WO2023274150A1 - 一种中药组合物在制备治疗咳嗽变异性哮喘药物中的用途 - Google Patents

一种中药组合物在制备治疗咳嗽变异性哮喘药物中的用途 Download PDF

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WO2023274150A1
WO2023274150A1 PCT/CN2022/101536 CN2022101536W WO2023274150A1 WO 2023274150 A1 WO2023274150 A1 WO 2023274150A1 CN 2022101536 W CN2022101536 W CN 2022101536W WO 2023274150 A1 WO2023274150 A1 WO 2023274150A1
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parts
chinese medicine
medicine composition
duhuo
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PCT/CN2022/101536
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English (en)
French (fr)
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张贵民
李欣
刘冬光
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山东新时代药业有限公司
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Priority to KR1020247002460A priority Critical patent/KR20240028437A/ko
Priority to US18/573,183 priority patent/US20240285712A1/en
Priority to CN202280008393.3A priority patent/CN116669750A/zh
Priority to JP2023579525A priority patent/JP2024522886A/ja
Priority to EP22831964.6A priority patent/EP4364748A1/en
Priority to CA3223310A priority patent/CA3223310A1/en
Publication of WO2023274150A1 publication Critical patent/WO2023274150A1/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)
    • A61K36/53—Lamiaceae or Labiatae (Mint family), e.g. thyme, rosemary or lavender
    • A61K36/538—Schizonepeta
    • A—HUMAN NECESSITIES
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    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/06—Fungi, e.g. yeasts
    • A61K36/07—Basidiomycota, e.g. Cryptococcus
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    • A61K36/06—Fungi, e.g. yeasts
    • A61K36/07—Basidiomycota, e.g. Cryptococcus
    • A61K36/076—Poria
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    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/23—Apiaceae or Umbelliferae (Carrot family), e.g. dill, chervil, coriander or cumin
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    • A61K36/18—Magnoliophyta (angiosperms)
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    • 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)
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    • A61K36/48—Fabaceae or Leguminosae (Pea or Legume family); Caesalpiniaceae; Mimosaceae; Papilionaceae
    • A61K36/484—Glycyrrhiza (licorice)
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    • 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
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Definitions

  • the invention relates to a new application of a Chinese medicine composition, in particular to the application of the Chinese medicine composition in the preparation of medicines for treating cough variant asthma, and belongs to the technical field of Chinese medicines.
  • Cough variant asthma also known as cough asthma, used to be called allergic bronchitis or allergic cough or masked asthma.
  • the main manifestations are recurrent dry cough, accompanied by itching in the throat, and occasionally a small amount of white sputum that is difficult to cough up. , There are also symptoms such as low voice and shortness of breath. Some patients cough violently at night, which seriously affects sleep. the
  • Cough variant asthma is characterized by a chronic cough. Modern medicine believes that the cause is mostly airway irritation (such as smoke, cold air or allergens), and sometimes cough is the only manifestation without wheezing, and the treatment is roughly the same as that of asthma. In Chinese medicine, it is often classified as “cough”, “whee syndrome”, “wind cough”, “pulmonary obstruction”, “pharyngeal cough”, etc., and it is also attributed to "wheeze syndrome”. The symptoms of cough and asthma can also be attributed to "cough” and "internal injury cough” for syndrome differentiation and treatment. The primary disease mostly belongs to evil, excess, positive and deficiency, and deficiency and excess are mixed.
  • the excess of evil is mainly phlegm-damp accumulation in the lungs, phlegm-heat stagnation in the lungs, and liver fire invading the lungs;
  • the deficiency of righteousness is mainly deficiency of lung yin, deficiency of both lung and spleen, and deficiency of both lung and kidney.
  • attention should be paid to strengthening the vital energy and invigorating deficiency while eliminating pathogenic factors and relieving cough, and taking into account the three viscera of the lung, spleen and kidney.
  • cough variant asthma Since the mechanism and etiology of cough variant asthma are still unclear, most researchers believe that it is consistent with the mechanism of typical asthma and is a kind of airway allergic inflammation, so the current treatment is basically symptomatic. Common treatments for cough variant asthma include environmental prophylaxis and hormone therapy. The acute phase is controlled with Western medicine, and the remission phase is treated with Chinese and Western medicine.
  • the common syndrome differentiation and classification methods of cough symptoms are as follows:
  • Wind-cold attacking the lungs severe cough, expectoration of thin and white phlegm, aversion to cold, or fever without sweating.
  • the tongue coating is thin and white, and the pulse is floating and tight.
  • Wind-heat invading the lung cough with rough breath, expectoration of sticky white or yellow phlegm, sore throat or hoarse cough, or fever, mild aversion to wind-cold, and slightly thirsty mouth.
  • the tip of the tongue is red, the fur is thin and white or yellow, and the pulse is floating and rapid.
  • Phlegm-heat obstructing the lungs coughing with thick breath, thick yellow phlegm, restless heat and dry mouth. Red tongue, yellow and greasy fur, slippery and rapid pulse.
  • Liver fire invading the lungs Coughing and choking qi in reverse, causing pain in the chest and hypochondrium when coughing, and even hemoptysis, red tongue, thin yellow fur with little fluid, and rapid pulse.
  • Phlegm-damp accumulation in the lungs heavy turbid cough, multicolored and white sputum, especially in the morning, chest tightness, abdominal distension, and loss of appetite.
  • the tongue coating is white and greasy, and the pulse is slippery.
  • Deficiency of lung yin chronic cough with little phlegm, nausea, sticky or bloodshot phlegm, dry throat and mouth, hot hands, feet and heart. Red tongue, less moss, thready pulse.
  • Deficiency of lung qi chronic cough with low sound, cough accompanied by wheezing, clear and thin white phlegm, lack of appetite, shortness of breath, chest tightness, fatigue and fatigue, spontaneous sweating and chills. Pale tongue, white coating, weak pulse.
  • Liu Xiaoshuai et al. Liu Xiaoshuai et al. (Liu Xiaoshuai, Zeng Nan, Liang Ke, Zhao Lu, Qu Liping, Song Meifang, Zhang Chongyan. Experimental study on the anti-inflammatory mechanism of Jingfang powder interfering with nitric oxide synthase-nitric oxide pathway[J].
  • Jingfang granule is composed of Schizonepeta, Fangfeng, Qianghuo, Duhuo, Bupleurum, Chuanxiong, Citrus aurantii, Poria, Campanulaceae, licorice, etc.
  • the main purpose of the present invention is to provide a traditional Chinese medicine composition prepared from Notopterygium, Duhuo, Poria, Fangfeng, Nepeta, Chuanxiong, Campanulaceae, Bupleurum, Peucedanum, Fructus Aurantii, and Licorice.
  • the present invention is a further development of the use of Jingfang granules, an existing product.
  • the inventor conducted research on the treatment of cough variant asthma by Jingfang granule, and found that Jingfang granule has a significant effect when applied to cough variant asthma, increasing the drug selection of patients.
  • One of the objectives of the present invention is to provide a traditional Chinese medicine composition mainly composed of Schizonepeta, Fangfeng, Notopterygium, Duhuo, Bupleurum, Chuanxiong, Citrus aurantium, Poria cocos, Platycodon grandiflorum, and licorice. Prepared from the following ingredients:
  • the traditional Chinese medicine composition is mainly prepared from the raw materials of the following components:
  • the traditional Chinese medicine composition is mainly prepared from the raw materials of the following components:
  • the second object of the present invention is to provide the application of the above-mentioned traditional Chinese medicine composition in the preparation of medicine for treating cough variant asthma.
  • Cough variant asthma of the present invention with cough as the main clinical manifestation, is based on long-term intractable dry cough, often can be inhaled irritating smell (paint, gasoline, perfume, pollen etc.), cold air, Exposure to allergens, strenuous exercise, and respiratory infections can cause asthma attacks, and some patients will also have asthma attacks without any incentives. Variant asthma mostly occurs at night and early morning, most common in spring and autumn.
  • the clinical features of the cough variant asthma described in the present invention are: chronic cough without reason for more than two months, the cough is paroxysmal irritating dry cough, or a small amount of white foamy sputum; The chemical smell can be aggravated; the application of various antibiotics is ineffective, and there is no obvious abnormality in filming or CT examination. 40% of patients may be combined with symptoms of allergic rhinitis such as sneezing and runny nose. Many foreign doctors call it allergic rhinitis-bronchitis.
  • the cough variant asthma of the present invention is classified according to TCM syndrome types, and the TCM syndrome types of cough variant asthma are cold wheezing, hot wheezing, external cold and internal heat type, and lung excess and kidney deficiency type.
  • Cough variant asthma also known as cough asthma, used to be called allergic bronchitis or allergic cough or masked asthma.
  • the main manifestations are recurrent dry cough, accompanied by itching in the throat, and occasionally a small amount of white sputum that is difficult to cough up. , There are also symptoms such as low voice and shortness of breath.
  • the third object of the present invention is to provide the preparation method of the above-mentioned Chinese medicine composition, and the preparation method mainly includes the following steps:
  • Step A distill and extract the volatile oils of Nepeta, Fangfeng, Notopterygium, Duhuo, Peucedanum, Chuanxiong, and Citrus aurantium for later use, and the distilled medicinal residues, distilled Chuanxiong, and Citrus aurantii aqueous solutions for later use;
  • Step B prepare 10-40% ethanol solution with the distilled aqueous solution of Rhizoma Chuanxiong and Fructus Aurantii obtained in Step A, and set aside;
  • Step C mixing Poria cocos, the distilled Rhizoma Chuanxiong and Citrus aurantii herb residues obtained in step A, percolating and extracting with the ethanol solution obtained in step B, and the percolating liquid is set aside;
  • Step D add water to decoct Bupleurum chinensis, Platycodon grandiflorum, Licorice root, Nepeta nepeta, Fangfeng, Qianghuo, Duhuo and Peucedanum herbal dregs obtained in step A after distillation, and decoct the decoction for later use after concentrating;
  • Step E Mix the percolation liquid obtained in step C and the decoction liquid obtained in step D, concentrate, add the volatile oil obtained in step A, and obtain.
  • the preparation method mainly includes the following steps:
  • Step A distill and extract the volatile oils of Nepeta, Fangfeng, Notopterygium, Duhuo, Peucedanum, Chuanxiong, and Citrus aurantium for later use, and the distilled medicinal residues, distilled Chuanxiong, and Citrus aurantii aqueous solutions for later use;
  • Step B Prepare the aqueous solution of Rhizoma Chuanxiong and Fructus Aurantii after distillation obtained in Step A into a 15-30% ethanol solution for later use;
  • Step C mixing Poria cocos, the distilled Rhizoma Chuanxiong and Citrus aurantii herb residues obtained in step A, percolating and extracting with the ethanol solution obtained in step B, and the percolating liquid is set aside;
  • Step D add water to decoct Bupleurum chinensis, Platycodon grandiflorum, Radix Glycyrrhizae, and distilled Schizonepetae, Fangfeng, Notopterygium, Duhuo and Peucedanum dregs obtained in Step A, and condense the decoction into a thick paste for later use;
  • Step E Mix the percolation liquid obtained in step C and the thick paste obtained in step D, concentrate into a clear paste, add the volatile oil obtained in step A, and obtain.
  • the preparation method mainly includes the following steps:
  • Step A distill and extract the volatile oils of Nepeta, Fangfeng, Notopterygium, Duhuo, Peucedanum, Chuanxiong, and Citrus aurantium for later use, and the distilled medicinal residues, distilled Chuanxiong, and Citrus aurantii aqueous solutions for later use;
  • Step B prepare the aqueous solution of Rhizoma Chuanxiong and Fructus Fructus Fructus Aurantii after distillation obtained in Step A into a 25% ethanol solution for subsequent use;
  • Step C mixing Poria cocos, the distilled Rhizoma Chuanxiong and Citrus aurantii herb residues obtained in step A, percolating and extracting with the ethanol solution obtained in step B, and the percolating liquid is set aside;
  • Step D add water to decoct Bupleurum chinensis, Platycodon grandiflorum, Radix Glycyrrhizae, and distilled Schizonepetae, Fangfeng, Notopterygium, Duhuo and Peucedanum dregs obtained in Step A, and condense the decoction into a thick paste for later use;
  • Step E Mix the percolation liquid obtained in step C and the thick paste obtained in step D, concentrate into a clear paste, add the volatile oil obtained in step A, and obtain.
  • the fourth object of the present invention is to provide a traditional Chinese medicine preparation containing the above traditional Chinese medicine composition, that is, the traditional Chinese medicine composition is prepared into a clinically acceptable dosage form directly or after adding pharmaceutically acceptable adjuvants through conventional techniques.
  • the clinically acceptable oral formulation is one or more of pills, capsules, tablets, granules or liquid oral formulations;
  • the oral preparation is a granule.
  • the traditional Chinese medicine composition of the invention can significantly reduce the cough frequency of guinea pigs with cough variant asthma, and reduce the percentage of eosinophils in the bronchoalveolar lavage fluid (BALF).
  • BALF bronchoalveolar lavage fluid
  • Another embodiment of the present invention shows that the traditional Chinese medicine composition of the present invention can significantly reduce the cough frequency of rats with cough variant asthma, and reduce the level of serum eosinophil cationic protein.
  • Eosinophil cationic protein (ECP) is a toxic protein released after EOS activation that damages the respiratory epithelium, which can lead to allergic pathological changes such as airway spasm and mucosal edema, resulting in airway hyperresponsiveness.
  • ECP Eosinophil cationic protein
  • the traditional Chinese medicine composition of the invention is safe for clinical use, and has remarkable therapeutic effect on cough variant asthma.
  • the inventor wants to explain that the following experimental studies are all carried out on the basis of acute toxicity tests and long-term toxicity tests to prove the safety of the drug, and the dosages in the experimental studies are all within the safe dosage range.
  • Step A Distill Nepeta, Fangfeng, Notopterygium, Duhuo, Peucedanum, Rhizoma Chuanxiong, and Citrus aurantium, respectively, to extract volatile oils for later use, and distilled medicinal residues, distilled Chuanxiong, and Citrus aurantii for later use;
  • Step B prepare the aqueous solution of Rhizoma Chuanxiong and Fructus Fructus Fructus Aurantii after distillation obtained in Step A into a 25% ethanol solution for subsequent use;
  • Step C mixing Poria cocos, the distilled Rhizoma Chuanxiong and Citrus aurantii herb residues obtained in step A, percolating and extracting with the ethanol solution obtained in step B, and the percolating liquid is set aside;
  • Step D decoct Bupleurum chinensis, Platycodon grandiflorum, Radix Glycyrrhizae, distilled Schizonepetae, Fangfeng, Notopterygium, Duhuo, and Peucedanum dregs obtained in Step A, decocting twice for 1.5 hours each time, combining the two decoction liquids, Concentrate into a thick paste after filtering and set aside;
  • Step E Mix the percolation liquid obtained in step C and the thick paste obtained in step D, let stand, filter and concentrate into a clear paste, add an appropriate amount of sucrose, mix well, make granules, dry, add the volatile oil obtained in step A, mix well, Instantly.
  • the preparation method is the same as in Example 1.
  • the preparation method is the same as in Example 1.
  • Step A Distill Nepeta, Fangfeng, Notopterygium, Duhuo, Peucedanum, Rhizoma Chuanxiong, and Citrus aurantium, respectively, to extract volatile oils for later use, and distilled medicinal residues, distilled Chuanxiong, and Citrus aurantii for later use;
  • Step B prepare the aqueous solution of Rhizoma Chuanxiong and Fructus Fructus Aurantii after distillation obtained in Step A into a 10% ethanol solution for subsequent use;
  • Step C mixing Poria cocos, the distilled Rhizoma Chuanxiong and Citrus aurantii herb residues obtained in step A, percolating and extracting with the ethanol solution obtained in step B, and the percolating liquid is set aside;
  • Step D decoct Bupleurum chinensis, Platycodon grandiflorum, Radix Glycyrrhizae, distilled Schizonepetae, Fangfeng, Notopterygium, Duhuo, and Peucedanum dregs obtained in Step A, decocting twice for 1.5 hours each time, combining the two decoction liquids, Concentrate into a thick paste after filtering and set aside;
  • Step E Mix the percolation liquid obtained in step C and the thick paste obtained in step D, let it stand, filter and concentrate into a clear paste, add an appropriate amount of sucrose, mix well, add the volatile oil obtained in step A, mix well, add water to 1000ml, and get .
  • Step A Distill Nepeta, Fangfeng, Notopterygium, Duhuo, Peucedanum, Rhizoma Chuanxiong, and Citrus aurantium, respectively, to extract volatile oils for later use, and distilled medicinal residues, distilled Chuanxiong, and Citrus aurantii for later use;
  • Step B prepare the aqueous solution of Rhizoma Chuanxiong and Fructus Fructus Fructus Aurantii after distillation obtained in Step A into a 40% ethanol solution for subsequent use;
  • Step C mixing Poria cocos, the distilled Rhizoma Chuanxiong and Citrus aurantii herb residues obtained in step A, percolating and extracting with the ethanol solution obtained in step B, and the percolating liquid is set aside;
  • Step D decoct Bupleurum chinensis, Platycodon grandiflorum, Radix Glycyrrhizae, distilled Schizonepetae, Fangfeng, Notopterygium, Duhuo, and Peucedanum dregs obtained in Step A, decocting twice for 1.5 hours each time, combining the two decoction liquids, Concentrate into a thick paste after filtering and set aside;
  • Step E Mix the percolation liquid obtained in step C and the thick paste obtained in step D, let stand, filter and concentrate into a clear paste, add an appropriate amount of sucrose, mix well, add 500ml of volatile oil and simple syrup obtained in step A, mix well, let stand , filter, add water to 1000ml, that is.
  • Step A Distill Nepeta, Fangfeng, Notopterygium, Duhuo, Peucedanum, Rhizoma Chuanxiong, and Citrus aurantium, respectively, to extract volatile oils for later use, and distilled medicinal residues, distilled Chuanxiong, and Citrus aurantii for later use;
  • Step B prepare the aqueous solution of Rhizoma Chuanxiong and Fructus Aurantii after distillation obtained in Step A into 15% ethanol solution, and set aside;
  • Step C mixing Poria cocos, the distilled Rhizoma Chuanxiong and Citrus aurantii herb residues obtained in step A, percolating and extracting with the ethanol solution obtained in step B, and the percolating liquid is set aside;
  • Step D decoct Bupleurum chinensis, Platycodon grandiflorum, Radix Glycyrrhizae, distilled Schizonepetae, Fangfeng, Notopterygium, Duhuo, and Peucedanum dregs obtained in Step A, decocting twice for 1.5 hours each time, combining the two decoction liquids, Concentrate into a thick paste after filtering and set aside;
  • Step E Mix the percolation liquid obtained in step C and the thick paste obtained in step D, let stand, filter and concentrate into a clear paste, add an appropriate amount of sucrose, mix well, make granules, dry, add the volatile oil obtained in step A, mix well, Make into granules, add appropriate amount of auxiliary materials, mix evenly, and compress into tablets.
  • Step A Distill Nepeta, Fangfeng, Notopterygium, Duhuo, Peucedanum, Rhizoma Chuanxiong, and Citrus aurantium, respectively, to extract volatile oils for later use, and distilled medicinal residues, distilled Chuanxiong, and Citrus aurantii for later use;
  • Step B prepare the aqueous solution of Rhizoma Chuanxiong and Fructus Aurantii after distillation obtained in Step A into a 30% ethanol solution for subsequent use;
  • Step C mixing Poria cocos, the distilled Rhizoma Chuanxiong and Citrus aurantii herb residues obtained in step A, percolating and extracting with the ethanol solution obtained in step B, and the percolating liquid is set aside;
  • Step D decoct Bupleurum chinensis, Platycodon grandiflorum, Radix Glycyrrhizae, distilled Schizonepetae, Fangfeng, Notopterygium, Duhuo, and Peucedanum dregs obtained in Step A, decocting twice for 1.5 hours each time, combining the two decoction liquids, Concentrate into a thick paste after filtering and set aside;
  • Step E Mix the percolation liquid obtained in step C and the thick paste obtained in step D, let stand, filter and concentrate into a clear paste, add an appropriate amount of sucrose, mix well, make granules, dry, add the volatile oil obtained in step A, mix well, Made into granules, dried, pulverized, and packed into capsules.
  • Step A Distill Nepeta, Fangfeng, Notopterygium, Duhuo, Peucedanum, Rhizoma Chuanxiong, and Citrus aurantium, respectively, to extract volatile oils for later use, and distilled medicinal residues, distilled Chuanxiong, and Citrus aurantii for later use;
  • Step B prepare the aqueous solution of Rhizoma Chuanxiong and Fructus Fructus Fructus Aurantii after distillation obtained in Step A into a 25% ethanol solution for subsequent use;
  • Step C mixing Poria cocos, the distilled Rhizoma Chuanxiong and Citrus aurantii herb residues obtained in step A, percolating and extracting with the ethanol solution obtained in step B, and the percolating liquid is set aside;
  • Step D decoct Bupleurum chinensis, Platycodon grandiflorum, Radix Glycyrrhizae, distilled Schizonepetae, Fangfeng, Notopterygium, Duhuo, and Peucedanum dregs obtained in Step A, decocting twice for 1.5 hours each time, combining the two decoction liquids, Concentrate into a thick paste after filtering and set aside;
  • Step E Mix the percolation liquid obtained in step C and the thick paste obtained in step D, let stand, filter and concentrate into a clear paste, add an appropriate amount of sucrose, mix well, make granules, dry, add the volatile oil obtained in step A, mix well, Dry, crush, sieve, add 40 ⁇ 60g of refined honey, appropriate amount of water to make pills, and dry to obtain.
  • Step A Distill Nepeta, Fangfeng, Notopterygium, Duhuo, Peucedanum, Rhizoma Chuanxiong, and Citrus aurantium, respectively, to extract volatile oils for later use, and distilled medicinal residues, distilled Chuanxiong, and Citrus aurantii for later use;
  • Step B prepare the aqueous solution of Rhizoma Chuanxiong and Fructus Fructus Fructus Aurantii after distillation obtained in Step A into a 25% ethanol solution for subsequent use;
  • Step C mixing Poria cocos, the distilled Rhizoma Chuanxiong and Citrus aurantii herb residues obtained in step A, percolating and extracting with the ethanol solution obtained in step B, and the percolating liquid is set aside;
  • Step D decoct Bupleurum chinensis, Platycodon grandiflorum, Radix Glycyrrhizae, distilled Schizonepetae, Fangfeng, Notopterygium, Duhuo, and Peucedanum dregs obtained in Step A, decocting twice for 1.5 hours each time, combining the two decoction liquids, Concentrate into a thick paste after filtering and set aside;
  • Step E Mix the percolation liquid obtained in step C and the thick paste obtained in step D, let it stand, filter and concentrate into a clear paste, add the volatile oil obtained in step A, mix well, and obtain.
  • Embodiment 1 granule
  • Ovalbumin (OVA) (GBCBIO Technologies company, lot number A20199006-59);
  • Aluminum hydroxide dry powder (Tianjin Huirui Chemical Technology Co., Ltd., batch number: 20201209);
  • Capsaicin (Batch number: 20200401 from Sigma, USA).
  • Embodiment 1 granule: 3.6g/kg high dose, 1.8g/kg middle dose, 0.9g/kg low dose;
  • mice were randomly divided into blank control group, model control group, Erma Hejing Fangbaidu powder group and Example 1 granule low, medium and high dose groups according to body weight, with 10 animals in each group.
  • mice were randomly divided into normal control group, model control group, high-, medium-, and low-dose groups of the granules of Example 1, and Erma Hejing Fangbaidu Powder groups.
  • mice in the model group were smoked for half an hour every day on the 1st to 28th day; on the 15th day, each guinea pig was injected with a suspension of 20g/L OVA 1mL and 200mg aluminum hydroxide; on the 22nd day, each guinea pig was injected with 20g/L OVA Suspension of 1 mL and 200 mg of aluminum hydroxide was used to enhance sensitization once; on the 29th day, 10 g/L OVA was used for aerosol challenge, once a day for 7 consecutive days; the normal control group was given the same volume of normal saline.
  • Smoke box and usage method The smoke box is a custom-made stainless steel box with a length, width, and height of 100cm ⁇ 60cm ⁇ 60cm.
  • the cigarettes used in this research are "Hongmei" filter cigarettes (Hongta Tobacco Co., Ltd.; flue-cured cigarettes, tar content 10 mg, smoke nicotine content 0.7 mg, smoke carbon monoxide content 12 mg). Each time, 10 cigarettes were lit in the smoking box, and after the cigarettes were lit, the smoke was discharged into the smoking box manually through a 300mL syringe and a three-way pipe until the cigarettes were burnt out.
  • each administration group was intragastrically administered the corresponding drug 10ml/kg, once a day, for 7 consecutive days.
  • the normal control group and the model control group were given the same volume of purified water.
  • Airway cough sensitivity was judged by capsaicin cough challenge test.
  • Whole-body plethysmography (Buxco Electronics) was used.
  • guinea pigs were placed in a body tracing box, and observed after nebulizing with 10 -4 mol/L capsaicin solution for 2 min. Record the number of coughs of guinea pigs for 5 minutes.
  • the bronchoalveolar was lavaged three times with phosphate buffered saline (PBS), 2 mL each time, and the bronchoalveolar lavage fluid (BALF) was recovered.
  • PBS phosphate buffered saline
  • BALF bronchoalveolar lavage fluid
  • the number of coughs in the treatment group was significantly lower than that of the model control group, and the number of coughs in the middle and high dose groups of the granules of Example 1 was significantly lower than that of the model control group, and the difference was statistically significant (P ⁇ 0.05 or P ⁇ 0.01);
  • the traditional Chinese medicine composition of the present invention can significantly reduce the cough frequency of the CVA guinea pig model and reduce the percentage of eosinophils in the bronchoalveolar lavage fluid (BALF).
  • BALF bronchoalveolar lavage fluid
  • Embodiment 1 granule
  • Ovalbumin (OVA) (GBCBIO Technologies company, lot number A20199006-59);
  • Aluminum hydroxide dry powder (Tianjin Huirui Chemical Technology Co., Ltd., batch number: 20201209);
  • Capsaicin (Batch number: 20200401 from Sigma, USA).
  • Example 1 the Granules of Example 1: 3.6g/kg high dose, 1.8g/kg medium dose, 0.9g/kg low dose;
  • Jingfangsan 2.5g/kg.
  • the sensitization method was stimulated and sensitized by ovalbumin and aluminum hydroxide. Except for 8 rats in the normal group, the other rats were subcutaneously injected with 1 mL of normal saline containing 1 mg of ovalbumin and 10 mg of aluminum hydroxide. A total of 10 points were taken on the two hind paws, groin, waist, back and neck, and 0.05 mL was injected subcutaneously at each point, and 0.5 mL was injected intraperitoneally at the same time, a total of 1 mL was repeated on the 8th day to strengthen the sensitization.
  • the rats were placed in a closed plexiglass cover, and the physiological saline containing 1% ovalbumin solution was given ultrasonic atomization for 20 minutes to stimulate asthma, and the obvious contraction of the abdominal muscles of the rats was positive until the occurrence of Symptoms of respiratory spasm such as deepened and accelerated breathing indicate successful modeling.
  • the successfully modeled rats were randomly divided into 5 groups (model group, high-, medium-, and low-dose groups of the granules of Example 1, and Jingfang powder group), with 8 rats in each group.
  • the low, medium and high dosages of the granules of the embodiment are respectively 0.9g/kg, 1.8g/kg, and 3.6g/kg.
  • the dosage of the Jingfang Powder group is 2.5g/kg, dissolved in purified water, Volume 10mL/kg.
  • the normal control group and the model group were intragastrically administered with an equal volume of purified water. Continuous administration for 13 days.
  • ECP eosinophil cationic protein
  • the rats in each group were placed in a closed box, and the number of coughs after inhalation of a capsaicin solution with a concentration of 1 ⁇ 10 -4 mol/L within 5 minutes was recorded and counted.
  • Embodiment 1 granule low dosage group 2.98 ⁇ 0.43* Embodiment 1 granule middle dosage group 2.6 ⁇ 0.52** ⁇ Embodiment 1 granule high-dose group 2.10 ⁇ 0.49** ⁇ Jing Fang San Group 3.20 ⁇ 0.41
  • the number of coughs in the model control group was significantly increased, and the difference was statistically significant (P ⁇ 0.01); compared with the model control group, the number of coughs in the low, middle and high dose groups of the granules of Example 1 was significantly reduced , the difference was statistically significant (P ⁇ 0.05, P ⁇ 0.01); compared with the Jingfang powder group, the number of coughs in the middle and high groups of the granule group of Example 1 was significantly reduced, and the difference was statistically significant (P ⁇ 0.05, P ⁇ 0.01). ⁇ 0.01);
  • Jingfang Granules can inhibit the cough response of rats, and have the effect of inhibiting the cough of cough variant asthma, and the effect of relieving cough is better than that of Jingfang San.
  • Embodiment 1 granule low dosage group 2.03 ⁇ 0.34 Embodiment 1 granule middle dosage group 1.79 ⁇ 0.24** ⁇ Embodiment 1 granule high-dose group 1.70 ⁇ 0.26** ⁇ Jing Fang San Group 2.06 ⁇ 0.21

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Abstract

一种中药组合物，由荆芥、防风、羌活、独活、柴胡、前胡、川芎、枳壳、茯苓、桔梗、甘草制成。该中药组合物可以减少咳嗽变异型哮喘豚鼠模型咳嗽次数、降低支气管肺泡灌洗液中嗜酸粒细胞百分率，降低血清嗜酸粒细胞阳离子蛋白水平，对咳嗽变异性哮喘具有防治作用。

Description

一种中药组合物在制备治疗咳嗽变异性哮喘药物中的用途 技术领域
本发明涉及一种中药组合物的新用途，具体涉及中药组合物在制备治疗咳嗽变异性哮喘症药物中的用途，属于中药技术领域。
 背景技术
咳嗽变异型哮喘（cough variant asthma,CVA）又称咳嗽型哮喘，过去曾称为过敏性支气管炎或过敏性咳嗽或隐匿性哮喘。主要表现为反复不断的干咳为主，伴有咽喉部发痒感，偶有难咳出的少量的白痰，咳嗽一般呈阵发性、挛急性，剧烈咳嗽时可伴有气急、气不得续，亦有声低气短等症状，部分患者夜间剧烈咳嗽，严重影响睡眠。  
咳嗽变异性哮喘以慢性咳嗽为特点。现代医学认为，诱因多为气道受刺激（如烟雾、冷空气或变应原），有时咳嗽是其唯一表现，不伴喘怠，治疗与哮喘方案大致相同。中医临床上多将其归属“咳嗽”、“哮证”、“风咳”、“肺痹”、“咽源性咳嗽”等，也有归于“喘证”。也可将其咳喘症状归属“咳嗽”，“内伤咳”来进行辨证治疗。本病多属邪实正虚，虚实夹杂。邪实主要为痰湿蕴肺、痰热郁肺、肝火犯肺；正虚主要为肺阴亏虚、肺脾两虚、肺肾两虚。治疗中应在祛邪止咳的同时注意扶正补虚，兼顾肺脾肾三脏。
由于对咳嗽变异性哮喘发生的机理和病因尚无确切了解，多数学者认为与典型的哮喘病的机制是一致的，是一种气道变应性炎症，所以目前治疗上基本为对症治疗。针对咳嗽变异性哮喘常见的治疗方法包括环境预防和激素疗法等。急性期用西药进行控制，缓解期用中西医配合治疗。
咳嗽症状常见的中医辨证分类方式如下：
（1）风寒袭肺：咳嗽声重，咯痰稀薄色白，恶寒，或有发热，无汗。舌苔薄白，脉浮紧。
（2）风热犯肺：咳嗽气粗，咯痰粘白或黄，咽痛或咳声嘶哑，或有发热，微恶风寒，口微渴。舌尖红，苔薄白或黄，脉浮数。
（3）燥邪伤肺：干咳少痰，咯痰不爽，鼻咽干燥，口干。舌尖红，苔薄黄少津，脉细数。
（4）痰热壅肺：咳嗽气粗，痰多稠黄，烦热口干。舌质红，苔黄腻，脉滑数。
（5）肝火犯肺：咳呛气逆阵作，咳时胸胁引痛，甚则咯血，舌红，苔薄黄少津，脉弦数。
（6）痰湿蕴肺：咳声重浊，痰多色白，晨起为甚，胸闷脘痞，纳少。舌苔白腻，脉滑。
（7）肺阴亏虚：咳久痰少，咯吐不爽，痰粘或夹血丝，咽干口燥，手足心热。舌红，少苔，脉细数。
（8）肺气亏虚：病久咳声低微，咳而伴喘，咯痰清稀色白，食少，气短胸闷，神倦乏力，自汗畏寒。舌淡嫩，苔白，脉弱。
杨德义（杨德义.《二麻合荆防败毒散治疗咳嗽变异型哮喘57例》[J]. 江西中医药，2006(7):32）用麻黄，麻黄根合荆防败毒散加减治疗咳嗽变异型哮喘57例,疗效显著。麻黄的主要有效成分麻黄碱可作用于机体的多个系统，对心血管和中枢神经系统可造成严重的副作用（王鑫，肖农，周江堡.《麻黄碱的副作用及相关研究现状》[J].    国外医学中医中药分册，2005，27（3）：155-156）。刘晓帅等（刘晓帅,曾南,梁珂,赵璐,瞿礼萍,宋美芳,张崇燕.荆防散干预一氧化氮合酶-一氧化氮通路的抗炎机制实验研究[J].时珍国医国药,2008,19(12):3014-3015.）采用卵白蛋白致小鼠哮喘模型及角叉菜胶致大鼠胸膜炎模型，观察荆防散干预后大鼠胸腔渗出液与小鼠肺组织匀浆中NOS，iNOS活力和NO含量的变化，探讨了荆防散的抗炎作用机制。荆防颗粒由荆芥、防风、羌活、独活、柴胡、川芎、枳壳、茯苓、桔梗、甘草等相互配伍而成，具有发汗解表，并且能够祛风祛痰、清肺止咳，已知用于外感风寒之后的一系列症状均具有非常良好的效果。而咳嗽变异性哮喘也可以在外感风寒后诱发或加重，在实际临床应用过程中发现其在此方面新的适应症，特别是咳嗽辨证为风寒袭肺，痰湿蕴肺等寒咳效果更好，这些临床经验为该产品的进一步开发利用提供了支持。目前尚未有荆防颗粒的组方用于咳嗽变异性哮喘的研究报道。
 技术问题
本发明的主要目的是提供一种中药组合物，所述中药组合物由羌活、独活、茯苓、防风、荆芥、川芎、桔梗、柴胡、前胡、枳壳、甘草制备而成。
 技术解决方案
本发明是在现有产品荆防颗粒的基础上所作的对其用途的进一步开发。
发明人进行了荆防颗粒治疗咳嗽变异性哮喘的研究，发现荆防颗粒应用于咳嗽变异性哮喘时效果显著，增加了患者的用药选择性。本发明使用的荆防颗粒组方中没有麻黄和麻黄根，减少了麻黄和麻黄根带来的副作用，降低了安全性风险。
本发明目的之一在于，提供一种主要由荆芥、防风、羌活、独活、柴胡、川芎、枳壳、茯苓、桔梗、甘草组成的中药组合物，即所述中药组合物主要由以下组分的原料制备而成：
荆芥5-30重量份  防风5-30重量份   羌活5-30重量份
独活5-30重量份  柴胡3-25重量份   前胡3-25重量份
川芎5-30重量份  枳壳3-25重量份   茯苓5-30重量份
桔梗3-25重量份  甘草1-10重量份。
优选地，所述中药组合物主要由以下组分的原料制备而成：
荆芥10-20重量份  防风10-20重量份   羌活10-20重量份
独活10-20重量份  柴胡3-20重量份   前胡3-20重量份
川芎10-20重量份  枳壳3-20重量份   茯苓10-25重量份
桔梗3-20重量份  甘草1-8重量份。
进一步优选地，所述中药组合物主要由以下组分的原料制备而成：
荆芥15重量份  防风15重量份   羌活15重量份
独活15重量份  柴胡15重量份   前胡15重量份
川芎15重量份  枳壳15重量份   茯苓15重量份
桔梗15重量份  甘草5重量份。
       本发明的目的之二在于提供上述中药组合物在制备治疗咳嗽变异性哮喘药物中的用途。
本发明所述的咳嗽变异性哮喘症，以咳嗽为主要的临床表现，是以长期的顽固性干咳为主，经常会在吸入刺激性气味(油漆、汽油、香水、花粉等)、冷空气、接触过敏原、剧烈运动后和呼吸道感染后引起病发，也会有部分患者在没有任何诱因的情况下哮喘病发。变异性哮喘多发生于夜间和凌晨，以春秋最为多见。
本发明所述的咳嗽变异性哮喘症的临床特征是：超过两个月的无原因的慢性咳嗽，咳嗽呈阵发性刺激性干咳，或有少量白色泡沫样痰；在吸入烟雾或油漆、敌敌畏等化学气味可加重；应用多种抗生素无效，拍片或CT检查无明显异常。40%的患者可合并打喷嚏、流鼻涕等过敏性鼻炎症状，国外许多医生称其为过敏性鼻-支气管炎。
本发明所述的咳嗽变异性哮喘症按照中医证型分类，所述的咳嗽变异性哮喘中医证型寒哮、热哮、外寒内热型、肺实肾虚型。
咳嗽变异型哮喘（cough variant asthma,CVA)又称咳嗽型哮喘，过去曾称为过敏性支气管炎或过敏性咳嗽或隐匿性哮喘。主要表现为反复不断的干咳为主，伴有咽喉部发痒感，偶有难咳出的少量的白痰，咳嗽一般呈阵发性、挛急性，剧烈咳嗽时可伴有气急、气不得续，亦有声低气短等症状。
本发明目的之三在于提供上述中药组合物的制备方法，所述制备方法主要包括以下步骤：
步骤A：将荆芥、防风、羌活、独活、前胡、川芎、枳壳，蒸馏提取挥发油备用，蒸馏后的药渣、蒸馏后的川芎、枳壳水溶液备用；
步骤B：将步骤A 所得蒸馏后的川芎、枳壳水溶液配制成10-40%的乙醇溶液，备用；
步骤C：将茯苓、步骤A所得蒸馏后的川芎、枳壳药渣混合，以步骤B所得乙醇溶液渗漉提取，渗漉液备用；
步骤D：将柴胡、桔梗、甘草、步骤A所得蒸馏后的荆芥、防风、羌活、独活、前胡药渣，加水煎煮，煎煮液浓缩后备用；
步骤E：将步骤C所得渗漉液、步骤D所得煎煮液混合，浓缩，加入步骤A所得挥发油，即得。
优选地，所述制备方法主要包括以下步骤：
步骤A：将荆芥、防风、羌活、独活、前胡、川芎、枳壳，蒸馏提取挥发油备用，蒸馏后的药渣、蒸馏后的川芎、枳壳水溶液备用；
步骤B：将步骤A 所得蒸馏后的川芎、枳壳水溶液配制成15-30%的乙醇溶液，备用；
步骤C：将茯苓、步骤A所得蒸馏后的川芎、枳壳药渣混合，以步骤B所得乙醇溶液渗漉提取，渗漉液备用；
步骤D：将柴胡、桔梗、甘草、步骤A所得蒸馏后的荆芥、防风、羌活、独活、前胡药渣，加水煎煮，煎煮液浓缩成稠膏，备用；
步骤E：将步骤C所得渗漉液、步骤D所得稠膏混合，浓缩成清膏，加入步骤A所得挥发油，即得。
进一步优选地，所述制备方法主要包括以下步骤：
步骤A：将荆芥、防风、羌活、独活、前胡、川芎、枳壳，蒸馏提取挥发油备用，蒸馏后的药渣、蒸馏后的川芎、枳壳水溶液备用；
步骤B：将步骤A 所得蒸馏后的川芎、枳壳水溶液配制成25%的乙醇溶液，备用；
步骤C：将茯苓、步骤A所得蒸馏后的川芎、枳壳药渣混合，以步骤B所得乙醇溶液渗漉提取，渗漉液备用；
步骤D：将柴胡、桔梗、甘草、步骤A所得蒸馏后的荆芥、防风、羌活、独活、前胡药渣，加水煎煮，煎煮液浓缩成稠膏，备用；
步骤E：将步骤C所得渗漉液、步骤D所得稠膏混合，浓缩成清膏，加入步骤A所得挥发油，即得。
本发明目的之四在于提供含有上述中药组合物的中药制剂，即所述中药组合物经过常规工艺直接或加入药学上可接受的辅料后制备成临床上可接受的剂型。
优选地，所述临床上可接受的口服制剂为丸剂、胶囊剂、片剂、颗粒剂或液体口服制剂中的一种或多种；
进一步更优选地，所述口服制剂为颗粒剂。
 有益效果
与现有技术相比，本发明取得了显著的技术效果:
本发明中药组合物可以显著减少咳嗽变异性哮喘模型豚鼠的咳嗽次数、降低其支气管肺泡灌洗液（BALF）中嗜酸性粒细胞百分率。本发明另一个实施例表明，本发明中药组合物可显著减低咳嗽变异性哮喘大鼠的咳嗽次数，降低血清嗜酸粒细胞阳离子蛋白水平。嗜酸粒细胞阳离子蛋白（ECP）是EOS激活后释放的一种损伤呼吸道上皮的毒性蛋白，可导致气道痉挛、黏膜水肿等变态反应性病理改变，从而造成气道的高反应性。本发明中药组合物临床用药安全，对于咳嗽变异性哮喘治疗效果显著。
 本发明的实施方式
为验证本发明中药组合物用于咳嗽变异性哮喘的功效，发明人开展了动物试验研究，以下仅以部分实验模型为例进行说明，对说明书中记载的其他咳嗽变异性哮喘症表现发明人亦进行了药理实验研究，本发明组合物可以达到相同或类似的效果，在此不再一一叙述。
发明人要说明的是，以下实验研究均是在急性毒性试验，长期毒性试验证明药物安全性基础之上开展，实验研究中的给药剂量均在安全剂量范围之内。
制备实施例1  颗粒剂制备
处方：
荆芥75g  防风75 g   羌活75 g   独活75 g  柴胡75 g   前胡75 g
川芎75 g  枳壳75 g   茯苓75 g   桔梗75 g  甘草25 g；
制备方法：
步骤A：将荆芥、防风、羌活、独活、前胡、川芎、枳壳，分别蒸馏提取挥发油备用，蒸馏后的药渣、蒸馏后的川芎、枳壳水溶液备用；
步骤B：将步骤A 所得蒸馏后的川芎、枳壳水溶液配制成25%的乙醇溶液，备用；
步骤C：将茯苓、步骤A所得蒸馏后的川芎、枳壳药渣混合，以步骤B所得乙醇溶液渗漉提取，渗漉液备用；
步骤D：将柴胡、桔梗、甘草、步骤A所得蒸馏后的荆芥、防风、羌活、独活、前胡药渣，加水煎煮两次，每次1.5小时，合并两次的煎煮液，过滤后浓缩成稠膏，备用；
步骤E：将步骤C所得渗漉液、步骤D所得稠膏混合，静置，过滤后浓缩成清膏，加蔗糖适量，混匀，制成颗粒，干燥，加入步骤A所得挥发油，混匀，即得。
制备实施例2  颗粒剂制备
处方：
荆芥10g  防风10 g   羌活12 g    独活12 g  柴胡5 g   前胡5 g
川芎12 g  枳壳5 g   茯苓20 g     桔梗5 g  甘草3 g；
制备方法同实施例1。
制备实施例3  颗粒剂制备
处方：
荆芥30 g  防风5 g   羌活30 g  独活5 g  柴胡25 g  前胡3 g
川芎30 g  枳壳3 g   茯苓30 g  桔梗3 g  甘草10 g；
制备方法同实施例1。
制备实施例4  口服液制备
处方：
荆芥5 g  防风30 g   羌活5 g   独活30 g  柴胡3 g   前胡25 g
川芎5 g  枳壳25 g   茯苓5 g   桔梗25 g  甘草1 g；
制备方法：
步骤A：将荆芥、防风、羌活、独活、前胡、川芎、枳壳，分别蒸馏提取挥发油备用，蒸馏后的药渣、蒸馏后的川芎、枳壳水溶液备用；
步骤B：将步骤A 所得蒸馏后的川芎、枳壳水溶液配制成10%的乙醇溶液，备用；
步骤C：将茯苓、步骤A所得蒸馏后的川芎、枳壳药渣混合，以步骤B所得乙醇溶液渗漉提取，渗漉液备用；
步骤D：将柴胡、桔梗、甘草、步骤A所得蒸馏后的荆芥、防风、羌活、独活、前胡药渣，加水煎煮两次，每次1.5小时，合并两次的煎煮液，过滤后浓缩成稠膏，备用；
步骤E：将步骤C所得渗漉液、步骤D所得稠膏混合，静置，过滤后浓缩成清膏，加蔗糖适量，混匀，加入步骤A所得挥发油，混匀，加水至1000ml，即得。
制备实施例5  糖浆剂制备
处方：
荆芥20 g  防风10 g   羌活20 g  独活10 g  柴胡20 g   前胡3 g
川芎20 g  枳壳3 g   茯苓25 g   桔梗3 g  甘草8 g；
  制备方法：
步骤A：将荆芥、防风、羌活、独活、前胡、川芎、枳壳，分别蒸馏提取挥发油备用，蒸馏后的药渣、蒸馏后的川芎、枳壳水溶液备用；
步骤B：将步骤A 所得蒸馏后的川芎、枳壳水溶液配制成40%的乙醇溶液，备用；
步骤C：将茯苓、步骤A所得蒸馏后的川芎、枳壳药渣混合，以步骤B所得乙醇溶液渗漉提取，渗漉液备用；
步骤D：将柴胡、桔梗、甘草、步骤A所得蒸馏后的荆芥、防风、羌活、独活、前胡药渣，加水煎煮两次，每次1.5小时，合并两次的煎煮液，过滤后浓缩成稠膏，备用；
步骤E：将步骤C所得渗漉液、步骤D所得稠膏混合，静置，过滤后浓缩成清膏，加蔗糖适量，混匀，加入步骤A所得挥发油和单糖浆500ml，混匀，静置，滤过，加水至1000ml，即得。
制备实施例6  片剂制备
处方：
荆芥10 g  防风20 g   羌活10 g  独活20 g  柴胡3 g   前胡20 g
川芎10 g  枳壳20 g   茯苓10 g  桔梗20 g  甘草1 g；
制备方法：
步骤A：将荆芥、防风、羌活、独活、前胡、川芎、枳壳，分别蒸馏提取挥发油备用，蒸馏后的药渣、蒸馏后的川芎、枳壳水溶液备用；
步骤B：将步骤A 所得蒸馏后的川芎、枳壳水溶液配制成15%的乙醇溶液，备用；
步骤C：将茯苓、步骤A所得蒸馏后的川芎、枳壳药渣混合，以步骤B所得乙醇溶液渗漉提取，渗漉液备用；
步骤D：将柴胡、桔梗、甘草、步骤A所得蒸馏后的荆芥、防风、羌活、独活、前胡药渣，加水煎煮两次，每次1.5小时，合并两次的煎煮液，过滤后浓缩成稠膏，备用；
步骤E：将步骤C所得渗漉液、步骤D所得稠膏混合，静置，过滤后浓缩成清膏，加蔗糖适量，混匀，制成颗粒，干燥，加入步骤A所得挥发油，混匀，制成颗粒，加入辅料适量，混匀，压片，即得。
制备实施例7 胶囊剂制备
处方：
荆芥20 g  防风10 g   羌活20 g  独活10 g 柴胡20 g   前胡3 g
川芎20 g  枳壳3 g   茯苓25 g   桔梗3 g  甘草8 g；
步骤A：将荆芥、防风、羌活、独活、前胡、川芎、枳壳，分别蒸馏提取挥发油备用，蒸馏后的药渣、蒸馏后的川芎、枳壳水溶液备用；
步骤B：将步骤A 所得蒸馏后的川芎、枳壳水溶液配制成30%的乙醇溶液，备用；
步骤C：将茯苓、步骤A所得蒸馏后的川芎、枳壳药渣混合，以步骤B所得乙醇溶液渗漉提取，渗漉液备用；
步骤D：将柴胡、桔梗、甘草、步骤A所得蒸馏后的荆芥、防风、羌活、独活、前胡药渣，加水煎煮两次，每次1.5小时，合并两次的煎煮液，过滤后浓缩成稠膏，备用；
步骤E：将步骤C所得渗漉液、步骤D所得稠膏混合，静置，过滤后浓缩成清膏，加蔗糖适量，混匀，制成颗粒，干燥，加入步骤A所得挥发油，混匀，制成颗粒，干燥，粉碎，装入胶囊，即得。
制备实施例8  丸剂制备
处方：
荆芥10 g  防风20 g   羌活10 g  独活20 g  柴胡3 g   前胡20 g
川芎10 g  枳壳20 g   茯苓10 g  桔梗20 g  甘草1g；
制备方法：
步骤A：将荆芥、防风、羌活、独活、前胡、川芎、枳壳，分别蒸馏提取挥发油备用，蒸馏后的药渣、蒸馏后的川芎、枳壳水溶液备用；
步骤B：将步骤A 所得蒸馏后的川芎、枳壳水溶液配制成25%的乙醇溶液，备用；
步骤C：将茯苓、步骤A所得蒸馏后的川芎、枳壳药渣混合，以步骤B所得乙醇溶液渗漉提取，渗漉液备用；
步骤D：将柴胡、桔梗、甘草、步骤A所得蒸馏后的荆芥、防风、羌活、独活、前胡药渣，加水煎煮两次，每次1.5小时，合并两次的煎煮液，过滤后浓缩成稠膏，备用；
步骤E：将步骤C所得渗漉液、步骤D所得稠膏混合，静置，过滤后浓缩成清膏，加蔗糖适量，混匀，制成颗粒，干燥，加入步骤A所得挥发油，混匀，干燥，粉碎，过筛，加炼蜜40~60g，适量的水泛丸，干燥，即得。
制备实施例9  浸膏制备
处方：
荆芥75g  防风75 g   羌活75 g   独活75 g  柴胡75 g   前胡75 g
川芎75 g  枳壳75 g   茯苓75 g   桔梗75 g  甘草25 g；
制备方法：
步骤A：将荆芥、防风、羌活、独活、前胡、川芎、枳壳，分别蒸馏提取挥发油备用，蒸馏后的药渣、蒸馏后的川芎、枳壳水溶液备用；
步骤B：将步骤A 所得蒸馏后的川芎、枳壳水溶液配制成25%的乙醇溶液，备用；
步骤C：将茯苓、步骤A所得蒸馏后的川芎、枳壳药渣混合，以步骤B所得乙醇溶液渗漉提取，渗漉液备用；
步骤D：将柴胡、桔梗、甘草、步骤A所得蒸馏后的荆芥、防风、羌活、独活、前胡药渣，加水煎煮两次，每次1.5小时，合并两次的煎煮液，过滤后浓缩成稠膏，备用；
步骤E：将步骤C所得渗漉液、步骤D所得稠膏混合，静置，过滤后浓缩成清膏，加入步骤A所得挥发油，混匀，即得。
 工业实用性
药效实施例一本发明中药组合物对咳嗽变异性哮喘模型豚鼠的影响
    1材料
    1.1动物
    普通级豚鼠雌雄60只，雌雄各半，60～90日龄，体质量（300±30）g，实验动物由鲁南制药集团股份有限公司新药药理中心提供，实验前适应性饲养一周。
    1.2药物、试剂
    1.2.1药物
    实施例1颗粒剂；
    二麻合荆防败毒散，文献（杨德义. 二麻合荆防败毒散治疗咳嗽变异型哮喘57例[J]. 江西中医药,2006(7):32-32）中的组方和配比；
鸡卵清白蛋白（OVA）（GBCBIO Technologies公司，批号A20199006-59）；
氢氧化铝干粉（天津惠瑞化工科技有限公司，批号：20201209）；
辣椒素（美国Sigma公司批号：20200401）。
1.2.2豚鼠用药剂量
实施例1颗粒剂：3.6g/kg高剂量，1.8g/kg中剂量，0.9g/kg低剂量；
二麻合荆防败毒散：1.8g/kg。
1.3主要试剂
苏木素、伊红、武汉博士德生物工程有限公司。
2.分组、建模及给药
2.1分组
动物适应性喂养1周后，按体质量随机分为空白对照组、模型对照组、二麻合荆防败毒散组和实施例1颗粒剂低、中、高剂量组，每组10只。
2.2造模
实验动物随机分为正常对照组，模型对照组，实施例1颗粒剂高、中、低剂量组，二麻合荆防败毒散组。
造模组动物在第1～28天，每天熏烟半小时；第15天每只豚鼠注射20g/L OVA 1mL和200mg氢氧化铝的混悬液；第22天每只豚鼠注射20g/L OVA 1mL和200mg氢氧化铝的混悬液加强致敏1次；第29天用10g/L OVA雾化攻击，连续7d，每天1次；正常对照组给予相同体积的生理盐水。
所有动物饲养在普通环境，12h/12h光照循环，自由饮水和食用颗粒饲料。熏烟箱及使用方法：熏烟箱为定制的长、宽、高分别为100cm×60cm×60cm的不锈钢箱体。本研究所用香烟为“红梅”过滤嘴香烟（红塔烟草有限责任公司；烤烟型香烟，焦油量10mg，烟气烟碱量0.7mg，烟气一氧化碳量12mg）。每次在熏烟箱中点燃10根香烟，将香烟点燃后，通过300mL注射器和三通管的人工操作将烟雾排入熏烟箱，直至香烟燃完。
       2.3 干预
在第29天雾化攻击当天开始给药，各给药组灌胃给予相应的药物10ml/kg，每天1次，连续7d。正常对照组和模型对照组给予相同体积的纯化水。
       2.4 标本采集及检测
2.4.1咳嗽敏感性的测定（CRS）。
       2.4.2支气管肺泡灌洗液中嗜酸性粒细胞计数百分比。
       2.5 统计学方法
采用SPSS19.0统计软件进行分析。实验数据以
Figure 336302dest_path_image001
表示，经方差齐性检验后，多组间比较采用方差分析，两两比较用LSD法。P<0.05表示差异有统计学意义。
       3.检查项
3.1各组豚鼠CRS测定
通过辣椒素咳嗽激发试验判断气道的咳嗽敏感性。采用全身体积描记法（Buxco Electronics），10g/LOVA最后1次雾化攻击后的第2天，将豚鼠放入体描箱内，用10 -4mol/L辣椒素溶液雾化2min后观察并记录豚鼠5min的咳嗽次数。
3.2各组豚鼠支气管肺泡灌洗液中嗜酸性粒细胞百分率的测定
待激发试验完成后，支气管肺泡用磷酸盐缓冲液（PBS）灌洗3次，每次2mL，并回收支气管肺泡灌洗液（BALF）。将收集的BALF取200uL，并以3000r/min离心10min后转移上清液，加入红细胞裂解液后，3000r/min离心10min后转移上清液，加入等量PBS涂片，苏木精—伊红（HE）染色。在显微镜下计连续视野中每200个细胞中嗜酸性粒细胞的数量，并计算出嗜酸性细胞的百分率。
4.结果及结论
4.1各组豚鼠CRS测定
表1结果显示：与正常对照组比较，模型对照组咳嗽次数显著升高，差异有统计学意义（P<0.05）；
治疗组的咳嗽次数显著低于模型对照组，实施例1颗粒剂中、高剂量组的咳嗽次数与模型对照组比较显著降低，差异有统计学意义（P<0.05或P<0.01）；
与二麻合荆防败毒散组相比，实施例1颗粒剂组高组咳嗽次数降低明显，差异有统计学意义（P<0.05）；
上述实验结果表明，荆防颗粒能抑制豚鼠的咳嗽反应，具有镇咳的作用，止咳的效果与颗粒剂的剂量有一定的关系。
表1各组豚鼠咳嗽次数比较（
Figure 675798dest_path_image001
，n=10）
Figure 216500dest_path_image002
注：与空白对照组比较， #P<0.05， ##P<0.01；
与模型对照组比较，*P<0.05，**P<0.01；
与二麻合荆防败毒散组比较， △P<0.05， △△P<0.01。
4.2各组豚鼠支气管肺泡灌洗液中嗜酸性粒细胞百分率的测定
表2结果显示：与正常对照组比较，模型对照组的嗜酸性粒细胞百分率显著上升，差异有统计学意义（P<0.05）；
与模型对照组比较，4个治疗组嗜酸性粒细胞百分率显著下降，差异均有统计学意义（P<0.05或P<0.01）；
与二麻合荆防败毒散组相比，实施例1颗粒剂组高剂量组嗜酸性粒细胞百分率下降明显，差异有统计学意义（P<0.05）。
表2各组豚鼠BALF中嗜酸性粒细胞百分率比较（
Figure 391130dest_path_image003
，n=10）
Figure 257455dest_path_image004
注：与空白对照组比较， #P<0.05， ##P<0.01；
与模型对照组比较，*P<0.05，**P<0.01；
与二麻合荆防败毒散组比较， △P<0.05， △△P<0.01。
综上所述，本发明中药组合物可以显著减少CVA豚鼠模型咳嗽次数、降低支气管肺泡灌洗液（BALF）中嗜酸粒细胞百分率。以上实验结果表明，本发明中药组合物可以达到治疗咳嗽变异性哮喘的目的。
药效实施例二 本发明中药组合物对咳嗽变异性哮喘大鼠的影响
1材料
    1.1动物
    6周龄雄性清洁级SD大鼠，体质量（220±20）g，实验动物由鲁南制药集团股份有限公司新药药理中心提供，实验前适应性饲养一周。
    1.2药物
    实施例1颗粒剂；
    荆防散，文献（刘晓帅,曾南,梁珂,赵璐,瞿礼萍,宋美芳,张崇燕.荆防散干预一氧化氮合酶-一氧化氮通路的抗炎机制实验研究[J].时珍国医国药,2008,19(12):3014-3015.）中的组分和制备方法制备；
鸡卵清白蛋白（OVA）（GBCBIO Technologies公司，批号A20199006-59）；
氢氧化铝干粉（天津惠瑞化工科技有限公司，批号：20201209）；
辣椒素（美国Sigma公司批号：20200401）。
1.2.2大鼠用药剂量
          实施例1颗粒剂：3.6g/kg高剂量，1.8g/kg中剂量，0.9g/kg低剂量；
荆防散：2.5g/kg。
2.分组、建模及给药
采用卵蛋白和氢氧化铝共同激发致敏的方法造模。除正常组8只大鼠外，其余大鼠以配制的含卵蛋白1mg和氢氧化铝10mg的生理盐水1mL作皮下注射。分别在两后足跖、腹股沟、腰、背和颈部共取10点，每点皮下注射0.05 mL，同时腹腔注射0.5 mL，共计1mL，第8天重复1次以加强致敏。从第15天起，将大鼠置于密闭有机玻璃罩内，给予含1%卵蛋白溶液的生理盐水超声雾化激发20 min，以激发哮喘，以大鼠腹肌明显收缩为阳性，直到出现呼吸加深、加快等呼吸道痉挛症状，表明造模成功。
将造模成功的大鼠随机分为5组（模型组，实施例1颗粒剂高、中、低剂量组，荆防散组），每组8只。实施例颗粒剂低、中、高剂量给药剂量分别为0.9g/kg，1.8g/kg，3.6g/kg，荆防散组给药剂量为2.5g/kg，溶于纯化水中，给药体积10mL/kg。正常对照组和模型组给予等体积纯化水灌胃。连续给药13天。
       3. 指标检测
3.1咳嗽次数测定
       3.2血清中嗜酸粒细胞阳离子蛋白（ECP）含量的测定。
       3.3统计学方法
采用SPSS19.0统计软件进行分析。实验数据以
Figure 314272dest_path_image003
表示，经方差齐性检验后，多组间比较采用方差分析，两两比较用LSD法。P<0.05表示差异有统计学意义。
4.结果
4.1各组大鼠咳嗽次数的测定结果比较
       给药第13天后，将每组大鼠放置在密闭箱内，记录5min内雾化吸入浓度为1×10 -4mol/L辣椒素溶液后的咳嗽次数并进行统计。
       表3各组大鼠咳嗽次数比较（
Figure 658666dest_path_image003
，n=8）
组别 咳嗽次数（次数/min）
正常对照组 0.65±0.28
模型对照组 3.85±0.79 ##
实施例1颗粒剂低剂量组 2.98±0.43*
实施例1颗粒剂中剂量组 2.6±0.52** △
实施例1颗粒剂高剂量组 2.10±0.49** △△
荆防散组 3.20±0.41
注：与空白对照组比较， #P<0.05， ##P<0.01；
与模型对照组比较，*P<0.05，**P<0.01；
与荆防散组比较， △P<0.05， △△P<0.01。
与正常对照组比较，模型对照组咳嗽次数显著升高，差异有统计学意义（P<0.01）；与模型对照组相比，实施例1颗粒剂低、中、高剂量组的咳嗽次数显著降低，差异有统计学意义（P<0.05，P<0.01）；与荆防散组相比，实施例1颗粒剂组中、高组咳嗽次数降低明显，差异有统计学意义（P<0.05 ，P<0.01）；
上述实验结果表明，荆防颗粒能抑制大鼠的咳嗽反应，具有抑制咳嗽变异性哮喘咳嗽的作用，止咳的效果优于荆防散。
4.2各组大鼠血清中ECP的含量比较
实验第14天处死动物后，腹主动脉取血5mL，，静置4℃、2000 r/min离心 10min，分离血清，-20℃保存。测定严格按照ECP ELISA 试剂盒说明书操作。
表4 各组大鼠血清中ECP浓度水平（
Figure 687802dest_path_image003
，n=8）
组别 ECP（ng/mL）
正常对照组 1.43±0.37
模型对照组 2.41±0.46 ##
实施例1颗粒剂低剂量组 2.03±0.34
实施例1颗粒剂中剂量组 1.79±0.24** △
实施例1颗粒剂高剂量组 1.70±0.26** △△
荆防散组 2.06±0.21
注：与空白对照组比较， #P<0.05， ##P<0.01；
与模型对照组比较，*P<0.05，**P<0.01；
与荆防散组比较， △P<0.05， △△P<0.01。
与正常对照组相比，模型组血清中ECP含量显著升高（P<0.01），各给药组经过治疗后，与模型对照组相比，实施例1颗粒剂中、高剂量组血清ECP含量明显降低（P<0.05，P<0.01），且实施例1颗粒剂中、高剂量血清ECP的降低效果优于荆防散组（P<0.05，P<0.01）。上述试验结果表明，荆防颗粒可降低机体ECP水平，缓解咳嗽变异性哮喘的变态反应性症状。

Claims (10)

  1. 一种由荆芥、防风、羌活、独活、柴胡、前胡、川芎、枳壳、茯苓、桔梗、甘草组成的中药组合物在制备治疗咳嗽变异性哮喘药物中的用途。
  2. 如权利要求1所述的用途，其特征在于，所述的咳嗽变异性哮喘是寒哮、热哮、外寒内热型、肺实肾虚型中的任意一种类型。
  3. 如权利要求1所述的用途，其特征在于，所述的中药组合物能够降低咳嗽变异性哮喘患者支气管肺泡灌洗液（BALF）中嗜酸性粒细胞百分率和血清嗜酸粒细胞阳离子蛋白水平。
  4. 如权利要求1-3任一项所述的用途，其特征在于，所述中药组合物主要由以下原料制备而成：
    荆芥5-30重量份  防风5-30重量份   羌活5-30重量份
    独活5-30重量份  柴胡3-25重量份   前胡3-25重量份
    川芎5-30重量份  枳壳3-25重量份   茯苓5-30重量份
    桔梗3-25重量份  甘草1-10重量份。
  5. 如权利要求4所述的用途，其特征在于，所述的中药组合物主要由以下原料制备而成：
    荆芥10-20重量份  防风10-20重量份   羌活10-20重量份
    独活10-20重量份  柴胡3-20重量份   前胡3-20重量份
    川芎10-20重量份  枳壳3-20重量份   茯苓10-25重量份
    桔梗3-20重量份  甘草1-8重量份。
  6. 如权利要求5所述的用途，其特征在于，所述的中药组合物主要由以下原料制备而成：
    荆芥15重量份  防风15重量份   羌活15重量份
    独活15重量份  柴胡15重量份   前胡15重量份
    川芎15重量份  枳壳15重量份   茯苓15重量份
    桔梗15重量份  甘草5重量份。
  7. 如权利要求1-6任一项所述的用途，其特征在于，所述中药组合物的制备方法包括以下步骤：
    步骤A：将荆芥、防风、羌活、独活、前胡、川芎、枳壳，蒸馏提取挥发油备用，蒸馏后的药渣、蒸馏后的川芎、枳壳水溶液备用；
    步骤B：将步骤A 所得蒸馏后的川芎、枳壳水溶液配制成10-40%的乙醇溶液，备用；
    步骤C：将茯苓、步骤A所得蒸馏后的川芎、枳壳药渣混合，以步骤B所得乙醇溶液渗漉提取，渗漉液备用；
    步骤D：将柴胡、桔梗、甘草、步骤A所得蒸馏后的荆芥、防风、羌活、独活、前胡药渣，加水煎煮，煎煮液浓缩后备用；
    步骤E：将步骤C所得渗漉液、步骤D所得煎煮液混合，浓缩，加入步骤A所得挥发油，即得；
    优选地，步骤B为将步骤A 所得蒸馏后的川芎、枳壳水溶液配制成15-30%的乙醇溶液，备用；
    进一步优选地，步骤B为将步骤A 所得蒸馏后的川芎、枳壳水溶液配制成25%的乙醇溶液，备用。
  8. 如权利要求7所述的用途，其特征在于，所述的中药组合物不含或含有一种或多种药学上可接受的药用辅料。
  9. 如权利要求8所述的用途，其特征在于，所述的中药组合物可以制备成片剂、口服液、胶囊剂、丸剂、颗粒剂或液体口服制剂中的一种或多种。
  10. 如权利要求9所述的用途，其特征在于，所述的口服制剂为颗粒剂。
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