WO2022148202A1 - 一种中药组合物在制备抗sars病毒药物中的应用 - Google Patents

一种中药组合物在制备抗sars病毒药物中的应用 Download PDF

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WO2022148202A1
WO2022148202A1 PCT/CN2021/136463 CN2021136463W WO2022148202A1 WO 2022148202 A1 WO2022148202 A1 WO 2022148202A1 CN 2021136463 W CN2021136463 W CN 2021136463W WO 2022148202 A1 WO2022148202 A1 WO 2022148202A1
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add
time
amount
clear paste
traditional chinese
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贾振华
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石家庄以岭药业股份有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A—HUMAN NECESSITIES
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    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/06—Aluminium, calcium or magnesium; Compounds thereof, e.g. clay
    • A—HUMAN NECESSITIES
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Definitions

  • the invention relates to the application of a traditional Chinese medicine composition in the preparation of antiviral drugs, in particular to the application of anti-SARS virus, and belongs to the field of Chinese herbal medicine.
  • SARS virus belongs to the coronavirus family (coronavirus), the virus particles are mostly round, with capsule, and there are coronal fibrils around the periphery, distributed in the cytoplasm, in a round shape, and the virus diameter is between 80 and 120 nm.
  • SARS virus is a variant of coronavirus, the pathogen that causes SARS.
  • Variant coronavirus is related to influenza virus, but it is a very unique type of coronavirus. This is the culprit behind the severe acute respiratory syndrome (SARS, SARS) that ravaged the world from the winter of 2002 to the spring of 2003. Coronavirus.
  • the SARS virus is extremely common around the world. About 15 different strains of the coronavirus have been identified, capable of infecting a variety of mammals and birds, and some can make people sick.
  • SARS virus Human diseases caused by SARS virus are mainly respiratory infections (including severe acute respiratory syndrome).
  • the virus is sensitive to temperature, growing well at 33°C, but inhibited at 35°C. Because of this characteristic, winter and early spring are the epidemic seasons for the virus disease.
  • SARS virus is one of the main pathogens of common cold in adults, and the infection rate in children is high, mainly in the upper respiratory tract, and generally rarely affects the lower respiratory tract. In addition, it can also cause acute gastroenteritis in infants and neonates.
  • the main symptoms are watery stool, fever, and vomiting. It can be pulled more than 10 times a day. In severe cases, bloody stools may even appear, and in rare cases, it can also cause neurological syndrome. .
  • the virus grows mostly in epithelial cells, but can also infect the liver, kidney, heart, and eye, and can grow in other cell types, such as macrophages.
  • animal model of human coronavirus refers to animals with human disease simulation performance established in various medical scientific research. Animal disease models mainly It is used in experimental physiology, experimental pathology and experimental therapeutics (including new drug screening) research), so the isolation of coronavirus is very difficult. Human liver cells, trachea and nasal mucosa cells are required to be isolated through organ culture. It is also difficult to use the above-mentioned materials for proliferating viruses.
  • the serotype and antigenic variability of the SARS virus are still unclear.
  • the SARS virus can be re-infected, indicating that there are multiple serotypes (at least 4 known) and antigenic variation, and its immunity is difficult.
  • coronaviruses include 11 species including human coronavirus 229E, bat coronavirus 1, and porcine epidemic diarrhea virus.
  • Beta coronaviruses include nine species, including mouse hepatitis virus, fruit bat coronavirus HKU9, and severe acute respiratory syndrome (SARS)-related viruses.
  • Gamma coronaviruses include two species, avian coronavirus and beluga coronavirus SW1.
  • Deltacoronaviruses include porcine deltacoronavirus (PDCoV).
  • coronaviruses can cause zoonotic diseases.
  • SARS severe Acute Respiratory Syndrome
  • MERS Middle East Respiratory Syndrome virus
  • Penetration and shedding inhibitors amantadine, rimantadine, enfuviride, maraviroc
  • DNA polymerase inhibitors acyclovir, ganciclovir, valacyclovir, famciclovir, foscarnet sodium
  • Nucleosides lamivudine, zidovudine, emtricitabine, tenofovir, adefovir dipivoxil
  • Non-nucleosides efavirenz, nevirapine
  • Neuraminidase inhibitors oseltamivir, zanamivir
  • each antiviral chemical drug will also be different.
  • ribavirin when used in large doses, it will cause damage to the heart, and it will also cause a decrease in white blood cells, leading to reversibility. of anemia.
  • Traditional Chinese medicine has become a research hotspot of Chinese professionals in recent years because of its unique perspective on the prevention and treatment of viral diseases. Studies have shown that a variety of traditional Chinese medicines and their active ingredients have a certain inhibitory effect on the virus.
  • the present invention is an improved invention based on the patent application No. 2008100894475, and the contents of the patent document are cited herein in its entirety.
  • the above-mentioned patent does not disclose that the traditional Chinese medicine composition has an antiviral effect.
  • the patent application No. 202010153827.1 discloses that the traditional Chinese medicine composition has the effect of anti-influenza virus and anti-new coronavirus, but does not disclose that the traditional Chinese medicine composition has the effect of anti-SARS virus.
  • the invention provides the application of a traditional Chinese medicine composition in the preparation of anti-SARS virus medicine, especially the effect of anti-SARS-CoV-2 virus.
  • the traditional Chinese medicine composition is made from the following raw materials by weight:
  • the ratio of parts by weight of the crude drug of the traditional Chinese medicine composition of the present invention is preferably:
  • the weight parts ratio of the crude drug of the traditional Chinese medicine composition of the present invention is also preferably:
  • the weight parts ratio of the crude drug of the traditional Chinese medicine composition of the present invention is also preferably:
  • the weight parts ratio of the crude drug of the traditional Chinese medicine composition of the present invention is also preferably:
  • the bitter almonds are fried bitter almonds
  • the fritillary fritillary is Zhe fritillaria
  • the honeysuckle is the honeysuckle
  • the pinellia is Qing pinellia.
  • the traditional Chinese medicine composition of the present invention is mainly composed of ephedra, gypsum, forsythia, skullcap, mulberry white skin, etc., and takes advantage of the overall adjustment advantage of compound traditional Chinese medicine, has the characteristics of multi-directional, multi-level and multi-target, and can be effectively killed by experiments. Eliminate SARS virus, the effect is remarkable.
  • the traditional Chinese medicine of the present invention can be replaced by traditional Chinese medicines with the same or similar efficacy, and these medicinal materials can be processed according to the "National Chinese Medicine Processing Standard” or "Chinese Medicine Dictionary”.
  • the active ingredient of Chinese medicine composition of the present invention is made by the following steps:
  • Fritillaria fritillary according to the proportion of the composition, pulverize it into fine powder, and set aside;
  • the dosage form of the medicine of the present invention is capsule, tablet, powder, granule, oral liquid, soft capsule, pill, tincture, syrup, suppository, gel, spray or injection.
  • auxiliary materials such as fillers, disintegrating agents, lubricants, suspending agents, binders, sweeteners, flavoring agents, preservatives, need to be added during the preparation of these dosage forms. , base, etc.
  • Fillers include: starch, pregelatinized starch, lactose, mannitol, chitin, microcrystalline cellulose, sucrose, etc.; disintegrants include: starch, pregelatinized starch, microcrystalline cellulose, sodium carboxymethyl starch, Cross-linked polyvinylpyrrolidone, low-substituted hydroxypropyl cellulose, cross-linked sodium carboxymethyl cellulose, etc.; lubricants include: magnesium stearate, sodium lauryl sulfate, talc, silicon dioxide, etc.; suspending agent Including: polyvinylpyrrolidone, microcrystalline cellulose, sucrose, agar, hydroxypropyl methylcellulose, etc.; binders include starch syrup, polyvinylpyrrolidone, hydroxypropyl methylcellulose, etc.; sweeteners include: Sodium saccharin, aspartame, sucrose, sodium cyclamate, glycyrrhetinic acid, etc.; flavoring
  • Fritillaria fritillary according to the proportion of the composition, pulverize it into fine powder, and set aside;
  • step D the clear paste that step C gained is merged is spray-dried, and the spray powder is collected for subsequent use;
  • step D gained spray powder and step A gained fine powder, take ethanol as binder to make soft material, sieve and granulate;
  • the preparation method of the preferred tablet is:
  • Fritillaria fritillary according to the proportion of the composition, pulverize it into fine powder, and set aside;
  • step D the clear paste that step C gained is merged is spray-dried, and the spray powder is collected for subsequent use;
  • step D gained spray powder and step A gained fine powder, take ethanol as binder to make soft material, sieve and granulate after drying, granulate, add sodium starch glycolate, microcrystalline cellulose, magnesium stearate, mix well , the tablet can be obtained.
  • the preparation method of other dosage forms of the medicine of the present invention is as follows: taking by weighing the crude drug in proportion, and preparing by a conventional preparation method, for example, the preparation technology recorded in Fan Biting's "Pharmaceutics of Traditional Chinese Medicine” (Shanghai Science Press, December 1997 1st edition), It is formulated into pharmaceutically acceptable conventional dosage forms.
  • the traditional Chinese medicine composition of the present invention can resist SARS virus, especially SARS-CoV-2 virus.
  • Fig. 1 Pathological changes of lung tissue, A model group mice on 5 days No. 3 animals with moderate interstitial pneumonia H.E.X200 B mice in the drug group of the present invention No. 5 animals on 5 days with mild interstitial pneumonia H.E.X200 C medicines of the present invention Group mice had moderate interstitial pneumonia H.E.X200 on day 2, animal No. 2.
  • Fritillaria fritillary according to the proportion of the composition, pulverize it into fine powder, and set aside;
  • step D the clear paste that step C gained is merged is spray-dried, and the spray powder is collected for subsequent use;
  • step E The spray powder obtained in step D and the fine powder obtained in step A are prepared by using 80% ethanol as a binder to prepare soft materials, sieved and granulated, dried at 60 degrees, and granulated. Add sodium carboxymethyl starch, microcrystalline cellulose, magnesium stearate, mix well, and prepare tablets according to conventional preparation methods.
  • step D the clear paste that step C gained is merged is spray-dried, and the spray powder is collected for subsequent use;
  • step E The spray powder obtained in step D and the fine powder obtained in step A are prepared by using 80% ethanol as a binder to prepare soft materials, sieved and granulated, dried at 60 degrees, and granulated. Add sodium carboxymethyl starch, microcrystalline cellulose, magnesium stearate, mix well, and prepare tablets according to conventional preparation methods.
  • Fritillaria fritillary according to the proportion of the composition, pulverize it into fine powder, and set aside;
  • step D the clear paste that step C gained is merged is spray-dried, and the spray powder is collected for subsequent use;
  • step E The spray powder obtained in step D and the fine powder obtained in step A are prepared by using 80% ethanol as a binder to prepare soft materials, sieved and granulated, dried at 60 degrees, and granulated. Add sodium carboxymethyl starch, microcrystalline cellulose, magnesium stearate, mix well, and prepare tablets according to conventional preparation methods.
  • the API formula is:
  • Fritillaria fritillary according to the proportion of the composition, pulverize it into fine powder, and set aside;
  • step D the clear paste that step C gained is merged is spray-dried, and the spray powder is collected for subsequent use;
  • step E The spray powder obtained in step D and the fine powder obtained in step A are prepared by using 80% ethanol as a binder to prepare soft materials, sieved and granulated, dried at 60 degrees, and granulated. Add sodium carboxymethyl starch, microcrystalline cellulose, magnesium stearate, mix well, and prepare tablets according to conventional preparation methods.
  • the above medicinal materials can be made into capsules according to the conventional method.
  • the above medicinal materials can be made into granules according to the conventional method.
  • the above medicinal materials can be prepared into injections according to conventional methods.
  • the above medicinal materials can be made into pills according to the conventional method.
  • the traditional Chinese medicine composition of the present invention has the curative effect of anti-SARS virus
  • the preparation method of the pharmaceutical composition embodiment 3 of the present invention the granules before the tableting are used as the test sample (hereinafter referred to as the medicine of the present invention), and the Chinese Academy of Medical Sciences is entrusted with the medical experiment.
  • the Institute of Zoology conducted the following pharmacological experimental studies:
  • Test drug The pharmaceutical composition of the present invention: provided by Shijiazhuang Yiling Pharmaceutical Co., Ltd.
  • the pharmaceutical composition granules used in the test are the batch number: A1911001. This product is brown-yellow powder, and each gram of granules is equivalent to 4.095 grams of crude drug.
  • the applicant has prepared the test drug, 360 mg/ml.
  • Infective dose 10 5 TCID 50 per animal; infection volume: 50 ⁇ l
  • Animal grouping divided into the pharmaceutical composition group of the present invention and the model group
  • Dosage 360 mg/ml, according to the volume of 1ml/100g body weight, and the final dosage of the pharmaceutical composition of the present invention is 14.67 crude drugs/Kg/d, which is 40 times the clinical dosage.
  • Dosing time 1 hour after challenge, once a day for 5 consecutive days, the model group was given distilled water according to the same volume.
  • mice were observed for 5 consecutive days after challenge, and the changes in body weight were recorded. On the 5th day after infection, all mice were euthanized, 3 mice were tested for viral load in lung tissue, and 3 mice were examined for lung histopathology.
  • mice in the model group experienced weight loss after infection, and the average weight loss percentage was the highest of 5.41%.
  • the body weight of the pharmaceutical composition group of the present invention increased on the 3rd day after infection, and increased by an average of 4.55% on the 5th day.
  • Other general states were good, showing that the symptoms of the mice in the group administered with the pharmaceutical composition of the present invention were relieved to a certain extent.
  • Table 2 The results are shown in Table 2.
  • the average viral load in the lung tissue was 10 5.97 copies/ml.
  • the average viral load in the lung tissue of the mice in the pharmaceutical composition group of the present invention was 10 5.26 copies/ml 5 days after infection, which was significantly lower than that in the model group.
  • the viral load of the group administered the pharmaceutical composition of the present invention decreased by 0.72lg value, as shown in Table 3.
  • the lung tissue of 3 cases (3/3) of mice in the hACE2 transgenic model group infected with SARS-CoV-2 for 5 days showed moderate interstitial pneumonia, with significantly widened alveolar septa, inflammatory cell infiltration, and a small amount of inflammatory cell infiltration around blood vessels , a small amount of inflammatory cells and serous exudation in the alveolar cavity.
  • the lung tissue of 2 cases (2/3) of the mice in the pharmaceutical composition group of the present invention showed moderate interstitial pneumonia, and the alveolar septum was obviously widened, inflammatory cells were infiltrated, and a small amount of inflammatory cells were infiltrated around blood vessels; 1 case (1/3) )
  • the lung tissue showed mild interstitial pneumonia, with mild widening of the alveolar septum, inflammatory cell infiltration, and a small amount of inflammatory cell infiltration around the blood vessels, as shown in Table 4.
  • the lung tissue lesions of the pharmaceutical composition group of the present invention were improved.
  • mice in the model group decreased by 5.41%
  • the viral load in the lung tissue was 10 5.97 copies/ml
  • the lung tissue showed moderate interstitial pneumonia.
  • the body weight increased by 4.55 % after infection, and the symptoms were significantly improved.

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Abstract

一种中药组合物在制备抑制SARS病毒药物中的应用。该中药组合物由麻黄、石膏、连翘、黄芩、桑白皮、苦杏仁、前胡、半夏、陈皮、贝母、牛蒡子、金银花、大黄、桔梗和甘草制成。该中药组合物发挥复方中药的整体调节优势，具有多向性、多层面、多靶点的特点，经体内和体外实验证实能有效杀灭SARS病毒，效果显著。

Description

一种中药组合物在制备抗SARS病毒药物中的应用 技术领域
本发明涉及一种中药组合物在制备抗病毒药物中的应用，特别是用于抗SARS病毒的应用，属于中草药领域。
背景技术
SARS病毒属于冠状病毒科(coronavirus)，病毒粒子多呈圆形，有囊膜，外周有冠状排列的纤突，分布于细胞浆中，呈圆形，病毒直径在80～120nm之间。SARS病毒是冠状病毒的一个变种，是引起非典型肺炎的病原体。变种冠状病毒与流感病毒具有亲缘关系，但它是非常独特的一种冠状病毒，在2002年冬到2003年春肆虐全球的严重急性呼吸综合征(SARS、传染性非典型肺炎)的元凶就是这种冠状病毒。
SARS病毒在世界各地极为普遍。大约有15种不同冠状病毒株被发现，能够感染多种哺乳动物和鸟类，有些可使人发病。
SARS病毒引起的人类疾病主要是呼吸系统感染(包括严重急性呼吸综合症)。该病毒对温度很敏感，在33℃时生长良好，但35℃就使之受到抑制。由于这个特性，冬季和早春是该病毒疾病的流行季节。SARS病毒是成人普通感冒的主要病原之一，儿童感染率较高，主要是上呼吸道感染，一般很少波及下呼吸道。另外，还可引起婴儿和新生儿急性肠胃炎，主要症状是水样大便、发热、呕吐，每天可拉10余次，严重者甚至出现血水样便，极少数情况下也引起神经系统综合征。
病毒的生长多位于上皮细胞内，也可以感染肝脏、肾、心脏和眼睛，在另外的一些细胞类型(例如巨噬细胞)中也能生长。如今人类冠状病毒还没有合适的可作研究用的动物模型(人类疾病的动物模型(animal model of human disease)是指各种医学科学研究中建立的具有人类疾病模拟表现的动物。动物疾病模型主要用于实验生理学、实验病理学和实验治疗学(包括新药筛选)研究)，因此对冠状病毒的分离工作难度很大，需用人肝脏细胞、气管及鼻黏膜细胞，经器官培养才能分离得到。增殖病毒也要用上述材料，亦很困难。
SARS病毒的血清型和抗原变异性还不明确。SARS病毒可以发生重复感染，表明其存在有多种血清型(至少有4种已知)并有抗原的变异，其免疫较困难。
冠状病毒科分为α、β、γ、δ属等4个属。α属冠状病毒包括人冠状病毒229E、长翼蝠冠状病毒1、猪流行性腹泻病毒等11种。β属冠状病毒包括鼠肝炎病毒、果蝠冠状病毒HKU9、严重急性呼吸综合征(SARS)相关病毒等9种。γ属冠状病毒包含禽冠状病毒 和白鲸冠状病毒SW1两个种。δ属冠状病毒包含猪δ冠状病毒(PDCoV)。
一些冠状病毒感染后可造成人畜共患病。已知的人类冠状病毒共有七型，其中三种对我们人类的"杀伤力"巨大。这就是新冠病毒(2019-nCoV)、SARS(严重急性呼吸系统综合症)病毒、MERS(中东呼吸综合征病毒)。作为迄今最神秘的人类冠状病毒，SARS病毒还有许多秘密需要破解。
病毒性疫病作为一类具有高度传染性的疾病，目前尚缺乏理想的抗病毒药物，目前上市的抗病毒化学药物分为以下几类：
1.穿入和脱壳抑制剂：金刚烷胺、金刚乙胺、恩夫韦地、马拉韦罗
2.DNA多聚酶抑制剂：阿昔洛韦、更昔洛韦、伐昔洛韦、泛昔洛韦、膦甲酸钠
3.逆转录酶抑制剂：
核苷类：拉米夫定、齐多夫定、恩曲他滨、替诺福韦、阿德福韦酯
非核苷类：依法韦仑、奈韦拉平
4.蛋白质抑制剂：沙奎那韦
5.神经氨酸酶抑制剂：奥司他韦、扎那米韦
6.广谱抗病毒药：利巴韦林、干扰素
每一种抗病毒的化学药物的副作用也会有所不同，比如临床上比较常用的抗病毒药物利巴韦林在大剂量使用时，会出现心脏的损害，还会引起白细胞的减少导致可逆性的贫血。而中药因其独特的病毒病防治视角，成为近年来我国学者们研究的热点。研究显示，多种中药及其有效成分对病毒有一定的抑制作用。
本发明是在申请号为2008100894475的专利基础上进行的改进发明，在此全文引用该专利文件记载的内容。上述专利未公开该中药组合物有抗病毒的作用。申请号为202010153827.1号专利公开了本中药组合物具有抗流感病毒和抗新冠病毒的作用，但是并未公开本中药组合物具有抗SARS病毒的作用。
发明内容
本发明提供一种中药组合物制备抗SARS病毒药物中的应用，特别是抗SARS-CoV-2病毒的作用。该中药组合物由下列重量份的原料药制成：
麻黄52-86；石膏194-324；连翘194-324；黄芩78-130；桑白皮194-324；苦杏仁78-130；前胡78-130；半夏78-130；陈皮78-130；贝母78-130；牛蒡子78-130；金银花78-130；大黄39-65；桔梗46-76；甘草39-65。
本发明中药组合物的原料药的重量份比优选为：
麻黄52；石膏324；连翘194；黄芩78；桑白皮194；苦杏仁130；前胡78；半夏130； 陈皮78；贝母78；牛蒡子130；金银花130；大黄39；桔梗76；甘草65。
本发明中药组合物的原料药的重量份比还优选为：
麻黄86；石膏194；连翘324；黄芩130；桑白皮324；苦杏仁78；前胡130；半夏78；陈皮130；贝母130；牛蒡子78；金银花78；大黄65；桔梗46；甘草39。
本发明中药组合物的原料药的重量份比还优选为：
麻黄69；石膏259；连翘259；黄芩104；桑白皮259；苦杏仁104；前胡104；半夏104；陈皮104；贝母104；牛蒡子104；金银花104；大黄52；桔梗61；甘草52。
本发明中药组合物的原料药的重量份比还优选为：
麻黄55；石膏254；连翘318；黄芩107；桑白皮203；苦杏仁107；前胡82；半夏105；陈皮84；贝母125；牛蒡子122；金银花113；大黄42；桔梗60；甘草50。
本发明中药组合物中，所述苦杏仁为炒苦杏仁、贝母为浙贝母、金银花为山银花、半夏为清半夏。
本发明中药组合物主要由麻黄、石膏、连翘、黄芩、桑白皮等组成，发挥复方中药的整体调节优势，具有多向性、多层面、多靶点的特点，经实验证实能有效杀灭SARS病毒，效果显著。
本发明所述中药可以被有相同或相似功效的中药代替，并且这些药材均可以按照《全国中药炮制规范》或《中药大辞典》炮制。
本发明中药组合物的活性成分由以下步骤制成:
A、按组方比例称取浙贝母，粉碎成细粉，备用；
B、按组方比例称取麻黄、连翘、炒苦杏仁、清半夏、牛蒡子、大黄加40-70％乙醇回流提取2次，每次1-4小时，第一次加8-10倍量，第二次加6-9倍量，提取液合并，滤过，滤液减压回收乙醇，浓缩至60℃热测相对密度为1.14-1.16的清膏，备用；
C、按组方比例称取石膏、桑白皮、前胡、陈皮、山银花、桔梗、甘草，加水煎煮两次，每次1-4小时，第一次加9-11倍量，第二次加7-9倍量，煎液合并，滤过，浓缩至60℃热测相对密度为1.14-1.16的清膏，与步骤B所得的清膏合并，备用；
步骤A所得细粉和步骤C所得合并后的清膏共同构成该药物组合物的活性成分。
本发明药物的剂型为胶囊剂、片剂、散剂、颗粒剂、口服液、软胶囊、丸剂、酊剂、糖浆剂、栓剂、凝胶剂、喷雾剂或注射剂。
为使上述剂型能够实现，需在制备这些剂型时加入药学可接受的辅料，例如：填充剂、崩解剂、润滑剂、助悬剂、粘合剂、甜味剂、矫味剂、防腐剂、基质等。填充剂包括：淀粉、预胶化淀粉、乳糖、甘露醇、甲壳素、微晶纤维素、蔗糖等；崩解剂包括：淀粉、预胶化淀粉、微晶纤维素、羧甲基淀粉钠、交联聚乙烯吡咯烷酮、低取代羟丙纤维素、交联 羧甲基纤维素钠等；润滑剂包括：硬脂酸镁、十二烷基硫酸钠、滑石粉、二氧化硅等；助悬剂包括：聚乙烯吡咯烷酮、微晶纤维素、蔗糖、琼脂、羟丙基甲基纤维素等；粘合剂包括，淀粉浆、聚乙烯吡咯烷酮、羟丙基甲基纤维素等；甜味剂包括：糖精钠、阿斯帕坦、蔗糖、甜蜜素、甘草次酸等；矫味剂包括：甜味剂及各种香精；防腐剂包括：尼泊金类、苯甲酸、苯甲酸钠、山梨酸及其盐类、苯扎溴铵、醋酸氯乙定、桉叶油等；基质包括：PEG6000，PEG4000，虫蜡等。
其中片剂由如下步骤制成：
A、按组方比例称取浙贝母，粉碎成细粉，备用；
B、按组方比例称取麻黄、连翘、炒苦杏仁、清半夏、牛蒡子、大黄加40-70％乙醇回流提取2次，每次1-4小时，第一次加8-10倍量，第二次加6-9倍量，提取液合并，滤过，滤液减压回收乙醇，浓缩至60℃热测相对密度为1.14-1.16的清膏，备用；
C、按组方比例称取石膏、桑白皮、前胡、陈皮、山银花、桔梗、甘草，加水煎煮两次，每次1-4小时，第一次加9-11倍量，第二次加7-9倍量，煎液合并，滤过，浓缩至60℃热测相对密度为1.14-1.16的清膏，与步骤B所得的清膏合并，备用；
D、将步骤C所得合并的清膏，喷雾干燥，收集喷雾粉备用；
E、步骤D所得喷雾粉与步骤A所得细粉，以乙醇为黏合剂制软材，过筛制粒；按药学常规方法压片即得。
优选的片剂的制备方法为：
A、按组方比例称取浙贝母，粉碎成细粉，备用；
B、按组方比例称取麻黄、连翘、炒苦杏仁、清半夏、牛蒡子、大黄加50％乙醇回流提取2次，每次3小时，第一次加10倍量，第二次加6倍量，提取液合并，滤过，滤液减压回收乙醇，浓缩至60℃热测相对密度为1.15的清膏，备用；
C、按组方比例称取石膏、桑白皮、前胡、陈皮、山银花、桔梗、甘草，加水煎煮两次，每次2小时，第一次加10倍量，第二次加7倍量，煎液合并，滤过，浓缩至60℃热测相对密度为1.15的清膏，与步骤B所得的清膏合并，备用；
D、将步骤C所得合并的清膏，喷雾干燥，收集喷雾粉备用；
E、步骤D所得喷雾粉与步骤A所得细粉，以乙醇为黏合剂制软材，过筛制粒干燥后整粒，加入羧甲淀粉钠、微晶纤维素、硬脂酸镁，混匀，压片即得。本发明药物其他剂型的制备方法为：按比例称取原料药，采用常规的制备方法制备，例如，范碧亭《中药药剂学》(上海科学出版社1997年12月第1版)记载的制备工艺，制成药剂学可接受的常规剂型。
本发明中药组合物可以抗SARS病毒，特别是SARS-CoV-2型病毒。
附图说明
图1：肺组织病理改变，A模型组小鼠5天3号动物中度间质性肺炎H.E.X200 B本发明药物组小鼠5天1号动物轻度间质性肺炎H.E.X200 C本发明药物组小鼠5天2号动物中度间质性肺炎H.E.X200。
具体实施方式
下述实施例用于举例说明本发明药物的制备，但其不能对本发明的范围构成任何限制。
实施例1
处方：
麻黄52克；石膏324克；连翘194克；黄芩78克；桑白皮194克；苦杏仁130克；前胡78克；半夏130克；陈皮78克；浙贝母78克；牛蒡子130克；山银花130克；大黄39克；桔梗76克；甘草65克。
制备方法：
A、按组方比例称取浙贝母，粉碎成细粉，备用；
B、按组方比例称取麻黄、连翘、苦杏仁、半夏、牛蒡子、大黄加50％乙醇回流提取2次，每次3小时，第一次加10倍量，第二次加6倍量，提取液合并，滤过，滤液减压回收乙醇，浓缩至60℃热测相对密度为1.15的清膏，备用；
C、按组方比例称取石膏、桑白皮、前胡、陈皮、山银花、桔梗、甘草，加水煎煮两次，每次2小时，第一次加10倍量，第二次加7倍量，煎液合并，滤过，浓缩至60℃热测相对密度为1.15的清膏，与步骤B所得的清膏合并，备用；
D、将步骤C所得合并的清膏，喷雾干燥，收集喷雾粉备用；
E、步骤D所得喷雾粉，步骤A所得细粉，以80％乙醇为黏合剂制备软材，过筛制粒，60度干燥后，整粒。加入羧甲基淀粉钠、微晶纤维素、硬脂酸镁混匀，按常规制剂方法制成片剂，即得。
实施例2
处方：
麻黄86克；石膏194克；连翘324克；黄芩130克；桑白皮324克；炒苦杏仁78克；前胡130克；半夏78克；陈皮130克；贝母130克；牛蒡子78克；山银花78克；大黄65克；桔梗46克；甘草39克。
制备方法：
A、按组方比例称取贝母，粉碎成细粉，备用；
B、按组方比例称取麻黄、连翘、炒苦杏仁、半夏、牛蒡子、大黄加40％乙醇回流提取2次，每次4小时，第一次加8倍量，第二次加9倍量，提取液合并，滤过，滤液减压回收乙醇，浓缩至60℃热测相对密度为1.14的清膏，备用；
C、按组方比例称取石膏、桑白皮、前胡、陈皮、山银花、桔梗、甘草，加水煎煮两次，每次4小时，第一次加9倍量，第二次加7倍量，煎液合并，滤过，浓缩至60℃热测相对密度为1.16的清膏，与步骤B所得的清膏合并，备用；
D、将步骤C所得合并的清膏，喷雾干燥，收集喷雾粉备用；
E、步骤D所得喷雾粉，步骤A所得细粉，以80％乙醇为黏合剂制备软材，过筛制粒，60度干燥后，整粒。加入羧甲基淀粉钠、微晶纤维素、硬脂酸镁混匀，按常规制剂方法制成片剂，即得。
实施例3
处方：
麻黄69克；石膏259克；连翘259克；黄芩104克；桑白皮259克；炒苦杏仁104克；前胡104克；清半夏104克；陈皮104克；浙贝母104克；牛蒡子104克；山银花104克；大黄52克；桔梗61克；甘草52克。
制备方法：
A、按组方比例称取浙贝母，粉碎成细粉，备用；
B、按组方比例称取麻黄、连翘、炒苦杏仁、清半夏、牛蒡子、大黄加70％乙醇回流提取2次，每次1小时，第一次加10倍量，第二次加6倍量，提取液合并，滤过，滤液减压回收乙醇，浓缩至60℃热测相对密度为1.16的清膏，备用；
C、按组方比例称取石膏、桑白皮、前胡、陈皮、山银花、桔梗、甘草，加水煎煮两次，每次1小时，第一次加11倍量，第二次加7倍量，煎液合并，滤过，浓缩至60℃热测相对密度为1.14的清膏，与步骤B所得的清膏合并，备用；
D、将步骤C所得合并的清膏，喷雾干燥，收集喷雾粉备用；
E、步骤D所得喷雾粉，步骤A所得细粉，以80％乙醇为黏合剂制备软材，过筛制粒，60度干燥后，整粒。加入羧甲基淀粉钠、微晶纤维素、硬脂酸镁混匀，按常规制剂方法制成片剂，即得。
实施例4：
原料药配方为：
麻黄55克；石膏254克；连翘318克；黄芩107克；桑白皮203克；炒苦杏仁107克；前胡82克；半夏105克；陈皮84克；浙贝母125克；牛蒡子122克；山银花113克；大 黄42克；桔梗60克；甘草50克。
制备方法：
A、按组方比例称取浙贝母，粉碎成细粉，备用；
B、按组方比例称取麻黄、连翘、炒苦杏仁、半夏、牛蒡子、大黄加60％乙醇回流提取2次，每次2小时，第一次加9倍量，第二次加7倍量，提取液合并，滤过，滤液减压回收乙醇，浓缩至60℃热测相对密度为1.15的清膏，备用；
C、按组方比例称取石膏、桑白皮、前胡、陈皮、山银花、桔梗、甘草，加水煎煮两次，每次2.5小时，第一次加10倍量，第二次加7倍量，煎液合并，滤过，浓缩至60℃热测相对密度为1.14的清膏，与步骤B所得的清膏合并，备用；
D、将步骤C所得合并的清膏，喷雾干燥，收集喷雾粉备用；
E、步骤D所得喷雾粉，步骤A所得细粉，以80％乙醇为黏合剂制备软材，过筛制粒，60度干燥后，整粒。加入羧甲基淀粉钠、微晶纤维素、硬脂酸镁混匀，按常规制剂方法制成片剂，即得。
实施例5：
麻黄62克 石膏220克 连翘256克 黄芩90克 桑白皮300克
苦杏仁90克 前胡90克 半夏90克 陈皮100克 贝母100克 牛蒡子100克 金银花100克 大黄50克 桔梗66克 甘草50克
以上药材，按常规方法制成胶囊剂即得。
实施例6：
麻黄68克 石膏215克 连翘215克 黄芩100克 桑白皮220克
苦杏仁90克 前胡90克 半夏90克 陈皮90克 贝母90克
牛蒡子90克 金银花90克 大黄50克 桔梗50克 甘草50克
以上药材，按常规方法制成颗粒剂即得。
实施例7：
麻黄50克 石膏200克 连翘300克 黄芩100克 桑白皮250克
苦杏仁100克 前胡100克 半夏100克 陈皮100克 贝母100克
牛蒡子100克 金银花100克 大黄50克 桔梗50克 甘草50克
以上药材，按常规方法制成注射剂即得。
实施例8：
麻黄60克 石膏200克 连翘200克 黄芩95克 桑白皮230克
苦杏仁95克 前胡95克 半夏95克 陈皮95克 贝母95克
牛蒡子95克 金银花95克 大黄50克 桔梗50克 甘草50克
以上药材，按常规方法制成丸剂即得。
实验例：
为证实本发明中药组合物具有抗SARS病毒的疗效，用按本发明药物组合物实施例3制备方法，压片前的颗粒作为供试品(以下称本发明药物)，委托中国医学科学院医学实验动物研究所进行了以下药理试验研究：
本发明药物组合物治疗SARS-CoV-2感染小鼠试验研究
1、药品与试剂：
受试药本发明药物组合物：由石家庄以岭药业股份有限公司提供。试验所用为本发明药物组合物颗粒，批号为：A1911001，本品性状为棕黄色粉末，每克颗粒相当于4.095克生药，申请人配置好受试药品，360mg/ml。
2、攻毒毒株：SARS-CoV-2；感染途径：滴鼻；
感染剂量：10 5TCID 50/只；感染体积：50微升
3、实验动物：HACE2转基因小鼠，SPF级别，动物年龄为10-12周龄，动物体重：20-24g，动物来源：中国医学科学院医学实验动物研究所
4、方法与结果
动物分组：分为本发明药物组合物组和模型组
每组动物数量：6只
给药剂量：360mg/ml，按照体积1ml/100g体重给予，最终给药剂量本发明药物组合物14.67生药/Kg/d，为临床拟用量的40倍。
给药途径：灌胃
给药时间：攻毒后1小时给药，每天1次，连续给药5天，模型组按照等体积给予蒸馏水。
表1 药物抗病毒效果实验动物分组
Figure PCTCN2021136463-appb-000001
5、观察指标
小鼠攻毒后连续观察5天，记录体重变化。感染后第5天，小鼠全部安乐死，3只检测肺组织病毒载量，3只进行肺组织病理学检查。
6数据统计处理方法
本实验所产生的定量数据，应用统计处理软件SPSS(Version.17.0)进行方差分析。
7、实验结果
7.1药物抗病毒效果
7.1.1实验结果
动物临床表现：模型组小鼠感染后出现体重下降，平均下降百分比最高为5.41％。与模型组比较，本发明药物组合物组感染后第3天体重升高，至第5天平均升高4.55％。其他一般状态良好，显示出给予本发明药物组合物组小鼠症状有一定程度缓解。结果见表2。
表2 受试药物给药后各组小鼠体重变化
Figure PCTCN2021136463-appb-000002
病毒载量：
模型组小鼠感染后5天，肺组织平均病毒载量检测结果为10 5.97copies/ml。本发明药物组合物组小鼠感染后5天肺组织平均病毒载量为10 5.26copies/ml，显著低于模型组。给予本发明药物组合物组病毒载量下降0.72lg值，见表3。
表3 受试药物给药后各组小鼠肺组织病毒载量log 10copies/ml
Figure PCTCN2021136463-appb-000003
各组受试物小鼠体重下降率与模型组比较， *P<0.05有显著差异
3病理诊断
SARS-CoV-2感染5天的hACE2转基因模型组小鼠3例(3/3)肺组织呈中度间质性肺炎改变，可见肺泡隔明显增宽，炎细胞浸润，血管周围少量炎细胞浸润，肺泡腔内少量炎细胞及浆液渗出。
本发明药物组合物组小鼠2例(2/3)肺组织呈中度间质性肺炎改变，可见肺泡隔明显增宽，炎细胞浸润，血管周围少量炎细胞浸润；1例(1/3)肺组织呈轻度间质性肺炎改变，可见肺泡隔轻度增宽，炎细胞浸润，血管周围少量炎细胞浸润，见表4。与模型组相比，本发明药物组合物组肺组织病变有改善。
表4 肺组织病理改变程度简表
Figure PCTCN2021136463-appb-000004
注：+，轻度病变；++，中度病变；+++，重度病变；++++，极重度病变。
附：病变分级标准：
1肺泡隔增宽：
+，轻度病变，肺泡隔轻度增宽。
++，中度病变，肺泡隔明显增宽，病变范围大于1/2。
+++，重度病变，肺泡隔明显增宽，并出现肺泡隔增宽、融合、肺泡腔明显缩窄，病变范围大于1/2。
++++，极重度病变，肺泡隔增宽、融合、肺泡腔明显缩窄以至消失，局部肺组织实变，病变范围大于3/4。
2其他病变(肺泡内渗出、血管周围炎细胞浸润等)
+，轻度病变，病变范围小于肺组织切面1/4。
++，中度病变，病变范围约占肺组织切面1/4-2/4。
+++，重度病变，病变范围约占肺组织切面2/4-3/4。
++++，极重度病变，病变范围大于肺组织切面3/4。
结论：模型组小鼠体重下降5.41％，肺组织病毒载量为10 5.97copies/ml，肺组织呈中度间质性肺炎改变。
本发明药物组合物组与模型组相比，感染后体重升高4.55％，症状有明显改善，肺组织病毒载量为10 5.26copies/ml，下降0.72lg值，肺组织病变有改善。

Claims (11)

  1. 一种中药组合物在制备抗SARS病毒药物中的应用，其特征在于所述中药组合物由下列重量份的原料药制成：
    麻黄52-86；石膏194-324；连翘194-324；黄芩78-130；桑白皮194-324；苦杏仁78-130；前胡78-130；半夏78-130；陈皮78-130；贝母78-130；牛蒡子78-130；金银花78-130；大黄39-65；桔梗46-76；甘草39-65。
  2. 根据权利要求1所述的应用，其特征在于由下列重量份的原料药制成：
    麻黄52；石膏324；连翘194；黄芩78；桑白皮194；苦杏仁130；前胡78；半夏130；陈皮78；贝母78；牛蒡子130；金银花130；大黄39；桔梗76；甘草65。
  3. 根据权利要求1所述的应用，其特征在于由下列重量份的原料药制成：
    麻黄86；石膏194；连翘324；黄芩130；桑白皮324；苦杏仁78；前胡130；半夏78；陈皮130；贝母130；牛蒡子78；金银花78；大黄65；桔梗46；甘草39。
  4. 根据权利要求1所述的应用，其特征在于由下列重量份的原料药制成：
    麻黄69；石膏259；连翘259；黄芩104；桑白皮259；苦杏仁104；前胡104；半夏104；陈皮104；贝母104；牛蒡子104；金银花104；大黄52；桔梗61；甘草52。
  5. 根据权利要求1所述的应用，其特征在于由下列重量份的原料药制成：
    麻黄55；石膏254；连翘318；黄芩107；桑白皮203；苦杏仁107；前胡82；半夏105；陈皮84；贝母125；牛蒡子122；金银花113；大黄42；桔梗60；甘草50。
  6. 根据权利要求1-5任一项所述的应用，其特征在于所述苦杏仁为炒苦杏仁、贝母为浙贝母、金银花为山银花、半夏为清半夏。
  7. 根据权利要求1-5任一项所述的应用，其特征在于所述药物的活性成分由以下步骤制成：
    A、按组方比例称取贝母，粉碎成细粉，备用；
    B、按组方比例称取麻黄、连翘、苦杏仁、半夏、牛蒡子、大黄加40-70％乙醇回流提取2次，每次1-4小时，第一次加8-10倍量，第二次加6-9倍量，提取液合并，滤过，滤液减压回收乙醇，浓缩至60℃热测相对密度为1.14-1.16的清膏，备用；
    C、按组方比例称取石膏、桑白皮、前胡、陈皮、金银花、桔梗、甘草，加水煎煮两次，每次1-4小时，第一次加9-11倍量，第二次加7-9倍量，煎液合并，滤过，浓缩至60℃热测相对密度为1.14-1.16的清膏，与步骤B所得的清膏合并，备用；
    步骤A所得细粉和步骤C所得合并后的清膏共同构成该药物组合物的活性成分。
  8. 根据权利要求1-5任一项所述的应用，其特征在于所述药物剂型为片剂、胶囊剂、散剂、颗粒剂、口服液、丸剂、酊剂、糖浆剂、栓剂、凝胶剂、喷雾剂或注射剂。
  9. 根据权利要求8所述的应用，其特征在于所述片剂由以下步骤制成：
    A、按组方比例称取贝母，粉碎成细粉，备用；
    B、按组方比例称取麻黄、连翘、苦杏仁、半夏、牛蒡子、大黄加40-70％乙醇回流提取2次，每次1-4小时，第一次加8-10倍量，第二次加6-9倍量，提取液合并，滤过，滤液减压回收乙醇，浓缩至60℃热测相对密度为1.14-1.16的清膏，备用；
    C、按组方比例称取石膏、桑白皮、前胡、陈皮、金银花、桔梗、甘草，加水煎煮两次，每次1-4小时，第一次加9-11倍量，第二次加7-9倍量，煎液合并，滤过，浓缩至60℃热测相对密度为1.14-1.16的清膏，与步骤B所得的清膏合并，备用；
    D、将步骤C所得合并的清膏，喷雾干燥，收集喷雾粉备用；
    E、步骤D所得喷雾粉与步骤A所得细粉，以乙醇为黏合剂制软材，过筛制粒；按药学常规方法压片即得。
  10. 根据权利要求9所述的应用，其特征在于所述片剂由以下步骤制成：
    A、按组方比例称取贝母，粉碎成细粉，备用；
    B、按组方比例称取麻黄、连翘、苦杏仁、半夏、牛蒡子、大黄加50％乙醇回流提取2次，每次3小时，第一次加10倍量，第二次加6倍量，提取液合并，滤过，滤液减压回收乙醇，浓缩至60℃热测相对密度为1.15的清膏，备用；
    C、按组方比例称取石膏、桑白皮、前胡、陈皮、金银花、桔梗、甘草，加水煎煮两次，每次2小时，第一次加10倍量，第二次加7倍量，煎液合并，滤过，浓缩至60℃热测相对密度为1.15的清膏，与步骤B所得的清膏合并，备用；
    D、将步骤C所得合并的清膏，喷雾干燥，收集喷雾粉备用；
    E、步骤D所得喷雾粉与步骤A所得细粉，以乙醇为黏合剂制软材，过筛制粒干燥后整粒，加入羧甲淀粉钠、微晶纤维素、硬脂酸镁，混匀，压片即得。
  11. 根据权利要求1-5任一项所述的应用，其特征在于该中药组合物在制备抗SARS-CoV-2病毒药物中的应用。
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