A cough-relieving and asthma-relieving compound medicine for atomization treatment of respiratory system and preparation and application thereof

Abstract

The application provides a compound medicine for relieving cough and asthma in atomization treatment of respiratory system and a preparation and application thereof. The medicine is prepared from white ginkgo, ephedra and other Chinese medicinal materials as main raw materials, and further comprises complex bacteria, an osmotic pressure regulator and a dissolving agent. The complex bacteria are composed of cordyceps sinensis, bamboo lotus and pine olive in a specific mass ratio, the osmotic pressure regulator is glucose and glycerol in a specific ratio, and the dissolving agent can be selected from multiple kinds. The preparation method comprises multiple steps, including unique processes such as extraction of medicinal materials, salt modification and ultrasonic extraction. Through clinical tests, compared with a control group and a placebo group, the compound medicine can significantly improve the lung function related indexes of patients, reduce the inflammatory factor level, and effectively relieve the cough and asthma symptoms through a visual analogue scale method. The medicine can be used for preparing an atomization inhalation medicine for treating bronchial asthma, chronic obstructive pulmonary disease and other respiratory diseases, and has a good application prospect.

Description

Technical Field

[0001] The present 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] Currently, a variety of clinical treatments and methods are available for cough and wheezing caused by respiratory diseases. Among them, aerosol therapy is widely used due to its direct effect on the respiratory tract, rapid onset of action, and minimal side effects. Among existing aerosol treatments, traditional medications primarily include bronchodilators and glucocorticoids. However, these drugs have limitations in practical application.

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

[0005] On the other hand, existing therapeutic drugs also have shortcomings in dosage form and administration. Some drugs require oral administration or injection, which not only causes inconvenience to patients but also complicates the absorption and distribution of drugs in the body, potentially leading to low drug utilization and relatively slow onset of action. Furthermore, traditional drug administration methods make it difficult to precisely target the drug to the affected area, affecting the therapeutic effect.

[0006] In terms of manufacturing processes, some drugs are produced using relatively simple methods, which fail to fully extract and retain the active ingredients in the medicinal materials, resulting in unstable drug efficacy. Furthermore, existing manufacturing processes may not adequately address issues such as drug solubility and stability, impacting drug quality and effectiveness. Summary of the Invention

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

[0008] The technical solution of the present invention is achieved as follows: a cough and asthma relieving compound medicine for aerosol 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 flowers, 10-15 parts of mulberry bark, 8-12 parts of perilla seeds, 9-13 parts of apricot kernel, 5-10 parts of liquorice, 10-15 parts of scutellaria, 6-10 parts of pinellia, 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 relieving 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 flowers, 12 parts of mulberry bark, 10 parts of perilla seeds, 11 parts of apricot kernel, 8 parts of licorice, 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, 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 cosolvent 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, Glycyrrhiza uralensis, and Citrus aurantium respectively, wash and dry them, crush them into 40-60 mesh, soak them in 40-60% ethanol solution, the mass volume ratio of powder to ethanol solution is 1:6-10 g / mL, soak for 1-3 h, heat to 70-80 ° C and perform heating reflux extraction for 2-4 h, separate the extract from the residue, repeat the extraction 2-4 times, mix the extracts, concentrate at 40-60 ° C, add 0.1-0.5 mol / L sodium hydroxide solution dropwise to the extract while stirring, adjust the solution pH to 7-8, the temperature is 40-50 ° C, react for 1-3 h, cool, and centrifuge to separate the precipitate to obtain drug I;

[0016] S2, after mixing ephedra and asarum, crush the powder through 80-100 mesh sieve, load it into an extraction kettle, introduce supercritical carbon dioxide fluid, control the extraction pressure to 10-30 MPa, the temperature to 35-50 ° C, the extraction time to 1-3 h, obtain the extract separation, collect the extract, slowly add 0.1-0.5 mol / 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 1-2 h, cool, centrifuge and precipitate to obtain drug II;

[0017] S3, remove impurities from perilla seed, apricot kernel, aster, ginkgo, ophiopogon flower, and mulberry bark, wash and dry them, grind them into coarse powder, pass them 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, fully infiltrate the medicinal materials, heat to 80-100°C and perform ultrasonic extraction for 30-60min. After the extraction, filter and remove the medicinal residues, collect the extract, concentrate, add a sugar donor material, the mass volume ratio of the sugar donor material to the extract is 1-10:1, and the sugar donor material is glucose and galactosidase in a mass ratio of 1:1-3. The reaction is carried out at pH 5-7 and a temperature of 30-40°C for 12-24h. After the reaction is completed, purify to obtain drug III;

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

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

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

[0021] Furthermore, the cough and asthma relieving compound medicine for aerosol treatment of the respiratory system 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 contains 15 Chinese medicinal materials, including ginkgo, ephedra, and ophiopogon japonicus, each of which cooperates with each other in terms of nature, flavor, meridians, and main functions. In the prescription of the present invention, ephedra promotes lung function and relieves asthma, while ginkgo astringes the lungs and relieves asthma. The two, one promoting and one astringing, jointly regulate lung qi; ophiopogon japonicus nourishes yin and moistens the lungs, while mulberry bark purges the lungs and relieves asthma, improving lung function from both the perspectives of nourishing yin and purging heat; perilla seed and apricot kernel descend qi, relieve cough and asthma, and liquorice harmonizes the various herbs, making the entire formula synergistic in its efficacy, playing a comprehensive therapeutic role for cough and asthma symptoms caused by respiratory diseases, with a more comprehensive and significant therapeutic effect than a single drug. The addition of composite bacteria, an osmotic pressure regulator, and a cosolvent further enhances the performance of the medicine. The Cordyceps sinensis, Dictamnus dasyphylla and Olea europaea 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 adapt it to the human physiological environment and reduce irritation to the respiratory tract; the cosolvent improves the solubility of the drug, ensuring that the drug can be evenly dispersed during the atomization process, thereby improving the stability of the drug and the atomization effect.

[0025] This invention screens ingredients with antitussive and antiasthmatic activity from traditional Chinese medicines and utilizes modern separation, purification, and identification techniques to improve their purity and activity. By modifying the ingredients into salts and introducing a sugar donor, the drug's targeting is enhanced, making it easier to bind to target sites in respiratory tissue. This also regulates the drug's release rate, prolongs its duration of action, and promotes its absorption and transport, enabling it to more precisely target lesions and improving therapeutic efficacy. DETAILED DESCRIPTION

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

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

[0028] Unless otherwise specified, the materials, reagents, etc. used in the examples 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 "Dictionary of Chinese Medicine".

[0030] Ginkgo: Nature and flavor: 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: warm in nature, pungent and slightly bitter in taste.

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

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

[0035] Functions and indications: Nourishes yin and produces body fluid, moistens the lungs and clears the heart, moistens the intestines and promotes bowel movements, and clears away heat and detoxifies. It is used to treat dry coughs due to lung dryness, coughs caused by yin deficiency, thirst due to loss of body fluid, restlessness and insomnia, and constipation due to dry intestines.

[0036] Morus alba bark: Nature and flavor: 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 lung heat cough, edema, gonorrhea, and cough and asthma caused by stagnation of lung qi.

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

[0039] Functions and indications: It can lower 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, Qi reversal, cough and asthma, dry intestines and constipation.

[0040] Almond: Nature and flavor: 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 cough, asthma, dry intestines and constipation.

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

[0043] Functions and indications: Tonifies the middle and replenishes Qi, clears away heat and toxins, moistens the lungs and eliminates phlegm, moderates the effects of the drug, and relieves pain. It is used to treat spleen and stomach deficiency, Qi and blood deficiency, 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, thick yellow phlegm, and asthma.

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

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

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

[0049] Functions and indications: Dispels wind and cold, relieves pain, warms the lungs and eliminates phlegm. Used to treat colds, headaches, toothaches, nasal congestion and other symptoms.

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

[0051] Functions and indications: Clears away heat and calms wind, dredges meridians, relieves asthma, and promotes urination. Used to treat symptoms such as high fever convulsions, epilepsy, hemiplegia, and asthma.

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

[0053] Functions and indications: It clears the lungs and eliminates phlegm, relieves cough and discharges pus. It is used to treat cough with phlegm, sore throat, lung abscess and other symptoms.

[0054] Belamcanda Root: Nature and flavor: bitter, cold in nature, enters the lung meridian.

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

[0056] Aster: Nature and flavor and meridians entered: spicy and bitter, 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 cough, asthma, and excessive phlegm.

[0058] Huajuhong: Nature and flavor: spicy 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 aerosol 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 flowers, 10 parts of mulberry bark, 8 parts of perilla seeds, 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 composite bacteria, 1 part of osmotic pressure regulator, and 3 parts of solvent.

[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 cosolvent is selected from 1,2-propylene glycol with a concentration of 3 v / v%. Example 2

[0064] A cough and asthma relieving compound medicine for aerosol 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 flowers, 15 parts of mulberry bark, 12 parts of perilla seeds, 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 vine, 12 parts of aster, 10 parts of tangerine peel, 8 parts of composite bacteria, 3 parts of an osmotic pressure regulator, and 10 parts of a 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 cosolvent is selected from polyethylene glycol with a concentration of 3 w / v%. Example 3

[0068] A cough and asthma relieving compound medicine for aerosol 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 flowers, 12 parts of mulberry bark, 10 parts of perilla seeds, 11 parts of apricot kernel, 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 an osmotic pressure regulator, and 7 parts of a 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, Glycyrrhiza uralensis, and Citrus aurantium respectively, wash and dry them, grind 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 for 2 hours, heat to 75°C and reflux for 3 hours, separate the extract from the residue, repeat the extraction 3 times, mix the extracts, concentrate at 50°C, add 0.3 mol / L sodium hydroxide solution dropwise to the extract while stirring, adjust the solution pH to 7.5, the temperature to 45°C, react for 2 hours, cool, and centrifuge to separate the precipitate to obtain Drug I;

[0074] S2, after mixing ephedra and asarum, crush the powder through a 90-mesh sieve, load it 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, obtain the extract separation, collect the extract, slowly add 0.3 mol / 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 2 h, cool, centrifuge and precipitate to obtain drug II;

[0075] S3, remove impurities from perilla seeds, apricot kernels, aster, ginkgo, ophiopogon japonicus, and 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 and perform ultrasonic extraction for 50 minutes, the ultrasonic frequency is 40kHz, the ultrasonic power is 200W, after the extraction is completed, filter and remove the medicinal residues, 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, temperature 35°C for 18 hours, and purify after the reaction to obtain drug III;

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

[0077] S5. Evenly mix the above-mentioned drugs I, II, III and IV, add the composite bacteria, osmotic pressure regulator and cosolvent for homogenization, control the speed to 12000 rpm, the temperature to 30 ° C, and the 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 a cough and antiasthma compound drug. Comparative Example 1

[0078] This comparative example differs from Example 3 in that the antitussive and antiasthmatic compound medicine does not contain Aster, Platycodon, or Belamcanda. Specifically, the following raw materials are included in parts by weight: 13 parts of Ginkgo, 8 parts of Ephedra, 15 parts of Ophiopogon japonicus, 12 parts of Morus alba 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 Pheretima, 8 parts of Citrus aurantium, 5 parts of composite bacteria, 2 parts of osmotic pressure regulator, and 7 parts of solvent. Comparative Example 2

[0079] This comparative example differs from Example 3 in that the antitussive and antiasthmatic compound medicine does not contain ephedra, apricot kernel, or perilla seed. Specifically, the following raw materials are included in parts by weight: 13 parts of ginkgo, 15 parts of lily of the valley, 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. Comparative Example 3

[0080] The difference between this comparative example and Example 3 is that the antitussive and antiasthmatic compound medicine does not contain composite bacteria. Comparative Example 4

[0081] The difference between this comparative example and Example 3 is that in the preparation method of the cough-relieving and asthma-relieving compound medicine, no sodium hydroxide solution and dilute hydrochloric acid solution are added dropwise in steps S1 and S2.

[0082] Specifically:

[0083] S1. Remove impurities from Pinellia ternata, Belamcanda chinensis, Scutellaria baicalensis, Glycyrrhiza uralensis, and Citrus aurantium respectively, wash and dry them, grind them into 50 mesh, soak them in 50% ethanol solution, with the mass volume ratio of powder to ethanol solution being 1:8 (g / mL), soak them for 2 h, heat them to 75°C and reflux them for 3 h, separate the extract from the medicinal residue, repeat the extraction three times, mix the extracts, concentrate them at 50°C, cool them, and separate the precipitate by centrifugation to obtain Drug I;

[0084] S2. Mix ephedra and asarum and grind them into powder through a 90-mesh sieve. Pour the powder into an extraction kettle and 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 and collect the extract. Cool the extract and centrifuge the precipitate to obtain drug II. Comparative Example 5

[0085] The difference between this comparative example and Example 3 is that no sugar donor material is added in step S3 of the preparation method of the antitussive and antiasthmatic compound medicine.

[0086] Specifically:

[0087] S3. Remove impurities from perilla seeds, apricot kernel, aster, ginkgo, ophiopogon flower, and mulberry bark, wash and dry them, grind them into coarse powder, pass them 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 and perform ultrasonic extraction for 50 minutes at an ultrasonic frequency of 40 kHz and an ultrasonic power of 200 W. After the extraction, filter out the medicinal residues, collect the extract, concentrate, and purify to obtain drug III.

[0088] Test Example 1-In vitro cell test

[0089] 1. Drug Metabolizing Enzyme Activity Detection

[0090] 1. Cell Culture: Human lung epithelial cell line (A549) was inoculated in high-glucose DMEM medium supplemented with 10% fetal bovine serum and 1% double-streptomycin (penicillin-streptomycin mixture) and cultured in a cell culture incubator at 37°C and 5% CO2. When the cells reached the logarithmic growth phase, they were digested with 0.25% trypsin-EDTA solution and subcultured at a ratio of 1:3-1:4 to ensure that the cells were in good condition.

[0091] 2. Drug treatment: A549 cells were cultured at 5×10 4 -1×10 5 Cells were seeded at a density of 100 cells / mL in a 24-well plate. After the cells adhered and grew for 24 hours, the culture medium containing the drugs of Examples 1-3 and Comparative Examples 1-4 was added. A control group was also set up, with an equal volume of medium containing no drug added. The culture plate was returned to the cell culture incubator and incubated for 24 hours.

[0092] 3. RNA Extraction and qRT-PCR: After incubation, discard the culture medium and gently wash the cells 1-3 times with PBS buffer. Extract total RNA according to the RNA extraction kit instructions. Perform reverse transcription according to the reverse transcription kit instructions to synthesize cDNA. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to measure gene and protein expression levels of enzymes involved in drug metabolism (cytochrome P450 enzymes).

[0093] 4. Metabolic enzyme activity determination: Use enzyme activity detection kits to determine the activity changes of these metabolic enzymes.

[0094] 5. Test results

[0095]

[0096] From the above results, it can be seen that the relative expression levels of CYP450 genes in the embodiment group are significantly higher than those 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 levels of genes, the relative expression levels of CYP450 proteins in the embodiment group are significantly higher than those in the control group and the comparative example group. This shows that the embodiments not only have 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 level of CYP450 proteins. The metabolic enzyme activity of the embodiment group is significantly higher than that of the control group and the comparative example group, which echoes 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.

[0097] 2. Drug Transporter Research Experiments

[0098] 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 Cells are seeded at a density of 100 cells / mL into a Transwell chamber (upper chamber) and an appropriate amount of culture medium is added to the lower chamber. After seeding, the Transwell chamber is placed in an incubator and cultured. Once the cells form a dense monolayer on the Transwell chamber (3-5 days), the integrity of the cell monolayer is confirmed by measuring the transepithelial electrical resistance (TEER).

[0099] 2. Drug transport experiment: Dissolve the above drugs in serum-free culture medium to 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. Simultaneously, set up a control group, which is treated with serum-free culture medium without the drug. Return the Transwell chamber to the incubator and incubate for 6 hours. After the incubation period, collect the solutions from the upper and lower chambers, and determine the drug concentration in the solutions using HPLC or other methods. 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 drug transport in the cell model.

[0100] 3. Experimental results

[0101]

[0102] The above results show that the uptake rate of the Example group was significantly higher than that of the Control and Comparative Example groups. This indicates that the Example group is more conducive to drug uptake by cells, thereby increasing intracellular drug concentration and providing a better foundation for drug efficacy. Corresponding to the uptake rate results, the efflux rate of the Example group was significantly lower than that of the Control and Comparative Example groups. The lower efflux rate means that the drug is retained in the cell for a longer time, can continue to work, and further enhances the drug's efficacy.

[0103] 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.

[0104] Compared with Comparative Example 4, steps S1 and S2 are respectively added with sodium hydroxide solution and dilute hydrochloric acid solution to the medicinal material, and the drug components therein are converted into corresponding salts, which contribute to the dispersion and dissolution of subsequent drugs in the solution, and ensure that the drug can be evenly dispersed in the atomized liquid during atomization treatment of the respiratory system, and can be more effectively inhaled and absorbed. This salt-forming reaction can cause the drug molecules to carry a specific charge, thereby changing the distribution characteristics of the drug in the body. In the respiratory system, drug salts with a specific charge may be more likely to bind to receptors or targets with opposite charges on the surface of respiratory tissue, 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.

[0105] Compared to Comparative Example 5, the introduction of a sugar donor into the medicinal material through a glycosylation reaction allows the drug components to combine with the sugar donor to form a new chemical structure. This reduces the exposure of unstable groups in the drug molecules, lowering the drug's chemical activity and thus improving the drug's stability. It also increases the polarity of the drug solution, thereby improving the solubility of some components in the extract. The glycosylated drug can specifically bind to glycoprotein receptors on the surface of respiratory epithelial cells, promoting drug absorption and transport, enabling the drug to act more precisely at the site of lesions and enhancing therapeutic efficacy.

[0106] Test Example 2-Clinical Trial

[0107] 1. Subject Selection

[0108] Inclusion criteria: patients aged 18-65 years with respiratory diseases such as bronchial asthma and chronic bronchitis who have mild to moderate cough and wheezing symptoms; voluntarily participate in this study and sign the informed consent.

[0109] 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 breastfeeding women; patients who have participated in other clinical trials recently (within 3 months).

[0110] 2. Test Drugs and Control Drugs

[0111] Test 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.

[0112] 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.

[0113] 3. Test Indicators and Evaluation Tools

[0114] 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 being no symptom and 10 being extremely severe.

[0115] Pulmonary function test: A spirometer was used to measure the subjects' forced expiratory volume in one second (FEV1), forced vital capacity (FVC), peak expiratory flow (PEF) and other indicators.

[0116] Inflammatory index detection: Blood samples are collected from subjects to detect the levels of inflammatory factors: interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α); sputum samples are collected to detect inflammatory cell counts, etc.

[0117] Safety indicators: Record the adverse reactions of the subjects during the trial, including local irritation symptoms (such as respiratory tract irritation, increased cough, etc.), systemic adverse reactions (such as allergic reactions, dizziness, nausea, etc.), and conduct blood routine, blood biochemistry, urine routine and other tests to evaluate the safety impact of the drug on the body.

[0118] IV. Clinical Trial Design

[0119] This study adopted a randomized, double-blind, positive drug parallel controlled research design.

[0120] 1. Grouping: The recruited subjects were randomly divided into 3 groups, with 50 subjects in each group.

[0121] Experimental group: The cough and asthma relieving compound medicine prepared in Example 3 was used for aerosol inhalation treatment.

[0122] Positive control group: A positive control drug commonly used in clinical practice was used for nebulized inhalation treatment.

[0123] 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.

[0124] 2. Dosage regimen

[0125] The experimental group and the positive control group: The drug was administered by aerosol inhalation twice a day, with each dose determined according to the actual clinical situation, and the treatment lasted for 4 weeks.

[0126] Placebo group: The frequency and method of administration are the same as those of the experimental group.

[0127] 5. Clinical Testing Process

[0128] 1. Screening period: After the subject signs the informed consent form, a comprehensive physical examination, medical history inquiry, pulmonary function test, laboratory test, etc. will be conducted to determine whether the subject meets the inclusion criteria and has no exclusion criteria, and baseline data will be recorded.

[0129] 2. Treatment period:

[0130] Subjects received corresponding medication or placebo nebulized inhalation treatment according to their group, and were followed up weekly. Follow-up included symptom assessment (VAS score), lung function test, and inquiry about adverse reactions.

[0131] During the treatment, subjects need to record their symptom changes, medication use and any adverse reactions, such as the frequency and severity of coughing and wheezing attacks.

[0132] 3. Observation period: After the end of 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.

[0133] 6. Test Results

[0134] 1. Symptom assessment results

[0135]

[0136] Note: *P<0.05, the difference is statistically significant compared with before treatment. #P<0.05, the difference is statistically significant compared with the control group.

[0137] The above data shows:

[0138] 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. There was a significant difference compared with before treatment (P<0.05). The difference was also significant compared with the control group (P<0.05), indicating that the cough and asthma compound drug can effectively and continuously relieve patients' symptoms.

[0139] 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.

[0140] The VAS score of the placebo group did not decrease significantly during the entire 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 the test drug and the control drug in alleviating symptoms.

[0141] 2. Pulmonary function test results

[0142]

[0143] Note: *P<0.05, the difference is statistically significant compared with before treatment. #P<0.05, the difference is statistically significant compared with the control group.

[0144] The above data shows that:

[0145] 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 cough and antiasthma compound drug is effective in improving patients' lung function.

[0146] The control group also showed some improvement after treatment, but the effect was relatively weak compared with the experimental group.

[0147] There was no significant change in various indicators in the placebo group before and after treatment, indicating that the lung function of this group of patients was not significantly improved due to the use of placebo, further highlighting the positive effects of experimental drugs and control drugs on lung function.

[0148] 3. Inflammatory index test results

[0149]

[0150] Note: *P<0.05, the difference is statistically significant compared with before treatment. #P<0.05, the difference is statistically significant compared with the control group.

[0151] The above data show that:

[0152] 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.

[0153] The levels of IL-6 and TNF-α in the control group also decreased after treatment, but the degree of reduction in inflammatory indicators was smaller than that in the experimental group.

[0154] There was basically no significant change in IL-6 and TNF-α levels 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.

[0155] 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 principles of the present invention should be included in the scope of protection of the present invention.

Claims

1. A cough and asthma relieving compound medicine for aerosol treatment of the respiratory system, characterized by: The invention is prepared from the following raw materials in parts by weight: 10-15 parts of ginkgo, 6-10 parts of ephedra, 12-18 parts of ophiopogon flower, 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, 6-10 parts of pinellia, 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, 6-10 parts of tangerine peel, 2-8 parts of composite bacteria, 1-3 parts of osmotic pressure regulator and 3-10 parts of solubility aid; the composite bacteria are cordyceps sinensis, bamboo fungus and olive in a mass ratio of (8-15):(1-3):(4-8).

2. The cough-relieving and asthma-relieving compound medicine for aerosol treatment of the respiratory system according to claim 1, characterized in that: The invention is prepared from the following raw materials in parts by weight: 13 parts of ginkgo, 8 parts of ephedra, 15 parts of ophiopogon flowers, 12 parts of mulberry bark, 10 parts of perilla seeds, 11 parts of apricot kernel, 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, and 8 parts of tangerine peel.

3. The cough-relieving and asthma-relieving compound medicine for aerosol treatment of the respiratory system according to claim 1, characterized in that: The osmotic pressure regulator is glucose and glycerol in a mass ratio of 3-5:

10.

4. The cough-relieving and asthma-relieving compound medicine for aerosol treatment of the respiratory system according to claim 1, characterized in that: The cosolvent 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.

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

6. The method for preparing a cough-relieving and asthma-relieving compound medicine for aerosol treatment of the respiratory system according to claim 5, characterized in that: The ultrasonic frequency in step S3 is 20-60 kHz, and the ultrasonic power is 100-300 W.

7. Use of the antitussive and antiasthmatic compound medicine for aerosol treatment of the respiratory system according to any one of claims 1 to 2 in the preparation of an aerosol inhalation medicine for treating cough and asthma symptoms caused by respiratory diseases.

8. The use according to claim 7, 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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