了中重度新型冠状病毒肺炎患者的死亡率。
进一步的，本发明中药组合物能够预防或减少新型冠状病毒肺炎患者血栓的形成，降低肺泡腔内浆液、纤维蛋白性渗出液及透明膜的形成。减少肺泡隔血管充血、水肿、降低单核和淋巴细胞浸润及血管内透明血栓的形成。能够抑制血小板聚集和粘附，因此预防全身血栓形成。
进一步的，本发明所述中药组合物能够通过调节血管舒缩状态，改变血管功能和改善微循环血流灌注，改善心脏，肺和其他器官中的氧气和营养物质交换，从而改善新型冠状病毒肺炎患者的微循环障碍。
进一步的，本发明中药组合物能够抑制新型冠状病毒肺炎患者的弥散性血管内凝血(DIC)，降低死亡率。
进一步的，根据临床分型症状：轻型(临床症状轻微，影像学未见肺炎表现)；普通型(发热、呼吸道等症状，影像学可见肺炎表现的)；重型(呼吸窘迫，RR≥30次/分；静息状态下，指氧饱和度≤93％；动脉血氧分压(PaO2)/吸氧浓度(FiO2)≤300mmHg)和危重型(出现呼吸衰竭，且需要机械通气；出现休克；合并其他器官功能衰竭需ICU监护治疗。)本发明所述中药组合物治疗普通、中重度型肺炎。
本发明所述的中药组合物，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。
本发明所述中药组合物是由以重量百分比计的丹参三七提取物90.0％～99.9％和冰片0.1％～10.0％组成的。
本发明所述的中药组合物，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＝(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)。
进一步优选中药组合物，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＝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。
本发明所述的中药组合物，其中，所述丹参三七提取物是由原材料按以下重量份制备得到的：丹参75～90份、三七10～25份。
本发明所述的中药组合物，其中，所述丹参三七提取物是由原材料按以下重量份制备得到的：丹参82～84份、三七16～17份。
本发明所述的中药组合物可以制成各种制剂，例如：注射剂、片剂、胶囊剂、滴丸/微滴丸及微滴丸胶囊等，优选微滴丸剂。所述“微滴丸”是指和现有的滴丸相比，体积更小的滴丸。具体而言，是指粒径为0.2mm～4mm的滴丸，特别是指粒径为0.2mm～2mm、优选粒径为1mm～2mm的滴丸。
本发明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。
本发明所述微滴丸剂的制备方法，所述方法包括以下步骤：
(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。
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。
进一步优选所述的制备方法，其中，所述方法包括如下步骤：
(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。
上述步骤(1)中，所述药物与所述滴丸基质的重量比为1:3～3:1，以3000～5000rpm均质混合，时间10～60min，然后，以4000～9000rpm均质化料，时间5～30min，在化料过程中，温度保持在70～90℃；优选所述药物与所述滴丸基质的重量比为1:(1～3)，以3000～4000rpm均质混合，时间10～30min，然后，以4000～6000rpm均质化料，时间6～30min，在化料过程中，温度保持在75～85℃。
上述步骤(2)中，滴头温度为70～100℃、优选75～85℃；滴制振动频率为50～300Hz、优选100～200Hz、更优选90～200Hz、更优选130～140Hz、最优选137Hz；加速度3.5～4.5G、优选4.0G；滴制压力为1.0～3.0Bar、优选1.8Bar；滴制速度为10～40kg/h，优选12～30kg/h，进一步优选15～25kg/h。
上述步骤(3)中，所述气体为空气、氮气、惰性气体；冷却温度为0～-150℃、优选-60～-140℃、更优选-80～-120℃；所述滴丸的直径为1.0mm～2.0mm。
本发明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。
进一步优选，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。
本发明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。
本发明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。
为了更好的证明本发明的有益效果，通过下述试验来说明。
具体实施方式
在一个实施方式中，本发明提供一种中药组合物。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％、冰片0.1％～50.0％组成的，其中，所述丹参三七提取物含有(重量份)：
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)。
本发明优选的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％、冰片0.1％～25.0％组成的。
本发明进一步优选的中药组合物是由以重量百分比计的丹参三七提取物90.0％～99.9％、冰片0.1％～10.0％组成的。
在上述中药组合物中，所述丹参三七提取物优选含有(重量份)：
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＝(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)。
在上述中药组合物中，所述丹参三七提取物更优选含有(重量份)：
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＝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。
上述中药组合物可以通过对丹参和三七进行提取加工得到提取物，再加入冰片进行混合而制备得到。
本发明的中药组合物优选通过下述方法制备：
(1)丹参、三七药材在碱性条件下，用水煎煮，煎煮液过滤，滤液浓缩醇沉，取上清液滤过，回收乙醇得浸膏(或进一步将浸膏干燥)，即为丹参三七提取物；
(2)向丹参三七提取物中加入冰片，进行混匀，
其中，丹参和三七可以在相同碱性条件下的水中分别进行煎煮；或在同一碱性条件下的水中煎煮。
优选地，所述丹参三七提取物可以通过下述方法制备：
步骤(1)：将丹参三七在碱性下水溶液中煎煮1～3次，每次1～3小时，过滤，得滤液I；
步骤(2)：将药渣加水煎煮1～3次，每次1～3小时，滤过，滤液II；
步骤(3)：将滤液I、II合并浓缩，浓缩液醇沉，静置，取上清液，过滤，回收乙醇，浓缩得浸膏，或将浸膏干燥，即得丹参三七提取物。
其中，步骤(1)中的碱性水溶液包括，但不限于碳酸氢钠、碳酸钠、磷酸氢钠、磷酸二氢钠、氢氧化钠、氢氧化钾、氢氧化镁水溶液中的一种或几种，pH为7.5～9.0，上述碱性水溶液中的碱的加入量为药材量的1～4.5重量％、优选2.25～3重量％，以保证丹参素钠和丹酚酸T提取完全。
步骤(3)中优选加入50％～100％的乙醇、优选95％的乙醇进行醇沉，优选醇沉至乙醇的浓度为60％～75％。
更优选地，本发明的丹参三七提取物通过下述方法制备：
步骤(1)将丹参药材切成5cm以下、优选1-2cm的段，将三七药材粉碎成1cm的颗粒，称取占总药材量2.25～3重量％的碳酸氢钠，将称量好的丹参、三七、碳酸氢钠投入提取罐中，每罐加5倍量工艺用水，加热煮沸，保持沸腾2h±20min，过滤，
步骤(2)将药渣进行第二次提取，加入4倍量水，加热煮沸，保持沸腾1h±15min，过滤，药渣弃去；
步骤(3)提取液减压浓缩至相对密度为1.16～1.20(80±5℃)或相应48％～52％的糖度，得浓缩液，将浓缩液打入醇沉罐中，加入适量乙醇调至含醇量为65％～70％，静置12～24小时，至沉淀完全，分离上清液，弃去沉淀，将上清液浓缩得浸膏，或将浸膏干燥，即得丹参三七提取物。
其中，步骤(1)中的5倍量是指药材总重量的5倍量，同样地，步骤(2)中的4倍量是指药渣总重量的4倍量。
本发明中的中药组合物是由原药材按重量份丹参75～90份、三七10～25份和冰片0.1～4份制成的。
优选的中药组合物由原药材按重量份丹参80～86份、三七15～18份和冰片0.2～2份制成。
最优选的中药组合物由原药材按重量份丹参82～84份、三七16～17份和冰片0.4～1.2份制成。
本发明的中药组合物可以是浸膏也可以是粉末。
在一个实施方式中，本发明提供了所述中药组合物的药物制剂，所述药物制剂包含本发明的中药组合物和一种或多种药学上可接受的载体。本发明的中药组合物在其制剂中所占重量百分比可以为0.1％～99.9％，其余为药学上可接受的载体。
本发明所述的药物制剂为单位剂量药物制剂形式，所述单位剂量是指制剂的单位，如片剂的每片、胶囊的每粒胶囊、口服液的每瓶、颗粒剂的每袋等，并且可以通过用药学领域熟知的任一种方法制备。所有方法包括使本发明的中药组合物与载体结合的步骤，该载体构成一种或多种辅助成分。一般来说，该制剂的制备过程如下：使本发明的中药组合物与液体载体、或微细粉碎的固体载体、或二者的结合均匀而紧密的结合，然后，如果必要的话，使产物成型为所必须的制剂。 通常可使用标准的制药技术，即可将本发明的中药组合物、和药用载体制得本发明的药物制剂，这些方法包括混合、制粒和压制。本领域技术人员所熟知的是，可药用载体或稀释剂的形式和特性取决于与其混合的活性成分的量、给药途径和其它已知因素。
其药物制剂形式可以是任何可药用的剂型，这些剂型包括：片剂、糖衣片剂、薄膜衣片剂、肠溶衣片剂、胶囊剂、硬胶囊剂、软胶囊剂、口服液、口含剂、颗粒剂、冲剂、丸剂、散剂、膏剂、丹剂、混悬剂、粉剂、溶液剂、注射剂、栓剂、软膏剂、硬膏剂、霜剂、喷雾剂、滴剂、贴剂。本发明的制剂，优选的是口服剂型，如：胶囊剂、片剂、口服液、颗粒剂、丸剂、散剂、丹剂、膏剂等。
其口服给药的制剂可含有常用的赋形剂，诸如粘合剂、填充剂、稀释剂、压片剂、润滑剂、崩解剂、着色剂、调味剂和湿润剂，必要时可对片剂进行包衣。
适用的填充剂包括纤维素、甘露糖醇、乳糖和其它类似的填充剂。适宜的崩解剂包括淀粉、聚乙烯吡咯烷酮和淀粉衍生物，例如羟基乙酸淀粉钠。适宜的润滑剂包括，例如硬脂酸镁。适宜的药物可接受的湿润剂包括十二烷基硫酸钠。
可通过混合、填充、压片等常用的方法制备固体口服组合物。进行反复混合可使活性物质分布在整个使用大量填充剂的那些组合物中。
口服液体制剂的形式例如可以是水性或油性悬浮液、溶液、乳剂、糖浆剂或酏剂，或者可以是一种在使用前可用水或其它适宜的载体复配的干燥产品。这种液体制剂可含有常规的添加剂，诸如悬浮剂，例如山梨醇、糖浆、甲基纤维素、明胶、羟乙基纤维素、羧甲基纤维素、硬脂酸铝凝胶或氢化食用脂肪，乳化剂，例如卵磷脂、脱水山梨醇一油酸酯或阿拉伯胶；非水性载体(它们可以包括食用油)，例如杏仁油、分馏椰子油、诸如甘油的酯的油性酯、丙二醇或乙醇；防腐剂，例如对羟基苯甲酯或对羟基苯甲酸丙酯或山梨酸，并且如果需要，可含有常规的香味剂或着色剂。
对于注射剂，制备的液体单位剂型含有本发明的活性物质和无菌载体。根据载体和浓度，可以将此化合物悬浮或者溶解。溶液的制备通常是通过将活性物质溶解在一种载体中，在将其装入一种适宜的小瓶或安瓿前过滤消毒，然后密封。辅料例如一种局部麻醉剂、防腐剂和缓冲剂也可以溶解在这种载体中。为了提高其稳定性，可在装入小瓶以后将这种组合物冰冻，并在真空下将水除去。
在制备成药剂时可选择性的加入适合的药学上可接受的载体，所述药学上可接受的载体选自：甘露醇、山梨醇、焦亚硫酸钠、亚硫酸氢钠、硫代硫酸钠、盐酸半胱氨酸、巯基乙酸、蛋氨酸、维生素C、EDTA二钠、EDTA钙钠，一价碱金属的碳酸盐、醋酸盐、磷酸盐或其水溶液、盐酸、醋酸、硫酸、磷酸、氨基酸、氯化钠、氯化钾、乳酸钠、木糖醇、麦芽糖、葡萄糖、果糖、右旋糖苷、甘氨酸、淀粉、蔗糖、乳糖、甘露糖醇、硅衍生物、纤维素及其衍生物、藻酸盐、明胶、聚乙烯吡咯烷酮、甘油、土温80、琼脂、碳酸钙、碳酸氢钙、表面活性剂、聚乙二醇、环糊精、β－环糊精、磷脂类材料、高岭土、滑石粉、硬脂酸钙、硬脂酸镁等。
本发明优选将中药组合物制成滴丸制剂，更优选微滴丸制剂。
在另一个实施方式中，本发明提供一种复方丹参微滴丸，所述的复方丹参微滴丸是由重量比为1:5～5:1的中药组合物与滴丸基质制成；优选地，本发明的复方丹参微滴丸是由重量比为1:3～3:1的中药组合物与滴丸基质制成；最优选地，本发明的复方丹参微滴丸是由重量比为1:(1～3)的中药组合物与滴丸基质组成。
本发明的复方丹参微滴丸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，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。
优选地，本发明的复方丹参微滴丸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，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。
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。步骤(1)的均质化可以提高含量均匀性，使含量均匀性由原来的RSD＝10％，提高至7％。
优选地，上述步骤(1)中，所述药物与所述滴丸基质的重量比为1:3～3:1，以3000～5000rpm均质混合，时间10～60min，然后，以4000～9000rpm均质化料，时间5～30min，在化料过程中，温度保持在70～90℃；最优选地，所述药物与所述滴丸基质的重量比为1:(1～3)，以3000～4000rpm均质混合，时间10-30min，然后，以4000～6000rpm均质化料，时间6～30min，在化料过程中，温度保持在75～85℃。
其中，优选地，上述步骤(2)中，滴头温度为70～100℃、优选75～85℃；滴制振动频率为 50～300Hz、优选100～200Hz、更优选90～200Hz、更优选130～140Hz、最优选137Hz；加速度3.5～4.5G、优选4.0G；滴制压力为1.0～3.0Bar、优选1.8Bar；滴制速度为10～40kg/h，优选12～30kg/h，进一步优选15～25kg/h。
上述步骤(3)中，气体冷却是指利用低温冷阱对下落药滴快速冷却，使其凝固成形。冷却气体的温度范围为0℃以下，优选0～-150℃、优选-60℃～-140℃、更优选-80℃～-120℃，优选冷却气体为空气、氮气、惰性气体。所得微滴丸的粒径优选1.0mm～2.0mm。
进一步地，本发明的微滴丸的制备方法还包括作为步骤(4)的干燥步骤，优选采用流化干燥设备干燥，在-20～100℃、优选-20～90℃干燥1～4h，得素丸。具体而言，经步骤(3)完成滴制后的低温滴丸，经过温度40～150℃、优选温度40～60℃的流化床干燥，干燥时间1～4h、优选1～3h、最优选为2h，得素丸。
上述步骤(4)中，优选如下的梯度升温干燥法：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；进一步优选如下的梯度升温干燥法：于0～20℃形成流化态，于25℃干燥60min，于45℃干燥30min，于55℃干燥0～30min。该步骤保持滴丸处于流化状态，解决了滴丸粘连的问题，还提高了效率，产能可达30kg/h。
进一步地，本发明的微滴丸的制备方法还包括作为步骤(5)的包衣步骤。该步骤是在所述步骤(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。
为了更好地实施本发明的微滴丸的制备方法，优选在步骤(1)前，还可以具有物料预混步骤，将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，以保证水分均一。该步骤可以弥补干粉投料的缺点。
由本发明的方法制得的滴丸可以直接包装，也可以装入胶囊壳后制成胶囊剂。在制成胶囊剂后，还可增加逐粒胶囊称重的步骤，灌装后的胶囊在包装之前进行高速逐粒称重，以剔除可能存在的不合格胶囊。
实施例
以下通过实施例对本发明的工艺进一步加以详细说明。该实施例仅用于说明本发明，而没有意图对本发明构成限制。
丹参三七提取物各组分的含量测定方法
在以下实施例中，各中药组合物的各组分：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、二氢丹参酮I、丹参酮I、隐丹参酮、丹参酮IIA、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的含量按照下述方法进行测定。
酚酸类和丹参酮类组分的检测：
对照品及供试品溶液的配制
对照品溶液：精密称取一定量对照品丹参素、丹酚酸T、原儿茶醛、丹酚酸D、迷迭香酸、丹酚酸B、丹酚酸A、二氢丹参酮I、丹参酮I、隐丹参酮、丹参酮IIA置于10ml量瓶中，用甲醇溶解后稀释至刻度，根据需要进行稀释、摇匀，分别制成以下浓度的溶液：丹参素0.0315mg/ml、 丹酚酸T 0.04596mg/ml、原儿茶醛0.07556mg/ml、丹酚酸D 0.04385mg/ml、迷迭香酸0.04263mg/ml、丹酚酸B 0.04248mg/ml、丹酚酸A 0.1118mg/ml、二氢丹参酮I 0.02098mg/ml、丹参酮I 0.02085mg/ml、隐丹参酮0.02442mg/ml、丹参酮IIA 0.01992mg/ml，经0.22μm膜过滤，即得对照品溶液。
供试品溶液：精密称取0.1g丹参三七提取物样品放置于10ml量瓶中，用纯水溶解后，稀释至刻度，然后经0.22μm膜过滤，即得供试品溶液。
测定方法：分别精密吸取对照品溶液与供试品溶液各10μl，注入超高效液相色谱仪，测定。
色谱柱：Agilent Zorbax SB C18(4.6×250mm，5μm)
流速：0.5mL/min
柱温：30℃
检测波长：281nm，洗脱条件如下表1：
表1
Figure PCTCN2021090690-appb-000001
皂苷类组分的检测：
对照品溶液的制备：取三七皂苷R1对照品、人参皂苷Rg1对照品、人参皂苷Rb1对照品、人参皂苷Re、人参皂苷Rd对照品适量，精密称定，加甲醇制成每1ml分别含0.5mg、2.0mg、1.0mg、0.5mg、0.5mg、0.5mg、1.0mg的溶液，即得。
供试品溶液的制备：精密称定0.1g样品，加4％的氨水溶液10ml溶解，通过D101型大孔吸附树脂柱(内径为0.7cm，柱高为5cm)，用30ml水洗脱，然后用30ml的30％的甲醇洗脱，再用10ml甲醇洗脱，收集甲醇溶液至10ml量瓶中，摇匀，即得。
色谱条件与系统适用性试验：以十八烷基硅烷键合的硅胶为填充剂；乙腈为流动相A，水为流动相B，按照下表2进行梯度洗脱；流速为每分钟1.0ml；检测波长为203nm；柱温30℃；记录时间为75分钟。
表2流动相梯度洗脱参照表
Figure PCTCN2021090690-appb-000002
测定：分别精密吸取对照品溶液、供试品溶液各10μl，注入液相色谱仪。
本发明中药组合物的制备
实施例1
取丹参药材820g切成1-2cm的小段，将三七药材160g粉碎成0.18cm颗粒；称取药材量2.25％的碳酸氢钠；将称量好的丹参、三七、碳酸氢钠投入提取罐中，每罐加5倍量工艺用水，加热煮沸，保持沸腾约2h，过滤，药渣进行第二次提取，加入4倍量水，加热煮沸，保持沸腾约1h，过滤，药渣弃去；将提取液减压浓缩至相对密度为1.16-1.20(80±5℃)或相应48-52％糖度，得浓缩液；浓缩液打入醇沉罐中，加入适量乙醇调至含醇量为65％～70％，静置12小时，至沉淀完全，分离上清液，沉淀弃去；上清液浓缩即得浸膏，浸膏干燥即得丹参三七提取物。
丹参三七提取物按上述测定方法进行测定，其中，丹参三七提取物中含有丹参素36mg/g、丹酚酸T 11mg/g、原儿茶醛17mg/g、丹酚酸D 6mg/g、迷迭香酸7mg/g、丹酚酸B 13mg/g、丹酚酸A 9mg/g、三七皂苷R 17mg/g、人参皂苷Rg1 24mg/g、人参皂苷Re 3mg/g、人参皂苷Rb118mg/g、人参皂苷Rd 4mg/g、二氢丹参酮I 0.3mg/g、丹参酮I 0.7mg/g、隐丹参酮0.6mg/g、丹参酮IIA 2.7mg/g。
取丹参三七提取物90g、冰片9g混合均匀，即得中药组合物。
实施例2
取实施例1中制备的丹参三七提取物75g、冰片25g，混合均匀匀，既得中药组合物。
实施例3
将丹参800.0g、三七150.0g在碱性条件下(pH＝9)的水中煎煮3次，每次煎煮1小时，过滤，得滤液I，药渣加水煎煮3次，每次1小时，滤过，得滤液II，将滤液I、II合并浓缩，浓缩液加入乙醇到醇浓度70％，静置，取上清液，过滤，回收乙醇，浓缩干燥得丹参三七提取物。
丹参三七提取物按上述测定方法进行测定，其中，丹参三七提取物中包括丹参素40mg/g、丹酚酸T 12mg/g、原儿茶醛20mg/g、丹酚酸D 7mg/g、迷迭香酸9mg/g、丹酚酸B 16mg/g、丹酚酸A 12mg/g、三七皂苷R1 9mg/g、人参皂苷Rg1 28mg/g、人参皂苷Re 4mg/g、人参皂苷Rb1 22mg/g、人参皂苷Rd 6mg/g、二氢丹参酮I 0.4mg/g、丹参酮I 0.8mg/g、隐丹参酮0.6mg/g、丹参酮IIA 2.8mg/g。
取丹参三七提取物99.9g、冰片0.1g混合均匀，即得中药组合物。
实施例4
取实施例3制备的丹参三七提取物90g、冰片10g，混合均匀，既得中药组合物。
实施例5
丹参750g、三七250g在碱性条件下(pH＝7.5)的水中煎煮2次，每次煎煮2小时，过滤，得滤液I，药渣加水煎煮2次，每次2小时，过滤，得滤液II，将滤液I、II合并浓缩，向浓缩液中加入乙醇至醇浓度70％，静置，取上清液，过滤，回收乙醇，浓缩干燥得丹参三七提取物。
丹参三七提取物按上述测定方法进行测定，其中，丹参三七提取物中含有的丹参素、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的量分别为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、2.6mg/g。
取丹参三七提取物50g、冰片50g混合均匀，即得中药组合物。
实施例6
取实施例5制备的丹参三七提取物99g、冰片1g，混合均匀，既得中药组合物。
实施例7
丹参83份、三七17份在碱性条件下(pH＝7.5)的水中煎煮2次，每次煎煮2小时，过滤，得滤液I；药渣加水煎煮2次，每次2小时，过滤，得滤液II；将滤液I、II合并浓缩，浓缩液加入乙醇至醇浓度70％，静置，取上清液，过滤，回收乙醇，浓缩干燥得丹参三七提取物；加入冰片1份混合均匀匀，既得中药组合物。冰片从市场上购买得到。
按上述测定方法进行测定，其中，丹参三七提取物中含有的丹参素、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的含量分别为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、2.8mg/g。
实施例8
取丹参药材400g切成1-2cm段，将三七药材80g粉碎成颗粒；称取药材量3％的碳酸氢钠，将称量好的丹参、三七、碳酸氢钠投入提取罐中，每罐加5倍量工艺用水，加热煮沸，保持沸腾约2h±20min，过滤，药渣进行第二次提取，加入4倍量水，加热煮沸，保持沸腾约1h±15min，过滤，药渣弃去；提取液减压浓缩至相对密度为1.16-1.20(80±5℃)或相应50％糖度，得浓缩液；浓缩液打入醇沉罐中，加入适量乙醇调至含醇量为68％，静置20小时，至沉淀完全，分离上清液，沉淀弃去；上清液浓缩即得浸膏，浸膏干燥即得丹参三七提取物。
按照上述测定方法进行测定，其中，丹参三七提取物中含有丹参素、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含量分别为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。
取丹参三七提取物90g、冰片10g混合均匀，即得中药组合物，
实施例9
取丹参药材500g切1-2cm段，将三七药材102g粉碎成颗粒，称取药材量2.5％的碳酸氢钠，将称量好的丹参、三七、碳酸氢钠投入提取罐中，每罐加6倍量工艺用水，加热煮沸，保持沸腾约2h，过滤，药渣进行第二次提取，加入6倍量水，加热煮沸，保持沸腾约1h，过滤，药渣弃去；提取液减压浓缩至相对密度为1.16-1.20(80±5℃)或相应48％糖度，得浓缩液；浓缩液打入醇沉罐中，加入适量乙醇调至含醇量为65％，静置24小时，至沉淀完全，分离上清液，沉淀弃去；上清液浓缩即得浸膏，浸膏干燥即得丹参三七提取物。
按照上述测定方法进行测定，其中，丹参三七提取物中含有的丹参素、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的含量分别为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、5mg/g。
取丹参三七提取物99.9g、冰片0.1g混合均匀，即得中药组合物。
本发明药物制剂的制备
实施例10
取实施例1-9任意一项所述的中药组合物0.5g与PEG-6000 10.5g混合均匀，加热熔融，化料后移至滴丸滴灌中，药液滴至6～8℃液体石蜡中，除油，制得滴丸400粒。
实施例11
取实施例1-9任意一项所述的中药组合物0.5g、葡萄糖4.5g、硫代硫酸钠0.9g和蒸馏水1ml，上述组分混合均匀后，冷冻干燥，分装500支，即得。
实施例12
取实施例1-9任意一项所述的中药组合物0.5g、甘露醇5.5g、依地酸钙钠0.9g和蒸馏水2ml，上述组分混匀后，冷冻干燥，分装300支，即得。
实施例13
取实施例1-9任意一项所述的中药组合物0.5g、淀粉50g、蔗糖50g，上述组分混匀后，制粒，压片即得片剂。
实施例14
取实施例1-9任意一项所述的中药组合物0.5g、淀粉50g、蔗糖50g，上述组分混匀后，制粒，装胶囊即得胶囊剂。
本发明复方丹参微滴丸的制备
实施例15
取实施例1制得的中药组合物82.5g、PEG-6000 165g。
(1)预混步骤：将中药组合物加水预混，40±10℃保温罐内搅拌60min以上，使中药组合 物的含水量为13.0wt％，得到中药组合物预混料，备用；
(2)化料步骤：先将PEG-6000加入化料罐中，加热至90℃，预先熔融，再加入中药组合物预混料，采用低速均质(3200rpm)混合物料，混合完成后，提高均质速度至5000rpm进行化料，时间6min，在化料过程中，物料的温度保持在80±5℃。由此，得到熔融药液。
(3)滴制步骤：将上述熔融药液输送至滴头，调节滴头的振动频率为137Hz，滴头温度控制在80℃，药液通过加压方式(滴制压力1.8Bar)流入滴头，并从滴头底部振动滴出，滴制速度与步骤(1)化料速度匹配；
(4)冷凝步骤：滴出的药滴到冷却管道中，采用低温惰性气体冷却，冷却温度-115±5℃，使滴出的药液冷却成固态滴丸；
(5)干燥步骤：将所述滴丸进行流化干燥，待物料在床体内形成较好的流态后，升温至25℃干燥60min，再升温至45℃干燥30min，继续升温至55℃干燥30min，然后降温至30℃以下出料。将滴丸水分控制在3.0～7.0wt％，得到中间体素丸；
(6)包衣步骤：按照包衣投料量和处方计算包衣粉用量，取素丸重量的4％的欧巴代配制成浓度为18wt％的包衣液，搅拌45min。设定进风温度为25℃，将合格素丸投入流化床后，提高设定进风温度至48℃，待物料温度达到38℃后，开始包衣。包衣过程中物料温度控制在35～45℃，包衣完成后降温至30℃以下出料，筛丸，得到中间体包衣丸。将中间体包衣丸的增重控制在3.3±0.7wt％，水分控制在3.0～7.0wt％；
(7)制胶囊、包装步骤：将制成粒径为1.0mm～2.0mm滴丸进行胶囊装填，并通过胶囊检重机完成100％在线检重，然后包装成最终产品。
其中，滴制过程中，滴丸成形情况通过频闪照射加目测，可进行实时在线监控及调整；在载药包衣后，为提高滴丸粒径均匀度及圆整度，还可加入筛丸整粒步骤。
实施例16
除所述中药组合物与PEG-6000的重量比为1:5外，其它与实施例15相同，制备复方丹参微滴丸。
实施例17
除所述中药组合物与PEG-6000的重量比为5:1外，其它与实施例15相同，制备复方丹参微滴丸。
实施例18
取实施例1制得的中药组合物82.5g，环糊精和琼脂1:1的混合物165g，制备成微滴丸，制备方法如下：
(1)化料步骤：将中药组合物与作为滴丸基质的环糊精和琼脂1:1的混合物投入到均质机中，以1000rpm均质混合，时间1min，然后，以3000rpm均质化料，时间1min，在化料过程中，物料的温度保持在60℃，由此得到熔融药液；
(2)滴制步骤：将上述熔融药液输送至滴头，在滴头温度70℃、滴制振动频率50Hz、滴 制压力为0.5Bar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的滴丸素丸，所述冷却气体的温度为0℃。
实施例19
取实施例1制得的中药组合物82.5g，阿拉伯胶和乳糖＝1:1的混合物165g，制备成复方丹参微滴丸，制备方法如下：
(1)化料步骤：将中药组合物与作为滴丸基质的阿拉伯胶和乳糖1:1的混合物投入到均质机中，以5000rpm均质混合，时间200min，然后，以10000rpm均质化料，时间100min，在化料过程中，物料的温度保持在100℃，由此得到熔融药液；
(2)滴制步骤：将上述熔融药液输送至滴头，在滴头温度300℃、滴制振动频率为300Hz、滴制压力为4.0Bar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4.0mm的滴丸素丸，所述冷却气体的温度为-150℃。
实施例20
取实施例1制得的中药组合物82.5g，乳糖醇165g，制备成复方丹参微滴丸，制备方法如下：
(1)化料步骤：将中药组合物与作为滴丸基质的乳糖醇投入到均质机中，以2500rpm均质混合，时间100min，然后，以6000rpm均质化料，时间50min，在化料过程中，物料的温度保持在80℃，由此得到熔融药液；
(2)滴制步骤：将上述熔融药液输送至滴头，在滴头温度150℃、滴制振动频率150Hz、滴制压力为2Bar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2mm的滴丸素丸，所述冷却气体的温度为-100℃。
(4)干燥步骤：将所述滴丸采用流化干燥设备进行流化干燥，于50℃干燥2h，得干燥滴丸素丸。
(5)包衣步骤：所述干燥滴丸素丸在流化床中包衣，包衣材料与素丸重量比为1:25，包衣液浓度为10wt％，于温度40℃进行包衣，得包衣滴丸，包衣材料为欧巴代。
实施例21
取实施例1制得的中药组合物82.5g，PEG8000 165g，制备成复方丹参微滴丸，制备方法如下：
将上述中药组合物粉末加水后，于60℃搅拌10min以上，得到中药组合物预混料。
(1)化料步骤：将上述中药组合物预混料与PEG-8000投入到均质机中，以2500rpm均质混合，时间100min，然后，以6000rpm均质化料，时间50min，在化料过程中，物料的温度保持在80℃，得熔融药液；
(2)滴制步骤：将上述熔融药液输送至滴头，在滴头温度150℃、滴制振动频率150Hz、 滴制压力为2Bar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2mm的滴丸素丸，所述冷却气体的温度为-100℃。
(4)干燥步骤：将所述滴丸采用流化干燥设备进行流化干燥，于50℃干燥2h，得干燥滴丸素丸。
(5)包衣步骤：所述干燥滴丸素丸在流化床中包衣，包衣材料与素丸重量比为1:25，包衣液浓度为10wt％，于温度40℃进行包衣，得包衣滴丸，包衣材料虫胶。
实施例22
取实施例1制得的中药组合物92g、PEG-1000 270g，制备成复方丹参微滴丸，制备方法如下：
将中药组合物粉末加水后，于30℃搅拌10min以上，得到药物预混料。
(1)化料步骤：将上述中药组合物与PEG-1000投入到均质机中，以2500rpm均质混合，时间100min，然后，以6000rpm均质化料，时间20min，在化料过程中，物料的温度保持在100℃，得熔融药液；
(2)滴制步骤：将上述熔融药液输送至滴头，在滴头温度70℃、滴制振动频率100Hz、滴制压力为1.0Bar、加速度1G，滴制速度10Kg/h的条件下，经滴头振动滴制，上述滴制速度与步骤(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2mm的滴丸素丸，所述冷却气体的温度为-80℃。
(4)干燥步骤：将所述滴丸采用梯度升温干燥法干燥，-20℃形成流化态，于15℃干燥10min，于35℃干燥10min，于55℃干燥30min，得干燥滴丸素丸。
(5)包衣步骤：所述干燥滴丸素丸在流化床中包衣，包衣材料与素丸重量比为1:25，包衣液浓度为10wt％，于温度40℃进行包衣，得包衣滴丸，包衣材料为苯二甲酸醋酸纤维素。
实施例23
取实施例1制得的中药组合物105g、PEG-4000和PEG-6000 1:1的组合35g，制备成复方丹参微滴丸，制备方法如下：
将中药组合物粉末加水后，于80℃搅拌10min以上，得到中药组合物预混料。
(1)化料步骤：将中药组合物预混料与PEG-4000和PEG-6000 1:1的组合投入到均质机中，以2500rpm均质混合，时间100min，然后，以6000rpm均质化料，时间80min，在化料过程中，物料的温度保持在80℃，得熔融药液；
(2)滴制步骤：将上述熔融药液输送至滴头，在滴头温度100℃、滴制振动频率200Hz、滴制压力为3.0Bar、加速度20G、滴制速度40Kg/h的条件下，经滴头振动滴制，上述滴制速度与步骤(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2mm的滴丸素丸，所述 冷却气体的温度为-120℃。
(4)干燥步骤：将所述滴丸采用梯度升温干燥法干燥，30℃形成流化态，于35℃干燥120min，于55℃干燥60min，于100℃干燥60min，得干燥滴丸素丸。
(5)包衣步骤：所述干燥滴丸素丸在流化床中包衣，包衣材料与素丸重量比为1:25，包衣液浓度为10wt％，于温度35℃进行包衣，得包衣滴丸，包衣材料是丙烯酸甲酯。
实施例24
取实施例1制得的中药组合物600g、冰片5g以及滴丸基质木糖醇600g。
(1)化料步骤：先将木糖醇加入化料罐中，加热至90℃，预先熔融，再加入中药组合物，混合均匀成熔融药液；
(2)滴制步骤：将上述熔融药液通过加压方式输送到滴头，滴头采用蒸汽夹套保温，在滴头温度为40℃、滴制振动频率为50Hz的条件下，使所述熔融药液流入滴头，并从滴头底部滴出；
(3)冷凝步骤：滴出的药滴在冷却管道内采用低温惰性气体进行冷却，冷却温度-20℃，使滴出的药液冷却成固态滴丸；
(4)干燥、包衣步骤：将冷却后的固态滴丸进行流化干燥及载药包衣，干燥温度为75℃，制成粒径为0.2mm～1.0mm的包衣微滴丸；
(5)包装步骤：将所述包衣微滴丸进行胶囊装填，并通过胶囊检重机完成100％在线检重，然后包装成最终产品，滴丸粒径0.2～1.0mm。
其中，在滴制过程中，滴丸成形情况通过频闪照射加目测，可进行实时在线监控及调整；在载药包衣后，为提高滴丸的粒径均匀度及圆整度，还可加入筛丸整粒步骤。
实施例25
取实施例1制得的中药组合物600g、冰片5g以及PEG-6000和PEG-4000滴丸基质3000g。
(1)化料步骤：先将PEG-6000和PEG-4000加入化料罐中，加热至120℃，预先熔融，再加入中药组合物，混合均匀成熔融药液；
(2)滴制步骤：将上述熔融药液通过加压方式输送到滴头，滴头采用蒸汽夹套保温，在滴头温度为80℃、滴制振动频率为20Hz的条件下，使所述熔融药液流入滴头，并从滴头底部滴出；
(3)冷凝步骤：滴出的药滴在冷却管道内采用低温惰性气体进行冷却，冷却温度-80℃，使滴出的药液冷却成固态滴丸；
(4)干燥、包衣步骤：将冷却后的固态滴丸进行流化干燥及载药包衣，干燥温度为150℃，制成粒径为0.5mm～1.0mm的包衣微滴丸；
(5)包装步骤：将所述包衣微滴丸进行胶囊装填，并通过胶囊检重机完成100％在线检重，然后包装成最终产品。
其中，在滴制过程中，滴丸成形情况通过频闪照射加目测，可进行实时在线监控及调整；在载药包衣后，为提高滴丸的粒径均匀度及圆整度，还可加入筛丸整粒步骤。
实施例26
取实施例1制得的中药组合物600g、冰片5g以及PEG-1000滴丸基质120g。
(1)化料步骤：先将PEG-1000加入化料罐中，加热至40℃，预先熔融，再加入中药组合物，混合均匀成熔融药液；
(2)滴制步骤：将上述熔融药液通过加压方式输送到滴头，滴头采用蒸汽夹套保温，在滴头温度为40～60℃，滴制振动频率为200Hz的条件下，使所述熔融药液流入滴头，并从滴头底部滴出；
(3)冷凝步骤：滴出的药滴在冷却管道内采用低温惰性气体进行冷却，冷却温度-100℃，使滴出的药液冷却成固态滴丸；
(4)干燥、包衣步骤：将冷却后的固态滴丸进行流化干燥及载药包衣，20℃形成流化态，25℃干燥60min，45℃干燥30min，55℃干燥30min，制成粒径为3.0mm～4.0mm的包衣微滴丸；
(5)包装步骤：将所述包衣微滴丸进行胶囊装填，并通过胶囊检重机完成100％在线检重，然后包装成最终产品。
其中，在滴制过程中，滴丸成形情况通过频闪照射加目测，可进行实时在线监控及调整；在载药包衣后，为提高滴丸的粒径均匀度及圆整度，还可加入筛丸整粒步骤。
实施例27
取实施例1制得的中药组合物600g、冰片5g以及PEG-6000、PEG-4000滴丸基质3000g。
(1)化料步骤：先将PEG-6000和PEG-4000加入化料罐中，加热至120℃，预先熔融，再加入中药组合物，投入均质机中，以1000rpm均质混合，时间1min，然后，以3000rpm均质化料，时间1min，在化料过程中，物料的温度保持在60℃，得熔融药液；
(2)滴制步骤：将上述熔融药液通过加压方式输送到滴头，滴头采用蒸汽夹套保温，在滴头温度为70℃，滴制振动频率为50Hz、滴制压力为0.5Bar的条件下，使所述熔融药液流入滴头，并从滴头底部滴出；
(3)冷凝步骤：滴出的药滴在冷却管道内采用低温惰性气体进行冷却，冷却温度0℃，使滴出的药液冷却成固态滴丸；
(4)干燥、包衣步骤：将冷却后的固态滴丸进行流化干燥及载药包衣，干燥温度为150℃，制成粒径为0.2mm的包衣微滴丸；
(5)包装步骤：将所述包衣微滴丸进行胶囊装填，并通过胶囊检重机完成100％在线检重，然后包装成最终产品。
实施例28
取实施例1制得的中药组合物600g、冰片5g以及PEG-6000滴丸基质1800g。
(1)化料步骤：先将PEG-6000加入化料罐中，加热至120℃，预先熔融，再加入中药组合物，投入均质机中，以5000rpm均质混合，时间200min，然后，以10000rpm均质化料，时间1min，在化料过程中，物料的温度保持在100℃，得熔融药液；
(2)滴制步骤：将上述熔融药液通过加压方式输送到滴头，滴头采用蒸汽夹套保温，在滴 头温度为300℃，滴制振动频率为300Hz、滴制压力为4.0Bar的条件下，使所述熔融药液流入滴头，并从滴头底部滴出；
(3)冷凝步骤：滴出的药滴在冷却管道内采用低温惰性气体进行冷却，冷却温度-150℃，使滴出的药液冷却成固态滴丸；
(4)干燥、包衣步骤：将冷却后的固态滴丸进行流化干燥及载药包衣，干燥温度为150℃，制成粒径为4.0mm的包衣微滴丸；
(5)包装步骤：将所述包衣微滴丸进行胶囊装填，并通过胶囊检重机完成100％在线检重，然后包装成最终产品。
实施例29
取实施例1制得的中药组合物600g、冰片5g以及PEG-4000滴丸基质2400g。
(1)化料步骤：先将PEG-4000加入化料罐中，加热至120℃，预先熔融，再加入中药组合物，以3000rpm均质混合，时间10min，然后，以4000rpm均质化料，时间5min，在化料过程中，物料的温度保持在70～90℃，得熔融药液；
(2)滴制步骤：将上述熔融药液通过加压方式输送到滴头，滴头采用蒸汽夹套保温，在滴头温度为70℃，滴制振动频率为90Hz、滴制压力为1.0Bar的条件下，使所述熔融药液流入滴头，并从滴头底部滴出；
(3)冷凝步骤：滴出的药滴在冷却管道内采用低温惰性气体进行冷却，冷却温度-140℃，使滴出的药液冷却成固态滴丸；
(4)干燥步骤：将冷却后的固态滴丸进行流化干燥，干燥温度为150℃，制成粒径为1.0mm的微滴丸素丸。
实施例30
取实施例1制得的中药组合物600g、冰片5g以及PEG-4000滴丸基质2400g。
(1)化料步骤：先将PEG-4000加入化料罐中，加热至120℃，预先熔融，再加入中药组合物，以4000rpm均质混合，时间60min，然后，以9000rpm均质化料，时间30min，在化料过程中，物料的温度保持在90℃，得熔融药液；
(2)滴制步骤：将上述熔融药液通过加压方式输送到滴头，滴头采用蒸汽夹套保温，在滴头温度为100℃，滴制振动频率为200Hz、滴制压力为3.0Bar的条件下，使所述熔融药液流入滴头，并从滴头底部滴出；
(3)冷凝步骤：滴出的药滴在冷却管道内采用低温惰性气体进行冷却，冷却温度-140℃，使滴出的药液冷却成固态滴丸；
(4)干燥步骤：将冷却后的固态滴丸进行流化干燥，干燥温度为150℃，制成粒径为2.0mm的微滴丸素丸。
实施例31
取实施例1制得的中药组合物600g、冰片5g以及PEG-6000滴丸基质2000g。
(1)化料步骤：先将PEG-6000加入化料罐中，加热至90℃，预先熔融，再加入中药组合物，混合均匀成熔融药液；
(2)滴制步骤：将上述熔融药液通过加压方式输送到滴头，滴头采用蒸汽夹套保温，在滴头温度为80℃，滴制振动频率为50Hz，使所述熔融药液流入滴头，并从滴头底部滴出；
(3)冷凝步骤：滴出的药滴在冷却管道内采用低温惰性气体进行冷却，冷却温度-20℃，使滴出的药液冷却成固态滴丸；
(4)干燥、包衣步骤：将冷却后的固态滴丸进行流化干燥及载药包衣，干燥温度为75℃，制成粒径为1.0～2.0mm的包衣微滴丸；
(5)包装步骤：将所述包衣微滴丸进行胶囊装填，并通过胶囊检重机完成100％在线检重，然后包装成最终产品。
其中，在滴制过程中，滴丸成形情况通过频闪照射加目测，可进行实时在线监控及调整；在载药包衣后，为提高滴丸的粒径均匀度及圆整度，还可加入筛丸整粒步骤。
实施例32
取实施例1制得的中药组合物82.5g、PEG-6000 165g。
(1)化料步骤：先将PEG-6000加入化料罐中，加热至90℃，预先熔融，再加入中药组合物，采用低速均质(3200rpm)混合物料，混合完成后，提高均质速度至5000rpm进行化料，时间6min，在化料过程中，物料的温度保持在80±5℃。由此，得到熔融药液。
(2)滴制步骤：将上述熔融药液输送至滴头，调节滴头的振动频率为137Hz，滴头温度控制在80℃，药液通过加压方式(滴制压力1.8Bar)流入滴头，并从滴头底部振动滴出，滴制速度与步骤(1)化料速度匹配；
(3)冷凝步骤：滴出的药滴到冷却管道中，采用低温惰性气体冷却，冷却温度-115±5℃，使滴出的药液冷却成固态滴丸；
(4)干燥步骤：将所述滴丸进行流化干燥，待物料在床体内形成较好的流态后，升温至25℃干燥60min，再升温至45℃干燥30min，继续升温至55℃干燥30min，然后降温至30℃以下出料。将滴丸水分控制在3.0～7.0wt％，得到中间体素丸；
(5)包衣步骤：按照包衣投料量和处方计算包衣粉用量，取素丸重量的4％的欧巴代配制成浓度为18wt％的包衣液，搅拌45min。设定进风温度为25℃，将合格素丸投入流化床后，提高设定进风温度至48℃，待物料温度达到38℃后，开始包衣。包衣过程中物料温度控制在35～45℃，包衣完成后降温至30℃以下出料，筛丸，得到中间体包衣丸。将中间体包衣丸的增重控制在3.3±0.7wt％，水分控制在3.0～7.0wt％；
(6)制胶囊、包装步骤：将制成粒径为1.0mm～2.0mm滴丸进行胶囊装填，并通过胶囊检重机完成100％在线检重，然后包装成最终产品。
其中，滴制过程中，滴丸成形情况通过频闪照射加目测，可进行实时在线监控及调整；在载药包衣后，为提高滴丸粒径均匀度及圆整度，还可加入筛丸整粒步骤。
经过发明人的研究和药效试验发现，比现有复方丹参滴丸产品而言，实施例15-32得到的微滴丸同样具有疗效好、生物利用度高、患者服用药物剂量小、依从性好等类似的有益效果。
药效例
药效例01 实施例32产品对LPS诱导DIC模型大鼠死亡率的影响
1实验材料与方法
1.1实验动物
SD大鼠，SPF级，雄性，220-250克。动物合格证编号：110011200105605444。
1.2受试物
依照实施例32得到的产品(以下简称微滴丸)
1.3剂量设计
本实验大鼠给药剂量为837mg微滴丸/kg
1.4实验方法
药品配置方法：准确称取微滴丸837mg，置于容器中，加入适量纯水超声至完全溶解后，定容至10ml。。
实验方法：参考文献以及前期实验研究，取大鼠14只(n＝7)，随机分为模型组、微滴丸组。各组实验动物称重后，根据体重尾静脉注射30mg/kg LPS复制DIC模型。模型组尾静脉注30mg/kgLPS，微滴丸组于复制模型后20min，根据每只大鼠体重进行灌胃给药，给药剂量为给药剂量837mg/kg，给药体积为10ml/kg。观察各组实验动物死亡率至复制模型后72h。
2实验结果
微滴丸对LPS诱导DIC模型大鼠死亡率的影响
实验结果显示，观察至复制模型后72h，尾静脉30mg/kg LPS，模型组死亡率为57.1％，口服给予微滴丸837mg微滴丸/kg，死亡率为14.3％。
表3微滴丸对LPS诱导DIC模型大鼠死亡率的影响
Figure PCTCN2021090690-appb-000003
3结论
本实验条件下，复制模型后单次口服给予本发明的微滴丸能明显提高LPS诱导SD大鼠生存率。
药效例02 实施例32的产品对LPS诱导DIC模型小鼠死亡率的影响
1实验材料与方法
1.1实验动物
昆明小鼠，SPF级，雄性，18-22克。动物合格证编号：110011200107075313。
1.2受试物
依照实施例32得到的产品(以下简称微滴丸)
1.3剂量设计
本实验小鼠给药剂量为1660.5mg微滴丸/kg
1.4实验方法
药品配置方法：准确称取微滴丸1660.5mg，置于容器中，加入适量纯水超声至完全溶解后，定容至10ml。
实验方法：取昆明小鼠16只(n＝8)，随机分为模型组、微滴丸组。各组实验动物称重后，根据体重腹腔注35mg/kg LPS复制DIC模型。模型组腹腔注射35mg/kg LPS，微滴丸组于复制模型后20min，根据每只小鼠体重进行灌胃给药，给药剂量为给药剂量1660.5mg微滴丸/kg，给药体积为10ml/kg。观察各组实验动物死亡率至复制模型后72h。
2实验结果
微滴丸对LPS诱导DIC模型小鼠死亡率的影响
实验结果显示，观察至复制模型后72h，腹腔注射35mg/kg LPS，模型组死亡率为87.5％，口服给予微滴丸1660.5mg微滴丸/kg，死亡率为12.5％
表4微滴丸对LPS诱导DIC模型小鼠死亡率的影响
Figure PCTCN2021090690-appb-000004
3结论
本实验条件下，复制模型后单次口服给予本发明的微滴丸能明显提高LPS诱导昆明小鼠生存率。
药效例03 实施例32的产品对LPS诱导DIC模型大鼠凝血酶原时间(PT)的影响
1实验材料与方法
1.1实验动物
SD大鼠，SPF级，雄性，220-250克。动物合格证编号：110011200105605444。
1.2受试物
依照实施例32制备得到的产品(以下简称微滴丸)
1.3剂量设计
本实验大鼠给药剂量为837mg微滴丸/kg
1.4实验方法
药品配置方法：准确称取微滴丸837mg，置于容器中，加入适量纯水超声至完全溶解后，定容至10ml。实验方法：取大鼠9只(n＝3)，随机分为正常组、模型组、微滴丸组。各组实验动物称重后，根据体重尾静脉注射5mg/kg LPS复制DIC模型。模型组尾静脉注5mg/kg LPS，微滴丸组于复制模型后20min，根据每只大鼠体重进行灌胃给药，给药剂量为给药剂量837mg微滴丸/kg，给药体积为10ml/kg。各组实验动物于复制模型后4h取血浆进行PT检测。
2实验结果
微滴丸对LPS诱导DIC模型大鼠凝血酶原时间(PT)的影响
实验结果显示，尾静脉注射5mg/kg LPS，4h后模型大鼠PT值较正常组延长，口服给予837微滴丸mg/kg微滴丸能明显改善LPS所致PT时间延长。
表5微滴丸对高剂量LPS诱导DIC模型大鼠PT的影响
Figure PCTCN2021090690-appb-000005
**：与正常组比较，P<0.01；##：与模型组比较，P<0.01
3结论
本实验条件下，模型大鼠PT值较正常组延长，口服给予837mg微滴丸/kg本发明的微滴丸能明显改善LPS所致PT时间延长。
药效例04 实施例32的产品对严重新冠肺炎病人全身弥漫性凝血指数(D-Dimer)的影响
下述药效实验是在美国FDA的临床批件允许条件下，以人道主义精神开展的临床实验。入组标准，主要是严重新冠肺炎住院病人，并且有显著的全身血液循环障碍和弥漫性凝血状态的病人。在病人保持必要的医疗条件的情况下，加服依据实施例32制备得到的产品，300毫克/次，每天3次，同时观察住院病人住院时间的改善以及全身弥漫性凝血指数D-Dimer的下降来反映本发明治疗新冠肺炎的医疗价值。
表6 D-Dimer变化表
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          
*表示无法获得线上数据
本实验中没有病人加重病情或被转入ICU(通常比例为4％)；
本实验中没有病人死亡(通常比例为2％)；
本实验平均住院时间为2.1天(通常为7天)。
综上，本实验入组病人除一位病人脱落外,其他病人的平均住院时间由同时期对照治疗组的7天下降到两天，生物化学指标D-Dimer均有明显下降，并且全身弥漫性凝血现象获得改善。至今没有一例病人恶化、进入紧急治疗病房、或死亡，显示了本发明治疗新冠肺炎的临床价值。

Claims (15)

  1. 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)。
  2. 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。
  3. 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。
  4. 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。
  5. 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。
  6. 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。
  7. 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。
  8. 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。
  9. 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。
  10. 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。
  11. 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。
  12. 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。
  13. 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。
  14. 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。
  15. 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。
PCT/CN2021/090690 2020-04-29 2021-04-28 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 Ceased WO2021219031A1 (zh)

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