WO2016019736A1 - 用于治疗咳嗽及减轻气道炎症的五味子提取物、其制备方法及应用 - Google Patents

用于治疗咳嗽及减轻气道炎症的五味子提取物、其制备方法及应用 Download PDF

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WO2016019736A1
WO2016019736A1 PCT/CN2015/076076 CN2015076076W WO2016019736A1 WO 2016019736 A1 WO2016019736 A1 WO 2016019736A1 CN 2015076076 W CN2015076076 W CN 2015076076W WO 2016019736 A1 WO2016019736 A1 WO 2016019736A1
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extract
schisandra
cough
group
schisandra chinensis
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PCT/CN2015/076076
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English (en)
French (fr)
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赖克方
钟山
甘振勇
刘晓东
聂怡初
钟南山
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广州医科大学附属第一医院
广州呼吸疾病研究所
呼吸疾病国家重点实验室
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Publication of WO2016019736A1 publication Critical patent/WO2016019736A1/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)
    • A61K36/57—Magnoliaceae (Magnolia family)
    • 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)
    • A61K36/79—Schisandraceae (Schisandra family)

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  • the invention relates to a traditional Chinese medicine extract, in particular to a Schisandra extract, a preparation method and application thereof, and belongs to the technical field of traditional Chinese medicine.
  • Cough is the most common symptom in medical clinics and is found in a variety of respiratory and non-respiratory diseases. Cough itself is a defense mechanism that removes excessive secretions from the airways and prevents foreign bodies from inhaling the airways.
  • chronic cough for a long time has seriously affected the quality of life of patients and caused a serious psychological burden on patients, and also significantly increased personal and public health expenditures.
  • Chronic cough is clinically referred to as cough as the sole symptom or main symptom.
  • the cough time is more than 8 weeks, and there is no obvious abnormality in chest X-ray examination.
  • the average duration of chronic cough patients is three years, some for decades, the average number of visits is 18, and the average number of medical institutions visited is 3, among which female patients are induced by cough.
  • the proportion of urinary incontinence is as high as 48%.
  • the incidence of chronic cough has increased: many foreign epidemiological studies have shown the incidence of chronic cough in the general population. The rate is about 9% to 33%.
  • a 2003 British epidemiological survey showed that the incidence of chronic cough in middle-aged people aged 50-59 was 12%, and that of chronic cough patients accounted for about 20% of respiratory specialist outpatients.
  • Schisandra is a magnolia plant, the fruit is used as medicine, tastes sour, sweet, and warm. Return to the lungs, heart, kidney.
  • Traditional Chinese medicine often uses Schisandra in combination with cough Chinese medicines such as ephedra, purpura, and coltsfoot, etc., for cough and innocence in the late stage of coughing or chronic cough with chronic cough. So far, there has been no report in the literature whether Schisandra extract can effectively treat cough, especially chronic cough.
  • the present invention provides a method for preparing a Schisandra extract, and the Schisandra extract prepared by the present invention can be applied to treat cough and reduce airway inflammation.
  • the present invention takes the following steps to prepare the Schisandra extract:
  • the medicinal residue obtained by the step 1) is boiled for 1 to 3 times with water, and decocted for 1 to 3 hours each time.
  • the volume (ml) of water used for each boiling is the mass of the schisandra chinensis (g) 4 ⁇ 8 times, the extract is combined, and then statically filtered to obtain extract B;
  • step 1) extracting the obtained extract A and extracting the obtained extract B in the step 2), followed by vacuum drying to obtain the schisandra extract.
  • the schisandra chinensis is at least one of Schisandra chinensis (Turcz.) Baill. or Schisandra sphenanthera Rehd.et Wils.
  • the ethanol solution is an aqueous ethanol solution having an ethanol concentration between 50 and 100%.
  • the Schisandra chinensis is dried and pulverized into 10 to 60 mesh.
  • the step of concentrating the filtrate under reduced pressure is further performed; after the extract obtained in the step 2) is combined and statically filtered, the filtrate is further subjected to filtration.
  • the step of concentration under reduced pressure is further performed after the extract obtained in the step 1) is combined and statically filtered.
  • the Schisandra extract of the invention has the advantages of simple preparation method, low equipment cost, low energy consumption, safe and non-toxic solvent, low price, industrialized production and easy promotion.
  • the present invention also provides the use of the Schisandra extract prepared by the above method or the composition containing the Schisandra extract for the preparation of a medicament for treating cough and/or a health care product, the cough comprising an acute, subacute or chronic cough.
  • the Schisandra extract prepared by the present invention has an antitussive effect, an inhibitory effect on cough-related airway inflammation and high sensitivity of cough.
  • the Schisandra extract of the present invention may be used alone or in combination with appropriate pharmaceutical excipients to prepare various pharmaceutically acceptable soft capsules, hard capsules, tablets, granules, pills, water pills, honey pills, oral liquids, and the like.
  • a dosage form of a drug or health supplement may be used alone or in combination with appropriate pharmaceutical excipients to prepare various pharmaceutically acceptable soft capsules, hard capsules, tablets, granules, pills, water pills, honey pills, oral liquids, and the like.
  • a dosage form of a drug or health supplement may be used alone or in combination with appropriate pharmaceutical excipients to prepare various pharmaceutically acceptable soft capsules, hard capsules, tablets, granules, pills, water pills, honey pills, oral liquids, and the like.
  • the present invention also provides a composition for treating cough and ameliorating airway inflammation, the active ingredients of which include the Schisandra extract prepared by the method described above.
  • the composition can be formulated into a pharmaceutically acceptable dosage form.
  • the Schisandra chinensis extract of the present invention may also be combined with other traditional Chinese medicine extracts to form a traditional Chinese medicine composition, and a suitable pharmaceutical auxiliary material is added to prepare soft capsules, hard capsules, tablets, granules, pills, water pills, honey pills, oral liquids. And other pharmaceutically acceptable dosage forms of drugs or health care products.
  • Figure 1 is a representative image of the lung tissue and airway pathological section of the guinea pig of Example 4 (HE ⁇ 200)
  • Figure 2 is the effect of schisandra extract on the frequency of coughing in guinea pigs at different time points.
  • Guinea pigs are housed in a relatively clean, quiet, constant temperature (23 ⁇ 3 ° C), constant humidity (55 ⁇ 15%) environment, day and night cycle of 12: 12 hours / day, caged, 5 / cage, free access to food And water.
  • Schisandra water extract (according to the following procedure: schisandra medicinal granules ⁇ 8 times water decoction for 2 h, total boiling 3 times ⁇ decoction liquid concentration, drying ⁇ Schisandra water extract); 0.9% sodium chloride injection: Dongguan Puji Pharmaceutical Co., Ltd. Sodium pentobarbital: Merck, USA. Codeine: Sinopharm Group Industrial Co., Ltd. "Hongmei" brand filter cigarette: Guangzhou China Tobacco Industry Co., Ltd. Other conventional reagents: Guangzhou Chemical Reagent Factory.
  • PM type single-cavity non-restricted small animal body scanner (1.0L): American Buxco company; digital photography integration system: Japan Nikon company; 0.6m ⁇ 0.6m ⁇ 1m cigarette smoke poisoning box: self-made in this laboratory; A1003 Electronic balance: Satorius, Germany; MDF-U53V-80°C low temperature refrigerator: Sanyo, Japan; 3-18K SIGMA high speed refrigerated centrifuge: Beckman, USA; 22G intravenous indwelling needle: Suzhou Medical Devices Co., Ltd.; Anke TGL-16B High-speed centrifuge: Shanghai Anshang Scientific Instrument Factory; 400-type desktop cryogenic centrifuge: Germany Heraeus Company; XW80A type vortex oscillator: Shanghai Precision Instrument and Meter Co., Ltd.; DK8A constant temperature water bath: Shanghai Jinghong Test Instrument Co., Ltd.
  • Smoked method After a week of adaptive quiet feeding, the guinea pigs were placed in a self-made cigarette poisoning box, and 10 cigarettes were ignited in the smoker tank each time (baked tobacco type, tar content 12 mg, smoke nicotine content 1.1 mg). The flue gas carbon monoxide content is 15mg), and the cigarette smoke is put into the poisoning box through the three-way valve, and the time is started from the burning of the cigarette. Each time the smoke is smoked for 20 minutes, the smoke is smoked twice a day, the interval between each two smokes is more than 6 hours, and the smoke is continuously smoked for 14 days.
  • Guinea pigs were completely randomly divided into normal group, model group, solvent control group (0.5% PEG400), codeine group, high-dose water extract group (dose 500 mg/kg guinea pig/day, drug concentration 50 mg/mL), Schisandra Extract high dose group (dose 500mg/kg guinea pig / day, drug concentration 50mg / mL), Schisandra extract dose group (dose 250mg / kg guinea pig / day, drug concentration 25mg / mL), Schisandra extract low dose group ( The dose was 125 mg/kg guinea pig/day, and the drug concentration was 12.5 mg/mL).
  • the other groups of animals were stimulated by the above-mentioned smoking method. Except for the normal group and the codeine group, the other groups of guinea pigs were orally administered with the corresponding drugs or solvents for 2 days from the first day of smoking, 2 hours before the second smoke every day.
  • the codeine group was orally administered 1 hour before the citrate cough sensitivity test (30 mg/kg guinea pig, codeine concentration 3 mg/mL). Normal group is kept normally, nowhere Reason.
  • the guinea pigs were placed in the body drawing box. After 2 minutes of adaptation, 0.4 mol/L citric acid was atomized for cough stimulation. After 10 minutes, the atomization was finished, and the observation was continued for 10 minutes. The total number of guinea pig coughs was recorded within 20 minutes from the start of atomization. And cough latency.
  • anesthetized animals were intraperitoneally injected with 3% sodium pentobarbital solution (1 mL/kg), and 10 mL of blood was taken from the heart. 6 mL of 0.1 mol/L pre-cooled PBS buffer was taken, and alveolar lavage was performed in 3 times. The left lung was uniformly irrigated and irrigated 3 times each time to obtain Bronchoalveolar Lavage Fluid (BALF).
  • BALF Bronchoalveolar Lavage Fluid
  • the cough latency of guinea pig citrate cough challenge test in each experimental group is shown in Table 2.
  • the results showed that compared with the model group, the cough latency of the high, middle and low doses of Schisandra extract was significantly prolonged; the high dose of water extract had no significant effect on the cough latency.
  • the total number of inflammatory cells in the bronchoalveolar lavage fluid of each experimental group and the comparison results of the classification are shown in Table 3.
  • the results showed that compared with the model group, the high, medium and low doses of Schisandra chinensis extract could significantly reduce the total number of inflammatory cells in BALF and significantly reduce the proportion of neutrophils in BALF.
  • the high dose of water extract had no significant effect on the total number of inflammatory cells and the proportion of neutrophils in BALF.
  • the lung tissue and tracheal pathology of the guinea pigs in each dose group of the present invention were significantly improved: the infiltration of inflammatory cells in the peripheral bronchioles of the guinea pigs was significantly reduced, the exudation in the lumen was alleviated, and the interval of the alveolar spaces was lighter.
  • the schisandra extract obtained by the invention can significantly alleviate airway inflammation in guinea pigs.
  • the lung tissue and tracheal pathology of guinea pigs were not significantly improved. Representative figures of lung tissue and tracheal pathology of guinea pigs in each experimental group are shown in Fig. 1.
  • cough sensitivity screening 0.8mol/L citric acid atomization stimulation for 1min, stop atomization, continue to observe for 5min, record the number of coughs within 6min from the start of nebulization, more than 10 times less than 50 times of guinea pigs Qualified guinea pig.
  • the qualified guinea pigs were completely randomly divided into normal group, solvent control group (0.5% PEG400), codeine group, water extract high dose group (dose 500 mg/kg guinea pig/day, drug concentration 50 mg/mL), Schisandra extract High dose group (dose 500mg/kg guinea pig/day, drug concentration 50mg/mL), Schisandra extract dose group (dose 250mg/kg guinea pig/day, drug concentration 25mg/mL), Schisandra extract low dose group (dose 125 mg/kg guinea pig/day, drug concentration 12.5 mg/mL).
  • the other groups of guinea pigs were orally administered with drugs or solvents for 5 days, once a day, 5 days after the fifth day of administration or after 1 h of solvent, citrate cough stimulation: 0.8 mol / L lemon
  • citrate cough stimulation 0.8 mol / L lemon
  • the acid atomization was stimulated for 1 min, the atomization was stopped, and the observation was continued for 5 min, and the number of coughs within 6 minutes from the start of the atomization was recorded.
  • the codeine group was orally administered 1 hour before the citrate cough challenge on the 5th day.
  • the normal group was raised normally, and the citrate cough was directly stimulated on the fifth day.
  • the number of coughs in each experimental group is shown in Table 5. The results showed that compared with the normal group, the number of coughs in the guinea pigs in the high, medium and low doses of Schisandra extract was significantly reduced, and there was no significant difference in the number of coughs in the high dose group.
  • the cough latency of each experimental group is shown in Table 6.
  • the results showed that the cough latency of guinea pigs in the high, middle and low dose groups of Schisandra chinensis extract was significantly prolonged compared with the normal group.
  • the cough latency of the high-dose group of water extracts was not significantly different from that of the normal group.
  • cough sensitivity screening 0.8mol/L citric acid atomization stimulation for 1min, stop atomization, continue to observe for 5min, record the number of coughs within 6min from the start of nebulization, more than 10 times less than 50 times of guinea pigs Qualified guinea pig.
  • the second largest group was randomly divided into 3 groups: normal group, codeine group (30 mg/kg, oral administration), and Schisandra extract group prepared in Example 3 (250 mg/kg, drug concentration 25 mg/mL, oral) Dosing), 10 in each group, the normal group was directly stimulated by citrate cough, the group of codeine and Schisandra extract group was given cough stimulation 1 hour after the administration, the excitation condition was the same as the first group; the third group and the third group The grouping and firing conditions of the four groups were the same as those of the second group, and the administration time of the codeine group and the Schisandra extract group was 3 h and 5 h before the challenge, respectively.
  • Fig. 2 The results are shown in Fig. 2. It is shown that the schisandra extract (250 mg/kg) prepared in Example 3 can significantly reduce the number of acute coughing induced by citric acid smoke stimulation after 1 hour of administration, and can still be expressed after 5 hours of administration. Significant drug efficacy was observed, and there was no significant difference in the number of coughs between the codeine and the normal group after 5 hours of administration.
  • the pharmacological studies of the Schisandra extract prepared in the three examples showed that the Schisandra extract prepared by the present invention can significantly prolong the cough latency, reduce the number of coughs, and significantly reduce the alveolar lavage of CS guinea pigs caused by CS guinea pigs and citric acid stimulation.
  • the total number of inflammatory cells and the proportion of neutrophils in the lotion, pathological section observation showed that the schisandra extract obtained by the present invention was significantly reduced in the peri-bronchial inflammatory cell infiltration, the intraluminal exudation was alleviated, and the alveolar interval was broadened. , suggesting that the Schisandra chinensis extract of the present invention has airway inflammation in guinea pigs Significant inhibition.
  • the extract of Schisandra chinensis prepared by the invention is obviously better than the extract of Schisandra chinensis, and has a dose-effect relationship, and exhibits application prospects of antitussive, relieving cough and reducing airway inflammation.
  • the method of administration for reference is: 1-3 times a day, 20 ml each time.
  • the schisandra syrup prepared in Example 5 was subjected to clinical trials, including 15 patients with chronic cough and 15 patients with acute cough.
  • the syrup prepared in Example 5 was consumed 1 to 3 times a day, 20 mL each time, and was continuously taken. 1 to 2 weeks, the total effective rate is 100%, the specific feedback results can be seen in the following table:
  • Case 1 Zhang, male, 55 years old, coughing for about 4 months, diagnosed as cough hypersensitivity syndrome, taking the schisandra extract syrup prepared in Example 5 for one week, the cough sensitivity was significantly reduced, and the number of coughing was significantly reduced.
  • Case 2 Liu, female, 35 years old, coughing for about 2 months, diagnosed as cough after infection, taking 2 bottles of Schisandra extract syrup prepared in Example 5, taking the medicine on the first day, taking 2 bottles and then coughing Basic relief.
  • Case 3 Baomou, female, 41 years old, coughing for about 1 month, with phlegm, sputum cough, diagnosed as cough after infection, taking 2 bottles of Schisandra extract syrup prepared in Example 5, after taking the drug After two days of treatment, after taking 2 bottles, the cough improved by 70%. After adding 1 bottle, the cough was completely relieved.
  • Case 4 You Mou, male, 24 years old, coughing for about 2 years, mainly dry cough, diagnosed as eosinophilic bronchitis, gastroesophageal reflux cough, taking 2 bottles of Schisandra extract syrup prepared in Example 5. The drug took effect on the third day, and the cough improved by 40%. After adding 2 bottles, the symptoms of cough were basically eliminated.
  • the oral administration of the schisandra extract syrup of the present invention can effectively alleviate cough and reduce airway inflammation.
  • the Schisandra extract prepared by the present invention is extracted from the traditional Chinese medicine Schisandra, and the Schisandra is a Chinese medicine which can be used for health foods announced by the Ministry of Health without any toxicity or side effects to the human body.
  • the schisandra extract of the present invention can also be made into other pharmaceutically acceptable dosage forms, such as tablets, hard capsules, soft capsules, powders, elixirs, pills, according to the needs of those skilled in the art.
  • granules, injections or other oral liquid dosage forms can be prepared by mixing the schisandra extract prepared by the present invention with the adjuvant starch, sucrose and a disintegrating agent, and then adding the mixture to the binder cellulose derivative solution dissolved in water for mixing.
  • the extrusion granulation method prepares the soft particles into a soft granule, which is dried, sieved, sieved and pulverized, and sieved to obtain uniform granules.
  • a tablet can also be prepared by mixing the schisandra extract of the present invention with an appropriate amount of starch and talc, moistening with 70% ethanol to prepare granules, and then pressing the tablet with a tableting machine to prepare a schisandra extract tablet.
  • the schisandra extract gum can also be prepared by adding an appropriate amount of carboxymethyl cellulose and cyclodextrin to the Schisandra chinensis extract of the present invention. bag.

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Abstract

五味子提取物及其制备方法和在制备治疗咳嗽及减轻气道炎症的药物或保健品中的应用，该提取物是以五味子为原料，采用乙醇回流提取3次，每次1-3h，合并提取液，静置后过滤，得提取物A；药渣水煎煮3次，每次1-3h，合并提取液，静置后过滤，得提取物B，合并提取物A和B，真空干燥，即得。

Description

用于治疗咳嗽及减轻气道炎症的五味子提取物、其制备方法及应用 技术领域
本发明涉及一种中药提取物，具体涉及一种五味子提取物及其制备方法和应用，属于中药技术领域。
背景技术
咳嗽是内科门诊最常见的症状，见于多种呼吸系统及非呼吸系统疾病。咳嗽本身是一种防御机制，清除气道内过多的分泌物及防止异物误吸入气道。但持续长时间的慢性咳嗽却严重影响了患者的生活质量并造成患者严重的心理负担，同时也显著增加了个人及公共医疗卫生支出。慢性咳嗽在临床上是指以咳嗽为唯一症状或主要症状，咳嗽时间超过8周，胸部X线检查无明显异常的症状。广州呼吸疾病研究所进行的一项调查显示，慢性咳嗽患者平均病程为三年，有的长达数十年，就诊的平均次数达18次，就诊医疗机构平均3间，其中女性患者因咳嗽诱发尿失禁比例高达48％。近年随着大气环境污染的逐渐加重(如PM2.5、PM10等)、生活压力加大，慢性咳嗽的发病率有升高的趋势：多份国外流行病学研究显示慢性咳嗽在普通人群的发病率约9％～33％，2003年一项英国流行病学调查显示，慢性咳嗽在50-59岁的中年人发病率达12％，慢性咳嗽患者约占呼吸专家门诊患者的20％。在我国，据广州呼吸疾病研究所统计，在青年大学生人群中慢性咳嗽的患病率超过3％，推测社区人群的咳嗽患病率将远高于这一数据。慢性咳嗽患者反复进行各种无意义的检查，使用各种抗生素和镇咳药物治疗均无效，严重影响患者的身心健康及工作生活，并造成公共医疗资源的极大浪费。
五味子为木兰科植物，果实入药，味酸、甘，性温。归肺、心、肾经。中医临床上常将五味子配伍止咳中药如麻黄、紫菀、款冬花等，用于咳嗽后期的干咳无痰或久咳不已的肺虚咳嗽病症。目前为止，一直未有文献报道五味子提取物是否能有效治疗咳嗽尤其是久咳。
发明内容
为了解决上述问题，本发明提供一种五味子提取物的制备方法，本发明制得的五味子提取物可应用于治疗咳嗽及减轻气道炎症。
本发明采取如下步骤来制备五味子提取物：
1)取五味子药材，将其干燥后进行粉碎，用乙醇溶液回流提取1～3次，每次提取1～3小时，每次提取所用的乙醇溶液的体积(ml)为五味子药材质量(g)的4～8倍(即，每1g五味子药材加入4～8ml的乙醇溶液进行提取)，合并提取液，然后静置过滤，得提取物A；
2)将步骤1)提取留下的药渣用水煎煮1～3次，每次煎煮1～3小时，每次煎煮所用的水的体积(ml)为五味子药材质量(g)的4～8倍，合并提取液，然后静置过滤，得提取物B；
3)合并步骤1)提取得到的提取物A和步骤2)提取得到的提取物B，然后进行真空干燥，制得所述五味子提取物。
所述五味子药材为五味子Schisandra chinensis(Turcz.)Baill.或华中五味子Schisandra sphenanthera Rehd.et Wils.中的至少一种
所述乙醇溶液其为乙醇体积浓度在50-100％之间的乙醇水溶液。
进一步的，步骤1)中，将五味子药材干燥后粉碎成10～60目。
优选的，在步骤1)获得的提取液合并且静置过滤后，还具有对过滤液进行减压浓缩的步骤；在步骤2)获得的提取液合并且静置过滤后还具有对过滤液进行减压浓缩的步骤。
本发明的五味子提取物，其制备方法简单、设备成本低、能耗消耗少、溶剂安全无毒、价格低廉，能实现工业化生产，易于推广。
本发明还提供由上述方法制备的五味子提取物或者含有所述五味子提取物的组合物在制备治疗咳嗽的药物和/或保健品中的应用，所述咳嗽包括急性、亚急性或慢性咳嗽。本发明制得的五味子提取物具有镇咳作用、对咳嗽相关的气道炎症和咳嗽高敏感性具有抑制作用。
本发明的五味子提取物可以单独应用，也可加入适当的药用辅料，制成软胶囊、硬胶囊、片剂、颗粒剂、滴丸剂、水丸剂、蜜丸剂、口服液等各种药学上允许剂型的药物或保健品。
本发明还提供用于治疗咳嗽及缓解气道炎症的组合物，其活性成分包括上文所述的方法制得的五味子提取物。该组合物可制成药学上允许的剂型。
本发明的五味子提取物还可以与其它中药提取物组成中药组合物，加入适当的药用辅料，制成软胶囊、硬胶囊、片剂、颗粒剂、滴丸剂、水丸剂、蜜丸剂、口服液等各种药学上允许剂型的药物或保健品。
附图说明
图1，为实施例4豚鼠肺组织和气道病理切片代表图(HE×200)
图2，为五味子提取物不同时间点对柠檬酸烟雾刺激豚鼠咳嗽次数的影响
具体实施方式
以下实施例用于说明本发明，但不用来限制本发明的范畴。
实施例1：
干燥的北五味子药材10kg，粉碎成30目粗粉，用95％(v/v)乙醇回流提取3次，每次3h，三次提取所用乙醇的体积(ml)分别为药材质量(g)的8倍、6倍、6倍，合并3次提取液，静置后过滤，减压浓缩，得提取物A；将提取后留下的药渣水煎煮2次，每次2h，两次煎煮所需水的体积(ml)分别为五味子药材质量(g)的8倍、6倍，合并2次提取液，静置后过滤，减压浓缩，得提取物B。合并提取物A和B，真空干燥，得五味子提取物5.69kg。
实施例2：
干燥的南五味子药材10kg，粉碎成40目粗粉，80％(v/v)乙醇水溶液回流提取3次，每次3h，三次提取乙醇的体积(ml)分别为五味子药材质量(g)的8倍、6倍、6倍，合并3次提取液，静置后过滤，减压浓缩，得提取物A；提取后留下的药渣水煎煮2次，每次2h，两次煎煮水的体积(ml)分别为五味子药材质量(g)的8倍、6倍，合并2次提取液，静置后过滤，减压浓缩，得提取物B。合并提取物A和B，真空干燥，得五味子提取物5.28kg。
实施例3：
干燥的北五味子药材10kg，粉碎成50目粗粉，60％(v/v)乙醇水溶液回流提取2次，每次3h，，两次提取乙醇的体积(ml)分别为五味子药材质量(g)的8倍、6倍，合并提取液，静置后过滤，减压浓缩， 得提取物A；提取留下的药渣水煎煮2次，每次2h，两次煎煮水的体积(ml)分别为五味子药材质量(g)的8倍、6倍，合并提取液，静置后过滤，减压浓缩，得提取物B。合并提取物A和B，真空干燥，得五味子提取物5.42kg。
实施例4：
实验动物
纯白Hartly豚鼠，普通级，雄性，体重300±50g，购自广东省实验动物中心，许可证号：SCXK(粤)2008-0002。饲养于广州呼吸疾病研究所国家重点实验室动物中心，许可证号：SYXK(粤)2008-0093。豚鼠饲养在相对清洁、安静、恒温(23±3℃)、恒湿(55±15％)环境中，日夜周期为12:12小时/天，分笼饲养，5只/笼，可自由获得食物和水。
药物与试剂
五味子水提取物(按照如下流程制得：五味子药材粉碎→8倍量水煎煮2h，共煎煮3次→煎煮液浓缩，干燥→五味子水提取物)；0.9％氯化钠注射液：东莞普济药业有限公司。戊巴比妥钠：美国Merck公司。可待因：国药集团工业股份有限公司。“红玫”牌过滤嘴香烟：广州中烟工业有限公司。其它常规试剂：广州化学试剂厂。
具体实施方式中所有数据用“均值±标准差”表示，各组间比较采用spss13.0进行单因素方差分析，方差齐用最小显著差异法(LSD)，方差不齐或非正态的数据采用秩和检验，P＜0.05表示差异有统计学意义。
实验仪器
PM型单腔非限制型小动物体描仪(1.0L)：美国Buxco公司；数码摄影一体化系统：日本Nikon公司；0.6m×0.6m×1m香烟烟雾染毒箱：本实验室自制；A1003电子天平：德国Satorius公司；MDF-U53V-80℃低温冰箱：日本三洋公司；3-18K SIGMA高速冷冻离心机：美国Beckman公司；22G静脉留置针：苏州医疗器械有限公司；Anke TGL-16B型普通高速离心机：上海安停科学仪器厂；400型台式低温离心机：德国Heraeus公司；XW80A型旋涡振荡器：上海精密仪器仪表有限公司；DK8A恒温水浴锅：上海精宏试验仪器有限公司。
(一)实施例1制备的五味子提取物对香烟烟雾刺激致咳嗽敏感性增高豚鼠(CS豚鼠)的药理作用
烟熏方法：豚鼠于实验前适应性安静饲养一周后，置于自制香烟染毒箱内，每次点燃10根香烟于烟熏槽内(烤烟型，焦油含量12mg，烟气烟碱含量1.1mg，烟气一氧化碳含量15mg)，通过三通阀将香烟烟雾打入染毒箱内，自香烟燃完开始计时。每次熏烟20分钟，每天熏烟2次，每二次熏烟间隔时间大于6小时，连续熏烟14天。
实验：豚鼠完全随机分成正常组、模型组、溶剂对照组(0.5％的PEG400)、可待因组、水提取物高剂量组(剂量500mg/kg豚鼠/天，药物浓度50mg/mL)、五味子提取物高剂量组(剂量500mg/kg豚鼠/天，药物浓度50mg/mL)、五味子提取物中剂量组(剂量250mg/kg豚鼠/天，药物浓度25mg/mL)、五味子提取物低剂量组(剂量125mg/kg豚鼠/天，药物浓度12.5mg/mL)。
除正常组外，其余各组动物均采用上述烟熏方法刺激。除正常组及可待因组外，其余各组豚鼠从烟熏第一天开始，于每天的第二次烟熏前2小时经口给予相应的药物或溶剂，连续14天。可待因组于柠檬酸咳嗽敏感性检查前1小时，经口给药(30mg/kg豚鼠，可待因浓度3mg/mL)。正常组正常饲养，不作任何处 理。第15天将豚鼠置于体描箱内，适应2min后，雾化0.4mol/L柠檬酸进行咳嗽激发，10min后雾化结束，继续观察10min，记录自雾化开始的20min内豚鼠咳嗽总次数及咳嗽潜伏期。
咳嗽激发实验24h后，3％戊巴比妥钠溶液(1mL/kg)腹腔注射麻醉动物，心脏取血10mL。取6mL 0.1mol/L预冷的PBS缓冲液，分3次进行肺泡灌洗，统一灌洗左肺，每次反复灌洗3次，得肺泡灌洗液(Bronchoalveolar Lavage Fluid，BALF)。将所得BALF震荡混悬，抽取0.5mL，用红细胞裂解液充分裂解，3000转/分钟离心10分钟，取10μL上清液滴入血细胞计数板，光学显微镜下计算BALF炎症细胞总数(细胞总数/mL＝(四大格细胞总数/4)×104/mL)；抽取0.5mL后剩余的BALF于3000rpm离心10min，沉淀用1mLPBS混悬，取100μL制作细胞涂片，自然风干，浸泡于10％中性甲醛中过夜固定，取出后依次进行流水冲洗10min、苏木素染色15sec、流水冲洗1min、1％盐酸酒精脱色2sec、流水冲洗10min、伊红染色5sec、流水冲洗10min、烘干，得中性树胶封片，光学显微镜下连续随机抽取20个400倍视野进行连续计数，每张涂片连续计数400个细胞，计算其中中性粒细胞、嗜酸粒细胞、巨噬细胞、淋巴细胞的比例。
豚鼠抽取BALF后，从心脏注入50mL PBS进行灌洗，从气管注入2.5mL4％多聚甲醛，然后剪取一块右下肺组织及一段气管，10％中性甲醛固定24h以上。取出已固定好的肺组织，依次进行乙醇梯度脱水、生物透明剂处理、浸蜡、包埋、切片、脱蜡、梯度酒精水化、双蒸水短暂漂洗，最后进行HE染色后，中性树胶封片，进行病理观察。
实验结果：与正常组比较，各实验组豚鼠气道阻力未见明显差异，提示本实验建模方法未造成豚鼠气道阻力增加，有别于慢性阻塞性肺疾病动物模型。
各实验组豚鼠柠檬酸激发咳嗽次数见表1。结果表明，与模型组比较，五味子提取物(高、中、低剂量组)均能显著减少模型豚鼠的咳嗽次数。
表1 实施例1制备的五味子提取物对CS豚鼠咳嗽次数的影响(
Figure PCTCN2015076076-appb-000001
)(n＝7)
Figure PCTCN2015076076-appb-000002
注：与正常组比较：**P<0.01；与模型组比较：#P<0.05，##P<0.01
各实验组豚鼠柠檬酸咳嗽激发实验咳嗽潜伏期见表2。结果表明，与模型组比较，五味子提取物的高、中、低剂量组咳嗽潜伏期显著延长；水提取物高剂量对咳嗽潜伏期的作用不明显。
表2 实施例1制备的五味子提取物对CS豚鼠咳嗽潜伏期的影响(
Figure PCTCN2015076076-appb-000003
)(n＝7)
Figure PCTCN2015076076-appb-000004
Figure PCTCN2015076076-appb-000005
注：与正常组比较：**P<0.01；与模型组比较：#P<0.05，##P<0.01
各实验组动物支气管肺泡灌洗液中炎症细胞总数及分类比较实验结果见表3。结果表明，与模型组比较，五味子提取物高、中、低剂量均能显著减少BALF中炎症细胞总数、显著减少BALF中中性粒细胞比例。水提取物高剂量对BALF中炎症细胞总数及中性粒细胞比例作用不明显。
表3 实施例1制备的五味子提取物对CS豚鼠支气管肺泡灌洗液炎症细胞总数和分类的影响(
Figure PCTCN2015076076-appb-000006
)(n＝7)
Figure PCTCN2015076076-appb-000007
注：与正常组比较：**P<0.01；与模型组比较：#P<0.05，##P<0.01
与模型组比较，本发明五味子提取物各剂量组豚鼠肺组织及气管病理均明显改善：豚鼠细支气管周炎症细胞浸润明显减少，管腔内渗出减轻，肺泡间隔增宽程度较轻，提示本发明制得的五味子提取物能显著减轻豚鼠气道炎症。而水提取物高剂量组豚鼠肺组织及气管病理改善不明显。各实验组豚鼠肺组织及气管病理切片代表图见附图1。
(二)实施例2制备的五味子提取物对柠檬酸烟雾刺激致急性咳嗽豚鼠的药理作用
豚鼠静养一周后，进行咳嗽敏感性筛选：0.8mol/L柠檬酸雾化刺激1min，停止雾化，继续观察5min，记录自雾化开始6min内的咳嗽次数，大于10次小于50次的豚鼠为合格豚鼠。
将筛选合格的豚鼠完全随机分成正常组、溶剂对照组(0.5％的PEG400)、可待因组、水提取物高剂量组(剂量500mg/kg豚鼠/天，药物浓度50mg/mL)、五味子提取物高剂量组(剂量500mg/kg豚鼠/天，药物浓度50mg/mL)、五味子提取物中剂量组(剂量250mg/kg豚鼠/天，药物浓度25mg/mL)、五味子提取物低剂量组(剂量125mg/kg豚鼠/天，药物浓度12.5mg/mL)。除正常组及可待因组外，其余各组豚鼠连续5天每天经口给予药物或溶剂，1次/天，第五日给药或溶剂后1h进行柠檬酸咳嗽激发：0.8mol/L柠檬酸雾化刺激1min，停止雾化，继续观察5min，记录自雾化开始6min内的咳嗽次数。可待因组于第5日柠檬酸咳嗽激发前1小时经口给药。正常组正常饲养，第五日直接进行柠檬酸咳嗽激发。
各实验组的咳嗽次数如表5所示。结果表明，与正常组比较，五味子提取物高、中、低剂量干预组的豚鼠咳嗽次数均显著减少，水提取物高剂量组豚鼠咳嗽次数无显著差异。
表5 实施例2制备的五味子提取物对柠檬酸致急性咳嗽豚鼠咳嗽次数的影响(
Figure PCTCN2015076076-appb-000008
)(n＝7)
Figure PCTCN2015076076-appb-000009
注：与正常组比较：*P<0.05，**P<0.01
各实验组的咳嗽潜伏期如表6所示。结果表明，与正常组比较，五味子提取物高、中、低剂量组豚鼠的咳嗽潜伏期均显著延长。水提取物高剂量组豚鼠的咳嗽潜伏期与正常组无显著差异。
表6 实施例2制备的五味子提取物对柠檬酸致急性咳嗽豚鼠咳嗽潜伏期的影响(
Figure PCTCN2015076076-appb-000010
)(n＝7)
Figure PCTCN2015076076-appb-000011
注：与溶剂对照组比较：*P<0.05，**P<0.01
(三)实施例3制备的五味子提取物对柠檬酸烟雾刺激致急性咳嗽豚鼠的时效性
豚鼠静养一周后，进行咳嗽敏感性筛选：0.8mol/L柠檬酸雾化刺激1min，停止雾化，继续观察5min，记录自雾化开始6min内的咳嗽次数，大于10次小于50次的豚鼠为合格豚鼠。
筛选合格的豚鼠正常饲养3天后，随机分为4大组，每大组30只。第一大组随机分为3小组，每小组10只，均直接进行柠檬酸咳嗽激发：0.8mol/L柠檬酸雾化刺激1min，停止雾化，继续观察5min，记录自雾化开始6min内的咳嗽次数。第二大组随机分为3小组：正常组、可待因组(30mg/kg，经口给药)、实施例3制备的五味子提取物组(250mg/kg，药物浓度25mg/mL，经口给药)，每小组10只，正常组直接进行柠檬酸咳嗽激发，可待因组和五味子提取物组给药1小时后进行咳嗽激发，激发条件同第一大组；第三大组和第四大组的分组及激发条件均与第二大组相同，可待因组和五味子提取物组给药时间分别为激发前3h和5h。
结果如图2所示，表明实施例3制备的五味子提取物(250mg/kg)一次性给药1h后即能显著减少柠檬酸烟雾刺激致豚鼠急性咳嗽次数，并且在给药5h后仍能表现出显著的药效，而可待因在给药5h后咳嗽次数与正常组已无显著差异。
3个实施例制备的五味子提取物的药理研究结果表明，本发明制得的五味子提取物能显著延长CS豚鼠及柠檬酸刺激致急性咳嗽豚鼠的咳嗽潜伏期、减少咳嗽次数，显著减少CS豚鼠肺泡灌洗液中炎症细胞总数及中性粒细胞比例，病理切片观察提示本发明制得的五味子提取物干预后豚鼠细支气管周炎症细胞浸润明显减少，管腔内渗出减轻，肺泡间隔增宽程度减轻，提示本发明五味子提取物对豚鼠的气道炎症具有 显著的抑制作用。并且本发明制备的五味子提取物的作用明显好于五味子水提取物，且呈一定量效关系，表现出镇咳、缓解咳嗽及减轻气道炎症方面的应用前景。
实施例5：
取实施例2制备的五味子提取物1kg，用适量水，加热煮沸溶解，制成五味子提取物溶液，备用；另取蔗糖1kg，加水煮沸，加入前面已制备好的五味子提取物溶液，同时向其中加入苯甲酸钠4g，混匀，静置，取上清液，加纯水至4000mL，混匀，过滤，灭菌，每瓶100ml分装，制成五味子提取物的糖浆。
可供参考的服用方法为：每天1-3次，每次20ml。
实施例6：
实施例5制得的五味子提取物糖浆经过临床实验，其中有慢性咳嗽患者15例和急性咳嗽患者15例，通过每日饮用实施例5制得的糖浆1～3次，每次20mL，连续服用1～2周，总有效率为100％，具体反馈结果可见下表：
病例 显效 有效 无效
急性咳嗽 12 3 0
慢性咳嗽 11 4 0
下面就其中4个典型病例进行详细介绍：
病例1：张某，男，55岁，咳嗽4个月左右，诊断为咳嗽高敏综合征，连续服用实施例5制得的五味子提取物糖浆一周，咳嗽敏感性显著减低，咳嗽次数显著减少。
病例2：刘某，女，35岁，咳嗽2个月左右，诊断为感染后咳嗽，服用实施例5制得的五味子提取物糖浆2瓶，服药第一天起效，服完2瓶后咳嗽基本缓解。
病例3：鲍某，女，41岁，咳嗽1个月左右，伴痰堵感，痰难咳出，诊断为感染后咳嗽，服用实施例5制得的五味子提取物糖浆2瓶，服药后第二天起效，服完2瓶后咳嗽好转7成，加服1瓶后，咳嗽基本完全缓解。
病例4：尤某，男，24岁，咳嗽2年左右，干咳为主，诊断为嗜酸性粒细胞性支气管炎，胃食管反流性咳嗽，服用实施例5制得的五味子提取物糖浆2瓶，服药第三天起效，咳嗽好转4成，加服2瓶后，咳嗽症状基本消除。
由上述实施例可知，仅通过口服本发明五味子提取物糖浆便能有效缓解咳嗽，减轻气道炎症。而且，本发明制得的五味子提取物提取自中药五味子，五味子为卫生部公布的可用于保健食品的中药，对人体无任何毒性及副作用。
本发明五味子提取物除了制成糖浆，本领域技术人员根据需要也可以采用现有制剂工艺将其制成药学上可接受的其他剂型，例如片剂、硬胶囊、软胶囊、散剂、酊剂、丸剂、颗粒剂、注射剂或其他口服液剂型等。例如可以通过如下方法制成颗粒剂：将本发明制备的五味子提取物和辅料淀粉、蔗糖以及崩解剂进行混合，再将混合物加入用水溶解的粘合剂纤维素衍生物溶液中进行混合，采用挤出制粒法将药物制成软粒，经干燥，过筛、筛上物适当粉碎、再过筛，可制成均匀颗粒。也可通过如下方法制成片剂：将本发明五味子提取物和适量淀粉、滑石粉混合，用70％乙醇湿润，制成颗粒，然后用压片机压片，从而制成五味子提取物片。还可通过向本发明五味子提取物中加入适量羧甲基纤维素、环糊精，来制备五味子提取物胶 囊。这些制剂工艺均为本技术领域现有技术，在此不再一一赘述。
以上所述，仅是本发明的较佳实施例而已，并非对本发明做任何形式上的限制，故凡未脱离本发明技术方案的内容，依据本发明的技术实质对以上实施例所做的任何简单修改、等同变化与修饰，均仍属于本发明技术方案的范围内。

Claims (12)

  1. 一种制备用于治疗咳嗽及缓解气道炎症的五味子提取物的方法，其特征在于，包括如下步骤：
    1)取五味子药材，将其干燥后进行粉碎，用乙醇溶液回流提取1～3次，每次提取1～3小时，每次提取所用的乙醇溶液的体积(ml)为五味子药材质量(g)的4～8倍，合并提取液，然后静置过滤，得提取物A；
    2)将步骤1)提取留下的药渣用水煎煮1～3次，每次煎煮1～3小时，每次煎煮所用的水的体积(ml)为五味子药材质量(g)的4～8倍，合并提取液，然后静置过滤，得提取物B；
    3)合并步骤1)提取得到的提取物A和步骤2)提取得到的提取物B，然后进行真空干燥，制得所述五味子提取物。
  2. 根据权利要求1所述的方法，其特征在于，所述五味子药材为五味子Schisandra chinensis(Turcz.)Baill.或华中五味子Schisandra sphenanthera Rehd.et Wils.中的至少一种
  3. 根据权利要求1所述的方法，其特征在于，所述乙醇溶液其为乙醇体积浓度在50-100％之间的乙醇水溶液。
  4. 根据权利要求1所述的方法，其特征在于，步骤1)中，将五味子药材干燥后粉碎成10～60目。
  5. 根据权利要求1所述的方法，其特征在于，步骤1)和/或步骤2)在各自获得的提取液静置过滤后还具有对过滤液进行减压浓缩的步骤。
  6. 一种由权利要求1～5任一项所述的方法制得的五味子提取物。
  7. 权利要求1～5任一项所述的方法制得的五味子提取物在制备用于治疗急性、亚急性或慢性咳嗽的药物或保健品中的应用。
  8. 根据权利要求7所述的应用，其特征在于，所述五味子提取物在制备用于镇咳、缓解咳嗽或缓解气道炎症的药物或保健品中应用。
  9. 根据权利要求7或8所述的应用，其特征在于，所述五味子提取物制成药学上允许的剂型。
  10. 根据权利要求9所述的应用，其特征在于，所述剂型为片剂、硬胶囊、软胶囊、散剂、酊剂、口服液、糖浆、颗粒剂、丸剂或注射剂。
  11. 一种用于治疗咳嗽及缓解气道炎症的组合物，其特征在于，其活性成分包括如权利要求1～5任一项所述的方法制得的五味子提取物。
  12. 根据权利要求11所述的组合物，其特征在于，所述组合物制成药学上允许的剂型。
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