A composition with cough-relieving efficacy and a preparation method and application thereof

Abstract

The application discloses a composition with cough-relieving efficacy and a preparation method and application thereof, and relates to the technical field of traditional Chinese medicines. The application comprises the following steps: crushing fritillaria, infiltrating with ethanol, obtaining fritillaria infiltration liquid through percolation extraction; decocting gypsum with water, obtaining gypsum decoction liquid through extraction; crushing bitter almonds, pinellia ternata, ginkgo nuts, placing the bitter almonds, pinellia ternata and ginkgo nuts in a bag for decoction, combining the bitter almonds, pinellia ternata and ginkgo nuts with ephedra, earthworms, mulberry bark, hundred-petal grass, licorice, perilla fruit and drupe, adding ethanol, heating and refluxing to obtain mixed extraction liquid 1; decocting and extracting scutellaria baicalensis, obtaining scutellaria baicalensis decoction liquid, and preparing scutellaria baicalensis extract fine powder; decocting and extracting honeysuckle and lonicera japonica with water to obtain mixed extraction liquid 2; mixing and concentrating the above products to obtain a clear paste; mixing the clear paste with the scutellaria baicalensis extract fine powder to obtain the composition with cough-relieving efficacy. Through improvement of an extraction method and a concentration method of a traditional Chinese medicine composition, the obtained extract has higher effective component transfer rate and better effect on treatment of cough.

Description

Technical Field

[0001] This invention relates to the field of traditional Chinese medicine technology, specifically to a composition with antitussive effects, its preparation method, and its application. Background Technology

[0002] Coughing is an important protective reflex that prevents aspiration and clears irritants and excess secretions from the airway. Involuntary coughing is a reflex activated by sensory nerves in the afferent regions of the vagus nerve. After the nociceptors in the airway detect a potential noxious stimulus, they transmit nerve impulses to the nucleus tractus solitarius and the trigeminal nerve in the brainstem, and then through secondary neurons to higher control centers to regulate the cough reflex.

[0003] Cough is a common clinical symptom, with causes including colds, bronchitis, emphysema, and asthma. It is an airway inflammation involving multiple cells and cellular components, and is also an immune-mediated systemic inflammatory disease. An imbalance in the cytokine and inflammatory factor release network plays an important role in the development of acute cough. After the acute symptoms such as fever, nasal congestion, runny nose, sore throat, and cough subside, a persistent, irritating dry cough becomes the main manifestation. Severe cough can affect a patient's normal life and sleep, leading to a decline in their quality of life. Furthermore, due to changes in the airway microenvironment, the congested and edematous mucosa becomes more sensitive to external stimuli. Therefore, when affected by relevant external factors, secondary bacterial infections can occur, worsening the condition.

[0004] Chinese Patent CN102580037A discloses a traditional Chinese medicine composition for treating post-infectious cough due to wind-cold type. This composition comprises active ingredients and medically acceptable excipients. The active ingredients are characterized by being made from the following raw materials: 4-8 parts by weight of processed ephedra, 9-11 parts by weight of coltsfoot flower, 2-3 parts by weight of asarum, 9-11 parts by weight of angelica root, 8-10 parts by weight of apricot kernel, 14-16 parts by weight of citronella root, 9-11 parts by weight of processed pinellia, 9-11 parts by weight of schizonepeta spike, 9-11 parts by weight of fresh ginger, 4-6 parts by weight of schisandra fruit, and 4-6 parts by weight of raw licorice root. This traditional Chinese medicine composition has the effects of dispelling wind and cold, clearing the lungs, resolving phlegm, and relieving cough, and can improve the symptoms of patients with post-infectious cough due to wind-cold type.

[0005] Chinese Patent CN108653550A discloses a cough-relieving drug containing ephedra and scutellaria, along with its preparation and detection methods. This cough-relieving drug is made from the following medicinal ingredients in parts by weight: 110-125g of honey-processed ephedra, 110-125g of mulberry bark, 225-240g of honeysuckle, 110-125g of scutellaria, 205-220g of centella asiatica, 205-220g of gypsum, 110-125g of fritillaria thunbergii, 110-125g of bitter almond, 110-125g of perilla seed, 110-125g of coltsfoot flower, 110-125g of lepidium seed, 205-220g of earthworm, 75-90g of ginger-processed pinellia, 110-125g of stir-fried ginkgo kernel, and 75-90g of prepared licorice root. This invention provides a method for simultaneously determining the content of active ingredients in a Maqin cough syrup using high-performance liquid chromatography. It also provides a novel application of Maqin cough syrup in the preparation of medications for treating chronic obstructive pulmonary disease. However, the extract obtained by the extraction method described in this patent still cannot guarantee the full utilization of the active ingredients.

[0006] Chinese patent CN106620498A discloses a traditional Chinese medicine composition for treating cough after a cold, which is composed of the following raw materials in parts by weight: Clematis chinensis 6.20g, Curcuma longa 6.20g, Acorus tatarinowii 3.10g, and Mentha haplocalyx 3.6g. Preparation: Clematis chinensis, peppermint, Acorus tatarinowii, and Curcuma longa are mixed with 6-12 times their total weight of water and steam distilled for 5-9 hours to extract volatile oil. The volatile oil is collected, solubilized with Tween 80 or dissolved in ethanol, and set aside. The steam distillation extract is filtered to obtain an oil extract mother liquor and a residue. The residue is decocted 1-3 times with 6-10 times its weight of water, 1-3 times each time for 1-3 hours. The decoctions and oil extract mother liquor are combined, and the supernatant is concentrated. 75-95% ethanol is added to achieve an alcohol content of 65-85%. After refrigeration and settling, the mixture is filtered, and the ethanol is recovered under reduced pressure until no alcohol odor remains. The solubilized volatile oil and conventional pharmaceutical excipients are added, and a suitable dosage form is prepared using conventional formulation methods in traditional Chinese medicine pharmaceutics. This invention also provides the application of this traditional Chinese medicine composition in the preparation of drugs for treating infectious coughs and various types of chronic coughs.

[0007] Currently, there are many traditional Chinese medicine formulas for treating coughs, but there is still a lack of technical solutions that break through the technological barriers by extracting effective ingredients. Summary of the Invention

[0008] In view of this, the purpose of the present invention is to provide a composition with antitussive effect, its preparation method and application. By improving the extraction and concentration methods of traditional Chinese medicine formulas, the obtained extract has a higher transfer rate and has a better effect on the treatment of cough.

[0009] To achieve the above-mentioned objectives, the technical solution of the present invention is as follows:

[0010] On one hand, the present invention provides a method for preparing a composition with antitussive effects, comprising the following steps:

[0011] (1) Fritillaria is crushed to obtain fine powder, soaked in ethanol, and extracted by percolation to obtain fritillaria percolate;

[0012] (2) Boil gypsum in water 1-3 times, combine the decoctions, filter, and obtain gypsum decoction;

[0013] (3) Powder bitter almonds, pinellia, and ginkgo kernels, place them in a decoction bag, and combine them with ephedra, earthworm, mulberry bark, centella asiatica, licorice, perilla seed, and lepidium seed. Add ethanol and heat under reflux to extract 2-4 times. Combine the extracts to obtain mixed extract 1.

[0014] (4) Scutellaria baicalensis is decocted and extracted 2-5 times. The decoction is filtered and the filtrates are combined to obtain Scutellaria baicalensis decoction. The decoction is concentrated, the pH value is adjusted to 1.5-2.5, and it is allowed to stand for 1-5 hours. It is then centrifuged to obtain crude extract. The crude extract is washed until the pH value is 3.5-4.5, dried, and pulverized to obtain fine powder of Scutellaria baicalensis extract.

[0015] (5) Add water to honeysuckle and coltsfoot flower and decoct 1-3 times to extract, combine the decoctions, filter and get mixed extract 2;

[0016] (6) Mix the fritillaria percolate, gypsum decoction, mixed extract 1 and mixed extract 2, concentrate them, and obtain clear extract;

[0017] (7) Mix the clear paste obtained in step (6) with the fine powder of Scutellaria baicalensis extract obtained in step (4) to obtain the composition with the cough-relieving effect.

[0018] Preferably, in the preparation method, the raw material formula is as follows: 110-125 parts by weight of honey-processed ephedra, 110-125 parts by weight of mulberry bark, 225-240 parts by weight of honeysuckle, 110-125 parts by weight of scutellaria baicalensis, 205-220 parts by weight of centella asiatica, 205-220 parts by weight of gypsum, 110-125 parts by weight of fritillaria thunbergii, 110-125 parts by weight of bitter almond, 110-125 parts by weight of perilla seed, 110-125 parts by weight of coltsfoot flower, 110-125 parts by weight of lepidium seed, 205-220 parts by weight of earthworm, 75-90 parts by weight of ginger-processed pinellia, 110-125 parts by weight of stir-fried ginkgo kernel, and 75-90 parts by weight of prepared licorice root.

[0019] Further preferred ingredients include: 117 parts by weight of honey-processed ephedra, 117 parts by weight of mulberry bark, 233 parts by weight of honeysuckle, 117 parts by weight of scutellaria, 212 parts by weight of centella asiatica, 212 parts by weight of gypsum, 117 parts by weight of fritillaria thunbergii, 117 parts by weight of bitter almond, 117 parts by weight of perilla seed, 117 parts by weight of coltsfoot flower, 117 parts by weight of lepidium seed, 212 parts by weight of earthworm, 83 parts by weight of ginger-processed pinellia, 117 parts by weight of stir-fried ginkgo kernel, and 83 parts by weight of prepared licorice root.

[0020] Preferably, in step (1), the ethanol refers to an aqueous solution of ethanol, wherein the volume concentration of ethanol is 60-80%, more preferably 70%.

[0021] Preferably, in step (1), the mass of the ethanol is 5-15 times the mass of the fritillaria bulb, more preferably 8-10 times, and even more preferably 9 times.

[0022] Preferably, in step (1), the soaking time is 6-12 hours, more preferably 8-10 hours, and even more preferably 9 hours.

[0023] Preferably, in step (1), the percolation extraction rate is 1-5 mL / kg / min, more preferably 3 mL / kg / min.

[0024] Preferably, in step (2), the decoction extraction is performed twice, with 4-6 times the weight of water added each time, and the decoction extraction time is 0.5-1h each time; more preferably, 5 times the weight of water is added each time, and the decoction extraction time is 50min each time.

[0025] Preferably, in step (3), the pulverization is pulverized to below 80 mesh.

[0026] Preferably, in step (3), the ethanol refers to an aqueous solution of ethanol, wherein the volume concentration of ethanol is 35-45%, more preferably 40%.

[0027] Preferably, in step (3), the heating and reflux extraction is performed three times. More preferably, 6-10 times the amount of ethanol is added for the first extraction, and 4-8 times the amount of ethanol is added for the second and third extractions, with each extraction lasting 0.5-1.5 hours. Most preferably, 8 times the amount of ethanol is added for the first extraction, and 6 times the amount of ethanol is added for the second and third extractions, with each extraction lasting 1 hour.

[0028] Preferably, in step (4), the concentration is to concentrate to a relative density of 1.10-1.20.

[0029] Preferably, in step (4), the drying process involves drying until the moisture content is no higher than 5.0%.

[0030] Preferably, step (4) specifically involves: extracting Scutellaria baicalensis by decoction three times, adding 8 times the amount of ethanol for the first time, and adding 6 times the amount of ethanol for the second and third times, extracting for 1 hour each time, filtering the decoction, combining the filtrates to obtain Scutellaria baicalensis decoction; concentrating the Scutellaria baicalensis decoction, adjusting the pH value to 2.0, letting it stand for 3 hours, centrifuging to obtain crude extract, washing the crude extract until the pH value reaches 4.0, drying, pulverizing to obtain fine powder of Scutellaria baicalensis extract.

[0031] Preferably, in step (5), the decoction is performed twice; more preferably, the first time 15-20 times the amount of water is added and the decoction is performed for 15-25 minutes; the second time 8-12 times the amount of water is added and the decoction is performed for 10-20 minutes. Most preferably, the first time 15 times the amount of water is added and the decoction is performed for 20 minutes; the second time 10 times the amount of water is added and the decoction is performed for 15 minutes.

[0032] Preferably, in step (6), the concentration is a double-effect concentration.

[0033] More preferably, the conditions for the double-effect concentration are: steam pressure: 0.1~0.2MPa; first-effect vacuum degree: -0.05~-0.1MPa, first-effect concentration temperature: 60~80℃; second-effect vacuum degree: -0.05~-0.1MPa, second-effect concentration temperature: 50~70℃.

[0034] Preferably, in step (6), the concentration is to concentrate to a relative density of 1.15-1.25 (50-60℃).

[0035] Secondly, the present invention provides a composition with antitussive effects prepared by the above preparation method.

[0036] Thirdly, the present invention provides the use of the above-mentioned composition with antitussive effect in the preparation of antitussive drugs.

[0037] Preferably, the cough remedy is for clearing the lungs and resolving phlegm, relieving cough and asthma. It is used for acute bronchitis and acute exacerbations of chronic bronchitis belonging to the syndrome of phlegm-heat stagnation in the lungs, with symptoms such as cough, wheezing, yellow or thick phlegm, fever, dry mouth, yellow and greasy tongue coating, and red tongue.

[0038] Fourthly, the present invention provides a medicine whose active ingredients include the above-mentioned traditional Chinese medicine composition.

[0039] The drug can be prepared into dosage forms such as granules, pills, capsules, mixtures, powders, tablets, and syrups. For different dosage forms, a suitable drug carrier in this field can be selected.

[0040] The drug carrier used can be solid, liquid, or gaseous. Examples of solid carriers include dextrin, maltodextrin, sucrose, lactose, starch, kaolin, talc, gelatin, agar, pectin, gum arabic, magnesium stearate, and stearic acid. Examples of liquid carriers include syrup, peanut oil, olive oil, and water. Examples of gaseous carriers include carbon dioxide and nitrogen.

[0041] In preparing compositions for oral dosage forms, any convenient pharmaceutical medium can be used. For example, water, ethanol, oils, alcohols, flavoring agents, preservatives, coloring agents, etc., can be used to form oral liquid dosage forms, such as suspensions and solutions; while carriers, such as dextrin, maltodextrin, starch, sugars, microcrystalline cellulose, diluents, granulators, emulsifiers, lubricants, binders, and disintegrants, can be used to form oral solid dosage forms, such as granules, powders, capsules, and tablets. Due to their ease of administration, granules, tablets, and capsules are preferred oral dosage units using solid pharmaceutical carriers. Tablets can be coated using standard aqueous or non-aqueous techniques.

[0042] Tablets containing the traditional Chinese medicine composition of the present invention can be prepared by compression or molding, and one or more excipients or adjuvants may be used. The active ingredient can be compressed in a free-flowing form (e.g., powder or granules) in a suitable machine, optionally mixed with binders, lubricants, inert diluents, surfactants, or dispersants. Molded tablets can be molded in a suitable machine, i.e., a powdery mixture moistened with an inert liquid diluent, each tablet preferably containing about 0.05 mg to about 5 g of active ingredient, and each sachet or capsule preferably containing about 0.05 mg to about 5 g of active ingredient. For example, a formulation intended for oral administration to humans may contain about 0.5 mg to about 5 g of active drug, mixed with a suitable and convenient carrier material, which may comprise about 5% to 95% of the total composition. Unit dosage forms typically contain about 1 mg to about 2 g of active ingredient, typically in doses of 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg, or 1000 mg.

[0043] The pharmaceutical compositions of this invention suitable for parenteral administration can be prepared as aqueous solutions or suspensions of the active compound and may include suitable surfactants, such as hydroxypropyl cellulose. Dispersions can also be prepared in mixtures of glycerol, liquid polyethylene glycol, and their oils. Furthermore, preservatives may be added to prevent harmful microbial growth.

[0044] The medicaments of the present invention can be in forms suitable for topical use, such as aerosols, creams, ointments, lotions, powders, or the like. Furthermore, the compositions can be in suitable forms for transdermal drug delivery devices. These formulations can be prepared using the traditional Chinese medicine compositions of the present invention through conventional processing methods. For example, a cream or ointment with a desired consistency can be prepared by mixing a hydrophilic material and water, and about 5 wt% to about 10 wt% of the compound.

[0045] The medicament of the present invention can be in a form suitable for rectal administration, wherein the carrier is solid. It is preferable to formulate the mixture into a single-dose suppository. Suitable carriers include cocoa butter and other materials commonly used in the art. Suppositories can be made by first forming a mixture containing a softened or melted carrier, followed by cooling and shaping in a mold.

[0046] In addition to the carrier components described above, the pharmaceutical formulations may include (if applicable) one or more additional carrier components, such as diluents, buffers, flavoring agents, binders, surfactants, thickeners, lubricants, preservatives (including antioxidants), etc. Furthermore, other excipients may be added, such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, colorants, and flavoring agents, and the components containing the traditional Chinese medicine composition of this invention can also be prepared in powder or concentrated form.

[0047] The beneficial effects of this invention are as follows:

[0048] (1) By optimizing the extraction method, the present invention further obtained an extract with significant antitussive effect.

[0049] (2) By disassembling the formula composition, the present invention can extract different medicinal ingredients separately and achieve efficient extraction of effective components, thereby improving the pharmacological activity of the extract.

[0050] (3) The present invention found that combining different extracts and then concentrating them greatly improves the transfer rate of active ingredients and reduces the loss of active ingredients compared with individual concentration treatment, thereby improving the efficacy. Detailed Implementation

[0051] To make the technical means, creative features, and achieved objectives and effects of this invention easier to understand, the invention is further illustrated below with specific embodiments. However, the following embodiments are only preferred embodiments of this invention and not all embodiments. Other embodiments obtained by those skilled in the art based on the embodiments described herein without creative effort are all within the protection scope of this invention. In the following embodiments, unless otherwise specified, the operating methods used are conventional operating methods, the equipment used is conventional equipment, and the equipment materials used in each embodiment are the same. Unless otherwise specified, all percentages mentioned are mass percentages. In the following embodiments, unless otherwise specified, the concentration method is evaporation concentration.

[0052] In the following embodiments, the medicinal material formulations within the following ranges are all suitable, and the extraction method of the present invention can enhance the efficacy of the herbs: 110-125 parts by weight of honey-processed ephedra, 110-125 parts by weight of mulberry bark, 225-240 parts by weight of honeysuckle, 110-125 parts by weight of scutellaria, 205-220 parts by weight of centella asiatica, 205-220 parts by weight of gypsum, 110-125 parts by weight of fritillaria thunbergii, 110-125 parts by weight of bitter almond, 110-125 parts by weight of perilla seed, 110-125 parts by weight of coltsfoot flower, 110-125 parts by weight of lepidium seed, 205-220 parts by weight of earthworm, 75-90 parts by weight of ginger-processed pinellia, 110-125 parts by weight of stir-fried ginkgo kernel, and 75-90 parts by weight of prepared licorice root.

[0053] In a specific embodiment, the exemplary formula used is as follows: 117 parts by weight of honey-processed ephedra, 117 parts by weight of mulberry bark, 233 parts by weight of honeysuckle, 117 parts by weight of scutellaria, 212 parts by weight of centella asiatica, 212 parts by weight of gypsum, 117 parts by weight of fritillaria thunbergii, 117 parts by weight of bitter almond, 117 parts by weight of perilla seed, 117 parts by weight of coltsfoot flower, 117 parts by weight of lepidium seed, 212 parts by weight of earthworm, 83 parts by weight of ginger-processed pinellia, 117 parts by weight of stir-fried ginkgo kernel, and 83 parts by weight of prepared licorice root.

[0054] Example 1

[0055] A method for preparing a composition with antitussive effects includes the following steps:

[0056] (1) Fritillaria thunbergii was pulverized to below 100 mesh to obtain Fritillaria thunbergii fine powder. It was soaked in 9 times its weight of 70% ethanol for 9 hours and then percolated at a rate of 3 mL / kg / min to obtain Fritillaria thunbergii percolate.

[0057] (2) Add water to gypsum and decoct twice, adding 5 times the weight of water each time. The decoction time is 50 minutes each time. Combine the decoctions, filter, and obtain gypsum decoction.

[0058] (3) Powder bitter almonds, ginger pinellia, and stir-fried ginkgo kernels to below 80 mesh, place them in a decoction bag, and combine them with honey ephedra, earthworm, mulberry bark, centella asiatica, roasted licorice root, perilla seed, and lepidium seed. Add 40% ethanol and heat under reflux to extract three times. Add 8 times the amount of ethanol for the first extraction, and 6 times the amount of ethanol for the second and third extractions. Extract for 1 hour each time, combine the extracts, filter, and obtain mixed extract 1.

[0059] (4) Scutellaria baicalensis was decocted and extracted 3 times. The first time, 8 times the amount of ethanol was added, and the second and third times, 6 times the amount of ethanol was added. Each extraction lasted 1 hour. The decoction was filtered and the filtrates were combined to obtain Scutellaria baicalensis decoction. The decoction was concentrated to a relative density of 1.10-1.20, the pH was adjusted to 2.0, and the mixture was allowed to stand for 3 hours. The mixture was then centrifuged to obtain crude extract. The crude extract was washed until the pH reached 4.0, dried until the moisture content was no more than 5.0%, and pulverized to obtain fine powder of Scutellaria baicalensis extract.

[0060] (5) Add water to honeysuckle and coltsfoot flower and decoct twice. Add 15 times the amount of water for the first time and decoct for 20 minutes. Add 10 times the amount of water for the second time and decoct for 15 minutes. Combine the decoctions, filter and obtain mixed extract 2.

[0061] (6) Mix the fritillaria percolate, gypsum decoction, mixed extract 1 and mixed extract 2, and concentrate them with double effect to obtain clear extract;

[0062] The conditions for double-effect concentration were: steam pressure: 0.1 MPa; first-effect vacuum: -0.05 to -0.1 MPa, first-effect concentration temperature: 70℃; second-effect vacuum: -0.05 to -0.1 MPa, second-effect concentration temperature: 60℃. The final clear extract had a relative density of 1.20 (50-60℃).

[0063] (7) Mix the clear paste obtained in step (6) with the fine powder of Scutellaria baicalensis extract obtained in step (4) to obtain the composition with the cough-relieving effect.

[0064] Example 2

[0065] A method for preparing a composition with antitussive effects includes the following steps:

[0066] (1) Fritillaria thunbergii was pulverized to below 100 mesh to obtain Fritillaria thunbergii fine powder. It was soaked in 60% ethanol at 15 times its weight for 6 hours and then percolated at a rate of 5 mL / kg / min to obtain Fritillaria thunbergii percolate.

[0067] (2) Gypsum was boiled and extracted twice with water, with 6 times the weight of water added each time. The boiling and extraction time was 60 minutes each time. The decoctions were combined, filtered, and gypsum decoction was obtained.

[0068] (3) Grind bitter almonds, ginger pinellia, and stir-fried ginkgo kernels into powder below 80 mesh, place them in a decoction bag, and combine them with honey ephedra, earthworm, mulberry bark, centella asiatica, roasted licorice root, perilla seed, and lepidium seed. Add 35% ethanol and heat under reflux to extract three times. Add 10 times the amount of ethanol for the first extraction, and 8 times the amount of ethanol for the second and third extractions. Extract for 1.5 hours each time. Combine the extracts, filter, and obtain mixed extract 1.

[0069] (4) Scutellaria baicalensis was decocted and extracted 3 times. The first time, 8 times the amount of ethanol was added, and the second and third times, 6 times the amount of ethanol was added. Each extraction lasted 1 hour. The decoction was filtered and the filtrates were combined to obtain Scutellaria baicalensis decoction. The decoction was concentrated to a relative density of 1.10-1.20, the pH was adjusted to 2.0, and the mixture was allowed to stand for 3 hours. The mixture was then centrifuged to obtain crude extract. The crude extract was washed until the pH reached 4.0, dried until the moisture content was no more than 5.0%, and pulverized to obtain fine powder of Scutellaria baicalensis extract.

[0070] (5) Add water to honeysuckle and coltsfoot flower and decoct twice. Add 15 times the amount of water for the first time and decoct for 15 minutes. Add 12 times the amount of water for the second time and decoct for 20 minutes. Combine the decoctions, filter and obtain mixed extract 2.

[0071] (6) Mix the fritillaria percolate, gypsum decoction, mixed extract 1 and mixed extract 2, and concentrate them with double effect to obtain clear extract;

[0072] The conditions for double-effect concentration were: steam pressure: 0.1 MPa; first-effect vacuum: -0.05 to -0.1 MPa, first-effect concentration temperature: 70℃; second-effect vacuum: -0.05 to -0.1 MPa, second-effect concentration temperature: 60℃. The final clear extract had a relative density of 1.25 (50-60℃).

[0073] (7) Mix the clear paste obtained in step (6) with the fine powder of Scutellaria baicalensis extract obtained in step (4) to obtain the composition with the cough-relieving effect.

[0074] Example 3

[0075] A method for preparing a composition with antitussive effects includes the following steps:

[0076] (1) Fritillaria thunbergii was pulverized to below 100 mesh to obtain Fritillaria thunbergii fine powder. It was soaked in 15 times its weight of 80% ethanol for 12 hours and then percolated at a rate of 1 mL / kg / min to obtain Fritillaria thunbergii percolate.

[0077] (2) Gypsum was boiled and extracted twice with water, each time adding 4 times the weight of water, and the extraction time was 30 minutes each time. The decoctions were combined, filtered, and gypsum decoction was obtained.

[0078] (3) Powder bitter almonds, ginger pinellia, and stir-fried ginkgo kernels to below 80 mesh, place them in a decoction bag, and combine them with honey ephedra, earthworm, mulberry bark, centella asiatica, roasted licorice root, perilla seed, and lepidium seed. Add 45% ethanol and heat under reflux to extract three times. Add 6 times the amount of ethanol for the first extraction, and 4 times the amount of ethanol for the second and third extractions. Extract for 0.5 hours each time. Combine the extracts, filter, and obtain mixed extract 1.

[0079] (4) Scutellaria baicalensis was decocted and extracted 3 times. The first time, 8 times the amount of ethanol was added, and the second and third times, 6 times the amount of ethanol was added. Each extraction lasted 1 hour. The decoction was filtered and the filtrates were combined to obtain Scutellaria baicalensis decoction. The decoction was concentrated to a relative density of 1.10-1.20, the pH was adjusted to 2.0, and the mixture was allowed to stand for 3 hours. The mixture was then centrifuged to obtain crude extract. The crude extract was washed until the pH reached 4.0, dried until the moisture content was no more than 5.0%, and pulverized to obtain fine powder of Scutellaria baicalensis extract.

[0080] (5) Add water to honeysuckle and coltsfoot flower and decoct twice. Add 20 times the amount of water for the first time and decoct for 25 minutes. Add 8 times the amount of water for the second time and decoct for 10 minutes. Combine the decoctions, filter and get mixed extract 2.

[0081] (6) Mix the fritillaria percolate, gypsum decoction, mixed extract 1 and mixed extract 2, and concentrate them with double effect to obtain clear extract;

[0082] The conditions for double-effect concentration were: steam pressure: 0.1 MPa; first-effect vacuum: -0.05 to -0.1 MPa, first-effect concentration temperature: 70℃; second-effect vacuum: -0.05 to -0.1 MPa, second-effect concentration temperature: 60℃. The final clear extract had a relative density of 1.20 (50-60℃).

[0083] (7) Mix the clear paste obtained in step (6) with the fine powder of Scutellaria baicalensis extract obtained in step (4) to obtain the composition with the cough-relieving effect.

[0084] Comparative Example 1

[0085] The preparation was carried out according to the steps described in paragraphs 0024-0028 of the specification of Chinese Patent CN108653550A.

[0086] Comparative Example 2

[0087] Unlike Example 1, in step (1), Fritillaria thunbergii was pulverized to obtain fine powder, which was then boiled with 5 times its weight of water to obtain a decoction, which was used to replace the percolate. All other conditions were the same.

[0088] Comparative Example 3

[0089] A method for preparing a composition with antitussive effects includes the following steps:

[0090] (1) Fritillaria thunbergii was pulverized to below 100 mesh to obtain Fritillaria thunbergii fine powder. It was soaked in 9 times its weight of 70% ethanol for 9 hours and then percolated at a rate of 3 mL / kg / min to obtain Fritillaria thunbergii percolate. The percolate was then concentrated to a clear extract with a relative density of 1.3 (80-85℃).

[0091] (2) Add water to gypsum and decoct twice, adding 5 times the weight of water each time. The decoction time is 50 min each time. Combine the decoctions, filter, and concentrate to a clear extract with a relative density of 1.3 (80-85℃).

[0092] (3) Powder bitter almonds, ginger pinellia, and stir-fried ginkgo kernels into powder below 80 mesh, place them in a decoction bag, and combine them with honey ephedra, earthworm, mulberry bark, centella asiatica, roasted licorice, perilla seed, and lepidium seed. Add 40% ethanol and heat under reflux to extract three times. Add 8 times the amount of ethanol for the first extraction, and 6 times the amount of ethanol for the second and third extractions. Extract for 1 hour each time. Combine the extracts, filter, and obtain mixed extract 1. Concentrate to a clear extract 3 with a relative density of 1.3 (80-85℃).

[0093] (4) Scutellaria baicalensis was decocted and extracted 3 times. The first time, 8 times the amount of ethanol was added, and the second and third times, 6 times the amount of ethanol was added. Each extraction lasted 1 hour. The decoction was filtered and the filtrates were combined to obtain Scutellaria baicalensis decoction. The decoction was concentrated to a relative density of 1.10-1.20, the pH was adjusted to 2.0, and the mixture was allowed to stand for 3 hours. The mixture was then centrifuged to obtain crude extract. The crude extract was washed until the pH reached 4.0, dried until the moisture content was no more than 5.0%, and pulverized to obtain fine powder of Scutellaria baicalensis extract.

[0094] (5) Add water to honeysuckle and coltsfoot flower and decoct twice to extract. Add 15 times the amount of water for the first time and decoct for 20 minutes. Add 10 times the amount of water for the second time and decoct for 15 minutes. Combine the decoctions, filter, and obtain mixed extract 2. Concentrate to a clear extract 4 with a relative density of 1.00 to 1.10 (50 to 60°C).

[0095] (6) Mix the fine powder of Qinggao 1, Qinggao 2, Qinggao 3, Qinggao 4 and Scutellaria baicalensis extract to obtain the composition with the antitussive effect.

[0096] Comparative Example 4

[0097] A method for preparing a composition with antitussive effects includes the following steps:

[0098] (1) Fritillaria thunbergii was pulverized to below 100 mesh to obtain Fritillaria thunbergii fine powder. It was soaked in 9 times its weight of 70% ethanol for 9 hours and then percolated at a rate of 3 mL / kg / min to obtain Fritillaria thunbergii percolate.

[0099] (2) Add water to gypsum and decoct twice, adding 5 times the weight of water each time. The decoction time is 50 minutes each time. Combine the decoctions, filter, and obtain gypsum decoction.

[0100] (3) Grind bitter almonds, ginger pinellia, and stir-fried ginkgo kernels into powder below 80 mesh, place them in a decoction bag, and combine them with honey ephedra, honeysuckle, coltsfoot flower, roasted licorice root, perilla seed, and lepidium seed. Add 40% ethanol and heat under reflux to extract three times. Add 8 times the amount of ethanol for the first extraction, and 6 times the amount of ethanol for the second and third extractions. Extract for 1 hour each time, combine the extracts, filter, and obtain mixed extract 1.

[0101] (4) Scutellaria baicalensis was decocted and extracted 3 times. The first time, 8 times the amount of ethanol was added, and the second and third times, 6 times the amount of ethanol was added. Each extraction lasted 1 hour. The decoction was filtered and the filtrates were combined to obtain Scutellaria baicalensis decoction. The decoction was concentrated to a relative density of 1.10-1.20, the pH was adjusted to 2.0, and the mixture was allowed to stand for 3 hours. The mixture was then centrifuged to obtain crude extract. The crude extract was washed until the pH reached 4.0, dried until the moisture content was no more than 5.0%, and pulverized to obtain fine powder of Scutellaria baicalensis extract.

[0102] (5) Add water to earthworm, mulberry bark and centella asiatica to decoct and extract twice. Add 15 times the amount of water for the first time and decoct for 20 minutes. Add 10 times the amount of water for the second time and decoct for 15 minutes. Combine the decoctions, filter and obtain mixed extract 2.

[0103] (6) Mix the fritillaria percolate, gypsum decoction, mixed extract 1 and mixed extract 2, and concentrate them with double effect to obtain clear extract;

[0104] The conditions for double-effect concentration were: steam pressure: 0.1 MPa; first-effect vacuum: -0.05 to -0.1 MPa, first-effect concentration temperature: 70℃; second-effect vacuum: -0.05 to -0.1 MPa, second-effect concentration temperature: 60℃. The final clear extract had a relative density of 1.20 (50-60℃).

[0105] (7) Mix the clear paste obtained in step (6) with the fine powder of Scutellaria baicalensis extract obtained in step (4) to obtain the composition with the cough-relieving effect.

[0106] Comparative Example 5

[0107] Unlike Example 1, in step (6), the sample was concentrated by evaporation to a relative density of 1.20 (50-60°C). All other conditions were the same.

[0108] Result detection

[0109] 1. Determination of the transfer rate of active ingredients

[0110] The total flavonoid content before and after the measurement was determined using the same method, and the total flavonoid transfer rate was calculated. As an example, the total flavonoid content before and after the measurement was determined by spectrophotometry.

[0111] (1) The total flavonoid content (M1) in the fritillaria percolate, gypsum decoction, mixed extract 1, and mixed extract 2 obtained in Examples 1-3 was determined, and the total flavonoid content (M2) in the clear extract obtained in step (6) of Examples 1-3 was determined. The transfer rate was calculated.

[0112] Transfer rate = M2 / M1 × 100%.

[0113] (2) The transfer rate of Comparative Example 1 is the ratio of the total flavonoid content in the extract obtained in step (4) to the total flavonoid content in the filtrate obtained in step (4).

[0114] (3) The method for calculating the transfer rate of Comparative Example 2 is the same as that of Examples 1-3, except that the fritillaria percolate is replaced with fritillaria decoction.

[0115] (4) The total flavonoid content (A1) in the fritillaria percolate, gypsum decoction, mixed extract 1, and mixed extract 2 obtained in Comparative Example 3 was determined, and the total flavonoid content (A2) in the clear extracts 1, 2, 3, and 4 of Comparative Example 3 was determined. The transfer rate was calculated.

[0116] Transfer rate = A2 / A1 × 100%.

[0117] (5) The calculation method for the transfer rate of Comparative Examples 4 and 5 is the same as that of Examples 1-3.

[0118] Test results:

[0119]

[0120]

[0121] The results show that the extraction process of the present invention significantly improves the transfer rate of total flavonoids. In particular, the results of Example 1 and Comparative Example 3 show that extracting each component separately and then mixing and concentrating them helps to maintain the stability of total flavonoids in the mixed extract and reduce the loss of effective components.

[0122] 2. The therapeutic effect of the composition of the present invention on mice with acute bronchitis

[0123] Model establishment: Male Kunming mice (weighing 18-22g) were acclimatized for one week. Then, the experimental group mice were placed in a 100cm×100cm×50cm smoke chamber and treated with a mixture of 20 cigarettes for 30 minutes each day, twice a day, for 2 weeks to obtain the acute bronchitis model mice. The control group was fed normally.

[0124] Experiment and Administration: Two weeks later, the model mice were randomly divided into groups of 10 each. Each group was administered the drug compositions of Examples 1-3 and Comparative Examples 1-5 (dose 1 g / kg) or Jizhi Syrup (Taiji, dose 20 mL / kg) once daily by gavage. The model group and the control group were administered the same volume of physiological saline by gavage. Administration continued for one week. One hour after the last administration, blood was collected from the orbital sinus of each group of mice. The serum was separated by centrifugation at 2000 rpm for 25 min at room temperature, and the levels of IL-6, IL-8, and TNF-α were measured using ELISA. The results are as follows:

[0125] IL-6 (pg / mL) IL-8 (pg / mL) TNF-α (pg / mL) Blank group 82.5±3.47 492.3±9.78 64.2±6.11 Model group 159.1±4.76*** 901.8±11.04*** 122.0±5.79*** Acute Bronchitis Syrup Group 89.9±2.54### 671.8±15.75## 70.5±4.34## Example 1 87.4±6.75### 624.4±13.55## 65.8±4.87### Example 2 90.1±5.88### 640.2±14.41## 71.7±5.10## Example 3 86.1±4.51### 637.8±10.57## 69.0±6.54## Comparative Example 1 101.3±7.20##△△ 723.4±14.33##△△ 84.9±3.13##△△ Comparative Example 2 96.4±3.45##△ 698.3±12.14##△ 80.7±8.32##△ Comparative Example 3 99.5±3.94##△△ 705.6±13.87##△△ 77.1±7.58## Comparative Example 4 114.6±5.36##△△ 750.4±15.51##△△ 91.5±5.08##△△ Comparative Example 5 98.7±2.41##△ 686.6±12.72##△ 81.6±4.33##△

[0126] Note: Compared with the control group, **P < 0.01; ***P < 0.001; Compared with the experimental group, #P < 0.01; ##P < 0.05; ###P < 0.001; Compared with Example 1, Comparative Examples 1-5 △ P<0.01; △△P<0.05; △△△P<0.001.

[0127] The results showed that the compositions of Examples 1-3 and Comparative Examples 1-5 of the present invention could significantly reduce the levels of IL-6, IL-8, and TNF-α in the serum of model mice. Among them, the effects of Examples 1-3 were significantly better than those of Comparative Examples 1-5, and comparable to those of Acute Bronchitis Syrup. In summary, the compositions prepared by the process of the present invention, through process optimization, significantly improve the therapeutic effect on acute bronchitis.

[0128] 2. The antitussive effect of the composition of the present invention

[0129] Model establishment: Male Kunming mice (weighing 18-22g) were acclimatized for one week and randomly divided into groups of 10 mice each. Each group was administered the drug compositions of Examples 1-3 and Comparative Examples 1-5 (dose 1g / kg) once daily by gavage. The control group was administered the same volume of physiological saline by gavage. After 3 consecutive days of administration, 1 hour after the last administration, the mice were placed in an inverted 1L glass beaker containing 100mg of sterile cotton balls (pre-injected with 0.5mL ammonia). The latency time to cough (from the moment the beaker was placed until the first cough) and the number of coughs within 3 minutes were recorded. Coughing was defined as a violent contraction of the mouse's abdominal muscles and opening of its mouth. Results are as follows:

[0130] Cough latency (s) Number of coughs in 3 minutes Blank group 21.24±7.67 62.5±15.44 Example 1 85.77±10.51*** 15.4±9.55*** Example 2 82.52±6.04*** 19.7±10.27*** Example 3 79.15±15.74*** 21.2±15.89*** Comparative Example 1 56.31±8.57**△△ 36.2±18.44**△△ Comparative Example 2 69.42±6.81***△ 27.1±12.17***△ Comparative Example 3 64.68±11.74***△ 29.6±14.78***△ Comparative Example 4 45.09±8.75**△△ 34.8±15.70**△△ Comparative Example 5 59.45±7.63***△△ 31.3±13.15**△

[0131] Note: Compared with the control group, *P<0.05; **P<0.01; ***P<0.001; Comparative Examples 1-5 compared with Example 1, △ P < 0.01; △△ P < 0.05; △△△P < 0.001.

[0132] The results showed that the compositions of Examples 1-3 and Comparative Examples 1-5 of the present invention could significantly prolong the cough latency time and alleviate the frequency of coughing in mice. Examples 1-3 were significantly more effective than Comparative Examples 1-5. These results indicate that the compositions prepared by the process of the present invention have a good therapeutic effect on cough.

[0133] 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 within the protection scope of the present invention.

Claims

1. A method for preparing a composition having an antitussive effect, characterized by, It comprises the following steps: (1) Zhejiang beimu is crushed to obtain fine Zhejiang beimu powder, which is soaked in ethanol and percolation extracted to obtain Zhejiang beimu percolation liquid; (2) Gypsum is decocted with water for 1-3 times, the decoction liquid is combined and filtered to obtain gypsum decoction liquid; (3) Bitter apricot kernel, Jiang Tianxu, fried white nut are crushed and put into a bag, combined with honey Ephedra, earthworm, mulberry bark, Bai Ricao, fried licorice, perilla fruit, and sesame seed, and then added with ethanol to heat and reflux extract 2-4 times, the extract liquid is combined to obtain mixed extract liquid 1; (4) Huangqi is decocted and extracted for 2-5 times, the decoction liquid is filtered, and the filtrate is combined to obtain Huangqi decoction liquid; the Huangqi decoction liquid is concentrated, the pH value is adjusted to 1.5-2.5, and then it is left to stand for 1-5 hours and centrifuged to obtain a crude extract, which is washed until the pH value is 3.5-4.5, dried, crushed to obtain Huangqi extract fine powder; (5) Flos Lonicerae and Flos Farfarae are decocted with water for 1-3 times, the decoction liquid is combined and filtered to obtain mixed extract liquid 2; (6) The Zhejiang beimu percolation liquid, gypsum decoction liquid, mixed extract liquid 1 and mixed extract liquid 2 are mixed and concentrated to obtain clear paste; the concentration is double-effect concentration, and the double-effect concentration conditions are as follows: steam pressure: 0.1-0.2 MPa; one-effect vacuum degree: -0.05--0.1 MPa, one-effect concentration temperature: 60-80℃; two-effect vacuum degree: -0.05--0.1 MPa, two-effect concentration temperature: 50-70℃; the relative density of the clear paste obtained by concentration: 1.15-1.25; (7) The clear paste obtained in step (6) is mixed with the Huangqi extract fine powder obtained in step (4) to obtain the composition with the effect of relieving cough, In the preparation method, the prescription of the traditional Chinese medicine composition is as follows: honey Ephedra 110-125 parts by weight, mulberry bark 110-125 parts by weight, Flos Lonicerae 225-240 parts by weight, Huangqi 110-125 parts by weight, Bai Ricao 205-220 parts by weight, gypsum 205-220 parts by weight, Zhejiang beimu 110-125 parts by weight, bitter apricot kernel 110-125 parts by weight, perilla fruit 110-125 parts by weight, Flos Farfarae 110-125 parts by weight, sesame seed 110-125 parts by weight, earthworm 205-220 parts by weight, Jiang Tianxu 75-90 parts by weight, fried white nut 110-125 parts by weight, and fried licorice 75-90 parts by weight.

2. The production method according to claim 1, characterized by, In step (1), the ethanol refers to an ethanol aqueous solution, and the volume concentration of ethanol is 60-80%; In step (1), the mass of ethanol is 5-15 times the mass of Zhejiang beimu, the soaking time is 6-12 hours, and the percolation extraction speed is 1-5 mL / kg / min; In step (2), the decoction extraction is performed for 2 times, 4-6 times the weight of water is added each time, and each decoction extraction is performed for 0.5-1 hour; In step (3), the ethanol refers to an ethanol aqueous solution, and the volume concentration of ethanol is 35-45%; In step (3), the heat reflux extraction is performed for 3 times, 6-10 times the amount of ethanol is added in the first time, and 4-8 times the amount of ethanol is added in the second and third times, and each extraction is performed for 0.5-1.5 hours.

3. The preparation method according to claim 1, characterized in that, Step (4) is specifically as follows: the Scutellaria is decocted and extracted for 3 times, 8 times of ethanol is added in the first time, 6 times of ethanol is added in the second and third times, and each time is extracted for 1 hour; the decocted liquid is filtered, the filtrates are combined, and a Scutellaria decoction is obtained; the Scutellaria decoction is concentrated, the pH value is adjusted to 2.0, and the mixture is left to stand for 3 hours; the mixture is centrifuged to obtain a crude extract; the crude extract is washed until the pH value is 4.0, dried, and pulverized to obtain a Scutellaria extract powder.

4. The production method according to claim 1, characterized by, In step (5), the number of decocting times is 2.

5. The preparation method according to claim 4, characterized in that, In step (5), the decocting is as follows: 15-20 times of water is added in the first time, and the mixture is decocted for 15-25 minutes; 8-12 times of water is added in the second time, and the mixture is decocted for 10-20 minutes.

6. The composition with the effect of relieving cough prepared by the preparation method in any one of claims 1-5.

7. The use of the composition with the effect of relieving cough in claim 6 in the preparation of a medicine for treating cough.

8. Use according to claim 7, characterized in that, The relieving cough is clearing lung and reducing phlegm, relieving cough and asthma, and is used for acute bronchitis, acute attack of chronic bronchitis, and phlegm-heat obstructing lung syndrome, and the symptoms are as follows: cough, wheezing, yellow or thick phlegm, fever, dry mouth, yellow and greasy fur, red tongue, and the like.

9. A medicament, characterized by comprising a compound of the formula (I) or a pharmaceutically acceptable salt thereof. The effective components include the composition with the effect of relieving cough in claim 6.

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