WO2021179881A1 - 中药组合物在制备用于防治冠状病毒合并肺损伤药物中的应用 - Google Patents

中药组合物在制备用于防治冠状病毒合并肺损伤药物中的应用 Download PDF

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WO2021179881A1
WO2021179881A1 PCT/CN2021/076341 CN2021076341W WO2021179881A1 WO 2021179881 A1 WO2021179881 A1 WO 2021179881A1 CN 2021076341 W CN2021076341 W CN 2021076341W WO 2021179881 A1 WO2021179881 A1 WO 2021179881A1
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coronavirus
medicine composition
psoralen
astragalus
application
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PCT/CN2021/076341
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French (fr)
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李全
李志斌
文春义
赵钰
王恒斌
翟云良
耿婉丽
刘文杰
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广东雷允上药业有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/48—Fabaceae or Leguminosae (Pea or Legume family); Caesalpiniaceae; Mimosaceae; Papilionaceae
    • A61K36/481—Astragalus (milkvetch)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/48—Fabaceae or Leguminosae (Pea or Legume family); Caesalpiniaceae; Mimosaceae; Papilionaceae
    • A61K36/487—Psoralea
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/65—Paeoniaceae (Peony family), e.g. Chinese peony
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/71—Ranunculaceae (Buttercup family), e.g. larkspur, hepatica, hydrastis, columbine or goldenseal
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2236/00—Isolation or extraction methods of medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicine
    • A61K2236/30—Extraction of the material
    • A61K2236/33—Extraction of the material involving extraction with hydrophilic solvents, e.g. lower alcohols, esters or ketones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2236/00—Isolation or extraction methods of medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicine
    • A61K2236/30—Extraction of the material
    • A61K2236/39—Complex extraction schemes, e.g. fractionation or repeated extraction steps

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  • the present invention claims the priority of an invention patent application filed in China on March 11, 2020, entitled “Application of Chinese Medicine Composition in the Preparation of Drugs for Preventing and Treating Coronavirus Combined with Lung Injury", and the application number is 202010165355.1, by reference
  • the method incorporates the entire content of the patent application into this article.
  • the invention relates to a traditional Chinese medicine composition, in particular to the application of the traditional Chinese medicine composition in the preparation of a medicine for preventing and treating coronavirus combined with lung injury.
  • the imaging manifestations of the new coronavirus showed multiple small patchy shadows and interstitial changes in the early stage, which were obvious outside the lungs. It then develops into multiple ground glass shadows and infiltration shadows in both lungs. In severe cases, lung consolidation may occur, and pleural effusion is rare.
  • the new coronavirus can cause diffuse alveolar damage, pulmonary hyaline membrane formation and pulmonary fibrosis, and can cause respiratory failure in severe cases.
  • the new type of coronavirus is a highly contagious virus, and its transmission is mainly through respiratory droplets and contact transmission. At present, there is no effective treatment drug for the new coronavirus SARS-CoV-2 on the market, which brings great harm to the lives and health of patients.
  • the present invention develops drugs for coronavirus combined with lung injury through a large number of experimental screenings, which is of great significance for improving the clinical cure rate of coronavirus.
  • the purpose of the present invention is to overcome the shortcomings of the prior art and develop new clinical uses of the traditional Chinese medicine composition.
  • the experimental results show that the traditional Chinese medicine composition has a good prevention and treatment of the new coronavirus (SARS-CoV-2) and other coronaviruses in the lungs. Damage, pulmonary fibrosis and other effects.
  • SARS-CoV-2 new coronavirus
  • the Chinese medicinal composition exerts the effect of treating coronavirus with lung injury by increasing the levels of albumin, lymphocytes, lymphocyte percentages, neutrophils and CD8 cells.
  • the Chinese medicinal composition plays the role of treating coronavirus with lung injury by reducing the levels of C-reactive protein and lactate dehydrogenase.
  • a traditional Chinese medicine composition comprising astragalus, red peony root and psoralen in the preparation of a medicine for improving the respiratory function and alleviating fatigue function in the recovery period of lung injury after coronavirus infection.
  • the coronavirus includes severe acute respiratory syndrome coronavirus 2 (abbreviated as SARS-CoV-2), SARS coronavirus, MERS coronavirus or HcoV-229E coronavirus.
  • SARS-CoV-2 severe acute respiratory syndrome coronavirus 2
  • SARS coronavirus SARS coronavirus
  • MERS coronavirus MERS coronavirus
  • HcoV-229E coronavirus HcoV-229E coronavirus
  • the traditional Chinese medicine composition of the present invention is made of astragalus, red peony root and psoralen.
  • the traditional Chinese medicine composition is made of 72 parts of Astragalus, 72 parts of Red Peony and 36 parts of Psoralen.
  • the preparation process of the traditional Chinese medicine composition of the present invention is as follows: pulverize slices of astragalus, red peony root and psoralen into coarse powder, add ethanol to infiltrate, percolate and extract, collect percolate, concentrate under reduced pressure to flow extract, and Vacuum drying to obtain a dry paste, pulverization; adding starch and mixing, 90% ethanol granulation, drying, taking the above-prepared extract and a pharmaceutically acceptable carrier to prepare capsules, tablets, granules or pills.
  • the preparation process of the traditional Chinese medicine composition of the present invention is: pulverize 72 parts of astragalus slices, 72 parts of red peony root, and 36 parts of psoralen to coarse powder, add 4-12 times the weight of the medicinal material to infiltrate with ethanol, and percolate Extract 2 times, collect the percolate, concentrate under reduced pressure to a liquid extract, and vacuum dry to obtain a dry paste, pulverize; add starch to mix, 90% ethanol for granulation, dry, take the above-prepared extract and pharmaceutically acceptable
  • the carrier is prepared into capsules, tablets, granules or pills.
  • the traditional Chinese medicine composition provided by the present invention and the prescription of the Nourishing Feihuoxue Capsule (Z20030063) produced by Guangdong Leiyunshang Pharmaceutical Co., Ltd. are both made of astragalus, red peony root and psoralen, and nourishing lung and blood circulation capsules It has the effects of invigorating the lung and kidney, diuresis and swelling, relieving cough and phlegm, replenishing qi and blood, and improving immunity. At present, it is clinically used for coughing, shortness of breath, coughing, wheezing, chest tightness, palpitations, and shortness of breath caused by the deficiency of both lung and kidney.
  • the present invention screens the intervention effect of the Chinese medicine composition on the novel coronavirus (SARS-CoV-2).
  • SARS-CoV-2 novel coronavirus
  • the experimental results show that the traditional Chinese medicine composition composed of astragalus, red peony and psoralen has a good inhibitory effect on the novel coronavirus ( SARS-CoV-2) caused lung injury and pulmonary fibrosis, especially the traditional Chinese medicine composition can increase albumin, lymphocytes, lymphocyte percentage, neutrophils and CD8 cell levels, and can reduce C-reactive protein and Lactate dehydrogenase levels. It can assist in the treatment of new coronaviruses and increase the cure rate.
  • the traditional Chinese medicine composition of the present invention has obvious effects on the respiratory function after the new coronavirus (SARS-CoV-2) lung injury infection, relieves patient fatigue, and enhances their exercise ability.
  • SARS-CoV-2 new coronavirus
  • Figure 1 is a CT image of Example 2 before and after treatment.
  • CT of 20 patients showed patchy ground glass shadows under the pleura of both lungs, and the texture of both lungs was thickened.
  • the consolidation of both lungs increased, and there were obviously varying degrees of lung inflammation and lung injury lesions, accompanied by cough and fever.
  • Biochemical indicators showed that lymphocytes, lymphocyte percentages, neutrophils and CD8 cell levels were significantly lower than normal, and blood oxygen levels were 87-96%.
  • A, B, and C are CT lung window images at the same level before treatment, after 1 week of treatment, and after 2 weeks of treatment, respectively.
  • Example 3 A randomized, double-blind, controlled clinical study on the treatment of patients with novel coronavirus pneumonia in the recovery period (lung-spleen-qi deficiency syndrome)
  • This trial adopts a randomized, double-blind, controlled clinical trial design.
  • Convalescent patients with new coronary pneumonia who are suitable and agree (sign the informed consent form) to participate in this trial will be randomly assigned to the test group or the control group, and the two groups will be allocated in equal proportions.
  • subjects in the experimental group were given 1.4g/time, 3 times/day orally of the study drug for 90 days after enrollment; subjects in the control group were treated with placebo only; each case was tested Participants will be visited during the baseline period, one month after enrollment, the first two months and after the end of the trial.
  • the serum new coronavirus-specific IgM and IgG antibodies are positive; the specific IgG antibody turns from negative to positive, or the recovery period is 4 times or more higher than the acute period.
  • the condition is in the recovery period and the syndrome is differentiated as "Lung Spleen Qi Deficiency Syndrome”.
  • this syndrome is mainly deficient syndrome with other symptoms.
  • the judgment refers to the following criteria, with at least one primary certificate combined with secondary certificates:
  • the tongue is pale and the fur is white, and the pulse is weak.
  • the condition is in the recovery period.
  • the syndrome differentiation of TCM is Lung Spleen Qi Deficiency
  • liver disease such as liver tumors, various types of hepatitis, etc.
  • drugs with potential liver damage drugs with potential liver damage (immunosuppressive agents) during the study period
  • drugs with potential liver damage include cyclosporine, tacrolimus, etc., anti-tuberculosis drugs such as rifampicin, isoniazid, etc., chemotherapeutic drugs such as cyclophosphamide, methotrexate, azathioprine, etc., and containing Polygonum multiflorum, Tusanqi, and Tripterygium wilfordii And other liver damage medicinal herbs) patients.
  • This product is a capsule, the content of which is brown fine particles and powder; the air is slightly fragrant. Slightly sour and bitter.
  • pulmonary heart disease (remission period) which belongs to Qi deficiency and blood stasis syndrome. Symptoms include: coughing, shortness of breath, or coughing and wheezing, chest tightness, palpitations, shortness of breath, cold limbs, weakness, waist and knees, cyanosis of the lips, pale tongue, white coating or dark purple tongue, etc.
  • Subjects in each group can take rehabilitation treatments such as oxygen inhalation, atomization inhalation, breathing training, exercise prescriptions, etc. according to the actual situation, and recheck viral nucleic acid in accordance with relevant national regulations.
  • Subjects in the test group took orally Bufei Huoxue Capsules, 1.4g (4 capsules) each time, 3 times a day on the basis of rehabilitation treatment for 90 days (the duration of medication can be adjusted according to changes in symptoms during the visit) .
  • Test period continuous observation for 90 days. During the baseline period, planned visits were conducted at the end of January, February, and March after enrollment.

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Abstract

本发明公开了中药组合物在制备用于防治新型冠状病毒合并肺损伤药物中的应用。本发明筛选中药组合物对新型冠状病毒(SARS-CoV-2)的干预作用，临床实验结果表明，中药组合物具有很好的抑制新型冠状病毒(SARS-CoV-2)导致的肺损伤和肺纤维化的作用，中药组合物可提高白蛋白、淋巴细胞、淋巴细胞百分比、中性粒细胞和CD8细胞水平，且可降低C反应蛋白和乳酸脱氢酶水平，可辅助治疗新型冠状病毒并发肺损伤，可提高治愈率。并且临床实验结果表明，本发明中药组合物对新型冠状病毒(SARS-CoV-2)感染后的呼吸功能和缓解患者疲劳，增强其运动能力具有明显的功效。

Description

中药组合物在制备用于防治冠状病毒合并肺损伤药物中的应用
相关申请的引用
本发明要求2020年3月11日在中国提交的，名称为“中药组合物在制备用于防治冠状病毒合并肺损伤药物中的应用”、申请号为202010165355.1的发明专利申请的优先权，通过引用的方式将该专利申请的全部内容并入本文。
技术领域
本发明涉及一种中药组合物，特别是涉及中药组合物在制备用于防治冠状病毒合并肺损伤药物中的应用。
背景技术
2月11日，国际病毒分类委员会(International Committee on Taxonomy of Viruses，ICTV)宣布新型冠状病毒的正式名称为严重急性呼吸综合征冠状病毒2(severe acute respiratory syndrome coronavirus 2，简称SARS-CoV-2)。
新型冠状病毒影像学表现，早期呈现多发小斑片影及间质改变，以肺外带明显。进而发展为双肺多发磨玻璃影、浸润影，严重者可出现肺实变，胸腔积液少见。新型冠状病毒会引起弥漫性肺泡损伤、肺透明膜形成和肺纤维化，严重时可引起呼吸衰竭。
因此，新型冠状病毒感染后，患者的肺都有较大程度的损伤，加重患者的病情，治愈难度升高。
新型冠状病毒是一种具有高度传染性的病毒，传播途径主要是通过呼吸道飞沫传播和接触传播等。目前还没有关于新型冠状病毒SARS-CoV-2的有效治疗药物上市，给患者生命健康带来极大的危害。
中医药在防治疾病方面具有其特有的优势，本发明通过大量实验筛选，开发出对冠状病毒合并肺损伤的药物，对提高冠状病毒临床治愈率具有重要的意义。
发明内容
发明目的
本发明的目的是为了克服现有技术的不足，开发中药组合物新的临床用途，实验结果表明，中药组合物具有很好的防治新型冠状病毒(SARS-CoV-2)等冠状病毒并发的肺损伤、肺纤维化等作用。
技术方案
为了实现以上目的，本发明采取的技术方案为：
中药组合物在制备用于防治冠状病毒合并肺损伤药物中的应用。
中药组合物在制备用于防治冠状病毒合并肺炎药物中的应用。
中药组合物在制备用于防治冠状病毒合并肺纤维化药物中的应用。
中药组合物通过提高白蛋白、淋巴细胞、淋巴细胞百分比、中性粒细胞和CD8细胞 水平来发挥治疗冠状病毒合并肺损伤的作用。
中药组合物通过降低C反应蛋白和乳酸脱氢酶水平来发挥治疗冠状病毒合并肺损伤的作用。
作为优选，包括黄芪、赤芍和补骨脂的中药组合物在制备用于改善冠状病毒感染后肺损伤恢复期的呼吸功能和缓解疲劳功能的药物中的应用。
作为优选，以上所述的应用，所述的冠状病毒包括严重急性呼吸综合征冠状病毒2(简称SARS-CoV-2)、SARS冠状病毒、MERS冠状病毒或HcoV-229E冠状病毒。
本发明所述的中药组合物由黄芪、赤芍和补骨脂制成。作为优选，所述的中药组合物由黄芪72份、赤芍72份和补骨脂36份制成。
本发明所述的中药组合物的制备工艺为：将黄芪切片、赤芍和补骨脂粉碎成粗粉，加乙醇浸润，渗漉提取，收集渗漉液，减压浓缩至流浸膏，并真空干燥得干膏，粉碎；加入淀粉混匀，90％乙醇制粒，干燥，取以上制备提取物与药学上可接受的载体制备成胶囊、片剂、颗粒剂或丸剂。
作为优选，本发明所述的中药组合物的制备工艺为：将黄芪72份切片、赤芍72份和补骨脂36份粉碎成粗粉，加药材重量4～12倍量乙醇浸润，渗漉提取2次，收集渗漉液，减压浓缩至流浸膏，并真空干燥得干膏，粉碎；加入淀粉混匀，90％乙醇制粒，干燥，取以上制备提取物与药学上可接受的载体制备成胶囊、片剂、颗粒剂或丸剂。
本发明提供的中药组合物与广东雷允上药业有限公司生产的补肺活血胶囊(国药准字Z20030063)的处方一种，均由黄芪、赤芍和补骨脂制成，补肺活血胶囊具有补肺固肾、利尿消肿、止咳化痰、益气补血、提高免疫力等功效。目前临床上用于肺肾两虚引起的咳嗽气促，或咳喘胸闷，心悸气短等。
有益效果
1、本发明筛选中药组合物对新型冠状病毒(SARS-CoV-2)的干预作用，实验结果表明，由黄芪、赤芍和补骨脂组成的中药组合物具有很好的抑制新型冠状病毒(SARS-CoV-2)导致的肺损伤和肺纤维化的作用，特别是中药组合物可提高白蛋白、淋巴细胞、淋巴细胞百分比、中性粒细胞和CD8细胞水平，且可降低C反应蛋白和乳酸脱氢酶水平。可辅助治疗新型冠状病毒，可提高治愈率。
2、本发明所述的中药组合物对新型冠状病毒(SARS-CoV-2)肺损伤感染后的呼吸功能和缓解患者疲劳，增强其运动能力具有明显的功效。
附图说明
图1为实施例2治疗前后CT图。
具体实施方式
下面结合具体实施例进一步阐明本发明，应理解这些实施例仅用于说明本发明而不用于限制本发明的范围，在阅读了本发明之后，本领域技术人员对本发明的各种等价形式的修改均落于本申请所附权利要求所限定的范围。
实施例1：
1、病例选择：
收集新型冠状病毒(SARS-CoV-2)确诊患者20例(男女各10例，年龄37～78岁)，20例患者CT显示双肺胸膜下现斑片状磨玻璃影，双肺纹理增粗，双肺实变影增多，出现明显不同程度的肺部炎症和肺部损伤病灶，伴咳嗽发热症状。生化指标示淋巴细胞、淋巴细胞百分比、中性粒细胞和CD8细胞水平均明显低于正常值，血氧水平87～96％。
2、治疗方法：
20例病例做基础给氧和生命体征维持治疗外，口服本发明中药组合物(补肺活血胶囊，国药准字Z20030063)，一次4粒(每粒0.35g)，每天3次，连续用药1、2周后，观察疗效。
3、临床效率观察：
服用1周后，部分新型冠状病毒患者咳嗽减弱，CT复查示双肺实变影有所减少，纹路和斑片状密度影减弱，且血氧水平均有一定程度升高，总有效率为45％。服用4周后双肺病灶范围减少、密度减低，实变影部位逐渐变为磨玻璃密度影，残留少许纤维条索影。且抽血检测生化指标白蛋白、淋巴细胞、淋巴细胞百分比、中性粒细胞和CD8细胞水平相比服药前明显提高，20例患者生命体征稳定，未出现危重恶化，总有效率为75％。表明本发明提供的中药制剂可较显著缓解新型冠状病毒(SARS-CoV-2)并发的肺损伤，可提高临床治愈率。
实施例2：
女性患者周某，40岁，武汉疫区接触史，发热，2019-nCoV核酸检测阳性，结合CT检查，确诊为新型冠状病毒(SARS-CoV-2)确诊患者。给予基本的生命体征营养和吸氧维持治疗，同时服用本发明补肺活血胶囊，国药准字Z20030063，一次4粒(每粒0.35g)，每天3次，连续用药1周和2周后，咳嗽明显减轻，如图1所示，A、B、C分别为治疗前、治疗1周后、治疗2周后同一层面CT肺窗图像，第1周及第2周左肺下叶炎症范围均减小，临床症状减轻，咳嗽，血氧低症状得到缓解。未出现向重症和危重恶化，预后良好。
实施例3：治疗新型冠状病毒肺炎恢复期(肺脾气虚证)患者的随机、双盲、对照临床研究
1.本试验采用随机、双盲、对照临床试验设计。适合且同意(签署知情同意书)参加本试验的恢复期新冠肺炎患者将被随机分配至试验组或对照组，两组等比例分配。试验组受试者在康复治疗的基础上，于入组后1.4g/次、3次/日口服研究药物，给药疗程90天；对照组受试者仅采用安慰剂治疗；每例受试者将在基线期，入组后1个月、第个2月与试验结束后进行访视。
试验期间，在入组前及入组后各规定的时间点进行六分钟步行、疲劳评定量表的变化评价，以评估研究药物的有效性。
入组前及入组后依计划进行血常规、尿常规、肝肾功能等指标进行检测，用以评估研究药物的安全性。
2.受试者招募与退出
2.1诊断标准
根据《新型冠状病毒肺炎诊疗方案(试行第七版)》确诊为新型冠状病毒肺炎：
在疑似病例的基础上具备以下之一：
(1)实时荧光RT-PCR检测新型冠状病毒核酸阳性；
(2)病毒基因测序，与已知的新型冠状病毒高度同源。
(3)血清新型冠状病毒特异性IgM和IgG抗体阳性；特异性IgG抗体由阴性转为阳性，或恢复期较急性期升高4倍及以上。
经治疗后已达到解除隔离/出院标准：
(1)体温恢复正常3天以上；
(2)呼吸道症状明显好转；
(3)肺部影像学检查显示急性渗出性病变明显改善；
(4)连续2次呼吸道标本核酸检测阴性(痰、鼻咽拭子等，采样时间至少间隔24小时)。
根据诊疗方案中“中医治疗”部分，病情处于恢复期、证候辨证为“肺脾气虚证”。
本证总体而言以虚证为主，兼有其它症状。判定参考以下标准，具有至少1项主证并结合次证：
主证：乏力、气短/喘息、咳嗽、纳差；
次证：腹胀、恶心/呕吐、稀便/腹泻；
舌淡苔白，脉细弱。
2.2纳入标准
(1)年龄≥18岁，性别不限；
(2)根据《新型冠状病毒肺炎诊疗方案(试行第七版)》诊断为新型冠状病毒肺炎；
(3)经治疗后病情达到《新型冠状病毒肺炎诊疗方案(试行第七版)》规定的出院标准；
(4)筛选时病情为恢复期，根据《新型冠状病毒肺炎诊疗方案(试行第七版)》诊断标准中医辨证为肺脾气虚证；
(5)自愿参加研究并签署知情同意书。
2.3排除标准
(1)已知或怀疑对研究药物的组成成分过敏。
(2)合并其他病毒、细菌急性感染，尚未临床治愈。
(3)肝肾功能检查异常(ALT、AST、SCr≥正常值上限1.5倍)。
(4)正在参加其它药物临床试验。
(5)怀孕与哺乳期女性；或不能于试验期间采取有效的避孕措施者。
(6)本身合并严重肝脏疾病(如肝脏肿瘤、各种类型肝炎等)或既往有药物性肝损伤病史的患者，以及正在使用或本研究期间预期使用具有潜在肝损害作用的药物(免疫抑制剂如环孢素、他克莫司等，抗结核药如利福平、异烟肼等，化疗药如环磷酰胺、甲氨 蝶呤、硫唑嘌呤等以及含何首乌、土三七、雷公藤等肝损害药材的中药)的患者。
(7)根据研究者的判断，具有不适合参加本试验的其它情况者。
3.治疗方案
3.1药物提供
补肺活血胶囊
【成份】黄芪，赤芍，补骨脂。
【性状】本品为胶囊剂，内容物为棕褐色的细颗粒和粉末；气微香。味微酸，苦。
【功能主治】益气活血，补肺固肾。用于肺心病(缓解期)属气虚血瘀证，症见：咳嗽气促，或咳喘胸闷，心悸气短，肢冷乏力，腰膝酸软，***紫绀，舌淡苔白或舌紫暗等。
【规格型号】0.35g/粒。
【用法用量】口服，—次4粒，一日3次。
【有效期】24个月。
【批准文号】国药准字Z20030063。
【生产企业】广东雷允上药业有限公司
3.2用药方法
各组受试者可根据实际情况采用吸氧、雾化吸入、呼吸训练、运动处方等康复治疗，并根据国家相关规定择期复查病毒核酸。
试验组受试者在康复治疗的基础上自入组起口服补肺活血胶囊，一次1.4g(4粒)，一日3次，连续服用90天(访视中可根据症状变化调整用药时长)。
对照组受试者同等剂量的安慰剂。
试验周期：连续观察90天。在基线期，入组后1月末、2月末及3月末进行计划访视。
注意：试验期间禁止使用同类/药理作用相仿的中药(其它含有黄芪，赤芍，补骨脂组分的中药/中药制剂)；除非病情要求，尽量避免使用影响疗效评价的药物，如病情要求必须使用，则需退出研究。
4.疗效评价标准
主要疗效指标
(1)六分钟步行实验(基线、1月末、2月末及3月末)
于基线、1月末、2月末、试验结束后进行评价，并比较相对于基线的变化。
(2)疲劳评定量表在各时间点的评价结果与改变情况
于基线、1月末、2月末、试验结束后进行评价。
5.样本量
本试验为特殊情况下进行的探索研究，不进行基于统计学考虑的样本量估算，计划观察120例，试验组和对照组各60例。
6.实验统计结果
6.1两组受试者六分钟步行距离对比
治疗前补肺组和安慰剂对照组六分钟步行距离比较，差异无统计学意义(P>0.05)， 具有可比性。经治疗3个月后，补肺组六分钟步行距离显著高于安慰剂组，差异具有统计学意义(P<0.05)，补肺组用药后六分钟步行试验行走距离较基线增加值非常显著高于安慰剂组，差异具有统计学意义(P<0.01)。
表6.1 两组受试者不同访视六分钟步行试验行走距离情况(FAS)
Figure PCTCN2021076341-appb-000001
表6.2 两组受试者用药后六分钟步行试验行走距离较基线变化值情况(FAS)
Figure PCTCN2021076341-appb-000002
6.2两组受试者疲劳评定量表评分对比
治疗前补肺组和安慰剂对照组疲劳评定量表评分比较差异无统计学意义(P>0.05)，具有可比性，经治疗3个月后，补肺组疲劳评定量表评分较前降低，显著低于安慰剂组，差异具有统计学意义(P<0.05)。
表6.3 两组受试者不同访视疲劳评定量表评分情况(FAS)
Figure PCTCN2021076341-appb-000003
以上实验结果表明，本发明提供的黄芪、赤芍和补骨脂的中药组合物对治疗新冠恢复期患者(脾肺气虚型)3个月后，与安慰剂比，能显著改善患者的生活质量和改善疲劳症状，延长6分钟步行距离，提高运动耐力。
上述仅是本发明的优选实施方式，应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明原理的前提下，还可以做出若干改进和润饰，这些改进和润饰也应视为本发明的保护范围。

Claims (9)

  1. 包括黄芪、赤芍和补骨脂的中药组合物在制备用于防治冠状病毒合并肺损伤药物中的应用。
  2. 包括黄芪、赤芍和补骨脂的中药组合物在制备用于防治冠状病毒合并肺炎药物中的应用。
  3. 包括黄芪、赤芍和补骨脂的中药组合物在制备用于防治冠状病毒合并肺纤维化药物中的应用。
  4. 包括黄芪、赤芍和补骨脂的中药组合物在制备用于改善冠状病毒感染后恢复期身体机能的药物中的应用。
  5. 包括黄芪、赤芍和补骨脂的中药组合物在制备用于改善冠状病毒感染后肺损伤恢复期的呼吸功能和缓解疲劳功能的药物中的应用。
  6. 根据权利要求1至5任一项所述的应用，其特征在于，其中所述中药组合物包括如下组分：黄芪50～100份、赤芍50～100份和补骨脂25～50份。
  7. 根据权利要求6所述的应用，其特征在于，所述的中药组合物由黄芪72份、赤芍72份和补骨脂36份制成。
  8. 根据权利要求6所述的应用，其特征在于，所述的中药组合物的制备工艺为：将黄芪切片、赤芍和补骨脂粉碎成粗粉，加乙醇浸润，渗漉提取，收集渗漉液，减压浓缩至流浸膏，并真空干燥得干膏，粉碎；加入淀粉混匀，90％乙醇制粒，干燥，取以上制备提取物与药学上可接受的载体制备成胶囊、片剂、颗粒剂或丸剂。
  9. 根据权利要求1至5任一项所述的应用，其特征在于，所述的冠状病毒包括严重急性呼吸综合征冠状病毒2、SARS冠状病毒、MERS冠状病毒或HcoV-229E冠状病毒。
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