WO2022242128A1 - 一种感染性疾病康复用的中药组合物及其用途 - Google Patents

一种感染性疾病康复用的中药组合物及其用途 Download PDF

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WO2022242128A1
WO2022242128A1 PCT/CN2021/137881 CN2021137881W WO2022242128A1 WO 2022242128 A1 WO2022242128 A1 WO 2022242128A1 CN 2021137881 W CN2021137881 W CN 2021137881W WO 2022242128 A1 WO2022242128 A1 WO 2022242128A1
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chinese medicine
traditional chinese
medicine composition
present
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PCT/CN2021/137881
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English (en)
French (fr)
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张伯礼
张俊华
刘清泉
杨丰文
黄明
郭永明
宋新波
张晗
王跃飞
常艳旭
刘二伟
郑文科
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天津中医药大学
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Priority to CA3219450A priority Critical patent/CA3219450A1/en
Publication of WO2022242128A1 publication Critical patent/WO2022242128A1/zh

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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18Magnoliophyta (angiosperms)
    • A61K36/185Magnoliopsida (dicotyledons)
    • A61K36/25Araliaceae (Ginseng family), e.g. ivy, aralia, schefflera or tetrapanax
    • A61K36/258Panax (ginseng)
    • AHUMAN NECESSITIES
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    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/06Fungi, e.g. yeasts
    • A61K36/07Basidiomycota, e.g. Cryptococcus
    • A61K36/076Poria
    • AHUMAN NECESSITIES
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    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K36/18Magnoliophyta (angiosperms)
    • A61K36/185Magnoliopsida (dicotyledons)
    • A61K36/23Apiaceae or Umbelliferae (Carrot family), e.g. dill, chervil, coriander or cumin
    • A61K36/233Bupleurum
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K36/18Magnoliophyta (angiosperms)
    • A61K36/185Magnoliopsida (dicotyledons)
    • A61K36/28Asteraceae or Compositae (Aster or Sunflower family), e.g. chamomile, feverfew, yarrow or echinacea
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    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K36/18Magnoliophyta (angiosperms)
    • A61K36/185Magnoliopsida (dicotyledons)
    • A61K36/48Fabaceae or Leguminosae (Pea or Legume family); Caesalpiniaceae; Mimosaceae; Papilionaceae
    • A61K36/484Glycyrrhiza (licorice)
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K36/18Magnoliophyta (angiosperms)
    • A61K36/185Magnoliopsida (dicotyledons)
    • A61K36/53Lamiaceae or Labiatae (Mint family), e.g. thyme, rosemary or lavender
    • A61K36/539Scutellaria (skullcap)
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    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P39/06Free radical scavengers or antioxidants

Definitions

  • the invention belongs to the field of traditional Chinese medicine, and specifically relates to a traditional Chinese medicine composition and traditional Chinese medicine suitable for effectively preventing, treating or alleviating sequelae or complications of infectious diseases or promoting the recovery of damaged tissues, organs or systems caused by infectious diseases preparation.
  • the present invention also relates to the method for preparing the Chinese medicine composition and Chinese medicine preparation of the present invention, and the Chinese medicine composition and Chinese medicine preparation are used for preventing, treating or alleviating the sequelae or complications of infectious diseases or promoting damage to tissues caused by infectious diseases, Use for restoration of function of an organ or system.
  • the new crown pneumonia epidemic is the most serious infectious disease pandemic that has occurred in the world in a century.
  • my country has completely and effectively controlled the new crown pneumonia epidemic and achieved major strategic results in the fight against the new crown pneumonia epidemic
  • the new crown pneumonia epidemic is still raging around the world.
  • the nucleic acid of the virus test turned negative twice, and the lung images tended to improve before they could be discharged from the hospital.
  • the patient was only non-infectious and not clinically cured.
  • the new type of coronavirus pneumonia is a syndrome of dampness and toxin stagnation in the lungs.
  • One object of the present invention is to provide a Chinese medicine composition and Chinese medicine preparation suitable for effectively preventing, treating or alleviating the sequelae or complications of infectious diseases or promoting the functional recovery of damaged tissues, organs or systems caused by infectious diseases
  • the traditional Chinese medicine composition and traditional Chinese medicine preparation comprise Chinese medicinal materials or active extracts thereof that are effective in preventing, treating or alleviating sequelae or complications of infectious diseases or promoting functional recovery of damaged tissues, organs or systems caused by infectious diseases.
  • Another object of the present invention is to provide a method for effectively preventing, treating or alleviating sequelae or complications of infectious diseases or promoting functional recovery of damaged tissues, organs or systems caused by infectious diseases by using traditional Chinese medicine compositions or preparations , or alternatively provide the use of the traditional Chinese medicine composition in the preparation of drugs for effectively preventing, treating or alleviating the sequelae or complications of infectious diseases or promoting the functional recovery of damaged tissues, organs or systems caused by infectious diseases.
  • the inventors of the present application have long been concerned about the recovery problems of patients with some major diseases including infectious diseases, and have been devoting themselves to researching and solving these problems.
  • the inventor According to the theory of traditional Chinese medicine, on the basis of the ancient proven prescriptions of traditional Chinese medicine, the inventor has researched and determined a Chinese medicine prescription, and it has been proved through experiments that this prescription can effectively prevent, treat or alleviate the sequelae or complications of infectious diseases or promote the treatment of infectious diseases. Impairment of recovery of function of a tissue, organ or system caused by an infectious disease. Based on these findings, the present inventors have completed the present invention.
  • the present invention provides a traditional Chinese medicine composition and preparation suitable for effectively preventing, treating or alleviating sequelae or complications of infectious diseases or promoting functional recovery of damaged tissues, organs or systems caused by infectious diseases.
  • the Chinese medicine composition of the present invention is made up of any form of the following Chinese medicinal materials:
  • the Chinese medicine composition of the present invention can be made up of the mixture of the original medicinal material powder or the powder of the original medicinal material mixture of the following Chinese medicinal materials:
  • the Chinese medicine composition of the present invention can also be made up of the respective formula granules of the following Chinese medicinal materials:
  • the Chinese medicine composition of the present invention can also be made up of the solvent extract of following Chinese medicinal material mixture:
  • the traditional Chinese medicine preparation of the present invention contains the traditional Chinese medicine composition of the present invention, and may also contain pharmaceutically acceptable auxiliary materials.
  • the traditional Chinese medicine preparation of the present invention comprises any form of the following Chinese medicinal materials or their solvent extracts:
  • the Chinese medicine preparation of the present invention may be an oral solution comprising the following Chinese medicinal materials or their solvent extracts:
  • the Chinese medicine preparation of the present invention can be a granule comprising the following Chinese medicinal materials or their solvent extracts:
  • the Chinese medicine preparation of the present invention can be a pill comprising the following Chinese medicinal materials or their solvent extracts:
  • the Chinese medicinal preparation of the present invention can be a capsule comprising the following Chinese medicinal materials or their solvent extracts:
  • the Chinese medicine preparation of the present invention can be a tablet comprising the following Chinese medicinal materials or their solvent extracts:
  • the Chinese medicine preparation of the present invention may be a syrup comprising the following Chinese medicinal materials or their solvent extracts:
  • the Chinese medicine preparation of the present invention may be an ointment comprising the following Chinese medicinal materials or their solvent extracts:
  • the present invention provides a traditional Chinese medicine composition according to the present invention, which is suitable for effectively preventing, treating or alleviating the sequelae or complications of infectious diseases or promoting the function of damaged tissues, organs or systems caused by infectious diseases. Use in recovery medicines.
  • the present invention provides a method for preventing, treating or alleviating the sequelae or complications of infectious diseases or promoting functional recovery of damaged tissues, organs or systems caused by infectious diseases, the method comprising administering to patients in need An effective dose of the traditional Chinese medicine composition or traditional Chinese medicine preparation according to the present invention.
  • the present invention provides a traditional Chinese medicine composition or traditional Chinese medicine preparation as described in this application, which is used for preventing, treating or alleviating sequelae or complications of infectious diseases or promoting damage to tissues, organs or organs caused by infectious diseases. The function of the system is restored.
  • the Chinese medicine composition and Chinese medicine preparation of the present invention can nourish qi and nourish yin, regulate the spleen and stomach, clear away deficiency heat, and relieve irritability, and are suitable for preventing, treating or relieving sequelae or complications of infectious diseases or promoting damage to tissues caused by infectious diseases , the restoration of function of an organ or system.
  • the traditional Chinese medicine composition and traditional Chinese medicine preparation of the present invention have significant beneficial effects such as anti-inflammation, anti-oxidation, enhancement of body immunity and organ protection. Therefore, it is expected that the traditional Chinese medicine composition and traditional Chinese medicine preparation according to the present invention can be used to prevent, treat or alleviate the sequelae or complications of infectious diseases or promote the functional recovery of damaged tissues, organs or systems caused by infectious diseases. Sequelae or complications include, but are not limited to, acute abdomen after acute infection; sepsis; qi deficiency and profuse sweating after surgery; and physical weakness, fatigue, fatigue, etc. after infection by pathogenic microorganisms.
  • ginseng used in the present invention refers to the dried root and rhizome of Panax ginseng C.A.Mey., a plant of Araliaceae.
  • Ophiopogon japonicus used in the present invention refers to the dry tuber root of Ophiopogon japonicus (L.f) Ker-Gawl.
  • Schisandra used in the present invention refers to the dry ripe fruit of Schisandra chinensis (Turcz.) Baill. Known as “Northern Schisandra”.
  • Poria cocos used in the present invention refers to the dried sclerotia of Poria cocos (Schw.) Wolf, a fungus of Polyporaceae.
  • Quading Pinellia used in the present invention refers to the product processed and processed according to the following method: take Pinellia clean, separate it in size, soak it in 8% alum solution until there is no dry core in it, and it feels slightly numb in the mouth , take out, wash, cut into thick slices, and dry.
  • Pinellia refers to the dry tuber of Pinellia ternata (Thunb.) Breit.
  • scrophulariae used in the present invention refers to the dry root of Scrophularia ningpoensis Hemsl.
  • the term "stir-fried Atractylodes Rhizome” used in the present invention is a product obtained by processing Atractylodes Rhizome slices according to the bran-fried method.
  • the term “Atractylodes” refers to the dried rhizome of Atractylodes lancea (Thunb.) DC. or Atractylodes chinensis (DC.) Koidz. of Compositae.
  • tangerine peel used in the present invention is the dry mature pericarp of Rutaceae plant Citrus reticulata Blanco and its cultivars.
  • licorice used in the present invention refers to the dried roots and rhizomes of Glycyrrhiza uralensis Fisch., Glycyrrhiza inflata Bat. or Glycyrrhiza glabra L. of the leguminous plant Glycyrrhiza uralensis Fisch.
  • Bupleurum used in the present invention refers to the dried root of Bupleurum chinense DC. or Bupleurum scorzonerifolium Willd. of Umbelliferae.
  • cimicifuga used in the present invention is the dry rhizome of Cimicifuga heracleifolia Kom., Cimicifuga dahurica (Turcz.) Maxim. or Cimicifuga foetida L. of the Ranunculaceae plant.
  • coix seed used in the present invention refers to the dry mature seed kernel of the grass Coixlacryma-jobi L.var.ma-yuen (Roman.) Stapf.
  • scutellaria baicalensis used in the present invention refers to the dry root of Scutellaria baicalensis Georgi, a plant of the Labiatae family.
  • verbena used in the present invention refers to the dry aerial part of Verbena officinalis L., a plant of the family Verbenaceae.
  • root used in the present invention refers to the fresh or dry rhizome of Phragmites communis Trin.
  • leaf of light bamboo used in the present invention refers to the dry stem and leaf of the leaf of grass Lophatherum gracile Brongn.
  • raw medicinal material powder used in the present invention refers to Chinese herbal medicine powder with all components and no additives processed from decoction pieces of Chinese herbal medicines by physical methods, such as coarse pulverization, fine pulverization, micronization and physical wall-breaking pulverization.
  • prescription granule used in the present invention refers to a single-flavored Chinese medicine product that is refined by extracting, concentrating, drying and other processes in the way of decocting traditional Chinese medicine decoctions by adopting modern science and technology.
  • the product maintains the nature, taste and efficacy of traditional Chinese medicine decoction pieces, and the quality is stable and reliable. It is used in the deployment of clinical prescriptions of traditional Chinese medicine, adapts to the needs of syndrome differentiation and treatment, and changes in prescriptions.
  • solvent extract used in the present invention refers to the extraction of any form of the Chinese herbal medicine (including Chinese herbal medicine decoction pieces, Chinese herbal medicine powder, such as Chinese herbal medicine micronized powder) with a suitable pharmaceutically acceptable solvent such as water or alcoholic aqueous solution
  • a suitable pharmaceutically acceptable solvent such as water or alcoholic aqueous solution
  • the obtained substances including specific active ingredients and mixtures containing active ingredients, are suitable for the recovery of patients with major diseases such as new crown pneumonia convalescence, effectively preventing, treating or relieving sequelae or complications of infectious diseases or promoting the recovery of damage caused by infectious diseases. Restoration of function of a tissue, organ or system caused by a disease.
  • Forms of solvent extracts include, but are not limited to, solids, semi-solids, solutions, suspensions, concentrates, pastes, and powders.
  • Water suitable for extracting Chinese medicinal materials to obtain extracts in the present invention includes various waters that can be used to prepare active extracts of traditional Chinese medicines, such as medicinal water, such as distilled water and deionized
  • alcohol aqueous solution refers to an alcohol-containing aqueous solution of suitable concentration (such as low concentration, especially 10-50% v/v), suitable alcohols include various alcohols, preferably ethanol. Under certain conditions, it is also possible to use alcoholic aqueous solutions with a concentration higher than 50% v/v.
  • patient and “subject” used in the present invention can be used interchangeably, and refer to a mammal suffering from a disease such as COVID-19, especially a human.
  • pharmaceutically acceptable adjuvant used in the present invention refers to any adjuvant commonly used in the field of pharmaceutical preparations, as long as the adjuvant does not have adverse reactions or effects on the expected quality and curative effect of the traditional Chinese medicine composition of the present invention.
  • unit dosage form means physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of the present invention calculated to produce the desired therapeutic effect.
  • traditional Chinese medicine compositions and traditional Chinese medicine preparations suitable for effectively preventing, treating or alleviating sequelae or complications of infectious diseases or promoting functional recovery of damaged tissues, organs or systems caused by infectious diseases.
  • the traditional Chinese medicine composition of the present invention consists of or is made from any form of Chinese medicinal materials in the following parts by weight:
  • the traditional Chinese medicine composition of the present invention is made up of the following Chinese medicinal materials in any form or made from these Chinese medicinal materials in parts by weight:
  • the traditional Chinese medicine composition of the present invention is a mixture of the powders of the original Chinese medicinal materials or a powder of the mixture of the original medicinal materials in the following parts by weight:
  • the traditional Chinese medicine composition of the present invention is a mixture of the powders of the original Chinese medicinal materials or a powder of the mixture of the original medicinal materials in the following parts by weight:
  • the traditional Chinese medicine composition of the present invention consists of the following formula granules of Chinese medicinal materials in parts by weight:
  • the traditional Chinese medicine composition of the present invention is made up of the respective formula granules of the following Chinese medicinal materials in parts by weight:
  • the traditional Chinese medicine composition of the present invention is any form of solvent extract of the following Chinese medicinal material mixture in parts by weight:
  • the solvent mentioned therein refers to any applicable solvent that can be used to extract the active ingredients of traditional Chinese medicine or prepare traditional Chinese medicine preparations as defined in this description, and the form of the extract can be solution, granule and freeze-dried powder.
  • the traditional Chinese medicine composition of the present invention is any form of solvent extract of the following Chinese medicinal material mixture in parts by weight:
  • the solvent mentioned therein refers to any applicable solvent that can be used to extract the active ingredients of traditional Chinese medicine or prepare traditional Chinese medicine preparations as defined in this description, and the form of the extract can be solution, granule and freeze-dried powder.
  • the Chinese medicinal composition of the present invention can also be a mixture of extracts extracted separately from Chinese medicinal materials in the following parts by weight:
  • the form of the extract can be solution, granule, freeze-dried powder and the like.
  • the Chinese medicine composition of the present invention may also be a mixture of extracts extracted separately from Chinese medicinal materials in the following parts by weight:
  • the form of the extract can be solution, granule, freeze-dried powder and the like.
  • the Chinese medicinal composition of the present invention is the water extract of the following Chinese medicinal material mixture in parts by weight:
  • the Chinese medicine composition of the present invention is the water extract of the following Chinese medicinal material mixture in parts by weight:
  • the traditional Chinese medicine composition of the present invention is the alcoholic aqueous extract of the following Chinese medicinal material mixture by weight:
  • the alcohol aqueous solution described therein includes as defined in this specification.
  • the traditional Chinese medicine composition of the present invention is the alcoholic aqueous extract of the following Chinese medicinal material mixture by weight:
  • the alcohol aqueous solution described therein includes as defined in this specification.
  • the traditional Chinese medicine composition of the present invention is the alcoholic aqueous extract of the following Chinese medicinal material mixture by weight:
  • the alcohol aqueous solution described therein includes as defined in this specification.
  • the Chinese medicine composition of the present invention is the alcoholic aqueous solution extract of the Chinese medicinal material mixture of following parts by weight:
  • the alcohol aqueous solution described therein includes as defined in this specification.
  • the traditional Chinese medicine composition of the present invention can be made into any clinically applicable formulation.
  • the traditional Chinese medicine preparation of the present invention may also contain pharmaceutically acceptable auxiliary materials.
  • the traditional Chinese medicine preparation of the present invention comprises any form of Chinese medicinal materials in the following parts by weight, or extracts obtained by extracting them separately or in combination:
  • It may additionally contain or not contain pharmaceutically acceptable excipients.
  • the traditional Chinese medicine preparation of the present invention comprises any form of Chinese medicinal materials in the following parts by weight, or the extracts extracted separately or combined:
  • It may additionally contain or not contain pharmaceutically acceptable excipients.
  • the traditional Chinese medicine preparation according to the present invention can be formulated into appropriate dosage forms according to clinical needs, such as solutions, decoctions, granules, powders, granules, pills, tablets, ointments, capsules or syrups.
  • the traditional Chinese medicine preparation of the present invention is an oral solution in unit dose form made of the following Chinese medicinal materials in parts by weight:
  • the traditional Chinese medicine preparation of the present invention is an oral solution in unit dose form made of the following Chinese medicinal materials in parts by weight:
  • the traditional Chinese medicine preparation of the present invention is a decoction in unit dose form made of the following Chinese medicinal materials in parts by weight:
  • the traditional Chinese medicine preparation of the present invention is a decoction in the form of a unit dose made of the following Chinese medicinal materials in parts by weight:
  • the traditional Chinese medicine preparation of the present invention is a granule in unit dosage form made of the following Chinese medicinal materials in parts by weight:
  • the traditional Chinese medicine preparation of the present invention is a granule, which comprises
  • Acceptable excipients in pharmaceutical granules for example, lactose, mannitol or a mixture thereof, preferably a 2:1 mixture of lactose:mannitol.
  • the traditional Chinese medicine preparation of the present invention is a granule, which comprises
  • the method described therein comprises the steps of:
  • Acceptable excipients in pharmaceutical granules for example, lactose, mannitol or a mixture thereof, preferably a 2:1 mixture of lactose:mannitol.
  • the traditional Chinese medicine preparation of the present invention is a granule in the form of a unit dosage made of the following Chinese medicinal materials in parts by weight:
  • the traditional Chinese medicine preparation of the present invention is a granule, which comprises
  • Acceptable excipients in pharmaceutical granules for example, lactose, mannitol or a mixture thereof, preferably a 2:1 mixture of lactose:mannitol.
  • the traditional Chinese medicine preparation of the present invention is a granule, which comprises
  • the method described therein comprises the steps of:
  • Acceptable excipients in pharmaceutical granules for example, lactose, mannitol or a mixture thereof, preferably a 2:1 mixture of lactose:mannitol.
  • the Chinese medicine preparation of the present invention is a powder in the form of a unit dose made of the following Chinese medicinal materials in parts by weight:
  • the traditional Chinese medicine preparation of the present invention is a powder in the form of a unit dosage made of the following Chinese medicinal materials in parts by weight:
  • the traditional Chinese medicine preparation of the present invention is a capsule made of the following Chinese medicinal material mixture in parts by weight:
  • the traditional Chinese medicine preparation of the present invention is a capsule made of the following Chinese medicinal material mixture by weight:
  • the traditional Chinese medicine preparation of the present invention is a pill made of the following Chinese medicinal material mixture in parts by weight:
  • the traditional Chinese medicine preparation of the present invention is a pill made of the following Chinese medicinal material mixture in parts by weight:
  • the traditional Chinese medicine preparation of the present invention is an ointment made of the following Chinese medicinal material mixture in parts by weight:
  • the traditional Chinese medicine preparation of the present invention is an ointment made of the following Chinese medicinal material mixture in parts by weight:
  • the traditional Chinese medicine preparation according to the present invention may also contain pharmaceutically acceptable auxiliary materials in addition to the traditional Chinese medicine composition of the present invention.
  • the pharmaceutically acceptable excipients that can be used in the traditional Chinese medicine composition of the present invention include any excipients commonly used in traditional Chinese medicine preparations, as long as the excipients do not adversely affect the quality, performance and therapeutic effect of the traditional Chinese medicine composition of the present invention.
  • Commonly used excipients in traditional Chinese medicine preparations include diluents, carriers, fillers, binders, wetting agents, disintegrants, absorption promoters, surfactants, adsorption carriers, and lubricants.
  • Commonly used diluents mainly include sucrose, dextrin, starch, lactose, mannitol, xylitol, bifidosaccharide, etc.
  • Commonly used wetting agents mainly include water, ethanol of different concentrations, etc.; commonly used adhesives include polymer adhesives, and there are many types, such as ethyl cellulose, polyvinylpyrrolidone, sodium carboxymethyl cellulose, polyvinyl Ethylene glycol, sodium alginate, etc.
  • Commonly used disintegrants include microcrystalline cellulose, sodium carboxymethyl starch, etc.
  • the traditional Chinese medicine preparation of the present invention may also contain suitable additives.
  • additives are known in the art, such as emulsifiers, fragrances, solubilizers, anticaking agents, defoamers, binders, buffers, pH regulators, propellants, chelating agents, and preservatives.
  • the Chinese medicinal materials can be soaked for a period of time, or the Chinese medicinal materials can be physically processed to facilitate the extraction of active substances.
  • the corresponding Chinese herbal medicines can be used alone or their mixtures, through conventional pulverization, leaching and separation methods in the field, such as maceration, diafiltration, liquid-liquid extraction , water extraction and alcohol precipitation, alcohol extraction and water precipitation and dialysis and other methods to prepare the active Chinese medicine extract and Chinese medicine preparation applicable in the present invention. It is also possible to purchase one or more active extracts of traditional Chinese medicines used in the present invention through commercial channels, and then mix them with the extracts of other traditional Chinese medicines to obtain the active extracts of traditional Chinese medicines of the present invention.
  • the Chinese medicine compositions and Chinese medicine preparations of these variations are all within the scope of the present invention.
  • the Chinese medicine composition and Chinese medicine preparation of the present invention can nourish qi and nourish yin, regulate the spleen and stomach, clear away deficiency heat, and relieve irritability, and are suitable for preventing, treating or relieving sequelae or complications of infectious diseases or promoting damage to tissues caused by infectious diseases , the restoration of function of an organ or system.
  • the traditional Chinese medicine composition and traditional Chinese medicine preparation of the present invention have significant beneficial effects such as anti-inflammation, anti-oxidation, enhancement of body immunity and organ protection. Therefore, the traditional Chinese medicine composition and traditional Chinese medicine preparation according to the present invention can be used for preventing, treating or alleviating the sequelae or complications of infectious diseases or promoting the functional recovery of damaged tissues, organs or systems caused by infectious diseases.
  • complications include but are not limited to acute abdomen after acute infection by pathogenic microorganisms; sepsis; Qi deficiency and profuse sweating after surgery; and physical weakness, fatigue, and fatigue after pathogenic microorganism infection.
  • the traditional Chinese medicine composition or traditional Chinese medicine preparation according to the present invention is provided for preventing, treating or alleviating the sequelae or complications of infectious diseases or promoting damage to tissues, organs or systems caused by infectious diseases The purpose of functional recovery.
  • the traditional Chinese medicine composition according to the present invention is provided in the preparation of drugs suitable for preventing, treating or alleviating the sequelae or complications of infectious diseases or promoting the functional recovery of damaged tissues, organs or systems caused by infectious diseases use in .
  • a Chinese medicine composition or Chinese medicine preparation of the present invention is provided to effectively prevent, treat or alleviate the sequelae or complications of infectious diseases or promote the function of damaged tissues, organs or systems caused by infectious diseases.
  • a recovery method which comprises administering an effective amount of the traditional Chinese medicine composition or traditional Chinese medicine preparation according to the present invention to a patient in need.
  • the traditional Chinese medicine composition according to the present invention is suitable for preventing, treating or alleviating the sequelae or complications of new coronary pneumonia or promoting the function of the damaged tissues, organs or systems caused by new coronary pneumonia in patients with new coronary pneumonia. Use in recovery medicines.
  • a method of using the Chinese medicine composition or Chinese medicine preparation of the present invention to prevent, treat or alleviate the sequelae or complications of new coronary pneumonia or to promote damage to the tissues, organs or systems caused by new coronary pneumonia in patients with new coronary pneumonia comprising administering an effective amount of the traditional Chinese medicine composition or traditional Chinese medicine preparation according to the present invention to a patient with new coronary pneumonia in need.
  • the use of the traditional Chinese medicine composition according to the present invention in the preparation of medicines suitable for preventing, treating or alleviating the sequelae or complications of new coronary pneumonia is provided, wherein the sequelae or complications include but are not limited to upset Symptoms include laxity, dry cough with little phlegm, bad throat, shortness of breath after movement, fatigue, fullness in the chest and abdomen, anorexia and soft stools, heaviness in limbs, and pale tongue with little fluid.
  • a method of using the Chinese medicine composition or Chinese medicine preparation of the present invention to prevent, treat or alleviate the sequelae or complications of new coronary pneumonia comprising administering an effective amount of the Chinese medicine according to the present invention to a patient in need
  • Traditional Chinese medicine composition or traditional Chinese medicine preparation wherein the sequelae or complications include but not limited to upset, dry cough with little phlegm, bad throat, shortness of breath after movement, fatigue, fullness in the chest and abdomen, anorexia and soft stool, heaviness of the limbs and Symptoms such as pale tongue and less fluid.
  • the traditional Chinese medicine composition according to the present invention in the preparation of medicines suitable for preventing, treating or alleviating sequelae or complications of infectious diseases, wherein said sequelae or complications include but are not limited to Acute abdomen after acute infection by pathogenic microorganisms; sepsis; qi deficiency and profuse sweating after surgery; and physical weakness, fatigue, and fatigue after infection by pathogenic microorganisms.
  • a method for preventing, treating or alleviating sequelae or complications of infectious diseases using the traditional Chinese medicine composition or Chinese medicine preparation of the present invention comprising administering an effective amount of the traditional Chinese medicine according to the present invention to a patient in need
  • the traditional Chinese medicine composition or traditional Chinese medicine preparation, wherein the sequelae or complications include but not limited to acute abdomen after acute infection by pathogenic microorganisms; sepsis; Qi deficiency and profuse sweating after surgery; and physical weakness after pathogenic microorganism infection, Burnout, fatigue, etc.
  • the use of the traditional Chinese medicine composition according to the present invention as an anti-oxidative and/or anti-inflammatory drug is provided, or the use of the traditional Chinese medicinal composition according to the present invention in the preparation of anti-oxidative and/or anti-inflammatory drugs is provided. Uses in medicine.
  • the traditional Chinese medicine composition according to the present invention in the preparation of a drug suitable for promoting the functional recovery of damaged tissues, organs or systems caused by infectious diseases, wherein the functions include respiratory related functions, functions related to bodily activities, and functions related to mental activities.
  • the traditional Chinese medicine composition and traditional Chinese medicine preparation of the present invention can be administered in any suitable manner and any suitable form commonly used in the art.
  • the traditional Chinese medicine composition and traditional Chinese medicine preparation of the present invention can be administered via a mode selected from: oral administration, spray inhalation, nasal cavity administration, and parenteral administration such as intravenous and intramuscular administration, among which oral administration, intramuscular injection or intravenous administration are preferred. Intravenous injection.
  • the traditional Chinese medicine composition of the present invention can be made into a unit dosage form for patients to take.
  • the dosage form for administration may be a liquid dosage form or a solid dosage form.
  • the liquid dosage form can be solution type, colloid type, emulsion dosage form or suspension dosage form etc.
  • Solid dosage forms may be, for example, tablets, powders, suppositories, granules, or capsules. Other dosage forms include aerosols, patches or liniments, and the like.
  • the traditional Chinese medicine composition of the present invention can be used orally, for example, twice a day, 5-30 grams each time, such as 10-20 grams, preferably 10 grams of the granules of the present invention or other forms of the present invention
  • Traditional Chinese medicine composition and traditional Chinese medicine preparation The specific dosage depends on the body weight of the patient to be treated, the nature and severity of the disease, the way of drug administration, the cycle or time interval of administration and other factors. For some patients with special circumstances, the specific administration should follow the doctor's advice.
  • the traditional Chinese medicine composition and traditional Chinese medicine preparation of the present invention can be used in combination with other medicines and techniques known in the art that can be used for the treatment of COVID-19 recovery period.
  • Those skilled in the art can think of and determine the medicines and techniques suitable for the treatment of new coronary pneumonia convalescence that can be used in combination with the traditional Chinese medicine composition and traditional Chinese medicine preparation of the present invention and will not produce adverse effects.
  • the Chinese medicine composition and Chinese medicine preparation of the present invention can be used in combination with appropriate techniques of traditional Chinese medicine, wherein said appropriate techniques of traditional Chinese medicine include moxibustion therapy, meridian massage, scraping therapy, cupping and acupuncture.
  • the Chinese medicinal materials used in the following examples are all purchased from the market and qualified through identification, the experimental reagents and experimental instruments used are commonly used experimental reagents and experimental instruments in this area, and the assay methods used are commonly used in this area methods, unless otherwise specified.
  • Embodiment 1 the preparation of Chinese medicine composition (granule) of the present invention
  • the above sixteen flavors are decocted twice, the first time is 60 minutes, the second time is 40 minutes, the amount of water added is 8 times and 6 times respectively, filtered, and the filtrate is concentrated to a relative density of 1.02-1.10 (60°C).
  • Spray drying add appropriate amount of auxiliary materials (lactose: mannitol (2:1)), mix well, dry press granules, divide into two bags, and obtain the traditional Chinese medicine composition granules of the present invention.
  • the Chinese medicine composition (granule) of the present invention prepared according to the method for embodiment 1.
  • tBHQ (Tertiary butylhydroquinone, tertiary butylhydroquinone), MedChemExpress Company. Batch number: HY-100489, within the validity period. Specification: 500mg, usage and dosage: refer to clinical usage, and prepare as 100mM mother solution.
  • 293T cells were purchased from ATCC cell bank.
  • Competent cells DH5a were purchased from Tiangen Biochemical Technology Co., Ltd.
  • the traditional Chinese medicine composition of the present invention 0.01 ⁇ g/mL, 0.1 ⁇ g/mL, 1 ⁇ g/mL, 10 ⁇ g/mL, 100 ⁇ g/mL.
  • Preparation of medicinal solution Before the test, the granules were prepared into a medicinal solution with a concentration of 100 mg/mL with distilled water, and diluted to the experimental concentration when used.
  • the triangular flask After the triangular flask is sterilized by high temperature and high pressure, add 2.5g dry powder of LB liquid medium into the bottle, and add 100mL sterilized ultrapure water to dissolve it completely. After the bottle mouth is pasted with a filter membrane, it is sterilized under high temperature and high pressure . When it is cooled to about 55°C, add 100 ⁇ L of 100 mg/mL ampicillin and mix well. The cells are cultured in DMEM medium containing 10% FBS, and subcultured when the cells in the culture flask grow to 80-90%.
  • Cytotoxicity detection is divided into blank control group and 0.01 ⁇ g/mL, 0.1 ⁇ g/mL, 1 ⁇ g/mL, 10 ⁇ g/mL, 100 ⁇ g/mL 5 concentration groups of traditional Chinese medicine composition of the present invention;
  • Antioxidant activity detection is divided into blank control group, positive drug tBHQ group and 0.01 ⁇ g/mL, 0.1 ⁇ g/mL, 1 ⁇ g/mL, 10 ⁇ g/mL, 100 ⁇ g/mL 5 concentration groups of traditional Chinese medicine composition of the present invention;
  • Anti-inflammatory effect detection is divided into blank control group, model group, positive drug dexamethasone group and 0.01 ⁇ g/mL, 0.1 ⁇ g/mL, 1 ⁇ g/mL, 10 ⁇ g/mL, 100 ⁇ g/mL 5 concentration groups of traditional Chinese medicine composition of the present invention .
  • Cell number/mL (cell number in four grid areas)/4 ⁇ 10 4 ⁇ dilution factor
  • CCK-8 and LDH kits were used to investigate the influence of different concentrations of the traditional Chinese medicine composition of the present invention on the viability of 293T cells.
  • the original 96-well plate was washed once with PBS, and 100 ⁇ L of diluted 1 ⁇ CCK-8 working solution was added to each well, and incubated at 37°C for 1 h. Set up a microplate reader to measure the absorbance (OD value) at 450 nm.
  • the cells transfected with the ARE luciferase reporter plasmid pGL4.37 were added with tBHQ (10 ⁇ M) and sample solutions of each group of Chinese medicine composition of the present invention at a safe concentration, and a Control group was set up, and cultured for 6 hours; transfected with NF -The cells of the ⁇ B luciferase reporter plasmid pGL4.32 were added with fully cultured and diluted dexamethasone (10 ⁇ M) containing TNF- ⁇ (10ng/mL), each group of sample solutions of the Chinese medicine composition of the present invention at a safe concentration, And set Control group, Model group (10ng/mL TNF- ⁇ ), culture 6h.
  • Table 1 Effects of different concentrations of traditional Chinese medicine composition of the present invention on ARE luciferase activity of 293T cells
  • 100 ⁇ g/mL of the traditional Chinese medicine composition of the present invention has obvious antioxidant effect.
  • Embodiment 3 The traditional Chinese medicine composition of the present invention is to the RAW264.7 induced by LPS
  • This experiment investigated the effect of the traditional Chinese medicine composition of the present invention on the release of inflammatory factors in RAW264.7 macrophages induced by LPS, and explored the anti-inflammatory effect of the traditional Chinese medicine composition of the present invention.
  • cryopreservation tube Take out the cryopreservation tube from the liquid nitrogen tank, quickly put it in a 37°C water bath, and shake it clockwise quickly to completely dissolve the cells within 1-2min.
  • the cells were removed from the cryopreservation tube, 3 mL of culture medium (10% FBS+90% DMEM) was added, mixed well and then centrifuged at 800 rpm/min at 4°C for 5 min. Discard the supernatant, resuspend the cell pellet with 5 mL of culture medium, transfer it to a 25 cm 2 culture flask, and culture it in a 37°C constant temperature carbon dioxide cell incubator.
  • the cell culture procedure was the same as the subculture experiment, and the cells to be frozen were centrifuged at 4°C and 800rpm/min for 5min.
  • the volume ratio of DMEM, fetal bovine serum, and DMSO reagent was 7:2:1 to prepare cell cryopreservation solution, and repeatedly pipet cells with a certain volume of cryopreservation solution to mix the cells evenly.
  • 1 mL per vial was divided into cryopreservation tubes, and put into a gradient cooling freezer according to the principle of slow freezing and instant dissolution, and placed in a -80°C refrigerator for 24 hours, then transferred to liquid nitrogen for long-term freezing.
  • Cell number/mL (cell number in four grid areas)/4 ⁇ 104 ⁇ dilution factor
  • CCK-8 and LDH kits were used to investigate the effect of different concentrations of the traditional Chinese medicine composition of the present invention on the viability of RAW264.7 cells.
  • the RAW264.7 cells in the logarithmic growth phase were collected and seeded in 96-well plates at a density of 2 ⁇ 10 5 cells/mL. After 24 hours, 0.01, 0.1, 1, 10, 100, 200, 400, 800, 1000 ⁇ g/mL of the traditional Chinese medicine composition of the present invention were added respectively, 100 ⁇ L per well, 6 duplicate wells for each concentration, and a Control group without adding medicine was set at the same time . After 24 hours of drug treatment, the culture plate was taken out, the supernatant was sucked off, 100 ⁇ L of 10-fold diluted CCK-8 solution was added to each well, and incubated at 37°C for 30 minutes. The absorbance OD value was detected at 450 nm by a microplate reader, and the cell viability was calculated.
  • the RAW264.7 cells in the logarithmic growth phase were collected and seeded in 96-well plates at a density of 2 ⁇ 10 5 cells/mL. After 24 hours, 0.01, 0.1, 1, 10, 100, 200, 400, 800, 1000 ⁇ g/mL of the traditional Chinese medicine composition of the present invention were added respectively, 100 ⁇ L per well, 6 duplicate wells for each concentration, and a Control group without adding medicine was set at the same time .
  • RAW264.7 cells were seeded in 96-well plates at a density of 2 ⁇ 10 5 cells/mL, and the cells were grouped 24 hours later.
  • LPS with a final concentration of 1 ⁇ g/mL was added; in the control group, DMEM was used instead of LPS; in addition to LPS, the culture medium of the drug treatment group was added with final concentrations of 0.01, 0.1, 1, 10, 100, 200, 400, 800, 1000 ⁇ g/mL of Qingjin Yiqi, LPS pre-stimulation for 2 hours, and then LPS stimulation for 20 hours to collect cells for testing.
  • the RAW264.7 cells in the logarithmic growth phase were collected and seeded in 96-well plates at a density of 2 ⁇ 10 5 cells/mL. After 24 hours, 0.1, 1, 10, 100, 200, 400, 800, and 1000 ⁇ g/mL of the traditional Chinese medicine composition of the present invention were added respectively, 100 ⁇ L per well, 6 duplicate wells for each concentration, and the Control group and Model without adding medicine were set at the same time. group (1 ⁇ g/mL LPS). After 24 hours of drug treatment, the culture plate was taken out to detect the amount of NO release. Take out Griess Reagent I and II and bring back to room temperature. Dilute standards (1-100 [mu]M) in DMEM + 10% FBS.
  • the concentrations of the standards are 0, 1, 2, 5, 10, 20, 40, 60, 100 ⁇ M.
  • the experimental data were analyzed using SPSS 25.0 software to conduct one-way ANOVA to evaluate the difference between the means. When P ⁇ 0.05, it was considered to be statistically different, and the data were expressed as mean ⁇ SD.
  • CCK-8 and LDH methods were used to detect the influence of the traditional Chinese medicine composition of the present invention on the viability of RAW264.7 cells at 0.01, 0.1, 1, 10, 100, 200, 400, 800, 1000 ⁇ g/mL.
  • the results showed that there was no significant difference in the viability of RAW264.7 cells in the 0.01-10 ⁇ g/mL Qingjin Yiqi group compared with the normal control group, and the 100-1000 ⁇ g/mL Qingjin Yiqi group could significantly promote the viability of RAW264.7 cells (P ⁇ 0.01, P ⁇ 0.001).
  • the anti-inflammatory effect of the traditional Chinese medicine composition of the present invention was investigated by using the safe concentration of the drug (Fig. 4-Fig. 5).
  • LPS stimulation significantly increased the NO expression of RAW264.7 cells (P ⁇ 0.001); compared with the LPS stimulation group, 100-1000 ⁇ g/mL of the Chinese medicine composition of the present invention can significantly inhibit the LPS-induced RAW264.7 Cellular NO release (P ⁇ 0.05, P ⁇ 0.001) ( Figure 6).

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Abstract

一种感染性疾病康复用的中药组合物,包含中药材人参2-4份、麦冬4-8份、五味子2-4份、茯苓6-10份、清半夏6-10份、玄参4-8份、麸炒苍术4-6份、陈皮4-8份、甘草2-4份、柴胡4-8份、升麻2-4份、薏苡仁8-12份、黄芩8-12份、马鞭草8-12份、芦根12-18份和淡竹叶1-3份。所述中药组合物可用于预防、治疗或缓解感染性疾病后遗症或并发症或促进受损由感染性疾病引起的组织、器官或系统的功能恢复的药物中的用途。

Description

一种感染性疾病康复用的中药组合物及其用途 技术领域
本发明属于中医药学领域,具体涉及一种适用于有效预防、治疗或缓解感染性疾病后遗症或并发症或促进受损由感染性疾病引起的组织、器官或系统的功能恢复的中药组合物和中药制剂。本发明还涉及制备本发明中药组合物和中药制剂的方法,以及该中药组合物和中药制剂用于预防、治疗或缓解感染性疾病后遗症或并发症或促进受损由感染性疾病引起的组织、器官或系统的功能恢复的用途。
背景技术
从疾病的临床治愈到患者生理机能的完全恢复,还需要经历一个较长的康复阶段。对于一些感染性疾病,包括传染性疾病,例如新型冠状病毒肺炎,患者出院后的恢复一直是医学界关注和研究的重要课题之一。实践证明,中医药不但可以有效预防和治疗疾病,而且可以加快疾病治愈和恢复进程、促进患者生理机能恢复和提高患者生活质量。特别是,中药在预防和治疗慢性疾病或严重疾病以及在疾病临床治愈后患者康复等方面的应用有着悠久历史和显著效果。
以新冠肺炎为例,新冠肺炎疫情是百年来全球发生的最严重的传染病大流行。当前,虽然我国已经完全有效地控制了新冠肺炎疫情,取得了抗击新冠肺炎疫情斗争重大战略成果,但新冠肺炎疫情仍在全球肆虐。新冠肺炎患者经过积极救治,病毒检测两次核酸转阴,肺部影像趋于好转就可以出院,而此时患者只是没有了传染性并不是临床治愈。根据中医学理论,新型冠状病毒性肺炎属于湿毒郁肺症,新冠肺炎病毒转阴后,由于经过高热、发炎的过程病人普遍阴阳俱损,气、阴俱虚且余热未清。新冠肺炎患者出院后有不少还存在呼吸活动后憋喘、肺的炎症尚未吸收、免疫指标紊乱、脏器功能损伤和嗅觉味觉障碍等,伴有头晕、疲乏、肌肉酸痛、心悸、盗汗、注意力难集中、焦虑、烦躁、失眠、抑郁状态等表现,这些后遗症需及时进行中西医康复干预,以使患者尽早康复。因此,如何有效处理新冠肺炎后遗症或并发症问题以使患者尽早康复具有十分重要和迫切的需求。
因此,对适用于预防、治疗或缓解感染性疾病后遗症或并发症或促进受损由感染性疾病引起的组织、器官或系统的功能恢复的中药组合物和中药制剂存在未满足的需求。
发明概述
本发明的一个目的是提供一种适用于有效预防、治疗或缓解感染性疾病后遗症或并发症或促进受损由感染性疾病引起的组织、器官或系统的功能恢复的中药组合物和中药制剂,该中药组合物和中药制剂包含有效预防、治疗或缓解感染性疾病后遗症或并发症或促进受损由感染性疾病引起的组织、器官或系统的功能恢复的中药材或其活性提取物。
本发明的另一个目的是提供一种使用中药组合物或中药制剂有效预防、治疗或缓解感染性疾病后遗症或并发症或促进受损由感染性疾病引起的组织、器官或系统的功能恢复的方法,或可替代地提供中药组合物在制备用于有效预防、治疗或缓解感染性疾病后遗症或并发症或促进受损由感染性疾病引起的组织、器官或系统的功能恢复的药物中的用途。
本申请的发明人长期关注一些重大疾病包括传染性疾病患者的康复问题,并一直致力于研究解决这些问题。根据中医药理论,在中医古代验方的基础上,本发明人研究确定了一个中药组方,且已通过试验证明了该组方能够有效预防、治疗或缓解感染性疾病后遗症或并发症或促进受损由感染性疾病引起的组织、器官或系统的功能恢复。基于这些研究结果,本发明人完成了本发明。
可以从不同方面描述本发明,这些方面及其任何形式中所描述的发明相互独立又彼此关联,相互结合构成本发明的内容。
一方面,本发明提供一种适用于有效预防、治疗或缓解感染性疾病后遗症或并发症或促进受损由感染性疾病引起的组织、器官或系统的功能恢复的中药组合物和中药制剂。
本发明的中药组合物由任何形式的如下中药材组成或制成:
人参、麦冬、五味子、茯苓、清半夏、玄参、麸炒苍术、陈皮、甘草、柴胡、升麻、薏苡仁、黄芩、马鞭草、芦根和淡竹叶。
本发明的中药组合物可以由如下中药材各自原药材粉末的混合物或原药材混合物的粉末组成:
人参、麦冬、五味子、茯苓、清半夏、玄参、麸炒苍术、陈皮、甘草、柴胡、升麻、薏苡仁、黄芩、马鞭草、芦根和淡竹叶。
本发明的中药组合物也可以由如下中药材各自的配方颗粒组成:
人参、麦冬、五味子、茯苓、清半夏、玄参、麸炒苍术、陈皮、甘草、柴胡、升麻、薏苡仁、黄芩、马鞭草、芦根和淡竹叶。
本发明的中药组合物还可以由如下中药材混合物的溶剂提取物组成:
人参、麦冬、五味子、茯苓、清半夏、玄参、麸炒苍术、陈皮、甘草、柴胡、升麻、 薏苡仁、黄芩、马鞭草、芦根和淡竹叶。
本发明的中药制剂包含本发明的中药组合物,且还可以包含药剂学上可接受的辅料。换言之,本发明的中药制剂包含任何形式的如下中药材或其溶剂提取物:
人参、麦冬、五味子、茯苓、清半夏、玄参、麸炒苍术、陈皮、甘草、柴胡、升麻、薏苡仁、黄芩、马鞭草、芦根和淡竹叶。
本发明的中药制剂可以为包含如下中药材或其溶剂提取物的口服溶液:
人参、麦冬、五味子、茯苓、清半夏、玄参、麸炒苍术、陈皮、甘草、柴胡、升麻、薏苡仁、黄芩、马鞭草、芦根和淡竹叶。
本发明的中药制剂可以为包含如下中药材或其溶剂提取物的颗粒剂:
人参、麦冬、五味子、茯苓、清半夏、玄参、麸炒苍术、陈皮、甘草、柴胡、升麻、薏苡仁、黄芩、马鞭草、芦根和淡竹叶。
本发明的中药制剂可以为包含如下中药材或其溶剂提取物的丸剂:
人参、麦冬、五味子、茯苓、清半夏、玄参、麸炒苍术、陈皮、甘草、柴胡、升麻、薏苡仁、黄芩、马鞭草、芦根和淡竹叶。
本发明的中药制剂可以为包含如下中药材或其溶剂提取物的胶囊剂:
人参、麦冬、五味子、茯苓、清半夏、玄参、麸炒苍术、陈皮、甘草、柴胡、升麻、薏苡仁、黄芩、马鞭草、芦根和淡竹叶。
本发明的中药制剂可以为包含如下中药材或其溶剂提取物的片剂:
人参、麦冬、五味子、茯苓、清半夏、玄参、麸炒苍术、陈皮、甘草、柴胡、升麻、薏苡仁、黄芩、马鞭草、芦根和淡竹叶。
本发明的中药制剂可以为包含如下中药材或其溶剂提取物的糖浆剂:
人参、麦冬、五味子、茯苓、清半夏、玄参、麸炒苍术、陈皮、甘草、柴胡、升麻、薏苡仁、黄芩、马鞭草、芦根和淡竹叶。
本发明的中药制剂可以为包含如下中药材或其溶剂提取物的膏剂:
人参、麦冬、五味子、茯苓、清半夏、玄参、麸炒苍术、陈皮、甘草、柴胡、升麻、薏苡仁、黄芩、马鞭草、芦根和淡竹叶。
本领域技术人员根据本申请说明书中所述的方法和本领域中已知的方法,可以轻易地制备得到本发明的中药组合物和中药制剂。
本领域技术人员根据本申请说明书中所述的方法和本领域中已知的方法,可以轻易地将本发明的中药组合物和中药制剂制备成临床上所需要的任何剂型。
另一方面,本发明提供一种根据本发明的中药组合物在制备适用于有效预防、治疗或缓解感染性疾病后遗症或并发症或促进受损由感染性疾病引起的组织、器官或系统的功能恢复的药物中的用途。
可替代地,本发明提供一种预防、治疗或缓解感染性疾病后遗症或并发症或促进受损由感染性疾病引起的组织、器官或系统的功能恢复的方法,该方法包括给予有需要的患者有效量的根据本发明的中药组合物或中药制剂。
或者,本发明提供一种如本申请中所述的中药组合物或中药制剂,其用于预防、治疗或缓解感染性疾病后遗症或并发症或促进受损由感染性疾病引起的组织、器官或系统的功能恢复。
本发明的中药组合物和中药制剂可以益气养阴、调理脾胃、清除虚热、除烦躁,适用于预防、治疗或缓解感染性疾病后遗症或并发症或促进受损由感染性疾病引起的组织、器官或系统的功能恢复。经研究证明,本发明的中药组合物和中药制剂具有显著的抗炎、抗氧化、增强机体免疫和脏器保护等有益效果。因此,预期根据本发明的中药组合物和中药制剂可以用于预防、治疗或缓解感染性疾病后遗症或并发症或促进受损由感染性疾病引起的组织、器官或系统的功能恢复,所述的后遗症或并发症包括但不限于急性感染后急腹症;脓毒血症;手术后气虚,大汗淋漓;以及病原微生物感染后身体虚弱,倦怠,乏力等。
附图简要说明
图1显示了CCK-8法检测本发明中药组合物样品对293T细胞活力的影响
Figure PCTCN2021137881-appb-000001
Figure PCTCN2021137881-appb-000002
(n=18)。
图2显示了LDH法检测本发明中药组合物样品对293T细胞活力的影响
Figure PCTCN2021137881-appb-000003
(n=18)。
图3显示了不同浓度本发明中药组合物样品对293T细胞ARE萤光素酶活性的影响(x±SD)(n=18)。 ***P<0.001相对于对照。
图4显示了CCK-8法检测本发明中药组合物样品对RAW264.7细胞活力的影响
Figure PCTCN2021137881-appb-000004
(n=18)。 ***P<0.001相对于对照, **0.001<P<0.01相对于对照。
图5显示了LDH法检测本发明中药组合物样品对RAW264.7细胞活力的影响
Figure PCTCN2021137881-appb-000005
Figure PCTCN2021137881-appb-000006
(n=18)。 ***P<0.001相对于对照
图6显示了不同浓度本发明中药组合物样品对RAW264.7细胞NO释放的影响(x±SD)(n=18)。 ***P<0.001相对于对照, ###P<0.001相对于模型, ##0.001<P<0.01相 对于模型, #P<0.5相对于模型。
发明详细说明
上文已从一般方面概述了本发明,下面将结合实施例进一步详细描述本发明。
为准确理解本发明中所使用的术语,下面特别定义部分术语的含义。对于在此没有特别定义的术语,它们具有本领域技术人员普遍理解和接受的含义。如果在此所定义的某个术语的含义与本领域技术人员普遍理解和接受的含义不一致,则该术语的含义以在此所定义的含义为准。
本发明中使用的术语“人参”是指五加科植物人参Panax ginseng C.A.Mey.的干燥根和根茎。
本发明中使用的术语“麦冬”是指百合科植物麦冬Ophiopogon japonicus(L.f)Ker-Gawl.的干燥块根。
本发明中使用的术语“五味子”是指木兰科植物五味子Schisandra chinensis(Turcz.)Baill.的干燥成熟果实。习称“北五味子”。
本发明中使用的术语“茯苓”为多孔菌科真菌茯苓Poria cocos(Schw.)Wolf的干燥菌核。
本发明中使用的术语“清半夏”为半夏按照如下方法炮制加工而成的产品:取净半夏,大小分开,用8%白矾溶液浸泡至内无干心,口尝微有麻舌感,取出,洗净,切厚片,干燥。术语“半夏”为天南星科植物半夏Pinellia ternata(Thunb.)Breit.的干燥块茎。
本发明中使用的术语“玄参”是指玄参科植物玄参Scrophularia ningpoensis Hemsl.的千燥根。
本发明中使用的术语“麸炒苍术”为按照麸炒法加工苍术片而成的产品。术语“苍术”是指菊科植物苍术Atractylodes lancea(Thunb.)DC.或北苍术Atractylodes chinensis(DC.)Koidz.的干燥根茎。
本发明中使用的术语“陈皮”为芸香科植物橘Citrus reticulata Blanco及其栽培变种的干燥成熟果皮。
本发明中使用的术语“甘草”是指豆科植物甘草Glycyrrhiza uralensis Fisch.、胀果甘草Glycyrrhiza inflata Bat.或光果甘草Glycyrrhiza glabra L.的干燥根和根茎。
本发明中使用的术语“柴胡”为伞形科植物柴胡Bupleurum chinense DC.或狭叶柴胡Bupleurum scorzonerifolium Willd.的干燥根。
本发明中使用的术语“升麻”为毛茛科植物大三叶升麻Cimicifuga heracleifolia Kom.、兴 安升麻Cimicifuga dahurica(Turcz.)Maxim.或升麻Cimicifuga foetida L.的干燥根茎。
本发明中使用的术语“薏苡仁”是指禾本科植物薏苡Coixlacryma-jobi L.var.ma-yuen(Roman.)Stapf的干燥成熟种仁。
本发明中使用的术语“黄芩”为唇形科植物黄芩Scutellaria baicalensis Georgi的干燥根。
本发明中使用的术语“马鞭草”是指马鞭草科植物马鞭草Verbena officinalis L.的干燥地上部分。
本发明中使用的术语“芦根”是指禾本科植物芦苇Phragmites communis Trin.的新鲜或干燥根茎。
本发明中使用的术语“淡竹叶”为禾本科植物淡竹叶Lophatherum gracile Brongn.的干燥茎叶。
本发明中使用的术语“原药材粉末”是指采用物理方法,例如粗粉碎、细粉碎、微粉化和物理破壁粉碎等方法将中药材饮片加工成的全成分无添加的中药材粉末。
本发明中使用的术语“配方颗粒”是指采用现代科学技术,仿照传统中药汤剂煎煮的方式,将中药饮片经浸提,浓缩,干燥等工艺精制而成的单味中药产品。产品保持了中药饮片的性味与功效,质量稳定可靠,应用于中医临诊处方的调配,适应辨证施治,处方变化的需要,且有不需煎煮,服用方便的优点。
本发明中使用的术语“溶剂提取物”是指用合适的可药用溶剂例如水或醇水溶液提取任何形式的所述中药材(包括中药材饮片、中药材粉末,例如中药材微粉化粉末)得到的物质,包括特定的有效成分和包含有效成分的混合物,该物质适用于重大疾病例如新冠肺炎恢复期患者康复,有效预防、治疗或缓解感染性疾病后遗症或并发症或促进受损由感染性疾病引起的组织、器官或系统的功能恢复。溶剂提取物的形式包括但不限于固体、半固体、溶液、混悬液、浓缩液、膏状体和粉末。适用于本发明中提取中药材以得到提取物的水包括可用于制备中药活性提取物的各种水,例如药用水,例如蒸馏水和去离子水等。
本发明中使用的术语“醇水溶液”是指适合浓度(例如低浓度,特别是10-50%v/v)的含醇水溶液,适用的醇包括各种醇,优选乙醇。在一定条件下,也可以使用浓度高于50%v/v的含醇水溶液。
本发明中使用的术语“患者”与“受试者”可以相互代替使用,是指患有疾病例如新冠肺炎的哺乳动物,特别是指人。
本发明中所用的术语“药剂学上可接受的辅料”意指在药物制剂领域中常规使用的任何辅料,只要该辅料不对本发明的中药组合物的预期质量和疗效产生不良反应或影响。
本发明中所用的术语“单位剂量形式”意指适合于作为用于人体受试者和其它哺乳动物的单位剂量的物理分散单位,每个单位包含计算产生所需治疗作用的预定量的本发明的中药活性提取物与合适的药物辅料。
本申请中公开的所有数值范围包括其端值在内且包括没有明确列出的该范围内的任何小范围。
根据本发明的一方面,提供适用于有效预防、治疗或缓解感染性疾病后遗症或并发症或促进受损由感染性疾病引起的组织、器官或系统的功能恢复的中药组合物和中药制剂。
在一个实施方案中,本发明的中药组合物由如下重量份的任何形式的中药材组成或由这些中药材制成:
人参2-4份、麦冬4-8份、五味子2-4份、茯苓6-10份、清半夏6-10份、玄参4-8份、麸炒苍术4-6份、陈皮4-8份、甘草2-4份、柴胡4-8份、升麻2-4份、薏苡仁8-12份、黄芩8-12份、马鞭草8-12份、芦根12-18份和淡竹叶1-3份。
在一个优选的实施方案中,本发明的中药组合物由如下重量份的任何形式的中药材组成或由这些中药材制成:
人参3份、麦冬6份、五味子3份、茯苓8份、清半夏8份、玄参6份、麸炒苍术5份、陈皮6份、甘草3份、柴胡6份、升麻3份、薏苡仁10份、黄芩10份、马鞭草10份、芦根15份和淡竹叶2份。
在一个实施方案中,本发明的中药组合物为如下重量份的中药材各自原药材粉末的混合物或原药材混合物的粉末:
人参2-4份、麦冬4-8份、五味子2-4份、茯苓6-10份、清半夏6-10份、玄参4-8份、麸炒苍术4-6份、陈皮4-8份、甘草2-4份、柴胡4-8份、升麻2-4份、薏苡仁8-12份、黄芩8-12份、马鞭草8-12份、芦根12-18份和淡竹叶1-3份。
在一个优选的实施方案中,本发明的中药组合物为如下重量份的中药材各自原药材粉末的混合物或原药材混合物的粉末:
人参3份、麦冬6份、五味子3份、茯苓8份、清半夏8份、玄参6份、麸炒苍术5份、陈皮6份、甘草3份、柴胡6份、升麻3份、薏苡仁10份、黄芩10份、马鞭草10份、芦根15份和淡竹叶2份。
在一个实施方案中,本发明的中药组合物由如下重量份的中药材各自的配方颗粒组成:
人参2-4份、麦冬4-8份、五味子2-4份、茯苓6-10份、清半夏6-10份、玄参4-8份、麸炒苍术4-6份、陈皮4-8份、甘草2-4份、柴胡4-8份、升麻2-4份、薏苡仁8-12份、黄 芩8-12份、马鞭草8-12份、芦根12-18份和淡竹叶1-3份。
在一个优选的实施方案中,本发明的中药组合物由如下重量份的中药材各自的配方颗粒组成:
人参3份、麦冬6份、五味子3份、茯苓8份、清半夏8份、玄参6份、麸炒苍术5份、陈皮6份、甘草3份、柴胡6份、升麻3份、薏苡仁10份、黄芩10份、马鞭草10份、芦根15份和淡竹叶2份。
在一个实施方案中,本发明的中药组合物为如下重量份的中药材混合物的任何形式的溶剂提取物:
人参2-4份、麦冬4-8份、五味子2-4份、茯苓6-10份、清半夏6-10份、玄参4-8份、麸炒苍术4-6份、陈皮4-8份、甘草2-4份、柴胡4-8份、升麻2-4份、薏苡仁8-12份、黄芩8-12份、马鞭草8-12份、芦根12-18份和淡竹叶1-3份,
其中所述的溶剂是指如本说明书中所定义可用于提取中药活性成分或制备中药制剂的任何适用的溶剂,且其中所述的提取物的形式可以是溶液、颗粒和冻干粉等。
在一个优选的实施方案中,本发明的中药组合物为如下重量份的中药材混合物的任何形式的溶剂提取物:
人参3份、麦冬6份、五味子3份、茯苓8份、清半夏8份、玄参6份、麸炒苍术5份、陈皮6份、甘草3份、柴胡6份、升麻3份、薏苡仁10份、黄芩10份、马鞭草10份、芦根15份和淡竹叶2份,
其中所述的溶剂是指如本说明书中所定义可用于提取中药活性成分或制备中药制剂的任何适用的溶剂,且其中所述的提取物的形式可以是溶液、颗粒和冻干粉等。
在一个实施方案中,本发明的中药组合物也可以是如下重量份的中药材分开提取的提取物的混合物:
人参2-4份、麦冬4-8份、五味子2-4份、茯苓6-10份、清半夏6-10份、玄参4-8份、麸炒苍术4-6份、陈皮4-8份、甘草2-4份、柴胡4-8份、升麻2-4份、薏苡仁8-12份、黄芩8-12份、马鞭草8-12份、芦根12-18份和淡竹叶1-3份,
其中所述的提取物的形式可以是溶液、颗粒和冻干粉等。
在一个优选的实施方案中,本发明的中药组合物也可以是如下重量份的中药材分开提取的提取物的混合物:
人参3份、麦冬6份、五味子3份、茯苓8份、清半夏8份、玄参6份、麸炒苍术5份、陈皮6份、甘草3份、柴胡6份、升麻3份、薏苡仁10份、黄芩10份、马鞭草10 份、芦根15份和淡竹叶2份,
其中所述的提取物的形式可以是溶液、颗粒和冻干粉等。
在一个实施方案中,本发明的中药组合物为如下重量份的中药材混合物的水提取物:
人参2-4份、麦冬4-8份、五味子2-4份、茯苓6-10份、清半夏6-10份、玄参4-8份、麸炒苍术4-6份、陈皮4-8份、甘草2-4份、柴胡4-8份、升麻2-4份、薏苡仁8-12份、黄芩8-12份、马鞭草8-12份、芦根12-18份和淡竹叶1-3份。
在一个优选的实施方案中,本发明的中药组合物为如下重量份的中药材混合物的水提取物:
人参3份、麦冬6份、五味子3份、茯苓8份、清半夏8份、玄参6份、麸炒苍术5份、陈皮6份、甘草3份、柴胡6份、升麻3份、薏苡仁10份、黄芩10份、马鞭草10份、芦根15份和淡竹叶2份。
在一个实施方案中,本发明的中药组合物为如下重量份的中药材混合物的醇水溶液提取物:
人参2-4份、麦冬4-8份、五味子2-4份、茯苓6-10份、清半夏6-10份、玄参4-8份、麸炒苍术4-6份、陈皮4-8份、甘草2-4份、柴胡4-8份、升麻2-4份、薏苡仁8-12份、黄芩8-12份、马鞭草8-12份、芦根12-18份和淡竹叶1-3份,
其中所述的醇水溶液包括如本说明书中所定义的。
在一个优选的实施方案中,本发明的中药组合物为如下重量份的中药材混合物的醇水溶液提取物:
人参3份、麦冬6份、五味子3份、茯苓8份、清半夏8份、玄参6份、麸炒苍术5份、陈皮6份、甘草3份、柴胡6份、升麻3份、薏苡仁10份、黄芩10份、马鞭草10份、芦根15份和淡竹叶2份,
其中所述的醇水溶液包括如本说明书中所定义的。
在一个实施方案中,本发明的中药组合物为如下重量份的中药材混合物的醇水溶液提取物:
人参2-4份、麦冬4-8份、五味子2-4份、茯苓6-10份、清半夏6-10份、玄参4-8份、麸炒苍术4-6份、陈皮4-8份、甘草2-4份、柴胡4-8份、升麻2-4份、薏苡仁8-12份、黄芩8-12份、马鞭草8-12份、芦根12-18份和淡竹叶1-3份,
其中所述的醇水溶液包括如本说明书中所定义的。
在一个优选的实施方案中,本发明的中药组合物为如下重量份的中药材混合物的醇水 溶液提取物:
人参3份、麦冬6份、五味子3份、茯苓8份、清半夏8份、玄参6份、麸炒苍术5份、陈皮6份、甘草3份、柴胡6份、升麻3份、薏苡仁10份、黄芩10份、马鞭草10份、芦根15份和淡竹叶2份,
其中所述的醇水溶液包括如本说明书中所定义的。
本发明的中药组合物可以被制成任何临床上适用剂型的制剂。本发明的中药制剂除包含本发明的中药组合物外,还可以包含药剂学上可接受的辅料。
在一个实施方案中,本发明的中药制剂包含如下重量份的任何形式的中药材,或其分开提取或合并提取得到的提取物:
人参2-4份、麦冬4-8份、五味子2-4份、茯苓6-10份、清半夏6-10份、玄参4-8份、麸炒苍术4-6份、陈皮4-8份、甘草2-4份、柴胡4-8份、升麻2-4份、薏苡仁8-12份、黄芩8-12份、马鞭草8-12份、芦根12-18份和淡竹叶1-3份,
可以另外包含或不包含药剂学上可接受的辅料。
在一个优选的实施方案中,本发明的中药制剂包含如下重量份的任何形式的中药材,或其分开提取或合并提取得到的提取物:
人参3份、麦冬6份、五味子3份、茯苓8份、清半夏8份、玄参6份、麸炒苍术5份、陈皮6份、甘草3份、柴胡6份、升麻3份、薏苡仁10份、黄芩10份、马鞭草10份、芦根15份和淡竹叶2份,
可以另外包含或不包含药剂学上可接受的辅料。
根据本发明的中药制剂可以根据临床需要被配制成适当的剂型,例如溶液剂、汤剂、颗粒剂、散剂、冲剂、丸剂、片剂、膏剂、胶囊剂或糖浆剂。
在一个实施方案中,本发明的中药制剂为由如下重量份的中药材制成的单位剂量形式的口服溶液:
人参2-4份、麦冬4-8份、五味子2-4份、茯苓6-10份、清半夏6-10份、玄参4-8份、麸炒苍术4-6份、陈皮4-8份、甘草2-4份、柴胡4-8份、升麻2-4份、薏苡仁8-12份、黄芩8-12份、马鞭草8-12份、芦根12-18份和淡竹叶1-3份。
在一个优选的实施方案中,本发明的中药制剂为由如下重量份的中药材制成的单位剂量形式的口服溶液:
人参3份、麦冬6份、五味子3份、茯苓8份、清半夏8份、玄参6份、麸炒苍术5份、陈皮6份、甘草3份、柴胡6份、升麻3份、薏苡仁10份、黄芩10份、马鞭草10 份、芦根15份和淡竹叶2份。
在一个实施方案中,本发明的中药制剂为由如下重量份的中药材制成的单位剂量形式的汤剂:
人参2-4份、麦冬4-8份、五味子2-4份、茯苓6-10份、清半夏6-10份、玄参4-8份、麸炒苍术4-6份、陈皮4-8份、甘草2-4份、柴胡4-8份、升麻2-4份、薏苡仁8-12份、黄芩8-12份、马鞭草8-12份、芦根12-18份和淡竹叶1-3份。
在一个优选的实施方案中,本发明的中药制剂为由如下重量份的中药材制成的单位剂量形式的汤剂:
人参3份、麦冬6份、五味子3份、茯苓8份、清半夏8份、玄参6份、麸炒苍术5份、陈皮6份、甘草3份、柴胡6份、升麻3份、薏苡仁10份、黄芩10份、马鞭草10份、芦根15份和淡竹叶2份。
在另一个实施方案中,本发明的中药制剂为由如下重量份的中药材制成的单位剂量形式的颗粒剂:
人参2-4份、麦冬4-8份、五味子2-4份、茯苓6-10份、清半夏6-10份、玄参4-8份、麸炒苍术4-6份、陈皮4-8份、甘草2-4份、柴胡4-8份、升麻2-4份、薏苡仁8-12份、黄芩8-12份、马鞭草8-12份、芦根12-18份和淡竹叶1-3份。
在另一个实施方案中,本发明的中药制剂为颗粒剂,其包含
(i)由如下重量份的中药材通过适合的方法制得的提取物:
人参2-4份、麦冬4-8份、五味子2-4份、茯苓6-10份、清半夏6-10份、玄参4-8份、麸炒苍术4-6份、陈皮4-8份、甘草2-4份、柴胡4-8份、升麻2-4份、薏苡仁8-12份、黄芩8-12份、马鞭草8-12份、芦根12-18份和淡竹叶1-3份;以及
(ii)药物颗粒剂中可接受的赋形剂,例如,乳糖、甘露醇或其混合物,优选乳糖:甘露醇的2:1的混合物。
在另一个实施方案中,本发明的中药制剂为颗粒剂,其包含
(i)由如下重量份的中药材通过适合的方法制得的提取物:
人参2-4份、麦冬4-8份、五味子2-4份、茯苓6-10份、清半夏6-10份、玄参4-8份、麸炒苍术4-6份、陈皮4-8份、甘草2-4份、柴胡4-8份、升麻2-4份、薏苡仁8-12份、黄芩8-12份、马鞭草8-12份、芦根12-18份和淡竹叶1-3份;
其中所述的方法包括如下步骤:
按比例称取所述16味药,加水煎煮一次或多次,每次加水量为中药材的2至10倍, 例如2、3、4、5、6、7、8、9或10倍,每次煎煮30至90分钟,例如30、40、50、60、70、80或90分钟,滤过,滤液合并后减压浓缩滤液浓缩至相对密度1.02~1.10(60℃),喷雾干燥,以及
(ii)药物颗粒剂中可接受的赋形剂,例如,乳糖、甘露醇或其混合物,优选乳糖:甘露醇的2:1的混合物。
在另一个优选的实施方案中,本发明的中药制剂为由如下重量份的中药材制成的单位剂量形式的颗粒剂:
人参3份、麦冬6份、五味子3份、茯苓8份、清半夏8份、玄参6份、麸炒苍术5份、陈皮6份、甘草3份、柴胡6份、升麻3份、薏苡仁10份、黄芩10份、马鞭草10份、芦根15份和淡竹叶2份。
在另一个实施方案中,本发明的中药制剂为颗粒剂,其包含
(i)由如下重量份的中药材通过适合的方法制得的提取物:
人参3份、麦冬6份、五味子3份、茯苓8份、清半夏8份、玄参6份、麸炒苍术5份、陈皮6份、甘草3份、柴胡6份、升麻3份、薏苡仁10份、黄芩10份、马鞭草10份、芦根15份和淡竹叶2份;以及
(ii)药物颗粒剂中可接受的赋形剂,例如,乳糖、甘露醇或其混合物,优选乳糖:甘露醇的2:1的混合物。
在另一个实施方案中,本发明的中药制剂为颗粒剂,其包含
(i)由如下重量份的中药材通过适合的方法制得的提取物:
人参3份、麦冬6份、五味子3份、茯苓8份、清半夏8份、玄参6份、麸炒苍术5份、陈皮6份、甘草3份、柴胡6份、升麻3份、薏苡仁10份、黄芩10份、马鞭草10份、芦根15份和淡竹叶2份;
其中所述的方法包括如下步骤:
按比例称取所述16味药,加水煎煮一次或多次,每次加水量为中药材的2至10倍,例如2、3、4、5、6、7、8、9或10倍,每次煎煮30至90分钟,例如30、40、50、60、70、80或90分钟,滤过,滤液合并后减压浓缩滤液浓缩至相对密度1.02~1.10(60℃),喷雾干燥,以及
(ii)药物颗粒剂中可接受的赋形剂,例如,乳糖、甘露醇或其混合物,优选乳糖:甘露醇的2:1的混合物。
在另一个实施方案中,本发明的中药制剂为由如下重量份的中药材制成的单位剂量形 式的散剂:
人参2-4份、麦冬4-8份、五味子2-4份、茯苓6-10份、清半夏6-10份、玄参4-8份、麸炒苍术4-6份、陈皮4-8份、甘草2-4份、柴胡4-8份、升麻2-4份、薏苡仁8-12份、黄芩8-12份、马鞭草8-12份、芦根12-18份和淡竹叶1-3份。
在另一个优选的实施方案中,本发明的中药制剂为由如下重量份的中药材制成的单位剂量形式的散剂:
人参3份、麦冬6份、五味子3份、茯苓8份、清半夏8份、玄参6份、麸炒苍术5份、陈皮6份、甘草3份、柴胡6份、升麻3份、薏苡仁10份、黄芩10份、马鞭草10份、芦根15份和淡竹叶2份。
在还一个实施方案中,本发明的中药制剂为由如下重量份的中药材混合物制成的胶囊剂:
人参2-4份、麦冬4-8份、五味子2-4份、茯苓6-10份、清半夏6-10份、玄参4-8份、麸炒苍术4-6份、陈皮4-8份、甘草2-4份、柴胡4-8份、升麻2-4份、薏苡仁8-12份、黄芩8-12份、马鞭草8-12份、芦根12-18份和淡竹叶1-3份。
在还一个优选的实施方案中,本发明的中药制剂为由如下重量份的中药材混合物制成的胶囊剂:
人参3份、麦冬6份、五味子3份、茯苓8份、清半夏8份、玄参6份、麸炒苍术5份、陈皮6份、甘草3份、柴胡6份、升麻3份、薏苡仁10份、黄芩10份、马鞭草10份、芦根15份和淡竹叶2份。
在还一个实施方案中,本发明的中药制剂为由如下重量份的中药材混合物制成的丸剂:
人参2-4份、麦冬4-8份、五味子2-4份、茯苓6-10份、清半夏6-10份、玄参4-8份、麸炒苍术4-6份、陈皮4-8份、甘草2-4份、柴胡4-8份、升麻2-4份、薏苡仁8-12份、黄芩8-12份、马鞭草8-12份、芦根12-18份和淡竹叶1-3份。
在还一个优选的实施方案中,本发明的中药制剂为由如下重量份的中药材混合物制成的丸剂:
人参3份、麦冬6份、五味子3份、茯苓8份、清半夏8份、玄参6份、麸炒苍术5份、陈皮6份、甘草3份、柴胡6份、升麻3份、薏苡仁10份、黄芩10份、马鞭草10份、芦根15份和淡竹叶2份。
在还一个实施方案中,本发明的中药制剂为由如下重量份的中药材混合物制成的膏剂:
人参2-4份、麦冬4-8份、五味子2-4份、茯苓6-10份、清半夏6-10份、玄参4-8份、 麸炒苍术4-6份、陈皮4-8份、甘草2-4份、柴胡4-8份、升麻2-4份、薏苡仁8-12份、黄芩8-12份、马鞭草8-12份、芦根12-18份和淡竹叶1-3份。
在还一个优选实施方案中,本发明的中药制剂为由如下重量份的中药材混合物制成的膏剂:
人参3份、麦冬6份、五味子3份、茯苓8份、清半夏8份、玄参6份、麸炒苍术5份、陈皮6份、甘草3份、柴胡6份、升麻3份、薏苡仁10份、黄芩10份、马鞭草10份、芦根15份和淡竹叶2份。
本领域技术人员理解,上述中药材的重量份是相对的,可以基于中医药学理论,根据实际需要,对其中一种或多种中药材的量进行合理调整。如此合理调整量的组方的所有显而易见的变化形式都在本发明的范围之内。
如上所述,根据本发明的中药制剂除包含本发明的中药组合物外,还可以包含药剂学上可接受的辅料。可用于本发明的中药组合物中的药剂学上可接受的辅料包括中药制剂中常用的任何辅料,只要该辅料不对本发明的中药组合物的质量、性能和治疗效果产生不利影响即可。中药制剂中常用的辅料包括稀释剂、载体、填充剂、粘合剂、湿润剂、崩解剂、吸收促进剂、表面活性剂、吸附载体和润滑剂等。常用的稀释剂主要有蔗糖、糊精、淀粉、乳糖、甘露醇、木糖醇、双歧糖等。常用的润湿剂主要有水、不同浓度的乙醇等;常用的粘合剂包括高分子粘合剂,其种类非常多,如乙基纤维素、聚乙烯吡咯烷酮、羧甲基纤维素钠、聚乙二醇、海藻酸钠等。常用的崩解剂包括微晶纤维素、羧甲基淀粉钠等。本领域技术人员根据本说明书公开的内容能够选择和确定本发明的中药制剂中适用的辅料。特定辅料的选择将取决于用于治疗特定患者的给药方式或疾病类型和状态。
必要时,本发明的中药制剂中还可以包含适用的添加剂。这些添加剂是本领域中已知的,例如乳化剂、芳香剂、增溶剂、抗结剂、消泡剂、粘合剂、缓冲剂、pH调节剂、推进剂、螯合剂以及防腐剂等。
本领域技术人员根据本说明书中所述的方法和本领域中的已知技术可以轻易地制备得到本发明的中药组合物和中药制剂。
例如,本领域技术人员可以通过包括如下步骤的方法制备得到本发明的中药制剂(口服溶液):
按比例称取所述16味药,加水煎煮一次或多次,每次加水量为中药材的2至10倍,每次煎煮30至90分钟,滤过,滤液合并后减压浓缩,分装,即得本发明的中药制剂(口服溶液)。
另外,本领域技术人员可以通过包括如下步骤的方法制备得到本发明的中药制剂(冻干粉):
按比例称取所述16味药,加水煎煮一次或多次,每次加水量为中药材的2至10倍,每次煎煮30至90分钟,滤过,滤液合并后减压浓缩,冻干,分装,即得本发明的中药制剂(冻干粉)。
此外,本领域技术人员可以通过包括如下步骤的方法制备得到本发明的中药制剂(颗粒剂):
按比例称取所述16味药,加水煎煮一次或多次,每次加水量为中药材的2至10倍,每次煎煮30至90分钟,滤过,滤液合并后减压浓缩滤液浓缩至相对密度1.02~1.10(60℃),喷雾干燥,加入适量辅料(例如,乳糖:甘露醇(2:1)),混匀,干压制粒,分装,即得本发明的中药制剂(颗粒剂)。
类似地,本领域技术人员根据本说明书中所述的方法和本领域中的已知技术可以轻易地制备得到其它剂型的本发明的中药制剂。
对于制备本发明的中药制剂的过程中所涉及的提取、过滤、浓缩、干燥和分装等步骤,本领域技术人员可以本领域中常用的方法和设备实施完成,例如提取液或滤液过滤采用例如100-300目筛过滤。
本领域技术人员知道,在制备本发明的中药制剂的过程中,所述的加水量、提取时间和提取次数不是绝对的,即应用在所述范围以外且接近所述范围端值的相应数值也能用于制备本发明的中药制剂。
本领域技术人员还知道,为了制备本发明的中药制剂,在上述方法步骤中可以增加一个或几个步骤。例如,在提取之前,可以浸泡中药材一段时间,也可以将中药材进行物理加工处理以便有利于活性物质的提取。
本领域技术人员理解,在本说明书公开内容的基础上,可以使用相应的中药材单独或它们的混合物,通过本领域中常规粉碎、浸提和分离方法,例如浸渍、渗滤、液-液萃取、水提醇沉、醇提水沉和透析等方法,制备得到本发明中适用的中药活性提取物和中药制剂。还可以通过商业途径购买本发明中所用中药的一种或几种的活性提取物,然后与其余中药的提取物配伍,得到本发明的中药活性提取物。这些变化形式的中药组合物和中药制剂都在本发明的范围之内。
因此,根据上述方法以及在以下实施例中举例说明的方法,本领域技术人员能够轻易地制备得到本发明的中药组合物,且可以进一步将其制备成所需剂型的中药制剂。
本发明的中药组合物和中药制剂可以益气养阴、调理脾胃、清除虚热、除烦躁,适用于预防、治疗或缓解感染性疾病后遗症或并发症或促进受损由感染性疾病引起的组织、器官或系统的功能恢复。经研究证明,本发明的中药组合物和中药制剂具有显著的抗炎、抗氧化、增强机体免疫和脏器保护等有益效果。因此,根据本发明的中药组合物和中药制剂可以用于预防、治疗或缓解感染性疾病后遗症或并发症或促进受损由感染性疾病引起的组织、器官或系统的功能恢复,所述的后遗症或并发症包括但不限于病原微生物急性感染后急腹症;脓毒血症;手术后气虚,大汗淋漓;以及病原微生物感染后身体虚弱,倦怠,乏力。
因此,根据本发明的另一方面,提供根据本发明的中药组合物或中药制剂用于预防、治疗或缓解感染性疾病后遗症或并发症或促进受损由感染性疾病引起的组织、器官或系统的功能恢复的用途。
在一个实施方案中,提供根据本发明的中药组合物在制备适用于预防、治疗或缓解感染性疾病后遗症或并发症或促进受损由感染性疾病引起的组织、器官或系统的功能恢复的药物中的用途。
在另一个实施方案中,提供一种使用本发明的中药组合物或中药制剂效预防、治疗或缓解感染性疾病后遗症或并发症或促进受损由感染性疾病引起的组织、器官或系统的功能恢复的方法,该方法包括给予有需要的患者有效量的根据本发明的中药组合物或中药制剂。
在一个优选的实施方案中,提供根据本发明的中药组合物在制备适用于预防、治疗或缓解新冠肺炎后遗症或并发症或促进新冠肺炎患者受损由新冠肺炎引起的组织、器官或系统的功能恢复的药物中的用途。
在另一个优选的实施方案中,提供一种使用本发明的中药组合物或中药制剂预防、治疗或缓解新冠肺炎后遗症或并发症或促进新冠肺炎患者受损由新冠肺炎引起的组织、器官或系统的功能恢复的方法,该方法包括给予有需要的新冠肺炎患者有效量的根据本发明的中药组合物或中药制剂。
在一个具体实施方案中,提供根据本发明的中药组合物在制备适用于预防、治疗或缓解新冠肺炎后遗症或并发症的药物中的用途,其中所述的后遗症或并发症包括但不限于心烦意懈、干咳少痰、咽喉不利、动后气短、倦怠乏力、胸腹满闷、纳呆便软、四肢沉重和舌淡少津等症状。
在另一个具体实施方案中,提供一种使用本发明的中药组合物或中药制剂预防、治疗或缓解新冠肺炎后遗症或并发症的方法,该方法包括给予有需要的患者有效量的根据本发 明的中药组合物或中药制剂,其中所述的后遗症或并发症包括但不限于心烦意懈、干咳少痰、咽喉不利、动后气短、倦怠乏力、胸腹满闷、纳呆便软、四肢沉重和舌淡少津等症状。
在再一个具体实施方案中,提供根据本发明的中药组合物在制备适用于预防、治疗或缓解感染性疾病后遗症或并发症的药物中的用途,其中所述的后遗症或并发症包括但不限于病原微生物急性感染后急腹症;脓毒血症;手术后气虚,大汗淋漓;以及病原微生物感染后身体虚弱,倦怠,乏力等。
在再一个具体实施方案中,提供一种使用本发明的中药组合物或中药制剂预防、治疗或缓解感染性疾病后遗症或并发症的方法,该方法包括给予有需要的患者有效量的根据本发明的中药组合物或中药制剂,其中所述的后遗症或并发症包括但不限于病原微生物急性感染后急腹症;脓毒血症;手术后气虚,大汗淋漓;以及病原微生物感染后身体虚弱,倦怠,乏力等。
在再一个具体实施方案中,提供根据本发明的中药组合物作为抗氧化和/或抗炎的药物的用途,或提供根据本发明的中药组合物在制备用于抗氧化和/或抗炎的药物中的用途。
在再一个具体实施方案中,提供根据本发明的中药组合物在制备适用于促进受损由感染性疾病引起的组织、器官或系统的功能恢复的药物中的用途,其中所述的功能包括呼吸有关的功能、躯体活动有关的功能和心理活动有关的功能。
可以通过本领域中常用的任意适用的方式和任意适用的形式施用本发明的中药组合物和中药制剂。例如,本发明的中药组合物和中药制剂可以经由选自如下的方式给药:口服、喷雾吸入、鼻腔给药以及非肠道给药如静脉和肌内等,其中优选口服、肌注或静脉内注射给药。
本发明的中药组合物可以制成单位剂量形式供患者服用。给药剂型可以是液体剂型或固体剂型。液体剂型可以是溶液类、胶体类、乳剂剂型或混悬剂型等。固体剂型可以是例如片剂、粉剂、栓剂、颗粒剂或胶囊等。其它剂型包括气雾剂、贴剂或擦剂等。
通常,本发明的中药组合物可经口服使用,例如,一日两次,每次5-30克,例如10-20克,优选10克本发明的颗粒剂或相应量的其它形式的本发明的中药组合物和中药制剂。具体给药的剂量取决于被治疗的患者的体重、疾病的性质和严重程度、药物的给药方式以及给药周期或时间间隔等因素。对于某些情况特殊的患者,具体给药应遵医嘱。
本发明的中药组合物和中药制剂可以与本领域中已知的其它可用于新冠肺炎恢复期治疗的药物和技术联合使用。本领域技术人员能够想到和确定可以与本发明的中药组合物和中药制剂联合使用且不会产生不利效果的适用于新冠肺炎恢复期治疗的药物和技术。例 如,本发明的中药组合物和中药制剂可以与中医适宜技术联合使用,其中所述的中医适宜技术包括艾灸疗法、经穴推拿、刮痧、拔罐和针刺疗法等。
实施例
为进一步说明本发明,提供下面的实施例。这些实施例仅用于举例说明本发明,本发明的范围不限于所提供的实施例。
下面实施例中使用的中药材均从市场购得且经鉴别合格,所使用的实验试剂和实验仪器为本领域中的常用实验试剂和实验仪器,并且所使用的测定方法为本领域中的常用方法,特别说明的除外。
实施例1:本发明中药组合物(颗粒剂)的制备
配方组成:
人参3克、麦冬6克、五味子3克、茯苓8克、清半夏8克、玄参6克、麸炒苍术5克、陈皮6克、甘草3克、柴胡6克、升麻3克、薏苡仁10克、黄芩10克、马鞭草10克、芦根15克和淡竹叶2克。
以上各中药材均从市场上购得。参照《中国药典》2020年版收载的上述各中药材项下的薄层鉴别方法,对各中药材进行了薄层鉴别研究,结果表明各中药材均合格。
制备方法:
以上十六味,水煎煮两次,第一次60分钟,第二次40分钟,加水量分别是8倍、6倍,滤过,滤液浓缩至相对密度1.02~1.10(60℃)。喷雾干燥,加入适量辅料(乳糖:甘露醇(2:1)),混匀,干压制粒,分装为二袋,即得本发明的中药组合物颗粒剂。
实施例2:本发明中药组合物抗氧化/抗炎药效学实验研究
本实验基于ARE和NF-κB的萤光素酶报告基因系统考察了本发明中药组合物对ARE、NF-κB活性的影响,探讨了本发明中药组合物的抗氧化、抗炎作用。
1材料与方法
1.1实验仪器
Figure PCTCN2021137881-appb-000007
Figure PCTCN2021137881-appb-000008
1.2实验试剂
Figure PCTCN2021137881-appb-000009
1.3实验药物
根据实施例1的方法制备的本发明中药组合物(颗粒剂)。
1.4阳性药物
地塞米松,MedChemExpress公司。批号:HY-14648,在有效期内。规格:500mg,用法用量:参照临床用法,配制成10mM母液。
tBHQ((Tertiary butylhydroquinone,特丁基对苯二酚),MedChemExpress公司。批号:HY-100489,在有效期内。规格:500mg,用法用量:参照临床用法,配置成100mM母液。
1.5试验细胞
293T细胞,购于ATCC细胞库。
1.6感受态细胞DH5a
感受态细胞DH5a购自天根生化科技有限公司
1.7剂量设计和药物配制
本发明中药组合物:0.01μg/mL、0.1μg/mL、1μg/mL、10μg/mL、100μg/mL。
药液配制:试验前用蒸馏水将颗粒剂配制成100mg/mL浓度的药液,使用时稀释成实验浓度。
1.8质粒提取
1.8.1 LB液体培养基的制备
将三角瓶经高温高压灭菌后,向瓶内加入2.5g LB液体培养基干粉,并加入100mL灭菌的超纯水使其溶解完全,瓶口贴上滤膜后,于高温高压下灭菌。待冷却至55℃左右时,加入100mg/mL氨苄西林100μL,混匀即得。细胞培养于含10%FBS的DMEM培养基中,待培养瓶内细胞长至80-90%时进行传代。
1.8.2 LB固体培基的制备
取LB固体培养基干粉0.4g,LB液体培养基干粉0.3g于经高温高压灭菌的三角瓶中,加入灭菌超纯水20mL,加热煮沸,搅拌溶解,高压灭菌,待冷却至50-60℃时,加入50μL氨苄西林(50μg/mL),混匀即得。将上述溶液分装于培养皿中,待冷却凝固后,盖上盖子,倒置,于4℃冰箱中保存。
1.8.3质粒载体的转化与验证
轻微混匀感受态细胞DH5a后取100μL于15mL离心管中,加入1μL质粒pGL4.37样品,置于冰上30min,立刻转入42℃水浴中孵育45s,后转置冰中停留1-2min,完成感受态细胞的转化。吸取上述转化的感受态细胞100μL到适量LB液体培养基中,混匀。用无菌的涂布器取适量上述菌液均匀涂布于LB固体培养基上,于室温放置至菌液完全被吸收。于37℃条件下倒置培养12h。
在生物安全柜中,挑取6个单克隆菌粒,分别加入到6个含有适量LB液体培养基的锥形瓶中得标号1-6的6份菌液样品。将上述样品于37℃恒温,160rpm振荡12h后,各编号样品各取1mL于离心管中,送华大基因测序,鉴定阳性克隆。
1.8.4质粒的提取及测定
(1)向吸附柱CP3中加入500μL的平衡液BL,12000rpm,离心1min,倒掉收集管中的废液,将吸附柱重新放回收集管中。
(2)取1-5mL过夜培养的菌液,加入离心管中,12000rpm,离心1min,尽量吸除上清,菌液较多时可以通过多次离心将菌体沉淀收集到一个离心管中。
(3)向留有菌体沉淀的离心管中加入250μL溶液P1,彻底悬浮菌体沉淀。
(4)向离心管中加入250μL溶液P2,温和地上下翻转6-8次使菌体充分地裂解。
(5)向离心管中加入350μL溶液P3,立即温和地上下翻转6-8次,充分混匀后,12000rpm离心10min。
(6)将上一步收集的上清液用移液器转移到吸附柱CP3中,12000rpm,离心30-60s,倒掉收集管中的废液,将吸附柱CP3放入收集管中。
(7)向吸附柱CP3中加入600μL漂洗液PW,12000rpm,离心30-60s,倒掉收集管中的废液,将吸附柱CP3放入收集管中。
(8)重复步骤(7)。
(9)将吸附柱CP3放入收集管中,12000rpm,离心2min。
(10)将吸附柱CP3置于一个干净的离心管中,向吸附膜的中间部位滴加50-100μL洗脱缓冲液EB,室温放置2min,12000rpm,离心2min,取上清于干净的离心管中,即得质粒溶液。
(11)取1μL质粒溶液,以DEPC水作空白对照。在紫外分光光度计上分别读取260nm、280nm波长下的光密度值。
1.9分组与检测
细胞毒性检测分为空白对照组以及0.01μg/mL、0.1μg/mL、1μg/mL、10μg/mL、100μg/mL 5个本发明中药组合物浓度组;
抗氧化活性检测分为空白对照组、阳性药tBHQ组以及0.01μg/mL、0.1μg/mL、1μg/mL、10μg/mL、100μg/mL 5个本发明中药组合物浓度组;
抗炎作用检测分为空白对照组、模型组、阳性药地塞米松组以及0.01μg/mL、0.1μg/mL、1μg/mL、10μg/mL、100μg/mL 5个本发明中药组合物浓度组。
1.10细胞培养
1.10.1 293T细胞复苏
将293T细胞株从液氮罐中取出,立即放入37℃的恒温水浴锅中,轻微晃动,使其快速融化。冻存管经酒精棉擦拭后转入生物安全柜,用移液枪将细胞吸至加入完全培养基的离心管中,1000rpm,4℃,离心3min,弃掉上清液,加入5mL完全培养基,用移液枪吹散均匀后转移到25cm 2的培养瓶中。于37℃,5%CO 2细胞培养箱中培养。24h后更换培养瓶内的培养液。根据细胞的生长状态进行传代培养。
1.10.2 293T细胞传代
在DMIL倒置相差显微镜下观察细胞,待培养瓶内细胞长至80-90%时进行传代。从培养箱中取出培养瓶,弃掉瓶内培养液,加入2mL PBS缓冲液润洗两次,加入500μL 0.25%的胰酶(含0.25%EDTA),消化约15s,至细胞大部分凸起变圆,加入1mL完全培养基终止消化。将细胞悬液转入离心管内,1000rpm,4℃,离心3min。弃上清,加入4mL完全培养基轻轻吹打至细胞分散均匀,1:4传至新的培养瓶。
1.10.3 293T细胞计数
取干净的细胞计数板,盖上盖玻片,将10μL分散均匀的细胞悬液从盖玻片与计数板的边沿加入使之充满计数板和盖玻片之间。置倒置显微镜镜下观察,计算四个方格区域内的细胞数,压线细胞只计算左线和上线细胞,成团细胞按单个细胞计算。
按照以下公式计算细胞密度:
细胞数/mL=(四个方格区域内的细胞数)/4×10 4×稀释倍数
1.11药物溶液的配制
分别精密称取本发明中药组合物0.1mg于1mL水中,得100mg/mL的本发明中药组合物标准储备液,采用DMEM培养基逐级稀释的方式配置其100μg/mL、10μg/mL、1μg/mL、0.1μg/mL、0.01μg/mL的样品溶液。
1.12细胞毒性实验
本实验使用CCK-8、LDH试剂盒考察不同浓度的本发明中药组合物对293T细胞活力的影响。
取对数生长期的293T细胞,以2×10 5个/mL的密度接种于96孔细胞培养板中,贴壁生长达70%-80%后,将0.01-100μg/mL的本发明中药组合物分别加入不同的细胞培养孔中,每孔100μL,每个浓度6个复孔,同时设置未加入药物的Control组,重复3次。培养24h后,吸取上清液置于另一新96孔板中,按LDH试剂盒操作检测LDH释放量。原96孔板用PBS清洗1次后每孔加入100μL稀释的1×CCK-8工作液,37℃孵育1h。置酶标仪于450nm处测定吸光度(OD值)。
按下列公式,计算细胞存活率:
细胞存活率(%)=(As-Ab)/(Ac-Ab)×100%
其中As代表实验孔的吸光度,Ab代表空白孔的吸光度,Ac代表对照孔的吸光度。
1.13 293T细胞瞬时共转染及ARE和NF-κB活性的测定
1.13.1 293T细胞瞬时共转染
取对数生长期的293T细胞,以2×10 5个/mL的密度接种于96孔细胞培养板中,待细 胞生长密度达到70%-80%时,使用PEI(1mg/mL)转染试剂分别同时转染ARE、NF-κB萤光素酶报告质粒pGL4.37、pGL4.32(100ng/孔)和海肾萤光素酶报告质粒pGL4.75(10ng/孔),培养24h。
1.13.2双萤光素酶报告系统检测分析测定ARE和NF-κB转录活性
培养24h后,转染ARE萤光素酶报告质粒pGL4.37的细胞,分别加入tBHQ(10μM)、安全浓度的本发明中药组合物各组样品溶液,并设置Control组,培养6h;转染NF-κB萤光素酶报告质粒pGL4.32的细胞,分别加入含TNF-α(10ng/mL)的全培稀释的地塞米松(10μM)、安全浓度的本发明中药组合物各组样品溶液,并设置Control组、Model组(10ng/mL TNF-α),培养6h。弃上清液,PBS漂洗细胞,裂解后用Dual-Luciferase检测系统检测。每组实验设置6个复孔,重复3次。通过萤火虫萤光素酶活性与海肾萤光素酶活性对比得到相对萤光素酶活性值。L/S=Luciferase活性值/Renilla活性值。
2实验结果
2.1本发明中药组合物对293T细胞毒性的测定
0.01-100μg/mL本发明中药组合物组293T细胞活力与正常对照组相比无显著性差异,为药物对293T细胞安全浓度。采用药物的安全浓度探讨本发明中药组合物的抗氧化、抗炎作用(见图1和图2)。
2.2本发明中药组合物对ARE报告基因活性的影响
采用293T细胞转染对本发明中药组合物样品溶液进行抗氧化活性验证。结果显示,100μg/mL本发明中药组合物可显著诱导ARE萤光素酶活性(P<0.001)(见表1,图3)。
表1:不同浓度本发明中药组合物对293T细胞ARE萤光素酶活性的影响
(x±SD)(n=18)
Figure PCTCN2021137881-appb-000010
注:***P<0.001,与对照相比。
3小结
100μg/mL本发明中药组合物具有明显抗氧化作用。
实施例3:本发明中药组合物对LPS诱导的RAW264.7
细胞炎性因子表达的作用研究
本实验考察了本发明中药组合物对LPS诱导的RAW264.7巨噬细胞炎性因子释放的影响,探讨了本发明中药组合物的抗炎作用。
1材料和方法
1.1实验仪器
Figure PCTCN2021137881-appb-000011
1.2实验试剂
Figure PCTCN2021137881-appb-000012
1.3实验药物:根据实施例1的方法制备的本发明中药组合物(颗粒剂)。
1.4实验细胞株:RAW264.7细胞,购买自中国科学院上海生命科学研究院细胞资源中心。
1.5溶解本发明中药组合物:
精密称取本发明中药组合物118.9mg溶于1.189mL灭菌超纯水中,得100mg/mL的本发明中药组合物标准储备液,采用灭菌超纯水梯度稀释的方式配制其10mg/mL、1mg/mL、0.1mg/mL、0.01mg/mL的备用溶液,采用DMEM倍数法稀释的方式配制其1000μg/mL、800μg/mL、400μg/mL、200μg/mL、100μg/mL、10μg/mL、1μg/mL、0.1μg/mL、0.01μg/mL的样品溶液。
1.6溶解LPS:
将10mL灭菌超纯水加入到规格为10mg的LPS粉末中充分溶解,用0.22μm滤膜过滤后,进行分装,置于-20℃保存。
1.7细胞培养方法
1.7.1 RAW264.7细胞复苏实验
从液氮罐中取出冻存管,迅速放于37℃水浴中,快速顺时针晃动,使细胞在1-2min内完全溶解。将细胞移出冻存管,加入3mL培养液(10%FBS+90%DMEM),混匀后在800rpm/min条件下4℃离心5min。弃去上清液,将细胞沉淀用5mL培养液重悬,转移至25cm 2的培养瓶中,放入37℃恒温二氧化碳细胞培养箱培养。
1.7.2 RAW264.7细胞传代实验
在显微镜下观察,细胞融合度至80-90%后,进行传代。提前预热完全培基与PBS。加入1mL PBS润洗细胞表面2次。加入DMEM 3mL,用细胞刮刮下培养瓶内贴壁的细胞。将刮下的细胞液转移至15mL离心管内,4℃,800rpm/min离心5min。离心结束后,弃上清,加5mL完全培养基,反复吹打均匀,按1:4-1:8比例传代。
1.7.3 RAW264.7细胞冻存实验
细胞培养步骤同传代实验,将待冻存细胞于4℃、800rpm/min离心5min。DMEM、胎牛血清、DMSO试剂体积比按7:2:1配制细胞冻存液,用一定体积的冻存液反复吹打细胞,将细胞混匀。按每瓶1mL分装入冻存管,以缓冻速溶原则,放入梯度降温冻存盒,置于-80℃冰箱24h后,转到液氮中长期冻存。
1.7.4 RAW264.7细胞计数
取干净的细胞计数板,盖上盖玻片,将10μL分散均匀的细胞悬液从盖玻片与计数板的边沿加入使之充满计数板和盖玻片之间。置倒显微镜镜下观察,计算四个方格区域内的细胞数,压线细胞只计算左线和上线细胞,成团细胞按单个细胞计算。
按照以下公式计算细胞密度:
细胞数/mL=(四个方格区域内的细胞数)/4×104×稀释倍数
1.8细胞活力检测
本实验使用CCK-8、LDH试剂盒考察不同浓度的本发明中药组合物对RAW264.7细胞活力的影响。
收集对数生长期的RAW264.7细胞,按2×10 5个/mL密度接种于96孔板。24h后分别加入0.01、0.1、1、10、100、200、400、800、1000μg/mL的本发明中药组合物,每孔100μL,每个浓度6个复孔,同时设置未加入药物的Control组。加药处理24h后,取出培养板,吸去上清液,每孔加入100μL稀释10倍的CCK-8溶液,37℃孵育30min,酶标仪于450nm处检测吸光度OD值,并计算细胞活力。
收集对数生长期的RAW264.7细胞,按2×10 5个/mL密度接种于96孔板。24h后分别加入0.01、0.1、1、10、100、200、400、800、1000μg/mL的本发明中药组合物,每孔100μL,每个浓度6个复孔,同时设置未加入药物的Control组。加药处理24h后,取出培养板,依照说明书,每孔取50μL上清平行转移到新的96孔空白培养板中,每孔加入配置好的Assay Buffer 50μL,震荡混匀后室温避光孵育15min。15min后每孔加入25μL Stop Solution,终止反应,于多功能酶标仪492nm处检测相应的吸光度OD值,并计算LDH漏出量。
1.9建立LPS诱导的RAW264.7细胞炎症模型
RAW264.7细胞以2×10 5个/mL密度接种于96孔板,24h后分组处理细胞。模型组加入终浓度为1μg/mL的LPS;对照组用DMEM代替LPS;药物处理组的培养基除加入LPS外,还分别加入终浓度含0.01、0.1、1、10、100、200、400、800、1000μg/mL的清金益气,LPS预刺激2h后,再加LPS刺激20h后收集细胞待测。
1.10 NO释放量检测
收集对数生长期的RAW264.7细胞,按2×10 5个/mL密度接种于96孔板。24h后分别加入0.1、1、10、100、200、400、800、1000μg/mL的本发明中药组合物,每孔100μL,每个浓度6个复孔,同时设置未加入药物的Control组和Model组(1μg/mL LPS)。加药处理24h后,取出培养板,进行NO释放量检测。取出Griess Reagent I和II,使恢复室 温。用DMEM+10%FBS稀释标准品(1-100μM)。标准品的浓度为0,1,2,5,10,20,40,60,100μM。按50μL/孔,在96孔板中加入标准品及样品(培养液上清)。按50μL/孔,在各孔中加入室温Griess Reagent I。按50μL/孔,各孔中加入室温Griess Reagent II。540nm测定吸光度。根据标准品曲线计算出样品中一氧化氮的浓度。
1.11统计方法
实验数据使用SPSS 25.0软件进行单因素方差分析(one-way ANOVA)评估均值之间的差异,P<0.05时认为具有统计学差异,数据表示为平均值±SD。
2实验结果
2.1本发明中药组合物对RAW264.7细胞的无毒剂量的筛选
用CCK-8和LDH法检测本发明中药组合物在0.01、0.1、1、10、100、200、400、800、1000μg/mL时,对RAW264.7细胞活力的影响。结果显示,0.01-10μg/mL清金益气组RAW264.7细胞活力与正常对照组相比无显著性差异,100-1000μg/mL清金益气组可显著促进RAW264.7细胞活力(P<0.01,P<0.001)。采用药物的安全浓度探讨本发明中药组合物的抗炎作用(图4-图5)。
2.2本发明中药组合物对LPS诱导的RAW264.7细胞NO释放量的影响
与对照组比较,LPS刺激使RAW264.7细胞的NO表达显著升高(P<0.001);与LPS刺激组比较,100-1000μg/mL的本发明中药组合物可以显著抑制LPS诱导的RAW264.7细胞NO释放(P<0.05,P<0.001)(图6)。
2.3小结:
100-1000μg/mL本发明中药组合物具有显著的抗氧化作用。

Claims (10)

  1. 一种中药组合物,其由任何形式的如下中药材组成或制成:
    人参、麦冬、五味子、茯苓、清半夏、玄参、麸炒苍术、陈皮、甘草、柴胡、升麻、薏苡仁、黄芩、马鞭草、芦根和淡竹叶。
  2. 根据权利要求1的中药组合物,其由如下重量份的中药材组成或制成:
    人参2-4份、麦冬4-8份、五味子2-4份、茯苓6-10份、清半夏6-10份、玄参4-8份、麸炒苍术4-6份、陈皮4-8份、甘草2-4份、柴胡4-8份、升麻2-4份、薏苡仁8-12份、黄芩8-12份、马鞭草8-12份、芦根12-18份和淡竹叶1-3份。
  3. 根据权利要求2的中药组合物,其由如下重量份的中药材组成或制成:
    人参3份、麦冬6份、五味子3份、茯苓8份、清半夏8份、玄参6份、麸炒苍术5份、陈皮6份、甘草3份、柴胡6份、升麻3份、薏苡仁10份、黄芩10份、马鞭草10份、芦根15份和淡竹叶2份。
  4. 一种中药制剂,其包含权利要求1至3任意一项的中药组合物,以及药剂学上可接受的辅料。
  5. 根据权利要求4的中药制剂,其中所述药剂学上可接受的辅料选自稀释剂、载体、填充剂、粘合剂、湿润剂、崩解剂、吸收促进剂、表面活性剂、吸附载体和润滑剂。
  6. 根据权利要求4或5的中药制剂,该制剂为液体制剂、颗粒剂、散剂、丸剂、片剂、胶囊剂、糖浆剂或膏剂。
  7. 权利要求1至3任意一项的中药组合物在制备用于预防、治疗或缓解感染性疾病后遗症或并发症或促进受损由感染性疾病引起的组织、器官或系统的功能恢复的药物中的用途。
  8. 权利要求1至3任意一项的中药组合物在制备用于预防、治疗或缓解新冠肺炎后遗症或并发症或促进新冠肺炎患者受损由新冠肺炎引起的组织、器官或系统的功能恢复的药物中的用途。
  9. 权利要求1至3任意一项的中药组合物在制备用于抗炎和/或抗氧化的药物中的用途。
  10. 权利要求1至3任意一项的中药组合物在制备用于预防、治疗或缓解感染性疾病后遗症或并发症的药物中的用途,其中所述的后遗症或并发症选自病原微生物急性感染后急腹症;脓毒血症;手术后气虚、大汗淋漓;以及病原微生物感染后身体虚弱、倦怠和乏力。
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