CN114533816B

CN114533816B - Medicament for treating chronic cough and pharmaceutical composition, preparation method and application thereof

Info

Publication number: CN114533816B
Application number: CN202210178835.0A
Authority: CN
Inventors: 赖克方; 刘晓东; 钟山; 黄婉怡
Original assignee: Guangzhou Institute Of Respiratory Health Guangzhou Institute Of Respiratory Diseases; First Affiliated Hospital of Guangzhou Medical University
Current assignee: Guangzhou Institute Of Respiratory Health Guangzhou Institute Of Respiratory Diseases; First Affiliated Hospital of Guangzhou Medical University
Priority date: 2022-02-25
Filing date: 2022-02-25
Publication date: 2022-11-22
Anticipated expiration: 2042-02-25
Also published as: CN114533816A

Abstract

The invention provides a medicament for treating chronic cough, a pharmaceutical composition thereof, a preparation method and application, and belongs to the field of pharmaceutical research. The pharmaceutical composition comprises: dark plum, chinese magnoliavine fruit, mulberry, aster, perilla leaf, bitter apricot seed, asarum, dwarf lilyturf tuber, raw liquorice and the like. The medicament is prepared by mixing and extracting the components in the medicinal composition. The medicament and the pharmaceutical composition have the effects of astringing lung and tonifying lung, and have the effects of dispersing lung qi, regulating body fluid and relieving cough. The medicament and the pharmaceutical composition have obvious therapeutic action on chronic cough, particularly refractory chronic cough (cough hypersensitive syndrome or idiopathic cough or chronic cough of unknown reason), upper airway cough syndrome or eosinophilic bronchitis, gastroesophageal reflux cough and cough variant asthma, can be used for preparing medicaments for treating corresponding diseases of chronic cough, and have quick response and small side effect.

Description

Medicament for treating chronic cough and pharmaceutical composition, preparation method and application thereof

Technical Field

The invention relates to the field of medicine research, in particular to a medicament for treating chronic cough, a pharmaceutical composition thereof, a preparation method and application thereof.

Background

Cough is a common and multiple symptom of the respiratory system and a common complaint of the outpatient department of respiratory department. Cough itself is a defensive reflex action generated when the respiratory system is stimulated, helps to remove external irritants and secretions from the airway, and is a beneficial action sometimes seen in healthy people. Generally, mild and infrequent cough can be naturally relieved without applying antitussives, and long-term frequent or excessively violent cough is a pathological reaction, which not only increases pain of patients, influences rest and sleep, increases physical strength consumption, but also promotes development of diseases in severe cases and generates other complications.

Cough can be classified into acute, subacute and chronic cough according to the course of disease. Acute cough is less than 3 weeks, subacute cough is 3-8 weeks, and chronic cough is more than or equal to 8 weeks. Clinically, the cough is usually the only symptom or the main symptom, the time is more than 8 weeks, and the chest X-ray examination shows that the patient has no obvious abnormality, so the chronic cough is called. Common causes of chronic cough are Eosinophilic Bronchitis (EB), upper airway cough syndrome (UACS, known as postnasal drip syndrome (PNDS)), gastroesophageal reflux cough (GERC), cough Variant Asthma (CVA), and the like. The average course of disease is longer in patients with chronic cough, and some patients have the disease even for decades.

There are many kinds of drugs clinically used for acute cough relief, but many patients with chronic cough cannot obtain effective relief after being treated by the drugs. The traditional Chinese medicine is a crystal with abundant practical experience for preventing and treating diseases of thousands of Chinese nations, the traditional Chinese medicine can distinguish the unknown symptoms of western medicines, the traditional Chinese medicine can treat the intractable and incurable symptoms of western medicines, and the traditional Chinese medicine has long history and abundant experience for treating cough and can be mutually supplemented with the western medicines. Aiming at the complex pathogenesis of chronic cough, the invention provides a medicament capable of effectively treating chronic cough for the first time.

Disclosure of Invention

The first object of the present invention is to provide a pharmaceutical composition for treating chronic cough, which can exert an effective antitussive effect against the multi-target pathogenesis of chronic cough.

The second purpose of the invention is to provide a medicament for treating chronic cough, which is prepared from the pharmaceutical composition, can treat diseases related to chronic cough, and has quick response and small side effect.

The third object of the present invention is to provide a method for preparing a pharmaceutical preparation for treating chronic cough, which is simple and easy to perform, and can largely prevent the destruction of the effective ingredients.

The fourth purpose of the invention is to provide the application of the pharmaceutical composition in preparing the medicine for treating chronic cough diseases, the pharmaceutical composition has the cough relieving effect through the multi-component and multi-target-point synergistic effect, and has good treatment effect on chronic cough related diseases.

In order to achieve the above purpose of the present invention, the following technical solutions are adopted:

a pharmaceutical composition for treating chronic cough comprises the following components in parts by weight:

18 to 23 parts of dark plum fruit, 7 to 13 parts of Chinese magnoliavine fruit, 18 to 23 parts of mulberry, 13 to 17 parts of tatarian aster root, 13 to 17 parts of perilla leaf, 7 to 15 parts of bitter apricot seed, 2 to 4 parts of manchurian wildginger, 7 to 13 parts of dwarf lilyturf tuber and 3 to 7 parts of raw liquoric root.

A medicament for treating chronic cough is prepared by mixing and extracting the components in the medicinal composition.

A method of preparing a medicament for treating chronic cough comprising: mixing the components of the pharmaceutical composition, and extracting by solvent extraction method.

An application of the above pharmaceutical composition in preparing medicine for treating chronic cough is provided.

Compared with the prior art, the invention has the beneficial effects that:

the pharmaceutical composition and the medicament provided by the disclosure are designed for the pathogenesis and the main symptoms of chronic cough, mainly astringe lung, moisten lung and relieve cough, are assisted by dispersing pathogenic factors and harmonizing body fluid and qi, and are compatible with each other and opposite to each other, so that lung qi is harmonized, lung yin is moistened and cough is self-leveled.

The research of the inventor shows that the pharmaceutical composition can well improve various indexes of cough sensitivity, airway inflammation and the like of chronic cough patients, and particularly has a remarkable effect of improving at least one patient condition of intractable chronic cough (cough hypersensitive syndrome, idiopathic cough or unexplained chronic cough), upper airway cough syndrome, eosinophilic bronchitis, gastroesophageal reflux cough and cough variant asthma. Clinical tests show that the medicament can greatly improve cough symptoms of intractable chronic cough patients, and has the advantages of quick response, small side effect and high effective rate of more than 70%. After the patient takes the medicament, the cough is obviously relieved or disappeared, and the uncomfortable symptoms of the throat part are obviously improved.

In addition, the inventor discovers through pharmacological research that the medicament can effectively reduce the total number of inflammatory cells and the proportion of neutrophils (statistically significant) in guinea pigs in chronic cough models, and has the effect of resisting airway inflammation. Meanwhile, the medicament can also obviously reduce the cough frequency of guinea pigs with chronic cough and prolong the cough latency period, thereby showing that the medicament has the effect of treating the chronic cough and has a dose-effect relationship.

Drawings

In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the embodiments or the prior art descriptions will be briefly described below.

FIG. 1 is a graph showing the number of coughs in the groups of intractable chronic cough guinea pigs before administration in Experimental example 1;

fig. 2 shows the number of coughs in the groups of refractory chronic cough guinea pigs after administration in experimental example 1 (VS model group, p <0.05, p <0.01, p < 0.001);

fig. 3 is cough latency in each group of refractory chronic cough guinea pigs after administration in experimental example 1 (VS model group,. P < 0.05);

fig. 4 shows total BALF cell counts after administration in experimental example 1 for each group of refractory chronic cough guinea pigs (VS model group, p <0.05, p <0.01, p < 0.001);

fig. 5 shows BALF cell differential counts (VS model group, p <0.05, p < 0.001) of each group of refractory chronic cough guinea pigs after administration in experimental example 1, in which Neu is neutrophil, mac is macrophage, eos is eosinophil, and Lym is lymphocyte;

FIG. 6 is a graph showing pathological changes in tracheal tissue (HE, X200) in groups of guinea pigs with refractory chronic cough after administration in Experimental example 1;

FIG. 7 is a graph showing changes in pulmonary tissue pathology (HE, X200) in groups of refractory chronic cough guinea pigs after administration in Experimental example 1;

fig. 8 is a graph showing the pulmonary tissue pathological inflammation scores of the treatment-refractory chronic cough guinea pigs in each group after the administration in experimental example 1 (VS normal group, ^## p<0.01, ^### p<0.001; VS model group,. About.p<0.05,**p<0.01)。

Detailed Description

Embodiments of the present invention will be described in detail below with reference to examples, but it will be understood by those skilled in the art that the following examples are only illustrative of the present invention and should not be construed as limiting the scope of the present invention. The examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products available commercially.

The embodiment provides a pharmaceutical composition for treating chronic cough, which comprises the following components in parts by weight:

Optionally, the weight parts of dark plum fruit are 19-22 parts, chinese magnoliavine fruit are 9-11 parts, mulberry fruit are 19-22 parts, aster root is 14-16 parts, perilla leaf is 14-16 parts, bitter apricot kernel is 9-11 parts, asarum herb is 2-3 parts, ophiopogon root is 9-11 parts, and licorice root is 4-6 parts.

Further, by weight, 20 parts of dark plum fruit, 10 parts of Chinese magnoliavine fruit, 20 parts of mulberry fruit, 15 parts of aster, 15 parts of perilla leaf, 10 parts of bitter apricot seed, 3 parts of asarum, 10 parts of dwarf lilyturf tuber and 5 parts of licorice root.

In the medicine formula provided by the embodiment, the dark plum fruit and the schisandra chinensis are used as monarch drugs. Chronic cough with little or no phlegm means that lung qi is disordered and lung qi can not be restrained, and chronic cough consumes qi and body fluid, and body fluid in lung is coagulated into phlegm due to body fluid injury, further aggravating the adverse condition of lung qi, and it is necessary to restrain lung qi, nourish lung yin and harmonize qi and body fluid. Wherein, the dark plum is sour, astringent and flat, and enters liver, spleen, lung and large intestine channels; has the efficacies of astringing lung and relieving cough, promoting the production of body fluid and quenching thirst, and has the functions of governing qi and removing heat and dysphoria (Shen nong Ben Cao Jing), and is commonly used for treating lung deficiency, chronic cough with little phlegm or dry cough without phlegm. Fructus Schisandrae chinensis, sour, sweet, warm, enters lung, heart, kidney meridians; has the effects of astringing, arresting discharge, benefiting qi, promoting production of body fluid, tonifying kidney and calming heart, astringes lung qi, nourishes kidney yin, mainly benefits qi, coughs adverse qi, strengthens qi, weakens the weakness of fatigue, tonifies deficiency and strengthens yin (Shennong Ben Cao Jing), and is a key medicine for chronic cough and asthma. The two herbs are mutually reinforced and emphasized in astringing the lung qi, and can nourish yin fluid and astringe body fluid in lung. The formula of the medicine aims at the pathogenesis of the chronic cough with the lung qi not astringing and the body fluid not distributing, and the effect of astringing the lung qi and nourishing the lung yin is taken to recover the lung to disperse and descend smoothly and harmonize qi and body fluid, so that the chronic cough is peaceful.

The medicine formula takes mulberry and aster as ministerial drugs. The mulberry is sweet, sour and cold, enters liver and kidney meridians, has the effects of nourishing yin, enriching blood, promoting fluid production and moistening dryness, can benefit kidney and consolidate essence (Yunnan herbal), is matched with monarch drug, not only strengthens the functions of promoting fluid production and moistening lung of the dark plum, but also combines the kidney tonifying and astringency of the schisandra to play the effect of synchronously regulating the growth of golden water and lung and kidney; aster tataricus, bitter, pungent and sweet, slightly warm, enters lung meridian, has the efficacy of moistening lung, reducing phlegm and relieving cough, and has the effect of moistening lung, reducing phlegm and relieving cough, wherein the main cough and ascending qi (Shen nong Ben Cao Jing) is better than moistening lung, descending qi, pungent and relieving lung stagnation, reducing phlegm and relieving cough, and can be used for treating both cold and heat, so the aster tataricus is designed for treating the main cough symptom. The two herbs are combined with the monarch drug to strengthen moistening lung and astringe descending lung qi.

The prescription of the medicine takes perilla leaf, bitter almond, asarum and dwarf lilyturf tuber as adjuvant drugs. Chronic cough with lung qi disorder of dispersing and descending, which can lead to adverse flow of body fluids; chronic cough consuming body fluid and consuming qi may lead to fluid consumption and dryness leading to phlegm, which further aggravates the adverse lung qi. Although dry cough with little phlegm is common in symptoms, the pathogenesis still has the symptoms of fluid accumulation in the lung, phlegm obstruction and qi depression, and if the lung is supplemented and astringed without dispersing lung qi and relieving cough and reducing phlegm, the lung function still can not be recovered. The perilla leaf, pungent and warm, enters lung and spleen channels, has the effects of relieving exterior syndrome and dispelling cold, and promoting qi circulation and harmonizing stomach, and can be used for ventilating the lung and dredging, dispersing pathogenic qi, promoting qi circulation and harmonizing stomach, and preventing stagnation of large-dose sour and astringent food and middle-jiao from damaging spleen and stomach. Bitter apricot kernel, bitter and slightly warm, enters lung and large intestine meridians, has the effects of depressing qi to relieve cough and asthma, moistening intestine to relieve constipation, and has the property of depressing qi and is good at depressing lung to relieve cough. The asarum herb, pungent and warm in property and entering lung, kidney and heart channels, has the efficacies of relieving exterior syndrome and dispelling cold, dispelling wind and relieving pain, dredging orifices, warming lung and transforming fluid, and has the advantages of pungent and dispersing property, capability of dispersing pathogenic qi in lung such as latent cold and phlegm fluid, and good effect of dispersing and collecting when being matched with the schisandra fruit. The dwarf lilyturf tuber is sweet, slightly bitter and slightly cold, enters the stomach, lung and heart channels, has the effects of nourishing yin, promoting the production of body fluid, moistening the lung and clearing away the heart-fire, helps monarch and ministerial drugs nourish lung yin and can clear deficiency heat caused by lung yin deficiency. The four herbs are used as adjuvant drugs for combining cold and warm properties, opening and closing the lung qi and regulating the body fluids and qi.

The medicine formula takes the raw liquorice as a guiding drug, can tonify qi, regulate the middle warmer and harmonize the drugs.

The formula is designed for the pathogenesis and the major symptoms of chronic cough, mainly astringes lung, moistens lung and relieves cough, and assists dispersing pathogenic factors and harmonizing body fluid and qi, and the medicines are compatible, astringe without stagnation, nourish but not greasy, and are opposite to each other, so that lung qi is harmonized, lung yin is moistened, and body fluid and qi in lung are harmonized to relieve cough.

Further, the pharmaceutical composition also comprises the following components in parts by weight: 7-13 parts of cicada slough and 3-7 parts of dried orange peel. Optionally, the cicada slough accounts for 9-11 parts by weight, and the dried orange peel accounts for 4-6 parts by weight; further, the cicada slough is 10 parts, and the dried orange peel is 5 parts.

In the formula of the medicine, the cicada slough, the dried orange peel, the perilla leaf, the bitter apricot seed, the asarum and the dwarf lilyturf root are used as adjuvant drugs to open and close lung qi and regulate qi movement. The cicada slough is sweet and cold, enters liver and lung channels, has the effects of dispelling wind and heat, relieving sore throat and producing voice, is light in weight and floats upwards, and is good at relieving sore throat, and is especially designed for common symptoms of chronic cough with pharynx itch and throat discomfort cough. The dried orange peel is pungent, bitter and warm, enters spleen and lung channels, has the effects of regulating qi, strengthening spleen, eliminating dampness and reducing phlegm, can promote the transportation and transformation of spleen and stomach, prevents the sour, astringent, sweet and moist products such as dark plum fruit, mulberry fruit and the like from causing the greasy taste and obstructing the qi, and ensures that the whole formula is moistened but not greasy; it can also prevent the generation of phlegm-turbidity in the lung due to the stagnation of body fluid and qi, so as to treat the source of phlegm.

Further, the pharmaceutical composition also comprises the following components in parts by weight: 13 to 17 portions of peucedanum praeruptorum and 7 to 13 portions of microcos paniculata. Optionally, by weight, 14-16 parts of decumbent bugle herb and 9-11 parts of microcos paniculata; or 15 parts of peucedanum root and 10 parts of microcos paniculata.

In the formula of the medicine, the whiteflower hogfennel root, the microcos paniculata, the perilla leaf, the bitter apricot seed, the asarum and the dwarf lilyturf tuber are used as adjuvant medicines for depressing qi, activating stagnancy and clearing away pathogenic qi in the lung. Wherein, the peucedanum root, pungent and slightly cold, which belongs to the lung, spleen and liver channels, has the efficacies of dispelling wind and heat, descending qi and reducing phlegm. The microcos paniculata is sour, sweet and flat, and has the effects of invigorating spleen and stomach channels, promoting digestion, removing food stagnation, clearing heat and promoting diuresis. Peucedanum praeruptorum, pungent and bitter with the action of dispersing the pathogenic factors of lung, can be used with lung astringing herbs to strengthen the effect of descending and relieving cough; the Buxi leaf is a commonly used herb for relieving stagnation and harmonizing stomach in Lingnan, and is used to assist dark plum and schisandra chinensis to astringe middle energizer, and mulberry and dwarf lilyturf root to moisten and nourish the body, so that lung astringing and yin nourishing products can be transported and transformed to take effect.

The medicine formula provided by the embodiment adopts a astringing and dispersing method to treat chronic cough, the medicine has the effect of dispersing and dispersing qi and descending, the medicine is nourishing but not greasy, the lung qi is adjusted, and the lung yin is moistened. The medicines are compatible with each other strictly and opposite to each other, astringe the lung, moisten the lung and relieve cough, and are coordinated with dispersing pathogenic factors and body fluid, so that the lung qi is regulated, the lung yin is moistened, and the body fluid in the lung is coordinated, and the multidirectional comprehensive regulation of qi activity of the lung is realized cooperatively, and the physiological functions of dispersing and descending are restored.

The research of the inventor shows that the pharmaceutical composition can obviously relieve or eliminate the cough of the chronic cough patient, and especially has obvious effect of improving the condition of the intractable chronic cough patient. Clinical tests show that the medicament can greatly improve various indexes of cough sensitivity, airway inflammation and the like of a patient with refractory chronic cough, has quick response and small side effect, and has the effective rate of over 70 percent. After the medicament is taken by a patient, the cough is obviously relieved or disappeared, and the discomfort symptom of the throat is also obviously improved.

The embodiment also provides a medicament with the effect of treating chronic cough, which is prepared by mixing and extracting the components in the medicinal composition.

Further, the dosage form of the medicament comprises: decoction, syrup, pill, powder, tablet, capsule, powder, emulsion, aerosol, patch, tincture, injection and granule. These dosage forms are all commonly used dosage forms in Chinese patent medicine, and can be prepared on the basis of the pharmaceutical composition.

Optionally, the medicament is a syrup, and the preparation method of the syrup comprises:

step S1: mixing the components of the pharmaceutical composition, and extracting with solvent to obtain total extract.

Step S2: and mixing the mixture with simple syrup to obtain a first mixture, wherein the simple syrup accounts for 50-70% of the total mass of the first mixture.

Further, the simple syrup is prepared by mixing monosaccharide with water, decocting monosaccharide with slow fire to completely dissolve and form syrup. Among these, monosaccharides include, but are not limited to: glucose, fructose, galactose, ribose and deoxyribose, optionally, the simple syrup accounts for 55 to 65 percent, more specifically 60 percent, of the total mass of the first mixture.

And mixing the simple syrup and the total extract to obtain a first mixture, and mixing the first mixture with sodium benzoate and ethyl hydroxybenzoate, wherein the mass of the sodium benzoate and the ethyl hydroxybenzoate is 0.2-0.4% or 0.3% of that of the first mixture.

And step S3: the first mixture is boiled and filtered.

The syrup can cover up the unpleasant smell of the medicine and improve the taste, is particularly popular with children, and has simple preparation process and strong quality controllability.

The present embodiment also provides a method for preparing a medicament for treating chronic cough, which comprises: mixing the components of the pharmaceutical composition, and extracting with solvent.

Further, the solvent extraction method includes, but is not limited to: decocting, percolating, heating and refluxing, soaking, and ultrasonic extracting. When the above medicinal materials are extracted by solvent extraction, the used extraction solution comprises water and ethanol-water mixed solution.

Optionally, the solvent extraction method is a heating reflux extraction method, wherein the extraction solvent in the heating reflux extraction method is an ethanol solution with the volume fraction of 60-80%. The effective components in the medicinal materials are easily dissolved in an ethanol solution with the volume fraction of 60-80%, and the heating reflux extraction method is adopted for extraction, so that the method is simple and convenient to control. Optionally, the heating temperature of the heating reflux extraction method is 70-80 ℃, or 74-76 ℃, or 75 ℃. Optionally, the extraction times are 2-3 times, or 2 times; optionally, the extraction time of each heating reflux extraction method is 1.5-2.5 h, or 1.8-2.3 h, or 2h.

Optionally, before the solvent extraction, drying and pulverizing the medicinal materials in the pharmaceutical composition to 4-20 meshes, or 6-14 meshes, or 8-12 meshes, or 10 meshes. Before the medicinal materials in the medicinal composition are extracted, the medicinal materials are firstly crushed into fine powder, so that the dissolution rate of medicinal substances is improved, the extraction efficiency is improved, and the medicinal effect of the medicament is further ensured.

The preparation method of the medicament is simple and easy to implement, has strong operability, can avoid the destruction of the effective components to a great extent, and reserves the content of effective substances in the medicament, thereby ensuring the medicinal effect.

The embodiment also provides application of the pharmaceutical composition in preparing a medicament for treating chronic cough diseases.

The chronic disease patients are clinically the cough patients with cough as the only symptom or the main symptom, the cough time is more than 8 weeks, and no obvious abnormality is caused by chest X-ray examination. The etiology of the disease is complex, the disease course is long, and the existing acute antitussive medicines are difficult to take effect.

The clinical application of the invention discovers that the cough of a part of chronic cough patients who are ineffectively treated by western medicines is obviously improved after the chronic cough patients are treated by the medicine, and the effective rate is up to more than 70%. After the patient takes the medicament, the cough is obviously relieved or disappeared, and the uncomfortable symptoms of the throat part are obviously improved.

In addition, the inventor discovers through pharmacological research that the medicament can effectively reduce the total number of inflammatory cells and the proportion of neutrophils (statistically significant) in guinea pigs in chronic cough models, and has the effect of resisting airway inflammation. Meanwhile, the medicament can also remarkably reduce the cough frequency of guinea pigs with chronic cough and prolong the cough incubation period, thereby indicating that the medicament has the effect of treating the chronic cough and has a dose-effect relationship.

Further, the chronic cough condition includes: refractory chronic cough (cough hypersensitive syndrome or idiopathic cough or chronic cough of unknown cause), upper airway cough syndrome, eosinophilic bronchitis, gastroesophageal reflux cough and cough variant asthma. The medicament provided by the invention has good curative effect on the chronic cough diseases, especially on intractable chronic cough.

The cause of some Chronic Cough patients is still unclear after a comprehensive examination, and the Chronic Cough patients are called Refractory Chronic Cough (Chronic reflectory Cough) or Chronic idiopathic Cough (Chronic idiopathetic Cough) or unknown Chronic Cough (unexplained Chronic Cough) or Cough high-sensitivity Syndrome (CHS).

Patients with CRC and CHS are clinically manifested as chronic irritant dry cough, which can be induced by one or more irritants such as cold air, dust, cigarette, oil smoke, etc. The increased cough sensitivity is a common pathophysiological characteristic of such patients, namely the category of "chronic cough" and "stubborn cough" in TCM. In the specialist outpatient service, the proportion of chronic cough is as high as 10% -38%, questionnaires of European and American countries show that the incidence rate of chronic cough is as high as 9% -33%, and a field survey of the Guangzhou respiratory disease institute 2006 aiming at the cough of 1087 college students shows that the total incidence rate of cough in the group is 10.9%, wherein the total incidence rate of chronic cough is 3.3%, and the incidence rate of cough in the community group can be presumed to be higher. The average course of disease in such patients is long, some even decades long.

There are many kinds of drugs clinically used for acute cough relief, but many patients with chronic cough cannot obtain effective relief after being treated by the drugs. At present, various large pharmaceutical companies at home and abroad research and develop corresponding medicines aiming at different pathogenesis of CRC, for example, selective antagonists BCTC and JNJ17203212 aiming at a cough receptor TRPV1 and selective antagonists HC-030031 and AP-18 aiming at TRPA1 show remarkable in-vivo and in-vitro antitussive activity, but the antagonists have side effects of hyperpyrexia, olfactory desensitization and the like in the clinical research process, so that the clinical application of the antagonists is limited. In addition, specific non-peptide NK1 receptor antagonists CP96345, CP99994, SR140333 and the like are respectively developed by the American Pfizer pharmaceutical company and the France Sanofi pharmaceutical company, and due to the problems of single action target or in-vivo instability or side effect and the like, no successfully developed medicine is used clinically so far, and no good medicine for CRC treatment exists at present.

The pathogenesis of CRC may involve multiple links and multiple targets such as airway cough receptor activation, neurogenic inflammation, cough central sensitization, immune dysfunction, and oxidative stress injury. However, the single-target antagonists developed at present have not been successfully used in clinical treatment due to poor curative effect or side effect.

In the invention, the inventor believes that the high cough sensitivity of CRC patients can be effectively reduced and cough symptoms can be relieved only by aiming at multi-target treatment. Under the guidance of this theory, the agent was developed. Clinical application shows that symptoms of CRC patients who are not effective in western medicine treatment are obviously improved after the CRC patients are treated by the medicament, and the medicament has unique characteristics in cough treatment of CRC and mainly shows multi-component, multi-target and synergistic effects.

The features and properties of the present invention are further described in detail below with reference to examples:

example 1

The present embodiment provides a medicament for treating chronic cough, wherein the pharmaceutical composition of the medicament is:

23 parts of dark plum fruit, 13 parts of Chinese magnoliavine fruit, 18 parts of mulberry fruit, 17 parts of tatarian aster root, 17 parts of perilla leaf, 7 parts of bitter apricot seed, 4 parts of asarum, 13 parts of dwarf lilyturf tuber and 3 parts of liquorice.

The preparation method of the medicament comprises the following steps:

mixing the above medicinal materials, decocting with water twice, and filtering to obtain decoction.

Example 2

The present embodiment provides a pharmaceutical agent for treating chronic cough, wherein the pharmaceutical composition of the pharmaceutical agent is:

20 parts of dark plum fruit, 10 parts of Chinese magnoliavine fruit, 20 parts of salt mulberry fruit, 15 parts of tatarian aster root, 15 parts of perilla leaf, 10 parts of bitter apricot seed, 3 parts of asarum, 10 parts of dwarf lilyturf tuber and 5 parts of liquorice.

The preparation method of the medicament comprises the following steps:

mixing the above medicinal materials, decocting with water twice, the first time with water amount 10 times of the medicinal materials, the second time with water amount 8 times of the medicinal materials, each time for 1 hr, and mixing the filtrates to obtain decoction.

Example 3

18 parts of dark plum fruit, 7 parts of Chinese magnoliavine fruit, 23 parts of mulberry, 13 parts of tatarian aster root, 13 parts of perilla leaf, 15 parts of bitter apricot seed, 2 parts of asarum, 7 parts of dwarf lilyturf tuber and 7 parts of liquorice.

The preparation method of the medicament comprises the following steps:

mixing the above medicinal materials, extracting with 90% ethanol at 75 deg.C under reflux for 2 hr twice, filtering, concentrating, and removing solvent.

Example 4

20 parts of dark plum fruit, 10 parts of Chinese magnoliavine fruit, 20 parts of salt mulberry, 15 parts of tatarian aster root, 15 parts of perilla leaf, 10 parts of bitter apricot seed, 3 parts of asarum, 10 parts of dwarf lilyturf tuber, 7 parts of cicada slough, 7 parts of dried orange peel and 5 parts of liquorice.

The preparation method of the medicament comprises the following steps:

mixing the above medicinal materials, decocting with water, and extracting to obtain total extract; mixing the total extract with simple syrup (the content of simple syrup is 60%), adding sodium benzoate and ethylparaben, boiling, and filtering to obtain syrup.

Example 5

20 parts of dark plum fruit, 10 parts of Chinese magnoliavine fruit, 20 parts of salt mulberry fruit, 15 parts of tatarian aster root, 15 parts of perilla leaf, 10 parts of bitter apricot seed, 3 parts of asarum, 10 parts of dwarf lilyturf tuber, 10 parts of cicada slough, 5 parts of dried orange peel and 5 parts of liquorice.

The preparation method of the medicament is substantially consistent with example 4.

Example 6

20 parts of dark plum fruit, 10 parts of Chinese magnoliavine fruit, 20 parts of salt mulberry fruit, 15 parts of tatarian aster root, 15 parts of perilla leaf, 10 parts of bitter apricot seed, 3 parts of asarum, 10 parts of dwarf lilyturf tuber, 13 parts of cicada slough, 3 parts of dried orange peel and 5 parts of liquorice.

Example 7

20 parts of dark plum fruit, 10 parts of Chinese magnoliavine fruit, 20 parts of salt mulberry fruit, 15 parts of tatarian aster root, 15 parts of perilla leaf, 10 parts of bitter apricot seed, 3 parts of asarum, 10 parts of dwarf lilyturf tuber, 14 parts of whiteflower hogfennel root, 11 parts of microcos paniculata, and 5 parts of liquorice.

Example 8

20 parts of dark plum fruit, 10 parts of Chinese magnoliavine fruit, 20 parts of salt mulberry fruit, 15 parts of tatarian aster root, 15 parts of perilla leaf, 10 parts of bitter apricot seed, 3 parts of asarum, 10 parts of dwarf lilyturf tuber, 15 parts of whiteflower hogfennel root, 10 parts of microcos paniculata leaf and 5 parts of liquorice.

The preparation method of the medicament is basically consistent with example 4.

Example 9

20 parts of dark plum fruit, 10 parts of Chinese magnoliavine fruit, 20 parts of salt mulberry fruit, 15 parts of tatarian aster root, 15 parts of perilla leaf, 10 parts of bitter apricot seed, 3 parts of asarum, 10 parts of dwarf lilyturf tuber, 16 parts of whiteflower hogfennel root, 9 parts of microcos paniculata and 5 parts of liquorice.

Example 10

20 parts of dark plum fruit, 15 parts of perilla leaf, 10 parts of Chinese magnoliavine fruit, 3 parts of asarum, 5 parts of liquorice root (licorice granules), 15 parts of tatarian aster root, 10 parts of bitter apricot seed (15 parts of northern apricot), 10 parts of cicada slough and 5 parts of dried orange peel.

Example 11

20 parts of dark plum fruit, 10 parts of Chinese magnoliavine fruit, 3 parts of asarum, 10 parts of cicada slough and 5 parts of dried orange peel.

Experimental example 1

The effect of the agent provided in example 2 of the present invention in treating chronic cough was evaluated in combination with animal experiments as follows.

At present, in the aspect of screening experimental models of cough relieving activity, most of researchers use a mouse ammonia water induced cough model to evaluate the cough relieving activity of the medicine, the cough characteristics of mice are not obvious, and the artificial counting of cough times has certain subjective factors. In addition, the mouse models cannot reflect the pathophysiological state of the chronic cough patients, so that the cough relieving medicines obtained by screening do not have good pertinence to the chronic cough patients.

In the experimental example 1, the self-established refractory chronic cough hypersensitive guinea pig model is a chronic cough model with airway nonspecific inflammation pathological conditions, mainly adopts neutrophil infiltration, shows that the cough sensitivity is increased, has a plurality of common pathophysiological characteristics with clinical chronic refractory cough patients, and provides a powerful tool for the research of chronic cough, particularly refractory chronic cough. Meanwhile, in the experimental example 1, the inventor introduces a non-invasive lung function detection system for BUXCO animals in America, and the instrument detects indexes such as cough times, cough latency and the like of the animals, so that human subjective factors can be eliminated, and the activity screening result is more scientific and reliable.

The specific test process is as follows:

1. the test mode is as follows:

1. molding: smoking with cigarette for 14 days, 2 times per day, 10 cigarettes each time (smoking for 20 min), and 4 hr interval between 2 times, and 8 guinea pigs per group, and setting 6 groups.

2. Administration: during molding, the preparation of example 2 (i.e. compound Chinese medicine) is administered by gavage with low dose (crude drug amount 8.84 g/kg), medium dose (crude drug amount 17.68 g/kg), and high dose (crude drug amount 35.36 g/kg) respectively for 1 time per day; the model group and the normal group are filled with equal volume of physiological saline; the positive drug group is administered with codeine solution of equal volume for intragastric administration.

3. And (3) detection: after 2 hours of the last administration, 0.8M citric acid is adopted to induce the Cough of the guinea pig, and a noninvasive Buxco Cough lung function detection system of animals is utilized to record the Cough latency and the Cough frequency; after completion of the guinea pig cough sensitivity test, alveolar lavage fluid (BALF) was collected, total cell counts and classifications were performed, and tracheal and lung tissues were taken for pathological observation.

2. And (3) test results:

1. the results of the guinea pig cough sensitivity test are shown in table 1:

table 1: EXAMPLE 2 results of cough sensitivity in guinea pigs in groups of different doses of the pharmaceutical agent

Note: comparing to model group, p <0.05, p <0.01, p <0.001

As shown in table 1 and fig. 1, there was no statistical difference in the number of coughs among the guinea pigs before administration.

As shown in fig. 2, the number of coughs was significantly decreased in the normal group (p < 0.001) and also in the codeine group (p < 0.05) compared to the model group; the cough frequency of each dose group of the compound traditional Chinese medicine is obviously reduced (p is less than 0.05 in a low dose group, p is less than 0.01 in a medium dose group, and p is less than 0.001 in a high dose group), and a dose-effect relationship is formed.

As shown in fig. 3, the cough latency of the normal group guinea pigs was significantly prolonged (p < 0.05), and the cough latency of the codeine group guinea pigs was also significantly prolonged (p < 0.05) compared to the model group; the cough incubation period of each dose group of the compound traditional Chinese medicine is prolonged, wherein the low dose group and the high dose group have statistical difference (p is less than 0.05), and the medium dose group has a descending trend.

Therefore, compared with the model group, the medicament (namely the compound traditional Chinese medicine) provided by the embodiment 2 of the invention has the advantages that the cough frequency is obviously reduced after administration, and the cough incubation period is also obviously prolonged after administration, so that the medicament has the cough relieving effect, and the medicament effect of the high-dose group is better than that of the positive medicament codeine group.

2. Guinea pig BALF cell total count, classification results, as shown in table 2:

in Table 2, neu refers to neutrophils, mac refers to macrophages, eos refers to eosinophils, and Lym refers to lymphocytes.

TABLE 2 Total and differential cell counts of guinea pigs in different dose groups of the compound preparation

As can be seen from table 2:

as shown in fig. 4, the total number of BALF cells in the model group was significantly increased (p < 0.001) compared to the normal group, and the model was successfully established; compared with a model group, the total number of BALF cells in the codeine group has no obvious change, which indicates that the codeine can only improve the symptoms of acute cough and can not eliminate airway inflammation and the like of chronic cough; the total number of inflammatory cells of guinea pig BALF in each dose group of the compound traditional Chinese medicine is obviously reduced (p is less than 0.05 in the low dose group, and p is less than 0.01 in the medium and high dose groups). Therefore, the medicament can obviously reduce the total number of inflammatory cells of guinea pig BALF and has the effect of resisting airway inflammation.

As shown in fig. 5, the model group BALF after 14d cigarette exposure had a significantly decreased proportion of macrophages (Mac) and a significantly increased proportion of neutrophils (Neu) compared to the blank group, with a very significant difference (p < 0.001), and the modeling was successful. Compared with the model group, the ratio of BALF inflammatory cells in the codeine group has no obvious change; the ratio of guinea pig BALF cell Neu in each dose group of the compound traditional Chinese medicine is reduced, and the statistical difference p between the medium and high dose groups is less than 0.05.

3. Pathological changes of guinea pig trachea tissues:

cigarette exposure and drug-dry prognosis of airway pathology for each group of animals is shown in figure 6. The observation of hematoxylin-eosin (HE) stained sections shows that the trachea epithelium of the guinea pigs in the normal group is complete, the cilia are arrayed regularly, and the lumens are regular; compared with a normal control group, the model group has the advantages that the guinea pig tracheal mucosa cilium is lodging, the epithelium is dropped off, the mucosa and the submucosa are infiltrated by a small amount of inflammatory cells, and the basement membrane is thickened; the pathological changes of the trachea of the codeine group are basically the same as those of the model group; compared with the model group, the compound traditional Chinese medicine has the advantages that the trachea pathology of each dose group is improved, the trachea mucosa abscission of the low dose group is reduced, the obvious basement membrane hyperplasia is not seen, the mucosa structures of the medium and high dose groups are complete, and the pathology is improved obviously.

4. Pathological changes in guinea pig lung tissue:

the pathological observation of lung tissues after cigarette exposure and drug intervention of each group of animals is shown in fig. 7, and the observation of HE stained sections shows that the structure of bronchi and alveoli of normal groups of guinea pigs is complete, and inflammatory cells do not infiltrate around the bronchi and blood vessels; compared with a normal control group, the guinea pig model group has the disadvantages of mucociliary shedding of bronchus, inflammatory exudation of organs and cavities, widened alveolar space, structural disorder and infiltration of a large amount of inflammatory cells around the bronchus and blood vessels; the codeine group lung tissue pathology changes basically to the same model group; compared with the model group, the lung tissue mechanism of the guinea pigs in each compound dose group is improved to different degrees, wherein the high and medium dose groups are improved obviously, the bronchial lumens of the low dose group are slightly exuded, the bronchial lumens of the medium and high dose groups are not exuded, the alveolar space of each dose group is slightly widened, and a small amount of inflammatory cells infiltrate around the bronchi and blood vessels.

After intervention of the compound traditional Chinese medicine, pathological inflammation scores of lung tissues of the guinea pigs are shown in fig. 8, compared with a model group, the inflammation scores of the lung tissues of the guinea pigs in a normal group are obviously reduced (p is less than 0.001), and inflammation scores of various dosage groups of the compound traditional Chinese medicine are obviously reduced (p is less than 0.05 in a low dosage group, p is less than 0.01 in a medium dosage group, and p is less than 0.001 in a high dosage group). This suggests that the drug can significantly improve inflammation in guinea pig lung tissue.

The results of the above experiments using the agents provided in the other examples were substantially the same as those of the agent of example 2, and thus they were not listed one by one.

Experimental example 2

The antitussive effects of the agents provided in examples 2, 5 and 8 of the present invention in the treatment of chronic cough were evaluated in combination with clinical medication observations as follows.

Case selection:

51 chronic cough patients treated by clinic treatment of respiratory disease research institute in Guangzhou city during the period of 2-2016-12 in 2015 are selected, the cough course is 2-240 months, the average is 51.6 months, the inclusion and exclusion criteria are met, the ages are 7-58 years old and the average is 34 years old. The groups were randomly divided into 3 groups of 17 cases, wherein the drug groups were groups 1-3. The data of age, sex, disease condition, etc. of the 3 patients were not significantly different and comparable.

The administration scheme is as follows:

based on crude drug amount, the drug provided by the invention in the embodiment 2 is taken by the drug 1 group, the drug provided by the invention in the embodiment 5 is taken by the drug 2 group, and the drug provided by the invention in the embodiment 5 is taken by the drug 3 group, and the dose is as follows: 2.9 g/kg-day, that is, 2.9g of crude drug is taken by each kg of body weight, and each person takes the drug 3 times a day.

And (4) observing results:

follow-up of improvement in cough symptoms was performed after treatment, with the following results:

in the drug 1 group, 11 patients complain about the effect, 4 patients do not effect, 2 patients lose visit, and the overall effective rate is 73%. The improvement of cough symptoms of patients is mainly shown as follows: cough is significantly relieved or disappeared, and the symptoms of the throat are not obviously improved.

In the medicine 2 group, 12 patients complain about the effect, 3 patients do not effect, 1 patient loses visit, and 1 patient is allergic after taking and can not take continuously, so that the overall effective rate is 80%. The improvement of cough symptoms of patients is mainly manifested by significant relief or disappearance of cough and obvious improvement of symptoms of throat.

In the drug 3 group, 11 patients complain about effectiveness, 3 patients do not respond, and 3 patients lose visit, so that the overall effective rate is 78%. The improvement of cough symptoms of patients is mainly shown as follows: cough was significantly relieved, and symptoms of the throat were not significantly improved.

In summary, the pharmaceutical composition and the medicament provided by the embodiment of the invention have good therapeutic effects on chronic cough patients, and especially have significant effects on improving the conditions of intractable chronic cough patients. Clinical tests show that the medicament can greatly improve cough sensitivity of intractable chronic cough patients, reduce various indexes such as airway inflammation and the like, and has quick response and small side effect. After the medicament is taken by a patient, the cough is obviously relieved or disappeared, and the discomfort symptom of the throat is also obviously improved.

While particular embodiments of the present invention have been illustrated and described, it would be obvious that various other changes and modifications can be made without departing from the spirit and scope of the invention. It is therefore intended to cover in the appended claims all such changes and modifications that are within the scope of this invention.

Claims

1. A pharmaceutical composition for treating chronic cough is characterized by comprising the following components in parts by weight:

18 to 23 portions of dark plum fruit, 7 to 13 portions of Chinese magnoliavine fruit, 18 to 23 portions of mulberry, 13 to 17 portions of tatarian aster root, 13 to 17 portions of perilla leaf, 7 to 15 portions of bitter apricot seed, 2 to 4 portions of asarum, 7 to 13 portions of dwarf lilyturf tuber and 3 to 7 portions of raw liquorice.

2. The pharmaceutical composition for treating chronic cough according to claim 1, wherein the weight portions of the dark plum fruit are 19-22, the schisandra fruit is 9-11, the mulberry fruit is 19-22, the aster root is 14-16, the perilla leaf is 14-16, the bitter apricot seed is 9-11, the asarum herb is 2-3, the ophiopogon root is 9-11, and the licorice root is 4-6.

3. The pharmaceutical composition for treating chronic cough according to claim 1, further comprising, in parts by weight: 7-13 parts of cicada slough and 3-7 parts of dried orange peel.

4. The pharmaceutical composition for treating chronic cough according to claim 1, further comprising, in parts by weight: 13 to 17 portions of peucedanum root and 7 to 13 portions of microcos paniculata.

5. A medicament for treating chronic cough, which is prepared by mixing and extracting the components of the pharmaceutical composition according to any one of claims 1 to 4.

6. The agent for treating chronic cough according to claim 5, wherein the dosage form of the agent comprises: decoction, syrup, pill, powder, tablet, capsule, powder, emulsion, aerosol, patch, tincture, injection and granule.

7. The medicament for treating chronic cough according to claim 5, wherein the medicament is a syrup, and the preparation method of the syrup comprises:

mixing the components in the pharmaceutical composition, extracting by adopting a solvent extraction method to obtain a total extract, and mixing with simple syrup to obtain a first mixture, wherein the simple syrup accounts for 50-70% of the total mass of the first mixture; and boiling and filtering the first mixture.

8. A method of preparing a medicament according to claim 5 for the treatment of chronic cough, comprising: mixing the components in the pharmaceutical composition, and extracting by a solvent extraction method.

9. Use of a pharmaceutical composition according to any one of claims 1 to 4 in the manufacture of a medicament for the treatment of chronic cough disorders.

10. The use according to claim 9, wherein the chronic cough disease comprises at least one of refractory chronic cough, cough hypersensitivity syndrome, idiopathic cough, unexplained chronic cough, upper airway cough syndrome, eosinophilic bronchitis, gastroesophageal reflux cough, and cough variant asthma.