Cough and asthma relieving compound medicine for nebulization treatment of respiratory system as well as preparation and application of cough and asthma relieving compound medicine

Abstract

The invention provides a cough and asthma relieving compound medicine for nebulization treatment of a respiratory system as well as preparation and application of the cough and asthma relieving compound medicine. The cough and asthma relieving compound medicine takes various traditional Chinese medicinal materials such as ginkgo and ephedra as main raw materials, and further comprises compound bacteria, an osmotic pressure regulator and a cosolvent. The compound bacteria are prepared from cordyceps sinensis, bamboo fungus and pine olive in a specific mass ratio, the osmotic pressure regulator is prepared from glucose and glycerol in a specific ratio, and the cosolvent has multiple selectable components. The preparation method comprises a plurality of steps and unique processes including medicinal material extraction, salifying modification, ultrasonic extraction and the like. Clinical tests show that compared with a control group and a placebo group, the compound medicine disclosed by the invention can remarkably improve lung function related indexes of patients and reduce the level of inflammatory factors, and a visual simulation scoring method also proves that the compound medicine can effectively relieve symptoms of cough and asthma. The medicine can be used for preparing aerosol inhalation medicines for treating various respiratory diseases such as bronchial asthma and chronic obstructive pulmonary diseases, and has a good application prospect.

Description

Technical Field

[0001] The invention relates to the technical field of respiratory system atomization medicine preparation, and in particular to a cough and asthma relieving compound medicine for respiratory system atomization treatment, and the preparation and application thereof. Background Art

[0002] Respiratory diseases are common and have a great impact on human health. Bronchial asthma, chronic obstructive pulmonary disease, bronchitis, pneumonia and other diseases are often accompanied by symptoms such as coughing and wheezing, which seriously affect the quality of life of patients and even threaten their life and health.

[0003] At present, there are many clinical treatment drugs and methods for cough and asthma caused by respiratory diseases. Among them, aerosol therapy is widely used because it directly acts on the respiratory tract, has a quick onset and few side effects. Among the existing aerosol treatment drugs, traditional treatment drugs mainly include bronchodilators, glucocorticoids, etc. However, these drugs have some limitations in practical application.

[0004] On the one hand, single-ingredient drugs can often only work on a specific pathological link, and it is difficult to comprehensively improve the complex symptoms of respiratory diseases. For example, although bronchodilators can quickly relieve bronchospasm, they have limited inhibitory effects on airway inflammation; although glucocorticoids have strong anti-inflammatory effects, long-term use may cause a variety of adverse reactions, such as osteoporosis, increased blood sugar, decreased immunity, etc., which limits their clinical application.

[0005] On the other hand, existing therapeutic drugs also have shortcomings in dosage form and administration method. Some drugs need to be taken orally or injected, which not only brings inconvenience to patients, but also the absorption and distribution process of drugs in the body is complicated, which may lead to low drug utilization rate and relatively slow onset of effect. In addition, traditional administration methods make it difficult for drugs to act accurately on the lesion site, affecting the treatment effect.

[0006] In terms of preparation technology, the preparation methods of some drugs are relatively simple and cannot fully extract and retain the active ingredients in the medicinal materials, resulting in unstable drug efficacy. Moreover, the existing preparation technology may not be able to solve the solubility and stability of the drug well, affecting the quality and use effect of the drug. Summary of the invention

[0007] In view of this, the present invention proposes a cough and asthma relieving compound medicine for atomization treatment of the respiratory system and its preparation and application to solve the above problems.

[0008] The technical scheme of the present invention is realized as follows: a cough and asthma relieving compound medicine for atomization treatment of the respiratory system comprises the following raw materials in parts by weight: 10-15 parts of ginkgo, 6-10 parts of ephedra, 12-18 parts of ophiopogon japonicus, 10-15 parts of mulberry bark, 8-12 parts of perilla seed, 9-13 parts of apricot kernel, 5-10 parts of liquorice, 10-15 parts of scutellaria baicalensis, 6-10 parts of pinellia ternata, 2-5 parts of asarum, 6-10 parts of earthworm, 6-10 parts of platycodon, 6-10 parts of belamcanda, 8-12 parts of aster and 6-10 parts of tangerine peel.

[0009] Furthermore, a cough and asthma relief compound medicine for aerosol treatment of the respiratory system includes the following raw materials in parts by weight: 13 parts of ginkgo, 8 parts of ephedra, 15 parts of ophiopogon japonicus, 12 parts of mulberry bark, 10 parts of perilla seed, 11 parts of apricot kernel, 8 parts of licorice, 13 parts of scutellaria baicalensis, 8 parts of pinellia ternata, 4 parts of asarum, 8 parts of earthworm, 8 parts of platycodon, 8 parts of belamcanda chinensis, 10 parts of aster, and 8 parts of tangerine peel.

[0010] Furthermore, a cough and asthma relieving compound medicine for aerosol treatment of the respiratory system also includes the following raw materials in parts by weight: 2-8 parts of compound bacteria, 1-3 parts of osmotic pressure regulator, and 3-10 parts of cosolvent.

[0011] Furthermore, the composite bacteria are Cordyceps sinensis, Dictyophora japonica, and Olea europaea in a mass ratio of (8-15):(1-3):(4-8).

[0012] Furthermore, the osmotic pressure regulator is glucose and glycerol in a mass ratio of 3-5:10.

[0013] Furthermore, the co-solvent is selected from 1,2-propylene glycol with a concentration of 3-10 v / v%, 0.45-0.65 w / v% saline or 1-5 w / v% polyethylene glycol.

[0014] Furthermore, a method for preparing a cough and asthma relieving compound medicine for aerosol treatment of the respiratory system comprises the following steps:

[0015] S1. Remove impurities from Pinellia ternata, Belamcanda chinensis, Scutellaria baicalensis, Licorice and Citrus grandis respectively, wash and dry, crush to 40-60 mesh, soak in 40-60% ethanol solution, the mass volume ratio of powder to ethanol solution is 1:6-10 g / mL, soak for 1-3h, heat to 70-80℃ for heating reflux extraction for 2-4h, separate the extract from the residue, repeat the extraction 2-4 times, mix the extract, concentrate at 40-60℃, add 0.1-0.5mol / L sodium hydroxide solution to the extract while stirring, adjust the solution pH to 7-8, the temperature to 40-50℃, react for 1-3h, cool, centrifuge and separate the precipitate to obtain drug I;

[0016] S2, after mixing ephedra and asarum, crush the powder through 80-100 mesh sieve, put it into an extraction kettle, introduce supercritical carbon dioxide fluid, control the extraction pressure to 10-30MPa, the temperature to 35-50°C, the extraction time to 1-3h, separate the extract, collect the extract, slowly dropwise add 0.1-0.5mol / L dilute hydrochloric acid solution to the extract, adjust the pH value of the solution to 3-4, control the reaction temperature to 30-40°C, the reaction time to 1-2h, cool, centrifuge and separate the precipitate to obtain drug II;

[0017] S3, remove impurities from perilla seeds, almonds, aster, ginkgo, ophiopogon japonicus, and white mulberry bark, wash and dry them, grind them into coarse powder, pass through a 40-60 mesh sieve, add 70-80% ethanol solution, the solid-liquid ratio g / mL is 1:5-20, soak for 1-2h to fully wet the medicinal materials, heat to 80-100°C for ultrasonic extraction for 30-60min, filter and remove the residue after the extraction, collect the extract, concentrate, add sugar donor material, the mass volume ratio of sugar donor material to extract is 1-10:1, the sugar donor material is glucose and galactosidase in a mass ratio of 1:1-3, react at pH 5-7 and temperature 30-40°C for 12-24h, purify after the reaction to obtain drug III;

[0018] S4, crush earthworm and platycodon into fine powder, pass through a 100-120 mesh sieve, add 7-9 times the weight of the powder in water, decoct for 2-4 times, each time for 1.5 hours, combine the decoction, filter, concentrate the filtrate and dry it to obtain drug IV;

[0019] S5. Evenly mix the above drugs I, II, III and IV, add compound bacteria, osmotic pressure regulator and cosolvent for homogenization, control the speed to 10000-15000rpm, temperature to 20-40°C and pressure to 10-30MPa for homogenization for 10-30min, take out and perform ultrasonic atomization at a frequency of 1-3MHz and a power of 20-50W to form atomized particles with a particle size of 1-5μm, and obtain a cough and asthma relief compound drug.

[0020] Furthermore, the ultrasonic frequency of step S3 is 20-60kHz, and the ultrasonic power is 100-300W.

[0021] Furthermore, the cough and asthma relieving compound medicine for respiratory system aerosol treatment is used in the preparation of an aerosol inhalation medicine for treating cough and asthma symptoms caused by respiratory diseases.

[0022] Furthermore, the respiratory diseases include but are not limited to bronchial asthma, chronic obstructive pulmonary disease, bronchitis, and pneumonia.

[0023] Compared with the prior art, the present invention has the following beneficial effects:

[0024] The compound medicine of the present invention comprises 15 Chinese medicinal materials such as ginkgo, ephedra, and ophiopogon japonicus, and each medicinal material cooperates with each other in nature, flavor, meridians, and functions. In the prescription of the present invention, ephedra promotes lung function and relieves asthma, and ginkgo astringes the lungs and calms asthma. The two, one promotes and the other astringes, jointly regulate the lung qi; ophiopogon japonicus nourishes yin and moistens the lungs, and mulberry bark relieves lung function and relieves asthma, which can improve lung function from the two perspectives of nourishing yin and purging heat; perilla seeds and apricots descend qi, relieve cough and relieve asthma, and licorice harmonizes various medicines, so that the entire formula has a synergistic effect, plays a comprehensive therapeutic role on cough and asthma symptoms caused by respiratory diseases, and has a more comprehensive and more significant therapeutic effect than a single drug. The addition of composite bacteria, osmotic pressure regulators and cosolvents further improves the performance of the medicine. The Cordyceps sinensis, Bamboo Fungus and Olive Oil in the composite fungus are matched in a specific mass ratio, which has the function of regulating the body's immunity and enhancing the efficacy of drugs; the osmotic pressure regulator can adjust the osmotic pressure of the drug solution to make it adapt to the physiological environment of the human body and reduce irritation to the respiratory tract; the cosolvent improves the solubility of the drug, ensures that the drug can be evenly dispersed during the nebulization process, and improves the stability of the drug and the nebulization effect.

[0025] The present invention selects ingredients with antitussive and antiasthmatic activity from traditional Chinese medicines, and uses modern separation, purification and identification technologies to improve their purity and activity. The targeting of the drug is enhanced by salt modification and introduction of sugar donor materials, making it easier to bind to the target points of respiratory tissues, while adjusting the release rate of the drug, prolonging the drug action time, promoting the absorption and transport of the drug, so that the drug can act more accurately on the lesion site and improve the therapeutic effect. DETAILED DESCRIPTION

[0026] In order to better understand the technical content of the present invention, specific embodiments are provided below to further illustrate the present invention.

[0027] Unless otherwise specified, the experimental methods used in the embodiments of the present invention are all conventional methods.

[0028] Unless otherwise specified, the materials, reagents, etc. used in the embodiments of the present invention can be obtained from commercial sources.

[0029] The following introduces the basic information of the main raw materials based on the "Chinese Pharmacopoeia" and "Chinese Materia Medica Dictionary".

[0030] Ginkgo: Nature and flavor and meridians: sweet, slightly bitter, astringent, warm in nature, slightly toxic, enters the lung and kidney meridians.

[0031] Functions and indications: It can calm the lungs and asthma, stop leucorrhea and reduce urination. It is used to treat cough, asthma, leucorrhea, frequent urination and other symptoms.

[0032] Ephedra: Nature and flavor and meridians: warm in nature, pungent and slightly bitter.

[0033] Functions and indications: dispel wind and cold, clear the lungs and relieve asthma, promote diuresis and reduce swelling. Mainly used to treat colds, chest tightness, asthma and cough, edema caused by wind and water.

[0034] Ophiopogon japonicus: Nature and flavor and meridians entered: sweet, slightly bitter, slightly cold in nature, enters the heart, lung and stomach meridians.

[0035] Functions and indications: nourishing yin and producing body fluid, moistening the lungs and clearing the heart, moistening the intestines and relieving constipation, clearing away heat and detoxifying. Used to treat dry cough due to lung dryness, cough due to yin deficiency, thirst due to loss of body fluid, restlessness and insomnia, dry intestines and constipation.

[0036] Morus alba bark: Nature and flavor and meridians: bitter, cold in nature, enters the lung meridian and bladder meridian.

[0037] Functions and indications: Drains the lungs and relieves asthma, promotes diuresis and reduces swelling. Used to treat cough due to lung heat, edema, gonorrhea, and cough and asthma caused by stagnation of lung qi.

[0038] Perilla seed: Nature and flavor and meridians: pungent and warm in nature, enters the lung meridian.

[0039] Functions and indications: It can reduce qi and resolve phlegm, relieve cough and asthma, and moisten the intestines and promote bowel movements. It is used to treat symptoms such as phlegm accumulation and qi reversal, cough and asthma, dry intestines and constipation.

[0040] Almond: Nature and flavor and meridians: bitter, slightly warm, slightly toxic, enters the lung and large intestine meridians.

[0041] Functions and indications: relieves cough and asthma, moistens the intestines and promotes bowel movements. Used to treat symptoms such as cough, asthma, dry intestines and constipation.

[0042] Licorice: Nature and flavor and meridians: sweet, neutral in nature, enters the twelve meridians.

[0043] Functions and indications: tonifying the middle qi, purging fire and detoxifying, moistening the lungs and removing phlegm, alleviating the medicinal properties, relieving urgency and relieving pain. It is used to treat symptoms such as spleen and stomach weakness, insufficient qi and blood, sores and swelling, sore throat, cough and asthma.

[0044] Scutellaria baicalensis: Nature and flavor and meridians entered: Cold in nature, bitter in taste, enters the lung, gallbladder, spleen, large intestine and small intestine meridians.

[0045] Functions and indications: Clears away heat and purges fire, dries dampness and detoxifies. Used to treat symptoms caused by febrile diseases and fire-heat pathogens, such as lung heat cough, yellow and sticky sputum, asthma, etc.

[0046] French Pinellia: Nature and flavor and meridians entered: warm in nature, pungent in taste, enters the spleen, stomach and lung meridians.

[0047] Functions and indications: Drying dampness and resolving phlegm, relieving adverse reactions and stopping vomiting, eliminating lumps and dispersing lumps. Used to treat symptoms such as cough due to excessive phlegm, upward reflux of stomach qi, abdominal distension, and chest tightness.

[0048] Asarum: Nature and flavor and meridians entered: Spicy in taste, warm in nature, enters the lung and kidney meridians.

[0049] Functions and indications: dispel wind and cold, relieve pain, warm the lungs and transform fluid. Used to treat colds, headaches, toothaches, nasal congestion and other symptoms.

[0050] Earthworm: Nature and flavor and meridians entered: salty in taste, cold in nature, enters the liver, spleen and bladder meridians.

[0051] Functions and indications: Clearing away heat and calming wind, unblocking meridians, relieving asthma, and promoting urination. Used to treat symptoms such as high fever convulsions, epilepsy, hemiplegia, and asthma.

[0052] Platycodon: Nature and flavor and meridians entered: bitter and spicy, neutral in nature, enters the lung meridian.

[0053] Functions and indications: Clearing lungs and removing phlegm, relieving cough and discharging pus. Used to treat cough with phlegm, sore throat, lung abscess and other symptoms.

[0054] Belamcanda chinensis: Nature and flavor and meridians entered: bitter in taste, cold in nature, enters the lung meridian.

[0055] Functions and indications: Clears away heat and detoxifies, removes phlegm and relieves sore throat, disperses blood and reduces swelling. Used to treat symptoms such as sore throat, cough and asthma, and yellow and sticky phlegm.

[0056] Aster: Nature and flavor and meridians entered: Spicy and bitter in taste, warm in nature, enters the lung meridian.

[0057] Functions and indications: moistens the lungs and relieves qi, resolves phlegm and relieves cough. Used to treat symptoms such as cough, asthma, and excessive phlegm.

[0058] Huajuhong: Nature and flavor and meridians: pungent and bitter, warm in nature, enters the lung and spleen meridians.

[0059] Functions and indications: Dispel cold and dampness, regulate qi and resolve phlegm, relieve fullness and promote digestion. Example 1

[0060] A cough and asthma relieving compound medicine for atomization treatment of the respiratory system comprises the following raw materials in parts by weight: 10 parts of ginkgo, 6 parts of ephedra, 12 parts of ophiopogon japonicus, 10 parts of mulberry bark, 8 parts of perilla seed, 9 parts of apricot kernel, 5 parts of liquorice, 10 parts of scutellaria baicalensis, 6 parts of pinellia ternata, 2 parts of asarum, 6 parts of earthworm, 6 parts of platycodon, 6 parts of belamcanda, 8 parts of aster, 6 parts of tangerine peel, 2 parts of compound bacteria, 1 part of osmotic pressure regulator and 3 parts of cosolvent.

[0061] The composite bacteria are cordyceps sinensis, bamboo fungus and olive in a mass ratio of 8:1:4.

[0062] The osmotic pressure regulator is glucose and glycerol in a mass ratio of 3:10.

[0063] The co-solvent is selected from 1,2-propylene glycol at a concentration of 3 v / v%. Example 2

[0064] A cough and asthma relieving compound medicine for atomization treatment of the respiratory system comprises the following raw materials in parts by weight: 15 parts of ginkgo, 10 parts of ephedra, 18 parts of ophiopogon japonicus, 15 parts of mulberry bark, 12 parts of perilla seed, 13 parts of apricot kernel, 10 parts of liquorice, 15 parts of scutellaria baicalensis, 10 parts of pinellia ternata, 5 parts of asarum, 10 parts of earthworm, 10 parts of platycodon, 10 parts of belamcanda, 12 parts of aster, 10 parts of tangerine peel, 8 parts of compound bacteria, 3 parts of osmotic pressure regulator and 10 parts of solvent.

[0065] The composite bacteria are cordyceps sinensis, bamboo fungus and olive in a mass ratio of 15:3:8.

[0066] The osmotic pressure regulator is glucose and glycerol in a mass ratio of 5:10.

[0067] The co-solvent is selected from polyethylene glycol with a concentration of 3 w / v%. Example 3

[0068] A cough and asthma relieving compound medicine for atomization treatment of the respiratory system comprises the following raw materials in parts by weight: 13 parts of ginkgo, 8 parts of ephedra, 15 parts of ophiopogon japonicus, 12 parts of mulberry bark, 10 parts of perilla seed, 11 parts of apricot kernel, 8 parts of liquorice, 13 parts of scutellaria baicalensis, 8 parts of pinellia ternata, 4 parts of asarum, 8 parts of earthworm, 8 parts of platycodon, 8 parts of belamcanda, 10 parts of aster, 8 parts of tangerine peel, 5 parts of compound bacteria, 2 parts of osmotic pressure regulator and 7 parts of solvent.

[0069] The composite bacteria are cordyceps sinensis, bamboo fungus and olive in a mass ratio of 12:2:6.

[0070] The osmotic pressure regulator is glucose and glycerol in a mass ratio of 4:10.

[0071] The co-solvent is selected from 0.45 w / v% saline.

[0072] The above examples 1-3 adopt the following preparation method:

[0073] S1. Remove impurities from Pinellia ternata, Belamcanda chinensis, Scutellaria baicalensis, Licorice and Citrus grandis respectively, wash and dry, crush to 50 mesh, soak in 50% ethanol solution, the mass volume ratio of powder to ethanol solution is 1:8 (g / mL), soak for 2 hours, heat to 75°C for heating reflux extraction for 3 hours, separate the extract from the residue, repeat the extraction for 3 times, mix the extract, concentrate at 50°C, add 0.3 mol / L sodium hydroxide solution to the extract while stirring, adjust the solution pH to 7.5, the temperature to 45°C, react for 2 hours, cool, centrifuge and separate the precipitate to obtain drug I;

[0074] S2, after mixing ephedra and asarum, crush the powder through a 90-mesh sieve, put it into an extraction kettle, introduce supercritical carbon dioxide fluid, control the extraction pressure to 20MPa, the temperature to 45°C, the extraction time to 2h, separate the extract, collect the extract, slowly dropwise add 0.3mol / L dilute hydrochloric acid solution to the extract, adjust the pH value of the solution to 3, control the reaction temperature to 35°C, the reaction time to 2h, cool, centrifuge and separate the precipitate to obtain drug II;

[0075] S3, remove impurities from perilla seeds, apricot kernels, aster, ginkgo, ophiopogon japonicus, and white mulberry bark, wash and dry them, grind them into coarse powder, pass through a 50-mesh sieve, add 75% ethanol solution, the solid-liquid ratio g / mL is 1:15, soak for 2 hours to fully soak the medicinal materials, heat to 90°C for ultrasonic extraction for 50 minutes, the ultrasonic frequency is 40kHz, the ultrasonic power is 200W, filter and remove the medicinal residues after the extraction, collect the extract, concentrate, add sugar donor material, the mass volume ratio of sugar donor material to extract is 5:1, the sugar donor material is glucose and galactosidase in a mass ratio of 1:2, react at pH=6 and temperature 35°C for 18 hours, purify after the reaction to obtain drug III;

[0076] S4. Grind earthworm and platycodon into fine powder, pass through a 110-mesh sieve, add 8 times the weight of the powder in water, boil for 3 times, each time for 1.5 hours, combine the decoctions, filter, concentrate the filtrate and dry it to obtain drug IV.

[0077] S5. Evenly mix the above drugs I, II, III and IV, add compound bacteria, osmotic pressure regulator and cosolvent for homogenization, control the speed to 12000 rpm, temperature to 30°C and pressure to 20 MPa for homogenization for 20 min, take out and perform ultrasonic atomization at a frequency of 2 MHz and a power of 30 W to form atomized particles with a particle size of 3 μm, and obtain the antitussive and antiasthmatic compound drug.

[0078] Comparative Example 1

[0079] The difference between this comparative example and Example 3 is that the antitussive and antiasthmatic compound medicine does not contain Aster, Platycodon grandiflorum, and Belamcanda. Specifically, it comprises the following raw materials in parts by weight: 13 parts of ginkgo, 8 parts of ephedra, 15 parts of ophiopogon japonicus, 12 parts of mulberry bark, 10 parts of perilla seeds, 11 parts of apricot kernel, 8 parts of liquorice, 13 parts of scutellaria baicalensis, 8 parts of pinellia tuber, 4 parts of asarum, 8 parts of earthworm, 8 parts of tangerine peel, 5 parts of composite bacteria, 2 parts of osmotic pressure regulator, and 7 parts of cosolvent.

[0080] Comparative Example 2

[0081] The difference between this comparative example and Example 3 is that the antitussive and antiasthmatic compound medicine does not contain ephedra, apricot kernel, or perilla seed. Specifically, the following raw materials are included in weight: 13 parts of ginkgo, 15 parts of ophiopogon, 12 parts of white mulberry bark, 8 parts of liquorice, 13 parts of scutellaria, 8 parts of pinellia, 4 parts of asarum, 8 parts of earthworm, 8 parts of platycodon, 8 parts of belamcanda, 10 parts of aster, 8 parts of tangerine peel, 5 parts of composite bacteria, 2 parts of osmotic pressure regulator, and 7 parts of cosolvent.

[0082] Comparative Example 3

[0083] The difference between this comparative example and Example 3 is that the antitussive and antiasthmatic compound medicine does not contain composite bacteria.

[0084] Comparative Example 4

[0085] The difference between this comparative example and Example 3 is that in the method for preparing the antitussive and antiasthmatic compound medicine, no sodium hydroxide solution and dilute hydrochloric acid solution are added dropwise in steps S1 and S2.

[0086] Specifically:

[0087] S1. Remove impurities from Pinellia ternata, Belamcanda chinensis, Scutellaria baicalensis, Licorice root and Citrus aurantium respectively, wash and dry them, crush them into 50 mesh, soak them in 50% ethanol solution, the mass volume ratio of powder to ethanol solution is 1:8 (g / mL), soak them for 2 hours, heat them to 75°C for heating and reflux extraction for 3 hours, separate the extract from the residue, repeat the extraction for 3 times, mix the extracts, concentrate them at 50°C, cool them, and centrifuge them to separate the precipitate, to obtain drug I;

[0088] S2. Mix ephedra and asarum and grind them into powder through a 90-mesh sieve, put them into an extraction kettle, introduce supercritical carbon dioxide fluid, control the extraction pressure to 20 MPa, the temperature to 45°C, and the extraction time to 2 h, separate the extract, collect the extract, cool it, and centrifuge it to separate the precipitate to obtain drug II.

[0089] Comparative Example 5

[0090] The difference between this comparative example and Example 3 is that in the method for preparing the antitussive and antiasthmatic compound medicine, no sugar donor material is added in step S3.

[0091] Specifically:

[0092] S3. Remove impurities from perilla seed, almond, aster, ginkgo, ophiopogon japonicus and mulberry bark respectively, wash and dry them, grind them into coarse powder, pass through a 50-mesh sieve, add 75% ethanol solution, and the solid-liquid ratio g / mL is 1:15. Soak for 2 hours to fully soak the medicinal materials, heat to 90°C for ultrasonic extraction for 50 minutes, the ultrasonic frequency is 40kHz, and the ultrasonic power is 200W. After the extraction, filter out the residue, collect the extract, concentrate, and purify to obtain drug III.

[0093] Test Example 1-In vitro cell experiment

[0094] 1. Drug Metabolizing Enzyme Activity Detection

[0095] 1. Cell culture: Human lung epithelial cell line (A549) was selected and inoculated in high-glucose DMEM medium containing 10% fetal bovine serum and 1% double antibody (penicillin-streptomycin mixture), and cultured in a cell culture incubator at 37°C and 5% CO2. When the cells grow to the logarithmic growth phase, they are digested with 0.25% trypsin-EDTA digestion solution and subcultured at a ratio of 1:3-1:4 to ensure that the cells are in good condition.

[0096] 2. Drug treatment: A549 cells were cultured at 5×10 4 -1×10 5 The cells were inoculated at a density of 100 cells / mL in a 24-well plate. After the cells were attached and grown for 24 hours, the culture medium containing the drugs of Examples 1-3 and Comparative Examples 1-4 was used. A control group was set up at the same time, and an equal volume of the culture medium without drugs was added to the control group. The culture plate was returned to the cell culture incubator and incubated for 24 hours.

[0097] 3. RNA extraction and qRT-PCR detection: After incubation, discard the culture medium and gently wash the cells 1-3 times with PBS buffer. Extract total RNA according to the instructions of the RNA extraction kit; perform reverse transcription reaction according to the instructions of the reverse transcription kit to synthesize cDNA. Real-time quantitative polymerase chain reaction (qRT-PCR) was used to detect the gene expression level and protein expression level of enzymes related to drug metabolism (cytochrome P450 enzyme system).

[0098] 4. Determination of metabolic enzyme activity: Determine the activity changes of these metabolic enzymes using enzyme activity detection kits.

[0099] 5. Test results

[0100]

[0101] From the above results, it can be seen that the relative expression of CYP450 genes in the embodiment group is significantly higher than that in the control group, indicating that these three embodiments can effectively induce the expression of CYP450 genes at a concentration of 5 μg / mL; similar to the trend of the relative expression of genes, the relative expression of CYP450 proteins in the embodiment group is significantly higher than that in the control group and the comparative group. This shows that the embodiment not only has a promoting effect at the gene transcription level, but can also effectively transfer this promoting effect to the protein synthesis stage, thereby increasing the expression of CYP450 proteins. The metabolic enzyme activity of the embodiment group is significantly higher than that of the control group and the comparative group, which corresponds to the expression trend of CYP450 genes and proteins. Higher gene and protein expression levels usually lead to an increase in metabolic enzyme activity, indicating that the embodiment group can more effectively activate the function of CYP450 metabolic enzymes.

[0102] 2. Drug transporter research experiments

[0103] 1. Cell culture and inoculation: MDCK-MDR1 cells were cultured in DMEM / F12 medium containing 10% fetal bovine serum and 1% double antibody at 37°C and 5% CO 2 , and cultured in a cell culture incubator. Cells were plated at 1×10 5 -2×10 5 The density of cells was inoculated in the Transwell chamber (upper chamber), and an appropriate amount of culture medium was added to the lower chamber. After inoculation, the Transwell chamber was placed in an incubator for culture. When the cells formed a dense monolayer on the Transwell chamber (3-5 days), the integrity of the cell monolayer was confirmed by measuring the transepithelial electrical resistance (TEER) value.

[0104] 2. Drug transport experiment: Dissolve the above drugs in serum-free culture medium and prepare a solution with a concentration of 10 μg / mL; add the drug-containing solution to the upper chamber of the Transwell chamber, and add an equal amount of serum-free culture medium to the lower chamber as the receiving solution. At the same time, set up a control group, and add serum-free culture medium without drugs to the control group. Return the Transwell chamber to the incubator and incubate for 6 hours. After the incubation, collect the solutions in the upper and lower chambers respectively, and use HPLC and other methods to determine the drug concentration in the solution. Calculate the drug uptake rate (the ratio of the drug concentration in the lower chamber to the initial drug concentration in the upper chamber) and efflux rate (the ratio of the remaining drug concentration in the upper chamber to the initial drug concentration) to evaluate the drug transport in the cell model.

[0105] 3. Experimental results

[0106]

[0107] The above results show that the uptake rate of the embodiment group is significantly higher than that of the control group and the comparative example group. This shows that the embodiment group is more conducive to the uptake of the drug by the cell, thereby increasing the drug concentration in the cell, providing a better basis for exerting the drug effect. Corresponding to the results of the uptake rate, the efflux rate of the embodiment group is significantly lower than that of the control group and the comparative example group. The lower efflux rate means that the drug is retained in the cell for a longer time, can continue to play a role, and further enhances the efficacy of the drug.

[0108] From the data of comprehensive uptake rate and efflux rate, it can be seen that Example 3 has the highest uptake rate and the lowest efflux rate, indicating that the drug of Example 3 has the best accumulation effect in cells and exhibits better ability to enter cells and reduce efflux compared with other groups.

[0109] Compared with Comparative Example 4, steps S1 and S2 drip sodium hydroxide solution and dilute hydrochloric acid solution to the medicinal material, respectively, and the drug components therein are converted into corresponding salts, which are helpful for the dispersion and dissolution of subsequent drugs in the solution, and ensure that the drugs can be evenly dispersed in the atomized liquid during the atomization treatment of the respiratory system, and can be inhaled and absorbed more effectively. This salt-forming reaction can make the drug molecules carry a specific charge, thereby changing the distribution characteristics of the drug in the body. In the respiratory system, drug salts with specific charges may be more likely to bind to receptors or targets with opposite charges on the surface of respiratory tissues, thereby enhancing the targeting of the drug and enabling the drug to act more accurately on the lesion site. At the same time, the dissolution and dissociation speed of these salts in the body are relatively slow, which can slowly release the drug in the respiratory tract, prolong the action time of the drug, and continuously exert the effect of relieving cough and asthma.

[0110] Compared with Comparative Example 5, the introduction of sugar donor materials into the medicinal materials through glycosylation reaction, the drug components and sugar donors are combined to form a new chemical structure, which can reduce the exposure of unstable groups in the drug molecules, reduce the chemical activity of the drug, thereby improving the stability of the drug, and at the same time increase the polarity of the drug solution, thereby improving the solubility of some components in the extract. The glycosylated drug can specifically bind to the glycoprotein receptors on the surface of respiratory epithelial cells, promote the absorption and transport of the drug, enable the drug to act more accurately on the lesion site, and improve the therapeutic effect.

[0111] Test Example 2-Clinical Trial

[0112] 1. Subject Selection

[0113] Inclusion criteria: patients aged between 18 and 65 years with respiratory diseases such as bronchial asthma, chronic bronchitis, etc. with mild to moderate cough and wheezing symptoms; voluntarily participate in this study and sign the informed consent.

[0114] Exclusion criteria: patients who are allergic to any component of this compound drug; patients with serious diseases of the heart, liver, kidney and other important organs; pregnant or lactating women; patients who have participated in other clinical trials recently (within 3 months).

[0115] 2. Experimental Drugs and Control Drugs

[0116] Experimental drug: The antitussive and antiasthmatic compound drug produced according to the above preparation method is made into a dosage form that can be used for aerosol inhalation.

[0117] Control drug: A compound preparation of salbutamol 1.0 mg and budesonide 0.5 mg was selected as a positive control, using the same nebulized inhalation dosage form.

[0118] 3. Test Indicators and Evaluation Tools

[0119] Symptom assessment: The visual analogue scale (VAS) was used to assess the severity of the subjects' symptoms such as cough, wheezing, and dyspnea, with 0 points indicating no symptoms and 10 points indicating extremely severe symptoms.

[0120] Pulmonary function test: Use a spirometer to measure the subject's forced expiratory volume in one second (FEV1), forced vital capacity (FVC), peak expiratory flow (PEF) and other indicators.

[0121] Inflammatory index detection: Collect blood samples from subjects to detect the levels of inflammatory factors: interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α); collect sputum samples to detect inflammatory cell counts, etc.

[0122] Safety indicators: Record the adverse reactions of the subjects during the trial, including local irritation symptoms (such as respiratory irritation, increased cough, etc.), systemic adverse reactions (such as allergic reactions, dizziness, nausea, etc.), and conduct blood routine, blood biochemistry, urine routine and other examinations to evaluate the safety of the drug on the body.

[0123] 4. Clinical Trial Design

[0124] This study adopted a randomized, double-blind, positive drug parallel controlled research design.

[0125] 1. Grouping: The recruited subjects were randomly divided into 3 groups, with 50 subjects in each group.

[0126] Experimental group: The antitussive and antiasthmatic compound medicine prepared in Example 3 was used for aerosol inhalation treatment.

[0127] Positive control group: Atomization inhalation treatment was performed using positive control drugs commonly used in clinical practice.

[0128] Placebo group: A placebo that looks and smells the same as the test drug but does not contain active ingredients is used for nebulized inhalation treatment.

[0129] 2. Dosage regimen

[0130] The experimental group and the positive control group: The drug was administered by aerosol inhalation twice a day, and the dosage was determined according to the actual clinical situation for 4 consecutive weeks.

[0131] Placebo group: The frequency and method of administration were the same as those of the experimental group.

[0132] 5. Clinical Testing Process

[0133] 1. Screening period: After the subject signs the informed consent form, a comprehensive physical examination, medical history inquiry, pulmonary function test, laboratory test, etc. are performed to determine whether the subject meets the inclusion criteria and has no exclusion criteria, and the baseline data are recorded.

[0134] 2. Treatment period

[0135] The subjects received corresponding medication or placebo nebulization inhalation treatment according to the group, and were followed up once a week. The follow-up content included symptom assessment (VAS score), lung function test, and inquiry about adverse reactions.

[0136] During the treatment, subjects are required to record their symptom changes, medication use and any adverse reactions, such as the frequency and severity of coughing and wheezing attacks.

[0137] 3. Observation period: After the treatment, the subjects will continue to be observed for 2 weeks, during which symptom assessment, lung function testing and adverse reaction monitoring will be performed to evaluate the continued efficacy and safety of the drug.

[0138] 6. Test Results

[0139] 1. Symptom Assessment Results

[0140]

[0141] Note: Compared with before treatment, *P<0.05, the difference is statistically significant. Compared with the control group, #P<0.05, the difference is statistically significant.

[0142] The above data shows:

[0143] After 4 weeks of treatment, the VAS score of the experimental group was significantly reduced, and the score further decreased after 2 weeks of observation, which was significantly different from before treatment (P<0.05). The difference was also significant compared with the control group (P<0.05), indicating that the antitussive and antiasthmatic compound drug can effectively and continuously relieve patients' symptoms.

[0144] The VAS score of the control group also decreased after 4 weeks of treatment, which was significantly different from before treatment (P<0.05), but the decrease was not as large as that of the experimental group. The score was also relatively high after 2 weeks of observation, indicating that although the control drug had a certain therapeutic effect, the effect was not as obvious as that of the experimental group drug.

[0145] The VAS score of the placebo group did not decrease significantly during the whole process, and there was no significant difference compared with before treatment, indicating that the placebo had limited effect on improving patients' symptoms, further highlighting the positive role of experimental drugs and control drugs in alleviating symptoms.

[0146] 2. Pulmonary function test results

[0147] Note: Compared with before treatment, *P<0.05, the difference is statistically significant. Compared with the control group, #P<0.05, the difference is statistically significant.

[0148] The above data shows that:

[0149] After 4 weeks of treatment, the FEV1, FVC and PEF indicators of the experimental group were significantly improved, and the degree of improvement was significantly better than that of the control group (P<0.05), indicating that the antitussive and antiasthmatic compound drug is effective in improving patients' lung function.

[0150] The control group also showed some improvement after treatment, but the effect was relatively weak compared with the experimental group.

[0151] There were no significant changes in various indicators in the placebo group before and after treatment, indicating that the lung function of patients in this group was not significantly improved due to the use of placebo, further highlighting the positive effects of test drugs and control drugs on lung function.

[0152] 3. Inflammatory index test results

[0153]

[0154] Note: Compared with before treatment, *P<0.05, the difference is statistically significant. Compared with the control group, #P<0.05, the difference is statistically significant.

[0155] The above data show that:

[0156] After 4 weeks of treatment, the levels of IL-6 and TNF-α in the experimental group were significantly reduced, and the reduction was significantly greater than that in the control group (P<0.05), indicating that the antitussive and antiasthmatic compound drug is effective in inhibiting inflammation.

[0157] The levels of IL-6 and TNF-α in the control group also decreased after treatment, but the reduction in inflammatory indicators was less than that in the experimental group.

[0158] There was basically no significant change in the levels of IL-6 and TNF-α in the placebo group before and after treatment, indicating that the placebo had no significant effect on inflammatory indicators, highlighting the anti-inflammatory effects of the test drug and the control drug.

[0159] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims

1. A cough and asthma relieving compound medicine for aerosol treatment of the respiratory system, characterized in that: The invention comprises the following raw materials in parts by weight: 10-15 parts of ginkgo, 6-10 parts of ephedra, 12-18 parts of ophiopogon japonicus, 10-15 parts of mulberry bark, 8-12 parts of perilla seed, 9-13 parts of apricot kernel, 5-10 parts of liquorice, 10-15 parts of scutellaria baicalensis, 6-10 parts of pinellia ternata, 2-5 parts of asarum, 6-10 parts of earthworm, 6-10 parts of platycodon, 6-10 parts of belamcanda, 8-12 parts of aster and 6-10 parts of tangerine peel.

2. The cough and asthma relieving compound medicine for aerosol treatment of the respiratory system according to claim 1, characterized in that: The invention comprises the following raw materials in parts by weight: 13 parts of ginkgo, 8 parts of ephedra, 15 parts of ophiopogon japonicus, 12 parts of mulberry bark, 10 parts of perilla seed, 11 parts of apricot kernel, 8 parts of liquorice, 13 parts of scutellaria baicalensis, 8 parts of pinellia ternata, 4 parts of asarum, 8 parts of earthworm, 8 parts of platycodon, 8 parts of belamcanda, 10 parts of aster, and 8 parts of tangerine peel.

3. The cough and asthma relieving compound medicine for aerosol treatment of the respiratory system according to claim 1, characterized in that: The invention also comprises the following raw materials in parts by weight: 2-8 parts of composite bacteria, 1-3 parts of osmotic pressure regulator and 3-10 parts of cosolvent.

4. The cough and asthma relieving compound medicine for aerosol treatment of the respiratory system according to claim 3, characterized in that: The composite bacteria are cordyceps sinensis, bamboo fungus and olive in a mass ratio of (8-15):(1-3):(4-8).

5. The cough and asthma relieving compound medicine for aerosol treatment of the respiratory system according to claim 3, characterized in that: The osmotic pressure regulator is glucose and glycerol in a mass ratio of 3-5:

10.

6. The cough and asthma relieving compound medicine for aerosol treatment of the respiratory system according to claim 3, characterized in that: The co-solvent is selected from 1,2-propylene glycol at a concentration of 3-10 v / v%, 0.45-0.65 w / v% saline or 1-5 w / v% polyethylene glycol.

7. The method for preparing a cough and asthma relieving compound medicine for aerosol treatment of the respiratory system as claimed in claim 3, characterized in that: The following steps are involved: S1. Remove impurities from Pinellia ternata, Belamcanda chinensis, Scutellaria baicalensis, Licorice and Citrus grandis respectively, wash and dry, crush to 40-60 mesh, soak in 40-60% ethanol solution, the mass volume ratio of powder to ethanol solution is 1:6-10 g / mL, soak for 1-3h, heat to 70-80℃ for heating reflux extraction for 2-4h, separate the extract from the residue, repeat the extraction 2-4 times, mix the extract, concentrate at 40-60℃, add 0.1-0.5mol / L sodium hydroxide solution to the extract while stirring, adjust the solution pH to 7-8, the temperature to 40-50℃, react for 1-3h, cool, centrifuge and separate the precipitate to obtain drug I; S2, after mixing ephedra and asarum, crush the powder through 80-100 mesh sieve, put it into an extraction kettle, introduce supercritical carbon dioxide fluid, control the extraction pressure to 10-30MPa, the temperature to 35-50°C, the extraction time to 1-3h, separate the extract, collect the extract, slowly dropwise add 0.1-0.5mol / L dilute hydrochloric acid solution to the extract, adjust the pH value of the solution to 3-4, control the reaction temperature to 30-40°C, the reaction time to 1-2h, cool, centrifuge and separate the precipitate to obtain drug II; S3, remove impurities from perilla seeds, almonds, aster, ginkgo, ophiopogon japonicus, and white mulberry bark, wash and dry them, grind them into coarse powder, pass through a 40-60 mesh sieve, add 70-80% ethanol solution, the solid-liquid ratio g / mL is 1:5-20, soak for 1-2h to fully wet the medicinal materials, heat to 80-100°C for ultrasonic extraction for 30-60min, filter and remove the residue after the extraction, collect the extract, concentrate, add sugar donor material, the mass volume ratio of sugar donor material to extract is 1-10:1, the sugar donor material is glucose and galactosidase in a mass ratio of 1:1-3, react at pH 5-7 and temperature 30-40°C for 12-24h, purify after the reaction to obtain drug III; S4, crush earthworm and platycodon into fine powder, pass through a 100-120 mesh sieve, add 7-9 times the weight of the powder in water, decoct for 2-4 times, each time for 1.5 hours, combine the decoction, filter, concentrate the filtrate and dry it to obtain drug IV; S5. Evenly mix the above drugs I, II, III and IV, add compound bacteria, osmotic pressure regulator and cosolvent for homogenization, control the speed to 10000-15000rpm, temperature to 20-40°C and pressure to 10-30MPa for homogenization for 10-30min, take out and perform ultrasonic atomization at a frequency of 1-3MHz and a power of 20-50W to form atomized particles with a particle size of 1-5μm, and obtain a cough and asthma relief compound drug.

8. The method for preparing a cough and asthma relieving compound medicine for aerosol treatment of the respiratory system as claimed in claim 3, characterized in that: The ultrasonic frequency of step S3 is 20-60kHz, and the ultrasonic power is 100-300W.

9. Use of the antitussive and antiasthmatic compound medicine for aerosol treatment of the respiratory system according to any one of claims 1 to 3 in the preparation of an aerosol inhalation medicine for treating cough and asthma symptoms caused by respiratory diseases.

10. The use according to claim 9, characterized in that: The respiratory diseases include, but are not limited to, bronchial asthma, chronic obstructive pulmonary disease, bronchitis, and pneumonia.

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