WO2021213058A1 - 一种中药组合物在制备治疗或预防冠状病毒感染的药物中的应用 - Google Patents

一种中药组合物在制备治疗或预防冠状病毒感染的药物中的应用 Download PDF

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WO2021213058A1
WO2021213058A1 PCT/CN2021/080152 CN2021080152W WO2021213058A1 WO 2021213058 A1 WO2021213058 A1 WO 2021213058A1 CN 2021080152 W CN2021080152 W CN 2021080152W WO 2021213058 A1 WO2021213058 A1 WO 2021213058A1
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parts
chinese medicine
medicine composition
traditional chinese
extract
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PCT/CN2021/080152
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English (en)
French (fr)
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肖伟
陶晓倩
张新庄
苏真真
柯志鹏
曹泽彧
曹亮
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江苏康缘药业股份有限公司
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Priority to US17/919,947 priority Critical patent/US20230158095A1/en
Priority to KR1020227036673A priority patent/KR20220156606A/ko
Publication of WO2021213058A1 publication Critical patent/WO2021213058A1/zh

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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)
    • A61K36/78—Saururaceae (Lizard's-tail family)
    • 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
    • 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)
    • 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)
    • A61K36/28—Asteraceae or Compositae (Aster or Sunflower family), e.g. chamomile, feverfew, yarrow or echinacea
    • A61K36/282—Artemisia, e.g. wormwood or sagebrush
    • 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)
    • A61K36/35—Caprifoliaceae (Honeysuckle family)
    • A61K36/355—Lonicera (honeysuckle)
    • 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)
    • A61K36/53—Lamiaceae or Labiatae (Mint family), e.g. thyme, rosemary or lavender
    • A61K36/534—Mentha (mint)
    • 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
    • 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
    • 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
    • A61K2236/33—Extraction of the material involving extraction with hydrophilic solvents, e.g. lower alcohols, esters or ketones
    • A61K2236/331—Extraction of the material involving extraction with hydrophilic solvents, e.g. lower alcohols, esters or ketones using water, e.g. cold water, infusion, tea, steam distillation or decoction
    • 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
    • A61K2236/333—Extraction of the material involving extraction with hydrophilic solvents, e.g. lower alcohols, esters or ketones using mixed solvents, e.g. 70% EtOH
    • 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
    • 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
    • A61K2236/50—Methods involving additional extraction steps
    • A61K2236/51—Concentration or drying of the extract, e.g. Lyophilisation, freeze-drying or spray-drying
    • 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
    • A61K2236/50—Methods involving additional extraction steps
    • A61K2236/53—Liquid-solid separation, e.g. centrifugation, sedimentation or crystallization
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the invention relates to the field of disease treatment drugs, and more specifically, to the application of a traditional Chinese medicine composition in the preparation of drugs for the treatment or prevention of coronavirus infections.
  • the present invention aims to provide a Chinese medicinal composition for the preparation of a medicine for the treatment or prevention of coronavirus infections, wherein, by weight, the Chinese medicinal composition comprises: 5-30 parts of Houttuynia cordata and 5-30 parts of honeysuckle. Servings, 5-20 servings of red peony, 3-15 servings of mugwort, and 3-15 servings of mint.
  • the diseases infected by the coronavirus include COVID-19 (New Coronavirus Pneumonia).
  • the traditional Chinese medicine composition comprises: 5-25 parts of Houttuynia cordata, 5-25 parts of honeysuckle, 5-15 parts of red peony root, 3-10 parts of mugwort leaf, and 3-10 parts of peppermint.
  • the traditional Chinese medicine composition includes: 15-25 parts of Houttuynia cordata, 15-25 parts of honeysuckle, 10-15 parts of red peony root, 5-10 parts of mugwort leaf, and 3-5 parts of mint.
  • the traditional Chinese medicine composition includes: 20 parts of Houttuynia cordata, 20 parts of honeysuckle, 12 parts of red peony root, 8 parts of wormwood, and 4 parts of peppermint.
  • the traditional Chinese medicine composition includes: 15 parts of Houttuynia cordata, 15 parts of honeysuckle, 12 parts of red peony root, 7 parts of wormwood, and 7 parts of peppermint.
  • the traditional Chinese medicine composition comprises: 10 parts of Houttuynia cordata, 10 parts of honeysuckle, 8 parts of red peony root, 4 parts of wormwood, and 4 parts of peppermint.
  • composition of the present invention can be directly ground into powder, or it can be an extract prepared by conventional means in the art.
  • the said composition can be directly ground into powder according to the traditional method, or the extract can be prepared by conventional means, so as to make different dosage forms, get better curative effect and be more conducive to the preparation of modern pharmaceutical dosage forms
  • the drugs for treating or preventing coronavirus infections include oral dosage forms, injection dosage forms or topical dosage forms.
  • the drugs for treating or preventing coronavirus infections include decoctions, tablets, capsules, granules, pills, injections, decoctions, suspensions, dispersions, syrups, suppositories, gels, and aerosols. Drugs, patches, oral liquids.
  • preparation method of the traditional Chinese medicine composition of the present invention may include the following steps:
  • Step A Weigh Chinese herbal medicines according to the weight ratio of the raw materials
  • Step B The honeysuckle is extracted with 6-12 times the amount of 50% to 80% ethanol, the extract is filtered, the ethanol is recovered, dried and crushed to obtain a dry paste powder;
  • Step C Put the houttuynia cordata, wormwood, and peppermint into the extraction tank, add 3-12 times of water to extract the volatile oil, add the dregs of red peony powder, add 6-12 times of water to decoc, and filter the extract to obtain a clear ointment. Add ethanol with a concentration of more than 90% to 60%-80% alcohol, settle with alcohol, stand still, and recover ethanol from the supernatant to obtain a thick paste, which is dried and crushed to obtain a dry paste powder;
  • Step D Mix the above-mentioned volatile oil and the above-mentioned dry paste powder.
  • preparation method of the traditional Chinese medicine composition of the present invention may include the following steps:
  • Step A Honeysuckle add 12 times the amount of 50% ethanol, reflux and extract twice, 0.5 hours each time, filter, combine the filtrate, reduce pressure (-0.07MPa ⁇ -0.09MPa, 65°C ⁇ 75°C) to recover ethanol and concentrate to The thick paste with a relative density of 1.20 ⁇ 1.25 (65°C) is dried under reduced pressure (-0.07MPa ⁇ -0.09MPa, 60°C ⁇ 65°C), and crushed to obtain part of the dry extract powder extracted by alcohol;
  • Step B Houttuynia cordata, mugwort leaf, peppermint, add 8 times the amount of water, steam distillation to extract the volatile oil, extract for 5 hours, filter the extract, and store in another device for later use;
  • Step C The obtained volatile oil is pulverized and clathrated with 10 times the amount of ⁇ -cyclodextrin and 20 times the amount of water for 20 minutes, and the inclusion compound (55°C) is dried and pulverized to obtain the volatile oil inclusion compound;
  • Step D After extracting the volatile oil, the dregs and red peony are combined, add 10 times the amount of water, and extract twice for 1 hour each time.
  • the extract is combined with the oil extraction liquid (the remaining liquid after the volatile oil is extracted), filtered, and the filtrate Concentrate under reduced pressure (-0.07MPa ⁇ -0.09MPa, 75°C ⁇ 85°C) to a clear paste with a relative density of 1.02 ⁇ 1.05 (70°C), cool to room temperature, add 95% ethanol to make the alcohol content reach 70%, statically Leave it for more than 12 hours, the alcohol precipitation supernatant is decompressed (-0.07MPa ⁇ -0.09MPa, 65°C ⁇ 75°C) to recover the ethanol and concentrate to a thick paste with a relative density of 1.25 ⁇ 1.30 (65°C). You can optionally add an appropriate amount The dextrin is dried under reduced pressure (-0.07MPa ⁇ -0.09MPa, 75°C) and pulverized to obtain a water-extracted part
  • the present invention investigates the inhibitory effect of the Chinese medicine composition on the new coronavirus SARS-CoV-2 at different concentrations on Vero cells.
  • the experimental results show that the Chinese medicine composition is at the concentration of 3000 ⁇ g/ml, 1000 ⁇ g/ml, and 200 ⁇ g/ml.
  • CoV-2 virus-infected Vero cells showed a good protective effect, which can inhibit SARS-CoV-2 from replicating in cells, so that the infected cells do not develop disease, indicating that the traditional Chinese medicine composition of the present invention has good treatment or prevention The effects of coronavirus-related diseases.
  • the present invention provides a use of a traditional Chinese medicine composition, and those skilled in the art can learn from the content of this article and appropriately improve the process parameters to achieve it.
  • all similar replacements and modifications are obvious to those skilled in the art, and they are all deemed to be included in the present invention.
  • the method and application of the present invention have been described through the preferred embodiments. It is obvious that relevant personnel can modify or appropriately change and combine the methods and applications herein without departing from the content, spirit and scope of the present invention to realize and apply the present invention.
  • Invent technology Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all the embodiments.
  • Houttuynia cordata 750g, honeysuckle 750g, red peony 450g, mugwort 300g, mint 150g.
  • Step A Honeysuckle add 12 times the amount of 50% ethanol, reflux and extract twice, 0.5 hours each time, filter, combine the filtrate, reduce pressure (-0.07MPa ⁇ -0.09MPa, 65°C ⁇ 75°C) to recover ethanol and concentrate to The thick paste with a relative density of 1.20 ⁇ 1.25 (65°C) is dried under reduced pressure (-0.07MPa ⁇ -0.09MPa, 60°C ⁇ 65°C), and crushed to obtain part of the dry extract powder extracted by alcohol;
  • Step B Houttuynia cordata, mugwort leaf, peppermint, add 8 times the amount of water, steam distillation to extract the volatile oil, extract for 5 hours, filter the extract, and store in another device for later use;
  • Step C The obtained volatile oil is pulverized and clathrated with 10 times the amount of ⁇ -cyclodextrin and 20 times the amount of water for 20 minutes, and the inclusion compound (55°C) is dried and pulverized to obtain the volatile oil inclusion compound;
  • Step D After the volatile oil is extracted, the medicine residue and red peony are combined, 10 times the amount of water is added, and the extraction is performed twice for 1 hour each time.
  • the extract and the oil extraction liquid are combined, filtered, and the filtrate is decompressed (-0.07MPa ⁇ -0.09) MPa, 75°C ⁇ 85°C)
  • Concentrate to a clear paste with a relative density of 1.02 ⁇ 1.05 (70°C) cool to room temperature, add 95% ethanol to make the alcohol content reach 70%, let stand for more than 12 hours, and precipitate the supernatant with alcohol Liquid decompression (-0.07MPa ⁇ -0.09MPa, 65°C ⁇ 75°C), recover ethanol and concentrate to thick paste with relative density of 1.25 ⁇ 1.30 (65°C), add appropriate amount of dextrin to reduce pressure (-0.07MPa ⁇ - 0.09MPa, 75°C), dried and pulverized to obtain a water-extracted part of dry extract powder.
  • Raw material medicine ratio Houttuynia cordata: 560g, honeysuckle 560g, red peony 450g, mugwort 275g, mint 275g.
  • Step A Weigh Chinese medicinal materials according to the weight ratio of the raw materials, honeysuckle purely selected, red peony coarsely crushed, mint whole herb crushed, houttuynia cordata and wormwood can be used directly;
  • Step B The honeysuckle was refluxed with 12 times the amount of 50% ethanol twice, 0.5h each time, the extracts were combined and filtered, and the ethanol was recovered to obtain extract 1, with a specific gravity of 1.20 to 1.30 (60 to 80°C), and dry to get dry Paste powder 1, spare;
  • Step C Add 8 times the amount of water, heat it to 80°C, add houttuynia cordata, wormwood, and peppermint in sequence, and extract the volatile oil for 5 hours to obtain the volatile oil, the dregs, add red peony powder, add 10 times the amount of water, and decoct 2
  • the extracts are combined and filtered, concentrated to a relative density of 1.02 ⁇ 1.05 (60°C), to obtain a clear paste, add 95% ethanol to 70% alcohol content, alcohol precipitation, and let stand for 12-32 hours , The supernatant is recovered with ethanol to obtain a thick paste 2 with a relative density of 1.20 ⁇ 1.30 (60°C), which is dried and crushed to obtain dry paste powder 2 for use;
  • Step D The obtained volatile oil is clathrated by a colloid mill grinding method to obtain volatile oil inclusion compound 3, which is pulverized for use.
  • the dry ointment powder 1, dry ointment powder 2, inclusion compound 3 and commonly used auxiliary materials for buccal tablets are mixed uniformly, granulated, granulated, compressed, and packaged.
  • Houttuynia cordata 350g, honeysuckle 350g, red peony 280g, wormwood 150g, mint 150g.
  • Step A Weigh Chinese medicinal materials according to the weight ratio of the raw materials, honeysuckle purely selected, red peony coarsely crushed, mint whole herb crushed, houttuynia cordata and wormwood leaves for immediate use;
  • Step B The honeysuckle was extracted twice with 12 times the amount of 50% ethanol at reflux, 0.5h each time, the extracts were combined and filtered, and the ethanol was recovered to obtain extract 1, with a specific gravity of 1.20 to 1.30 (60 to 80°C), to obtain thick paste 1. ,spare;
  • Step C Add 8 times the amount of water, heat to 80°C, add houttuynia cordata, wormwood, and peppermint in sequence, extract the volatile oil for 5 hours, add the dregs of red peony powder, add 10 times the amount of water, decoct 2 times, each After 1 hour, the extracts are combined and filtered, concentrated to a relative density of 1.02 ⁇ 1.05 (60°C), to obtain a clear paste, add 95% ethanol to 70% alcohol content, alcohol precipitation, stand for 12-32 hours, supernatant Recover ethanol from the liquid to obtain thick paste 2 with a relative density of 1.20 ⁇ 1.30 (60°C) for use;
  • Step D Mix the above thick paste 1 and thick paste 2 uniformly, prepare common auxiliary materials by spraying, add volatile oil and mix evenly, and encapsulate in a pressure-resistant container with a special valve system.
  • Test drug the drug prepared in Example 1 of the present invention.
  • Virus SARS-CoV-2, titer of 10 7 CCID 50 /ml, stored by the virus bank of the Institute of Microbiology and Epidemiology and the P3 virus species in a refrigerator at -80°C.
  • the virus titer used is 100 CCID 50 /well.
  • the sample prepared according to Example 1 of the present invention can inhibit SARS-CoV-2 from replicating in cells at three concentrations of 3000 ⁇ g/ml, 1000 ⁇ g/ml, and 200 ⁇ g/ml, suggesting the present invention
  • the drug has good anti-SARS-CoV-2 activity in vitro.

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Abstract

一种中药组合物在制备治疗或预防冠状病毒感染的药物中的应用，包括鱼腥草5-30份、金银花5-30份、赤芍5-20份、艾叶3-15份、薄荷3-15份，所述中药组合物具有良好的治疗或预防冠状病毒相关疾病的效果。

Description

一种中药组合物在制备治疗或预防冠状病毒感染的药物中的应用 技术领域
本发明涉及疾病治疗药物领域，更具体地说，涉及一种中药组合物在制备治疗或预防冠状病毒感染的药物中的应用。
背景技术
2020年3月11日，世界卫生组织(WHO)正式将COVID-19定性为全球大流行病。目前，尚无有效疫苗和药物来防治，因此寻找针对该病毒的有效药物显得尤为迫切。中医药在治疗瘟疫方面历史悠久，在各种疫情防控中发挥了重大作用。本发明涉及的双鱼颗粒，是以现代工艺提取鱼腥草、金银花、赤芍、艾叶、薄荷中的有效成分精制而成，能够显著改善外感风热、肺胃热盛所致的咽干、咽痛、喉核肿大、口渴、发热，以及急慢性扁桃体炎、急慢性咽炎、上呼吸道感染等。其能否成为有效预防及治疗冠状病毒相关疾病特别是COVID-19亟待开展科学研究。
发明内容
有鉴于此，本发明旨在提出一种中药组合物在制备治疗或预防冠状病毒感染的药物，其中，以重量计所述的中药组合物包括：鱼腥草5-30份、金银花5-30份、赤芍5-20份、艾叶3-15份、薄荷3-15份。
进一步地，所述冠状病毒感染的疾病包括COVID-19(新型冠状病毒肺炎)。
进一步地，所述中药组合物包括：鱼腥草5-25份、金银花5-25份、赤芍5-15份、艾叶3-10份、薄荷3-10份。
进一步地，所述中药组合物包括：鱼腥草15-25份、金银花15-25份、赤芍10-15份、艾叶5-10份、薄荷3-5份。
可选地，所述中药组合物包括：鱼腥草20份、金银花20份、赤芍12份、艾叶8份、薄荷4份。
可选地，所述中药组合物包括：鱼腥草15份、金银花15份、赤芍12份、艾叶7份、薄荷7份。
可选地，所述中药组合物包括：鱼腥草10份、金银花10份、赤芍8份、艾叶4份、薄荷4份。
本发明的组合物可以直接研磨成粉，也可以是经过本领域常规手段制得的提取物等。所述的组合物，可以按传统方法直接将几味组合物直接研磨成粉，也可以是经过常规手段制得提取物，以便制成不同剂型，得到疗效更好并且更利于制备成现代药物剂型
具体地，所述治疗或预防冠状病毒感染的药物包括口服给药剂型、注射给药剂型或外用给药制剂。
具体地，所述治疗或预防冠状病毒感染的药物包括汤剂、片剂、胶囊剂、颗粒剂、丸剂、注射剂、煎膏剂、悬浮剂、分散剂、糖浆剂、栓剂、凝胶剂、气雾剂、贴剂、口服液。
进一步地，本发明所述中药组合物制备方法可以包括以下步骤：
步骤A:按照原料药的重量比例称取中药材；
步骤B:金银花用6-12倍量50％～80％乙醇提取，提取液滤过，回收乙醇，干燥粉碎，得干膏粉；
步骤C:鱼腥草、艾叶、薄荷投入提取罐中，加水3～12倍，提取挥发油，药渣加赤芍粗粉，加水6-12倍量煎煮，提取液滤过，得清膏，加入浓度为90％以上的乙醇，至含醇量60％～80％，醇沉，静置，上清液回收乙醇，得稠膏，干燥粉碎，得干膏粉；
步骤D：将上述挥发油和上述干膏粉混合。
进一步地，本发明所述中药组合物制备方法可以包括以下步骤：
步骤A:金银花加12倍量50％乙醇，回流提取二次，每次0.5小时，滤 过，合并滤液，减压(-0.07MPa～-0.09MPa，65℃～75℃)回收乙醇并浓缩至相对密度为1.20～1.25(65℃)的稠膏，减压干燥(-0.07MPa～-0.09MPa，60℃～65℃)，粉碎，得到醇提部分干浸膏粉；
步骤B:鱼腥草、艾叶、薄荷，加8倍量水，水蒸气蒸馏提取挥发油，提取5小时，提取液滤过，另器存放，备用；
步骤C:所得挥发油以10倍量β-环糊精，20倍量水研磨包合20分钟，包合物(55℃)干燥，粉碎，得到挥发油包合物；
步骤D：提取挥发油后药渣与赤芍合并，加10倍量水，提取二次，每次1小时，提取液与提油药液(提取挥发油后的剩余药液)合并，滤过，滤液减压(-0.07MPa～-0.09MPa，75℃～85℃)浓缩至相对密度为1.02～1.05(70℃)的清膏，冷却至室温，加入95％乙醇使含醇量达70％，静置12小时以上，醇沉上清液减压(-0.07MPa～-0.09MPa，65℃～75℃)回收乙醇并浓缩至相对密度为1.25～1.30(65℃)的稠膏，可选加入适量的糊精减压(-0.07MPa～-0.09MPa，75℃)干燥，粉碎，得到水提部分干浸膏粉；将以上三种中间体混合。
本发明在Vero细胞上考察中药组合物在不同浓度下对新型冠状病毒SARS-CoV-2抑制效果，实验结果表明在3000μg/ml、1000μg/ml、200μg/ml浓度下，中药组合物在SARS-CoV-2病毒感染的Vero细胞上表现出良好的保护作用，可抑制SARS-CoV-2在细胞内复制，使感染后的细胞不发生病变，说明本发明的中药组合物具有良好的治疗或预防冠状病毒相关疾病的效果。
具体实施方式
本发明提供了一种中药组合物的用途，本领域技术人员可以借鉴本文内容，适当改进工艺参数实现。特别需要指出的是，所有类似的替换和改动对本领域技术人员来说是显而易见的，它们都被视为包括在本发明。本发明的方法及应用已经通过较佳实施例进行了描述，相关人员明显能在不脱离本发明内容、精神和范围内对本文的方法和应用进行改动或适当变更与组合，来实现和应用本发明技术。显然，所描述的实施例仅仅是本发明一部分实施例，而不是全部的实施例。
本发明如未注明具体条件者，均按照常规条件或制造商建议的条件进行，所用原料药或辅料，以及所用试剂或仪器未注明生产厂商者，均为可以通过市购获得的常规产品。下面结合实施例，进一步阐述本发明：
实施例1中药组合物颗粒剂的制备
原料药配比：鱼腥草：750g、金银花750g，赤芍450g，艾叶300g，薄荷150g。
步骤A:金银花加12倍量50％乙醇，回流提取二次，每次0.5小时，滤过，合并滤液，减压(-0.07MPa～-0.09MPa，65℃～75℃)回收乙醇并浓缩至相对密度为1.20～1.25(65℃)的稠膏，减压干燥(-0.07MPa～-0.09MPa，60℃～65℃)，粉碎，得到醇提部分干浸膏粉；
步骤B:鱼腥草、艾叶、薄荷，加8倍量水，水蒸气蒸馏提取挥发油，提取5小时，提取液滤过，另器存放，备用；
步骤C:所得挥发油以10倍量β-环糊精，20倍量水研磨包合20分钟，包合物(55℃)干燥，粉碎，得到挥发油包合物；
步骤D：提取挥发油后药渣与赤芍合并，加10倍量水，提取二次，每次1小时，提取液与提油药液合并，滤过，滤液减压(-0.07MPa～-0.09MPa，75℃～85℃)浓缩至相对密度为1.02～1.05(70℃)的清膏，冷却至室温，加入95％乙醇使含醇量达70％，静置12小时以上，醇沉上清液减压(-0.07MPa～-0.09MPa，65℃～75℃)回收乙醇并浓缩至相对密度为1.25～1.30(65℃)的稠膏，加入适量的糊精减压(-0.07MPa～-0.09MPa，75℃)干燥，粉碎，得到水提部分干浸膏粉。将以上三种中间体与适量糊精、甜菊素，混匀，干法制粒，制成1000g颗粒，即得。
实施例2中药组合物口含片的制备
原料药配比：鱼腥草：560g、金银花560g，赤芍450g，艾叶275g，薄荷275g。
步骤A:按照原料药的重量比例称取中药材，金银花净选、赤芍粗粉碎、薄荷全草粉碎，鱼腥草和艾叶直接备用即可；
步骤B:金银花用12倍量50％乙醇回流提取2次，每次0.5h，提取液合并滤过，回收乙醇得浸膏1，比重为1.20～1.30(60～80℃)，干燥，得干膏粉1，备用；
步骤C:加8倍量的水，加热至80℃，依次投入鱼腥草、艾叶、薄荷，提取挥发油持续5h，得到挥发油，药渣加赤芍粗粉，加10倍量水，煎煮2次，每次1h，提取液合并滤过，浓缩至相对密度为1.02～1.05(60℃)，得清膏，加入95％乙醇，至含醇量70％，醇沉，静置12-32小时，上清液回收乙醇，得相对密度为1.20～1.30(60℃)的稠膏2，干燥，粉碎得干膏粉2，备用；
步骤D：将所得的挥发油，采用胶体磨研磨方式进行包合，得到挥发油包合物3，粉碎后，备用。将干膏粉1、干膏粉2、包合物3与口含片常用辅料混合均匀，制粒，整粒、压片、内包装即得。
实施例3中药组合物喷雾剂的制备
原药材配比：鱼腥草350g、金银花350g，赤芍280g、艾叶150g、薄荷150g。
步骤A：按照原料药的重量比例称取中药材，金银花净选、赤芍粗粉碎、薄荷全草粉碎、鱼腥草和艾叶直接备用；
步骤B:金银花用12倍量50％乙醇回流提取2次，每次0.5h，提取液合并滤过，回收乙醇得浸膏1，比重为1.20～1.30(60～80℃)，得稠膏1，备用；
步骤C:加8倍量的水，加热至80℃，依次投入鱼腥草、艾叶、薄荷，提取挥发油持续5h，药渣加赤芍粗粉，加10倍量水，煎煮2次，每次1h，提取液合并滤过，浓缩至相对密度为1.02～1.05(60℃)，得清膏，加入95％乙醇，至含醇量70％，醇沉，静置12-32小时，上清液 回收乙醇，得相对密度为1.20～1.30(60℃)的稠膏2，备用；
步骤D：将以上稠膏1和稠膏2混合均匀，采用喷雾剂制备常用的辅料，加入挥发油混合均匀，封装于具有特制阀门系统的耐压容器中即得。
实施例4中药组合物对SARS-CoV-2的抑制作用
1.实验材料
受试药物：本发明实施例1制得的药物。
细胞：Vero细胞，由微生物流行病研究所细胞库保存。
病毒：SARS-CoV-2，滴度为10 7CCID 50/ml，由微生物流行病研究所病毒库及P3毒种冰箱-80℃保存。使用病毒滴度为100CCID 50/孔。
2.实验方法
无菌96孔培养板，每孔加入100μl浓度为1×10 5cell/ml Vero细胞，37℃5％CO 2培养24小时；受试药物稀释成3000μg(制剂)/ml、1000μg(制剂)/ml、200μg(制剂)/ml三个浓度，每个浓度3个复孔，每孔100μl作用1h，然后每孔再加入等体积100CCID 50病毒，作用1h；1h后，弃去96孔培养板中所有液体，加入稀释的药液；同时设立细胞对照、空白对照(溶剂对照)和病毒对照(阴性对照)；细胞37℃，5％CO 2孵箱孵育5天；光学显微镜下观察细胞病变(CPE)，细胞出现病变程度按以下5级标准记录：细胞完全病变记录为“++++”，75％病变记录为“+++”，50％病变记录为“++”，25％病变记录为“+”，未病变记录为“－”。
3.实验条件：以上实验操作均在BSL-3实验室内完成。
4.结果判断：细胞不出现CPE为有效抑制病毒的浓度，出现CPE为无效。
5.实验结果：
本发明药物组设置的3个浓度，细胞均未出现病变，结果见表1。
表1.药物抗SARS-CoV-2效果(CPE)
Figure PCTCN2021080152-appb-000001
备注：“－”为未病变；“++++”为细胞完全病变。
6.结论：
根据细胞水平的筛选结果，根据本发明实施例1制得的样品在3000μg/ml、1000μg/ml、200μg/ml三个浓度下，均可抑制SARS-CoV-2在细胞内复制，提示本发明药物具有良好的体外抗SARS-CoV-2活性。
需要指出的是，本领域技术人员可以借鉴本文内容，适当改进工艺参数实现，所有类似的替换和改动对本领域技术人员来说是显而易见的，它们都被视为包括在本发明。

Claims (10)

  1. 一种中药组合物在制备治疗或预防冠状病毒感染的药物中的应用，其特征在于所述中药组合物包括：鱼腥草5-30份、金银花5-30份、赤芍5-20份、艾叶3-15份、薄荷3-15份。
  2. 根据权利要求1所述的应用，其特征在于所述冠状病毒感染包括COVID-19。
  3. 根据权利要求1所述的应用，其特征在于，所述中药组合物包括：鱼腥草5-25份、金银花5-25份、赤芍5-15份、艾叶3-10份、薄荷3-10份。
  4. 根据权利要求1所述的应用，其特征在于，所述中药组合物包括：鱼腥草15-25份、金银花15-25份、赤芍10-15份、艾叶5-10份、薄荷3-5份。
  5. 根据权利要求1所述的应用，其特征在于，所述中药组合物包括：鱼腥草15份、金银花15份、赤芍12份、艾叶7份、薄荷7份。
  6. 根据权利要求1所述的应用，其特征在于，所述中药组合物包括：鱼腥草20份、金银花20份、赤芍12份、艾叶8份、薄荷4份。
  7. 根据权利要求1-6任一所述的应用，其特征在于，所述治疗或预防冠状病毒感染的药物包括口服给药剂型、注射给药剂型或外用给药制剂。
  8. 根据权利要求7所述的应用，其特征在于，所述治疗或预防冠状病毒感染的药物包括汤剂、片剂、胶囊剂、颗粒剂、丸剂、注射剂、煎膏剂、悬浮剂、分散剂、糖浆剂、栓剂、凝胶剂、气雾剂、贴剂、口服液。
  9. 根据权利要求1-6任一所述的应用，其特征在于，所述中药组合物制备方法包括以下步骤：
    步骤A：按照原料药的重量比例称取中药材；
    步骤B：金银花用6-12倍量50％～80％乙醇提取，提取液滤过，回收乙醇，干燥粉碎，得干膏粉；
    步骤C：鱼腥草、艾叶、薄荷加水3～12倍，提取挥发油，药渣加赤芍粗粉，加水6-12倍量煎煮，提取液滤过，得清膏，加入浓度为90％以上的乙醇，至含醇量60％～80％，醇沉，静置，上清液回收乙醇，得稠膏，干燥粉碎，得干膏粉；
    步骤D：将上述挥发油和上述两种干膏粉混合。
  10. 根据权利要求9所述的应用，其特征在于，所述中药组合物制备方法包括以下步骤：
    步骤A:金银花加12倍量50％乙醇，回流提取二次，每次0.5小时，滤过，合并滤液，减压回收乙醇并浓缩至相对密度为1.20～1.25的稠膏，减压干燥，粉碎，得到醇提部分干浸膏粉；
    步骤B:鱼腥草、艾叶、薄荷，加8倍量水，水蒸气蒸馏提取挥发油，提取5小时，提取液滤过，备用；
    步骤C:所得挥发油以10倍量β-环糊精，20倍量水研磨包合20分钟，包合物干燥，粉碎，得到挥发油包合物；
    步骤D：提取挥发油后药渣与赤芍合并，加10倍量水，提取二次，每次1小时，提取液与提油药液合并，滤过，滤液减压浓缩至相对密度为1.02～1.05的清膏，冷却至室温，加入95％乙醇使含醇量达70％，静置12小时以上，醇沉上清液减压回收乙醇并浓缩至相对密度为1.25～1.30的稠膏，减压干燥，粉碎，得到水提部分干浸膏粉；混合所述醇提部分干浸膏粉、所述挥发油包合物和所述水提部分干浸膏粉。
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