Composition for relieving cough and eliminating phlegm and preparation method thereof

Abstract

The invention provides a cough-relieving and phlegm-eliminating composition and a preparation method thereof. The cough-relieving and phlegm-eliminating composition is prepared from the following raw materials: anhydrous morphine, anhydrous codeine phosphate, apigenin, liquiritin, isoliquiritin, liquiritigenin, isoliquiritigenin, glycyrrhizic acid, trans-anethole, camphor and sodium benzoate. The composition further comprises a luffa stem extract, an atractylodes lancea rhizome extract and a radix ranunculi ternati bark extract. The cough-relieving and phlegm-eliminating composition provided by the invention has the advantages of few impurities, clear and remarkable drug effect and small side effect. Under the action of the core antitussive drug, three plant extracts of luffa stem, Atractylodes lancea and Ranunculus ternatus Thunb. Are creatively added, so that the phlegm eliminating capacity and the overall antitussive effect of the whole formula are remarkably enhanced. The cough-relieving and phlegm-eliminating composition disclosed by the invention realizes the synergistic interaction of '1 + 1 + 1gt, 3' on the core indexes of inhibiting the cough frequency, prolonging the cough latency period, promoting sputum excretion and the like, and realizes the cough-relieving and phlegm-eliminating effects of treating both symptoms and root causes through the multi-target-point and multi-mechanism synergistic effect.

Description

Technical Field

[0001] This invention relates to the field of feed and its preparation technology, specifically to an antitussive and expectorant composition and its preparation method. Background Technology

[0002] In the existing system of antitussive and expectorant medications, classic compound preparations, represented by compound glycyrrhiza tablets, occupy an important position. Their typical formulation often centers on glycyrrhiza extract powder, opium powder (or containing morphine, codeine, etc.), camphor, anise oil, and benzoates. The design logic of this preparation is mainly based on combining the anti-inflammatory and expectorant effects of glycyrrhizic acid with the central antitussive effects of opioids, supplemented by the local stimulating and mild expectorant effects of camphor and other ingredients, aiming to achieve the dual therapeutic goals of "antitussive" and "expectorant." For a long time, this approach has played a positive role in relieving acute cough symptoms. However, for intractable coughs with thick, sticky phlegm, its expectorant effect is limited, making it difficult to quickly relieve symptoms. Summary of the Invention

[0003] In view of this, the present invention proposes an antitussive and expectorant composition and its preparation method to solve the above problems.

[0004] The technical solution of this invention is implemented as follows:

[0005] An antitussive and expectorant composition comprising the following raw materials by weight: [Material formula C] 17 H 19 NO3, anhydrous morphine 1.08–1.50 mg, molecular formula C 18 H 21 Anhydrous codeine phosphate 0.42–0.60 mg, with the molecular formula C3H3PO4. 26 H 30 O 13 Celery syrup and licorice 1.50–6.0 mg, molecular formula C 21 H 22 O9 contains 1.20–3.90 mg of glycyrrhizin, with the molecular formula C. 21 H 22 O9 isoglycyrrhizin 0.30–2.40 mg, glycyrrhizin with molecular formula C15H12O4 0.30–2.40 mg, and C 15 H 12 O4 contains 0.30–2.40 mg of isoliquiritigenin, with the molecular formula C. 42 H 62 O 16 The glycyrrhizic acid content is 21.9–39.0 mg, and its molecular formula is C2. 10 H 12 O's trans-anisole 4.8–6.0 mg, molecular formula C 10 H 16The content of camphor (O) is 5.4–6.6 mg, and the content of sodium benzoate (C7H5NaO2) is 5.4–6.6 mg.

[0006] Furthermore, the antitussive and expectorant composition also includes 20-30 mg of loofah vine extract, 40-60 mg of Atractylodes lancea rhizome extract, and 30-50 mg of Uncaria rhynchophylla bark extract.

[0007] Furthermore, the loofah vine extract is prepared by the following method: During the vigorous growth period, the main stem and primary lateral branches of the loofah vine are harvested, washed, drained, and then cut into 1-2 cm short sections. The sections are then dried at ≤60℃ until the moisture content is ≤8%. The dried sections are then pulverized through a 10-20 mesh sieve to obtain loofah vine powder. Eight to twelve times the weight of the loofah vine is added to a 0.05 M phosphate buffer solution with a pH of 7.0-7.5. Then, 0.5-1.5% (by weight of the loofah vine powder) of a complex protease is added. The mixture is stirred at 50-55℃ for 2-3 hours. After enzymatic hydrolysis, the temperature is raised to 90-95℃. Inactivate the enzyme by maintaining the solution for 8-10 minutes, then filter and collect the filtrate. Concentrate the filtrate at ≤60℃ to a relative density of 1.05-1.10 to obtain loofah vine extract. Add 95% ethanol to the loofah vine extract while stirring. The amount of ethanol added should be 2.5-3.5 times the volume of the loofah vine extract. Then let it stand at 3-5℃ for 20-30 hours. After ethanol precipitation, recover the ethanol from the supernatant, redissolve it in water, and filter it using an ultrafiltration membrane system with a molecular weight cutoff of 10 kDa. Collect the permeate, and then filter it again using an ultrafiltration membrane with a molecular weight cutoff of 3 kDa. Collect 3-10 kDa of the permeate. The retentate fraction of kDa was loaded onto a nonpolar macroporous resin adsorption column, eluted first with water, then with a 30-50% ethanol solution. The eluent was collected, and after recovering the ethanol, it was freeze-dried under vacuum. It was first pre-frozen to ≤-40℃ and held for 2 hours, then sublimated at -22 to -28℃ for 19-21 hours under the conditions of cold trap temperature ≤-50℃ and vacuum degree ≤20Pa, and finally desorbed and dried at 23-27℃ for 5-7 hours to obtain the loofah vine extract.

[0008] Furthermore, the complex protease is composed of papain and neutral protease in a mass ratio of 1:0.9-1.1.

[0009] Furthermore, the rhizome extract of Atractylodes lancea was prepared by the following method: dried rhizomes of Atractylodes lancea were pulverized and passed through a 10-20 mesh sieve to obtain Atractylodes lancea powder; the powder was dried at ≤60℃ until the moisture content was ≤8%; then, 8-10 times its weight of a 70% ethanol solution was added to the dried powder, and the mixture was refluxed twice at 80-85℃, each time for 1.4-1.6 hours; the two ethanol extracts were combined and filtered through a 100-200 mesh filter cloth to obtain the ethanol. Extract filtrate A; drain the residue after alcohol extraction, add 10-12 times its weight of purified water, heat to 95-100℃, and extract twice by boiling, 0.9-1.1 hours each time. Combine the two water extracts and filter through a 100-200 mesh filter cloth to obtain water extract filtrate B; concentrate ethanol from alcohol extract filtrate A under reduced pressure at ≤60℃, and continue to concentrate to a thick paste C with a relative density of 1.10-1.15; concentrate water extract filtrate B under reduced pressure at ≤70℃ to a relative density of 1.10-1.15. A concentrated aqueous extract D with a density of 1.05-1.10 is prepared. While stirring, a thick paste C is slowly added to the concentrated aqueous extract D, and the mixture is stirred for 25-35 minutes to obtain a mixed extract E. While stirring, 0.8-1.0 times the volume of 95% ethanol is added to the mixed extract E. The mixture is then allowed to stand at 3-5°C for 10-15 hours, centrifuged, and the supernatant is collected. While stirring, 1.8-2.2 times the volume of 95% ethanol is added to the supernatant. The extract was prepared by adding % ethanol, allowing it to stand at 3-5℃ for 20-30 hours, centrifuging, collecting the precipitate, washing the precipitate twice with 85% ethanol, draining the washed precipitate, and then freeze-drying it under vacuum. First, it was pre-frozen to ≤-40℃ and held for 2 hours, then sublimated and dried at -18~-22℃ for 20-30 hours under cold trap temperature ≤-50℃ and vacuum degree ≤20Pa, and then desorbed and dried at 24-26℃ for 7-9 hours to obtain the rhizome extract of Atractylodes lancea.

[0010] Furthermore, the extract of *Cat's Claw Vine* bark is prepared by the following method: Dried *Cat's Claw Vine* bark is pulverized and passed through a 10-20 mesh sieve to obtain *Cat's Claw Vine* powder. The powder is dried at ≤60℃ until the moisture content is ≤8%. Eight to ten times its weight of a 60% ethanol solution is added to the dried powder, and the mixture is heated to 75-80℃ for extraction twice, each time for 1.4-1.6 hours. The two extracts are combined and filtered through a 100-200 mesh filter. The extract was filtered through a cloth to obtain an alcohol extract filtrate. The filtrate was then concentrated under reduced pressure at ≤60℃ to recover ethanol, and further concentrated to a final extract with a relative density of 1.10-1.15. Under stirring, 2.0-2.5 times the volume of 95% ethanol was slowly added to the extract. The mixture was allowed to stand at 3-5℃ for 20-30 hours, centrifuged, and the supernatant was collected. This supernatant was then concentrated under reduced pressure at ≤50℃ to 15-25% of its original volume. Subsequently, under stirring, the extract was... The pH was adjusted to 2.0-3.0 with a 1% hydrochloric acid solution, and the mixture was allowed to stand at 3-5℃ for 6-8 hours. After centrifugation, the precipitate was collected. The precipitate was washed once with purified water, and then 3-5 times its weight of purified water was added to the precipitate. Under stirring, the pH was adjusted to 9.0-10.0 with a 10% ammonia solution to obtain an alkaline solution. The alkaline solution was extracted with an equal volume of ethyl acetate, and the extraction was repeated 3 times. The ethyl acetate extracts from the 3 extractions were combined, and the combined ethyl acetate extract was concentrated under reduced pressure at ≤40℃ until no ethyl acetate distilled off, yielding an extract with a relative density of 1.15-1.25. The extract was then freeze-dried under vacuum. It was first pre-frozen at ≤-40℃ and held for 2 hours, and then sublimated at -24~-26℃ for 20-30 hours under cold trap temperature ≤-50℃ and vacuum degree ≤20Pa. Finally, it was desorbed and dried at 24~26℃ for 7-9 hours to obtain the bark extract of *Cat's Claw*.

[0011] Furthermore, the antitussive and expectorant composition is formulated into tablets.

[0012] Further, the tablets are prepared by the following method: Sodium benzoate is dissolved in 8-10 times its mass of purified water at a temperature of 50-60°C, stirred until completely dissolved, and then cooled to room temperature to obtain a sodium benzoate solution; trans-anisole and camphor are dissolved in 3-5 times their mass of a 95% ethanol solution to obtain a volatile oil ethanol solution; the sodium benzoate solution and the volatile oil ethanol solution are mixed and stirred evenly, and 15-25 mg of hydroxypropyl methylcellulose is added and stirred evenly to obtain a binder solution; 8-12 mg of microcrystalline cellulose is added to a mixer, along with anhydrous morphine and anhydrous codeine phosphate, and three-dimensional mixing is performed for 15-20 min to obtain mixture A; then 3-5 times the mass of microcrystalline cellulose is added to mixture A and stirred evenly to obtain mixture B; loofah vine Extracts, including Atractylodes lancea rhizome extract, Uncaria rhynchophylla bark extract, glycyrrhizic acid, celery licorice, glycyrrhizin, isoglycyrrhizin, glycyrrhizin, and isoglycyrrhizin, are added to a wet granulator. 150-250 mg of microcrystalline cellulose and 8-12 mg of croscarmellose sodium are added, and the mixture is dry-mixed for 10-15 min to obtain mixture C. Mixture B is slowly and gradually added to mixture C, and stirred for 15-20 min. While stirring, a binder solution is added to form a soft mass. The soft mass is then placed in a granulator and granulated, passing through a 14-20 mesh sieve. It is then dried at 50-60℃ until the moisture content is ≤5%. The granules are then transferred to a three-dimensional motion mixer, and 2-3 mg of magnesium stearate is added. The mixture is stirred for 5-10 min, and then compressed into tablets using a rotary tablet press. The tablet hardness is 4-8 kPa.

[0013] Furthermore, the above tablets are for a single dose, taken three times daily.

[0014] Furthermore, the antitussive and expectorant composition can also be formulated into one of the following: oral liquid, granules, or orally disintegrating tablets.

[0015] Compared with the prior art, the beneficial effects of the present invention are:

[0016] 1. The antitussive and expectorant composition of the present invention has few impurities, clear and significant efficacy, and few drug side effects.

[0017] 2. This invention, under the action of the core antitussive drugs (morphine, codeine), significantly enhances the overall expectorant ability and antitussive effect by innovatively adding extracts of three plants: loofah vine, Atractylodes lancea, and Uncaria rhynchophylla. The antitussive and expectorant composition of this invention achieves a synergistic effect of "1+1+1>3" in key indicators such as inhibiting the frequency of coughs, prolonging the latency period of coughs, and promoting sputum secretion.

[0018] 3. This invention not only relieves symptoms through central antitussive and anti-inflammatory expectorant effects, but also intervenes at multiple cutting-edge pathological stages by utilizing newly added plant ingredients, including regulating mucus rheology, enhancing airway ciliary clearance function, and regulating immune and neurogenic inflammation. This makes this invention particularly suitable for treating complex coughs accompanied by difficulty expectorating, airway hyperresponsiveness, or post-infectious chronic coughs, upgrading it from simple "cough suppression" to a comprehensive management approach of "cough relief, expectoration, anti-inflammation, and repair." Detailed Implementation

[0019] To better understand the technical content of this invention, specific embodiments are provided below to further illustrate the invention.

[0020] Unless otherwise specified, the experimental methods used in the embodiments of this invention are all conventional methods.

[0021] Unless otherwise specified, all materials and reagents used in the embodiments of this invention are commercially available.

[0022] Example 1

[0023] An antitussive and expectorant composition comprising the following raw materials by weight: [Material formula C] 17 H 19 NO3, anhydrous morphine 1.08–1.50 mg, molecular formula C 18 H 21 Anhydrous codeine phosphate 0.42–0.60 mg, with the molecular formula C3H3PO4. 26 H 30 O 13 Celery syrup and licorice 1.50–6.0 mg, molecular formula C 21 H 22 O9 contains 1.20–3.90 mg of glycyrrhizin, with the molecular formula C. 21 H 22 O9 contains 0.30–2.40 mg of isoliquiritigenin, with the molecular formula C. 15 H 12 O4 contains 0.30–2.40 mg of glycyrrhizin with the molecular formula C. 15 H 12 O4 contains 0.30–2.40 mg of isoliquiritigenin, with the molecular formula C. 42 H 62 O 16 The glycyrrhizic acid content is 21.9–39.0 mg, and its molecular formula is C2. 10 H 12 O's trans-anisole 4.8–6.0 mg, molecular formula C 10 H 16 The content of camphor (O) is 5.4–6.6 mg, and the content of sodium benzoate (C7H5NaO2) is 5.4–6.6 mg.

[0024] This antitussive and expectorant composition is formulated into tablets, which are prepared by the following method: Sodium benzoate is dissolved in 8 times its mass of purified water at 50°C, stirred until completely dissolved, and then cooled to room temperature to obtain a sodium benzoate solution; trans-anisole and camphor are dissolved in 3 times their mass of a 95% ethanol solution to obtain a volatile oil ethanol solution; the sodium benzoate solution and the volatile oil ethanol solution are mixed and stirred evenly, and 15 mg of hydroxypropyl methylcellulose is added and stirred evenly to obtain a binder solution; 8 mg of microcrystalline cellulose is added to a mixer, along with anhydrous morphine and anhydrous codeine phosphate, and three-dimensionally mixed for 15 min to obtain mixture A; then, 3 times the mass of the first-diluted mixture of microcrystalline cellulose is added to the mixture... Mixture A and stir until homogeneous to obtain mixture B. Add glycyrrhizic acid, celery licorice, glycyrrhizin, isoglycyrrhizin, glycyrrhizin, and isoglycyrrhizin to a wet granulator, add 280 mg of microcrystalline cellulose and 8 mg of croscarmellose sodium, and dry mix for 10 min to obtain mixture C. Slowly and in batches, add mixture B to mixture C and stir for 15 min. While stirring, add binder solution to form a soft mass. Place the soft mass into a granulator and granulate it through a 14-mesh sieve. Then dry it at 50°C to a moisture content of 5%. Then transfer the granules to a three-dimensional motion mixer, add 2 mg of magnesium stearate, mix for 5 min, and then compress it into tablets using a rotary tablet press. The tablet hardness is 4 kPa.

[0025] The above tablets are for a single dose, to be taken three times daily.

[0026] Example 2

[0027] An antitussive and expectorant composition comprising the following raw materials by weight: [Material formula C] 17 H 19 NO3, anhydrous morphine 1.30 mg, molecular formula C 18 H 21 0.51 mg of anhydrous codeine phosphate (NO3H3PO4), with the molecular formula C 26 H 30 O 13 Celery syrup and licorice 3.75mg, molecular formula C 21 H 22 O9 contains 2.55 mg of glycyrrhizin, with the molecular formula C. 21 H 22 O9 contains 1.75 mg of isoliquiritigenin, with the molecular formula C. 15 H 12 O4 contains 1.75 mg of glycyrrhizin with the molecular formula C. 15 H 12 O4 contains 1.75 mg of isoliquiritigenin with the molecular formula C. 42 H 62 O 16 Glycyrrhizic acid 30.5 mg, molecular formula C10 H 12 5.4 mg of trans-anisole (O), with the molecular formula C 10 H 16 Camphor 6.0mg, sodium benzoate (C7H5NaO2) 6.0mg, loofah vine extract 25mg, Atractylodes lancea rhizome extract 50mg, and cat's claw vine bark extract 40mg.

[0028] The loofah vine extract was prepared by the following method: During the vigorous growth period, the main stems and primary lateral branches of the loofah vine were harvested, washed, drained, and then cut into 1cm short sections. The sections were then dried at 55℃ until the moisture content reached 7%, and then pulverized through a 15-mesh sieve to obtain loofah vine powder. Ten times its mass of a 0.05M phosphate buffer solution (pH 7.3) was added to the loofah vine powder, followed by 1.0% (by mass) of a complex protease. The mixture was stirred at 52℃ for 2.5 hours. After enzymatic hydrolysis, the temperature was raised to 93℃ and maintained for 9 minutes to inactivate the enzyme. The mixture was then filtered, and the filtrate was collected. The filtrate was concentrated at 55℃ to a relative density of 1.08 to obtain loofah vine extract. 95% ethanol was added to the loofah vine extract while stirring. The volume of the extract was 3.0 times that of the loofah vine extract. The mixture was then allowed to stand at 4°C for 25 hours. After ethanol precipitation, the supernatant was recovered from the ethanol, redissolved in water, and filtered using an ultrafiltration membrane system with a molecular weight cutoff of 10 kDa. The permeate was collected, and then filtered again using an ultrafiltration membrane with a molecular weight cutoff of 3 kDa. The 3-10 kDa retentate fraction was collected and loaded onto a non-polar macroporous resin adsorption column. The column was eluted first with water, then with a 40% ethanol solution. The eluent was collected, and after recovering the ethanol, it was freeze-dried under vacuum. The column was pre-frozen to -42°C and held for 2 hours, then sublimated at -25°C for 20 hours under a cold trap temperature of -53°C and a vacuum of 18 Pa. Finally, it was desorbed at 25°C for 6 hours to obtain the loofah vine extract. The complex protease consisted of papain and neutral protease in a 1:1 mass ratio.

[0029] The rhizome extract of Atractylodes lancea was prepared by the following method: Dried rhizomes of Atractylodes lancea were pulverized and passed through a 15-mesh sieve to obtain Atractylodes lancea powder; the powder was dried at 55℃ to a moisture content of 7%, and then 9 times its mass of a 70% ethanol solution was added to the dried powder. The mixture was refluxed at 82℃ twice, 1.5 hours each time. The two ethanol extracts were combined and filtered through a 150-mesh filter cloth to obtain ethanol extract filtrate A; the residue after ethanol extraction was drained, and 11 times its mass of purified water was added. The mixture was heated to 98℃ and decocted twice, 1 hour each time. The two water extracts were combined and filtered through a 150-mesh filter cloth to obtain water extract filtrate B; ethanol extract A was concentrated under reduced pressure at 55℃ to recover ethanol, and then further concentrated to a thick paste C with a relative density of 1.13; water extract filtrate B was concentrated under reduced pressure at 65℃ to a relative density... The aqueous extract concentrate D was prepared at a concentration of 1.08. While stirring, the thick paste C was slowly added to the aqueous extract concentrate D and stirred for 30 minutes to obtain a mixed extract E. While stirring, 0.9 times the volume of 95% ethanol was added to the mixed extract E, followed by standing at 4°C for 12 hours. The mixture was then centrifuged, and the supernatant was collected. While stirring, 2.0 times the volume of 95% ethanol was added to the supernatant, followed by standing at 4°C for 25 hours. The mixture was then centrifuged, and the precipitate was collected. The precipitate was washed twice with 85% ethanol. The washed precipitate was drained and then freeze-dried under vacuum. It was first pre-frozen to -42°C and held for 2 hours, then sublimated at -20°C for 25 hours under a cold trap temperature of -53°C and a vacuum of 18 Pa, followed by desorption at 25°C for 8 hours to obtain the rhizome extract of Atractylodes lancea.

[0030] The extract of *Cat's Claw Vine* bark was prepared by the following method: Dried *Cat's Claw Vine* bark was pulverized and passed through a 15-mesh sieve to obtain *Cat's Claw Vine* powder. The powder was dried at 55℃ until the moisture content reached 7%. Nine times its mass of a 60% ethanol solution was added to the dried powder, and the mixture was heated to 78℃ for extraction twice, 1.5 hours each time. The two extracts were combined and filtered through a 150-mesh filter to obtain the ethanol extract filtrate. The ethanol extract filtrate was concentrated under reduced pressure at 55℃ to recover the ethanol, and further concentrated to a relative density of 1.13. Under stirring, 2.2 times its volume of 95% ethanol was slowly added to the extract. The mixture was allowed to stand at 4℃ for 25 hours, centrifuged, and the supernatant was collected. The supernatant was concentrated under reduced pressure at 48℃ to 20% of its original volume. Then, under stirring, the solution was further concentrated using a concentrated... The pH of the 1% hydrochloric acid solution was adjusted to 2.5, and the mixture was allowed to stand at 4℃ for 7 hours. After centrifugation, the precipitate was collected. The precipitate was washed once with purified water, and then 4 times its weight of purified water was added to the precipitate. Under stirring, the pH was adjusted to 9.5 with a 10% ammonia solution to obtain an alkaline solution. The alkaline solution was extracted with an equal volume of ethyl acetate, and the extraction was repeated 3 times. The ethyl acetate extracts from the 3 extractions were combined, and the combined ethyl acetate extract was concentrated under reduced pressure at 38℃ until no ethyl acetate distilled off, yielding an extract with a relative density of 1.20. The extract was then freeze-dried under vacuum. It was first pre-frozen at -42℃ and held for 2 hours, and then sublimated at -25℃ for 25 hours under a cold trap temperature of -53℃ and a vacuum of 18 Pa. Finally, it was desorbed and dried at 25℃ for 8 hours to obtain the bark extract of *Cat's Claw*.

[0031] The above-mentioned antitussive and expectorant composition is made into tablets, which are prepared by the following method: Sodium benzoate is dissolved in 9 times its mass of purified water at 55°C, stirred until completely dissolved, and then cooled to room temperature to obtain a sodium benzoate solution; trans-anisole and camphor are dissolved in 4 times their mass of a 95% ethanol solution to obtain a volatile oil ethanol solution; the sodium benzoate solution and the volatile oil ethanol solution are mixed and stirred evenly, and 20 mg of hydroxypropyl methylcellulose is added and stirred evenly to obtain a binder solution; 10 mg of microcrystalline cellulose is added to a mixer, along with anhydrous morphine and anhydrous codeine phosphate, and three-dimensionally mixed for 18 min to obtain mixture A; then, 4 times the mass of microcrystalline cellulose is added to mixture A and mixed evenly to obtain a mixture. Compound B; Extracts of loofah vine, rhizome extract of Atractylodes lancea, bark extract of Cat's Claw Vine, glycyrrhizic acid, celery licorice, glycyrrhizin, isoglycyrrhizin, glycyrrhizin, and isoglycyrrhizin were added to a wet granulator, along with 200 mg of microcrystalline cellulose and 10 mg of croscarmellose sodium. The mixture was dry-mixed for 12 min to obtain compound C. Compound B was slowly and gradually added to compound C, and stirred for 18 min. While stirring, a binder solution was added to form a soft mass. The soft mass was then placed in a granulator and granulated, passing through an 18-mesh sieve. It was then dried at 55°C to a moisture content of 4.5%. The granules were then transferred to a three-dimensional motion mixer, and 2.5 mg of magnesium stearate was added. The mixture was mixed for 8 min, and then compressed into tablets using a rotary tablet press. The tablet hardness was 6 kPa.

[0032] The above tablets are for a single dose, to be taken three times daily.

[0033] Example 3

[0034] An antitussive and expectorant composition comprising the following raw materials by weight: [Material formula C] 17 H 19 NO3, anhydrous morphine 1.50 mg, molecular formula C 18 H 21 0.60 mg of anhydrous codeine phosphate (NO3H3PO4), with the molecular formula C 26 H 30 O 13 Celery syrup and licorice 6.0mg, molecular formula C 21 H 22 O9 contains 3.90 mg of glycyrrhizin, with the molecular formula C. 21 H 22 O9 contains 2.40 mg of isoliquiritigenin, with the molecular formula C. 15 H 12 O4 contains 2.40 mg of glycyrrhizin with the molecular formula C. 15 H 12 O4 contains 2.40 mg of isoliquiritigenin with the molecular formula C. 42 H 62 O16 Glycyrrhizic acid 39.0 mg, molecular formula C 10 H 12 O trans-anisole 6.0 mg, molecular formula C 10 H 16 The product contains 6.6 mg of camphor (O), 6.6 mg of sodium benzoate (C7H5NaO2), 30 mg of loofah vine extract, 60 mg of Atractylodes lancea rhizome extract, and 50 mg of cat's claw vine bark extract.

[0035] The loofah vine extract was prepared by the following method: During the vigorous growth period, the main stems and primary lateral branches of the loofah vine were harvested, washed, drained, and then cut into 2cm short sections. The sections were then dried at 50℃ to a moisture content of 6%, and subsequently pulverized through a 20-mesh sieve to obtain loofah vine powder. A 0.05M phosphate buffer solution with a pH of 7.5 was added to the loofah vine powder at 12 times its mass. Then, a complex protease at 1.5% of the loofah vine powder mass was added, and the mixture was stirred at 55℃ for 2 hours. After enzymatic hydrolysis, the temperature was raised to 95℃ and maintained for 8 minutes to inactivate the enzyme. The mixture was then filtered, and the filtrate was collected. The filtrate was concentrated at 50℃ to a relative density of 1.05 to obtain loofah vine extract. 95% ethanol was added to the loofah vine extract while stirring. The amount of ethanol added was... The volume of the extract was 3.5 times that of the loofah vine extract. It was then allowed to stand at 5°C for 20 hours. After ethanol precipitation, the supernatant was recovered from the ethanol, redissolved in water, and filtered using an ultrafiltration membrane system with a molecular weight cutoff of 10 kDa. The permeate was collected, and then filtered again using an ultrafiltration membrane with a molecular weight cutoff of 3 kDa. The 3-10 kDa retentate fraction was collected and loaded onto a non-polar macroporous resin adsorption column. Elution was first performed with water, followed by elution with a 50% ethanol solution. The eluent was collected, and after recovering the ethanol, it was freeze-dried under vacuum. Pre-freezing to -45°C for 2 hours, followed by sublimation drying at -28°C for 19 hours under a cold trap temperature of -55°C and a vacuum of 15 Pa, and finally desorption drying at 27°C for 5 hours to obtain the loofah vine extract. The complex protease consisted of papain and neutral protease in a mass ratio of 1:1.1.

[0036] The rhizome extract of Atractylodes lancea was prepared by the following method: Dried rhizomes of Atractylodes lancea were pulverized and passed through a 20-mesh sieve to obtain Atractylodes lancea powder; the powder was dried at 50℃ to a moisture content of 6%, and then 9 times its mass of a 70% ethanol solution was added to the dried powder. The mixture was refluxed at 85℃ twice, 1.5 hours each time. The two ethanol extracts were combined and filtered through a 150-mesh filter cloth to obtain ethanol extract filtrate A; the residue after ethanol extraction was drained, and 11 times its mass of purified water was added. The mixture was heated to 98℃ and decocted twice, 1.0 hour each time. The two water extracts were combined and filtered through a 150-mesh filter cloth to obtain water extract filtrate B; ethanol extract A was concentrated under reduced pressure at 50℃ to recover ethanol, and then further concentrated to a thick paste C with a relative density of 1.10; water extract filtrate B was concentrated under reduced pressure at 60℃ to a relatively dense paste C. A concentrated aqueous extract D with a viscosity of 1.05 was prepared. While stirring, a thick paste C was slowly added to the concentrated aqueous extract D and stirred for 35 minutes to obtain a mixed extract E. While stirring, 1.0 times the volume of 95% ethanol was added to the mixed extract E, followed by standing at 5°C for 10 hours. The mixture was then centrifuged, and the supernatant was collected. While stirring, 2.2 times the volume of 95% ethanol was added to the supernatant, followed by standing at 5°C for 20 hours. The mixture was then centrifuged, and the precipitate was collected. The precipitate was washed twice with 85% ethanol. The washed precipitate was drained and then freeze-dried under vacuum. It was first pre-frozen to -45°C and held for 2 hours, then sublimated at -22°C for 20 hours under a cold trap temperature of -55°C and a vacuum of 15 Pa, and finally desorbed at 25°C for 8 hours to obtain the rhizome extract of Atractylodes lancea.

[0037] The extract of *Cat's Claw Vine* bark was prepared by the following method: Dried *Cat's Claw Vine* bark was pulverized and passed through a 20-mesh sieve to obtain *Cat's Claw Vine* powder. The powder was dried at 50℃ until the moisture content reached 6%. Nine times its mass of a 60% ethanol solution was added to the dried powder, and the mixture was heated to 78℃ for extraction twice, 1.5 hours each time. The two extracts were combined and filtered through a 150-mesh filter to obtain the ethanol extract filtrate. The ethanol extract filtrate was concentrated under reduced pressure at 50℃ to recover the ethanol, and further concentrated to a relative density of 1.10. Under stirring, 2.5 times its volume of 95% ethanol was slowly added to the extract. The mixture was allowed to stand at 5℃ for 20 hours, centrifuged, and the supernatant was collected. The supernatant was concentrated under reduced pressure at 40℃ to 15% of its original volume. Then, under stirring, the mixture was further concentrated with concentrated... The pH was adjusted to 3.0 with 1% hydrochloric acid solution, and the mixture was allowed to stand at 5℃ for 6 hours. After centrifugation, the precipitate was collected. The precipitate was washed once with purified water, and then 5 times its weight of purified water was added to the precipitate. Under stirring, the pH was adjusted to 9 with 10% ammonia solution to obtain an alkaline solution. The alkaline solution was extracted with an equal volume of ethyl acetate, and the extraction was repeated 3 times. The ethyl acetate extracts from the 3 extractions were combined, and the combined ethyl acetate extract was concentrated under reduced pressure at 35℃ until no ethyl acetate distilled off, yielding an extract with a relative density of about 1.15. The extract was then freeze-dried under vacuum. It was first pre-frozen to -45℃ and held for 2 hours, and then sublimated at -26℃ for 20 hours under a cold trap temperature of -55℃ and a vacuum of 15 Pa. Finally, it was desorbed and dried at 26℃ for 7 hours to obtain the bark extract of *Cat's Claw*.

[0038] The above-mentioned antitussive and expectorant composition is made into tablets, which are prepared by the following method: Sodium benzoate is dissolved in 10 times its mass of purified water at 60°C, stirred until completely dissolved, and then cooled to room temperature to obtain a sodium benzoate solution; trans-anisole and camphor are dissolved in 5 times their mass of a 95% ethanol solution to obtain a volatile oil ethanol solution; the sodium benzoate solution and the volatile oil ethanol solution are mixed and stirred evenly, and 25 mg of hydroxypropyl methylcellulose is added and stirred evenly to obtain a binder solution; 12 mg of microcrystalline cellulose is added to a mixer, along with anhydrous morphine and anhydrous codeine phosphate, and three-dimensionally mixed for 20 min to obtain mixture A; then, 5 times the mass of the first-diluted mixture of microcrystalline cellulose is mixed with mixture A and stirred evenly to obtain... Mixture B is prepared by adding the following ingredients: Luffa vine extract, Atractylodes lancea rhizome extract, Cat's Claw vine bark extract, glycyrrhizic acid, celery licorice, glycyrrhizin, isoglycyrrhizin, glycyrrhizin, and isoglycyrrhizin to a wet granulator. 250 mg of microcrystalline cellulose and 12 mg of croscarmellose sodium are added, and the mixture is dry-mixed for 15 min to obtain mixture C. Mixture B is slowly and gradually added to mixture C, and stirred for 20 min. While stirring, a binder solution is added to form a soft mass. The soft mass is then placed in a granulator and granulated, passing through a 20-mesh sieve. It is then dried at 60°C to a moisture content of 4%. The granules are then transferred to a three-dimensional motion mixer, and 3 mg of magnesium stearate is added. The mixture is mixed for 10 min, and then compressed into tablets using a rotary tablet press. The tablet hardness is 4 kPa.

[0039] The above tablets are for a single dose, to be taken three times daily.

[0040] Comparative Example

[0041] The difference between this comparative example and Example 2 is that commercially available compound licorice tablets were used instead of the antitussive and expectorant composition described herein.

[0042] Cough suppression test

[0043] One hundred SPF-grade ICR mice, weighing 18-22g, with half males and half females, were randomly divided into 5 groups: Example 1 group, Example 2 group, Example 3 group, comparative group, and blank control group. For Example 1-3 groups and the comparative group, 10mg of the drug was ground and added to 20 times its volume of purified water, then sonicated to form a suspension. The suspension was administered by gavage once daily in the morning for 5 consecutive days at a dose of 20mL / kg. The blank control group was administered the same volume of physiological saline by gavage. One hour after the last administration, an ammonia-induced cough test was performed. Mice in each group were placed in a 2L transparent glass bell jar, and 0.3mL of 25% ammonia was sprayed in. The cough latency and the total number of coughs within 3 minutes were recorded. The average cough latency and total number of coughs for each group were calculated and recorded in Table 1.

[0044] Expectorant test

[0045] One hundred SPF-grade ICR mice, weighing 18-22g, with half males and half females, were randomly divided into 5 groups: Example 1 group, Example 2 group, Example 3 group, comparative group, and blank control group. For Example 1-3 groups and the comparative group, 10mg of the drug was ground, added to twice the amount of purified water, and sonicated to form a suspension. The suspension was administered by gavage once daily in the morning at a dose of 20mL / kg for 5 consecutive days. The blank control group was administered the same volume of physiological saline by gavage. Thirty minutes after the last administration, a 0.25% phenol red solution was injected intraperitoneally at a dose of 0.1g / 10g. The mice were sacrificed 30 minutes later, and the trachea was separated and rinsed with 2mL of 5% NaHCO3 solution. The absorbance of the rinsing fluid was measured at 546nm. The tracheal phenol red excretion was calculated based on the phenol red standard curve, and the average phenol red excretion for each group was recorded in Table 1.

[0046] Table 1

[0047] Group Cough incubation period Number of coughs within 3 minutes Phenol red excretion rate (ug / Kg) Example 1 60 91 0.274 Example 2 68 83 0.283 Example 3 65 87 0.280 Comparative Example 54 98 0.269 Blank comparison example 36 119 0.231

[0048] As can be seen from Table 1, the antitussive and expectorant effects of Example 1 of the present invention are better than those of commercially available compound licorice tablets, and the antitussive and expectorant effects of Examples 2-3 are better than those of Example 1.

[0049] Compared to commercially available compound licorice tablets, Example 1 of this invention uses a precise dose of glycyrrhizic acid as the main expectorant and anti-inflammatory component to ensure stable basic efficacy. Simultaneously, glycyrrhizin, isoglycyrrhizin, glycyrrhizin, isoglycyrrhizin, and celery licorice, among other full-spectrum licorice components, are added. These components, through multiple pathways including inhibiting inflammatory factors, anti-oxidative stress, and immune regulation, synergistically exert anti-inflammatory and mucosal protective effects with glycyrrhizic acid, more effectively inhibiting excessive sputum production and airway inflammation from the source, resulting in stronger antitussive and expectorant efficacy.

[0050] The core of this invention's formula is anhydrous morphine and codeine phosphate, which directly act on the central cough reflex, exerting a strong and rapid antitussive effect—this is the "symptomatic treatment." Glycyrrhizic acid, glycyrrhizin, celery syrup, and other licorice-based components work synergistically to exert clear anti-inflammatory, antioxidant, immunomodulatory, and sputum-thinning effects, reducing airway inflammation and sputum viscosity at the source—this is the "root cause treatment." Trans-anisole and camphor, as adjuvants, have the effects of local mild stimulation, promoting secretion, and clearing the nasal passages, assisting in sputum expectoration and improving subjective discomfort. Furthermore, the innovative addition of loofah vine extract, Atractylodes lancea rhizome extract, and Uncaria rhynchophylla bark extract enhances the therapeutic effect from a new dimension of modern pharmacology: loofah vine extract potentially promotes ciliary movement to enhance airway clearance; Atractylodes lancea extract regulates mucus rheology, making it easier to cough up; and Uncaria rhynchophylla extract intervenes in the neuroimmunological basis of cough by regulating immunity and anti-inflammation. The formula integrates multiple mechanisms such as central nervous system inhibition, peripheral expectoration, anti-inflammatory repair, physical regulation and immune intervention. The components work synergistically to effectively suppress cough while systematically addressing the root causes of excessive and viscous sputum that is difficult to expectorate. It may also reduce dose dependence on opioids, thereby achieving a highly efficient and more comprehensive cough suppressant and expectorant effect.

[0051] The rhizome extract of Atractylodes lancea of ​​this invention, rich in polysaccharide-sterol complexes, can regulate the rheological properties of sputum, effectively reducing its viscosity and elasticity, making the originally viscous and sticky sputum thinner and easier to flow. The active ingredients in the loofah vine extract can potentially promote the regular movement of respiratory cilia, enhance the function of the mucociliary transport system, and provide a strong expulsive force for diluted sputum. The bark extract of Uncaria rhynchophylla, through its immunomodulatory and anti-inflammatory activities, helps to inhibit the excessive proliferation and secretion of mucous glands, reducing sputum production; simultaneously, it synergistically works with glycyrrhizic acid, glycyrrhizin, and other components to reduce airway mucosal inflammation and edema, repair the epithelial barrier, and support the normalization of airway function. Therefore, this invention, through the addition of these three plant extracts, forms a closed loop with the antitussive and anti-inflammatory effects of the original components, thereby achieving an upgraded treatment for intractable cough with copious and viscous sputum, moving from symptom relief to pathological intervention.

[0052] 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 cough suppressant expectorant composition characterized in that, comprising the following raw materials by weight: anhydrous morphine of the formula C 17 H 19 NO3 1.08-1.50 mg, anhydrous codeine phosphate of the formula C 18 H 21 NO3 H3PO4 0.42-0.60 mg, anhydrous theophylline of the formula C 26 H 30 O 13 1.50-6.0 mg, anhydrous glycyrrhizin of the formula C 21 H 22 O 9 1.20-3.90 mg, anhydrous isoglycyrrhizin of the formula C 21 H 22 O 9 0.30-2.40 mg, anhydrous glycyrrhetic acid of the formula C 15 H 12 O 4 0.30-2.40 mg, anhydrous isoglycyrrhizin of the formula C 15 H 12 O 4 0.30-2.40 mg, anhydrous glycyrrhetic acid of the formula C 42 H 62 O 16 21.9-39.0 mg, anhydrous trans-anethole of the formula C 10 H 12 O 4.8-6.0 mg, anhydrous camphor of the formula C 10 H 16 O sodium benzoate content of 5.4-6.6 mg.

2. A cough suppressant expectorant composition as claimed in claim 1 wherein, The cough-relieving and phlegm-removing composition further comprises Luffa cylindrica stem extract 20-30 mg, Rhizoma et Radix Notopterygii extract 40-60 mg, and Periploca sepium stem bark extract 30-50 mg.

3. A cough suppressant expectorant composition as claimed in claim 2 wherein, The Luffa cylindrica stem extract is prepared by the following method: harvesting the main stems and first-order lateral branches of Luffa cylindrica in the vigorous growth period, washing and draining, then cutting into 1-2 cm short sections, then drying at ≤60℃ until the water content is ≤8%, then crushing through a 10-20 mesh screen to obtain Luffa cylindrica powder; adding 8-12 times the mass of the Luffa cylindrica powder of a phosphate buffer solution with a concentration of 0.05 M and a pH of 7.0-7.5, then adding 0.5-1.5% of the mass of the Luffa cylindrica powder of a complex protease composed of 1:0.9-1.1 mass ratio of papain and neutral protease, stirring and reacting at 50-55℃ for 2-3 h, then raising the temperature to 90-95℃ for 8-10 min to inactivate the enzyme, then filtering, collecting the filtrate, concentrating the filtrate at ≤60℃ to a relative density of 1.05-1.10 to obtain Luffa cylindrica extract; adding 95% ethanol to the Luffa cylindrica extract while stirring, the amount of ethanol added being 2.5-3.5 times the volume of the Luffa cylindrica extract, then standing at 3-5℃ for 20-30 h, then recovering the ethanol from the supernatant after alcohol precipitation, redissolving with water, filtering using an ultrafiltration membrane system with a molecular weight cut-off of 10 kDa, collecting the permeate, then filtering the permeate using an ultrafiltration membrane with a molecular weight cut-off of 3 kDa, collecting the 3-10 kDa fraction, and loading the fraction onto a non-polar macroporous resin adsorption column, first eluting with water, then eluting with an ethanol solution with a concentration of 30-50%, collecting the eluate, recovering the ethanol from the eluate, and vacuum freeze-drying, first pre-freezing to ≤-40℃ for 2 h, then sublimation drying at -22~-28℃ under a vacuum of ≤20 Pa for 19-21 h, and finally desorption drying at 23-27℃ for 5-7 h to obtain the Luffa cylindrica stem extract.

4. A cough suppressant expectorant composition as claimed in claim 2, wherein, The Radix Rhizoma seu Praeparatae Atractylodis Kusnezoffii extract is prepared by the following method: dried Radix Rhizoma seu Praeparatae Atractylodis Kusnezoffii is ground to pass through a 10-20 mesh screen to obtain Radix Rhizoma seu Praeparatae Atractylodis Kusnezoffii powder; the Radix Rhizoma seu Praeparatae Atractylodis Kusnezoffii powder is dried at a temperature of ≤60°C until the moisture content is ≤8%, and then 8-10 times the mass of the dried Radix Rhizoma seu Praeparatae Atractylodis Kusnezoffii powder is added with 70% ethanol solution, and the mixture is refluxed at 80-85°C for 2 times, each time for 1.4-1.6 h; the two times of alcohol extracts are combined and filtered through 100-200 mesh filter cloth to obtain alcohol extract A; the alcohol-extracted residue is drained, and 10-12 times the mass of the residue is added with purified water, and the mixture is heated to 95-100°C and extracted for 2 times, each time for 0.9-1.1 h; the two times of water extracts are combined and filtered through 100-200 mesh filter cloth to obtain water extract B; alcohol extract A is concentrated under reduced pressure at a temperature of ≤60°C to recover ethanol, and the concentration is continued until a thick paste C with a relative density of 1.10-1.15 is obtained; water extract B is concentrated under reduced pressure at a temperature of ≤70°C until a water extract concentrate D with a relative density of 1.05-1.10 is obtained; thick paste C is slowly added to water extract concentrate D under stirring for 25-35 min to obtain mixed extract E; 0.8-1.0 times the volume of 95% ethanol is added to mixed extract E under stirring, and then the mixture is allowed to stand at 3-5°C for 10-15 h, and the supernatant is collected by centrifugation; 1.8-2.2 times the volume of 95% ethanol is added to the supernatant under stirring, and then the mixture is allowed to stand at 3-5°C for 20-30 h, and the precipitate is collected by centrifugation; the precipitate is washed twice with 85% ethanol, and then the washed precipitate is drained and vacuum freeze-dried by pre-freezing to ≤-40°C for 2 h, followed by sublimation drying at a cold trap temperature of ≤-50°C and a vacuum degree of ≤20 Pa at a temperature of -18 to -22°C for 20-30 h, and desorption drying at 24-26°C for 7-9 h to obtain the Radix Rhizoma seu Praeparatae Atractylodis Kusnezoffii extract.

5. A cough suppressant expectorant composition as claimed in claim 2, wherein, The extract of Paederia scandens (Lour.) Meisn. is prepared by the following method: dry Paederia scandens (Lour.) Meisn. is crushed to pass through a 10-20 mesh screen to obtain Paederia scandens (Lour.) Meisn. powder, the Paederia scandens (Lour.) Meisn. powder is dried at a temperature of ≤60°C until the moisture content is ≤8%, 8-10 times the mass of the dried Paederia scandens (Lour.) Meisn. powder is added to 60% ethanol solution, heated to 75-80°C, extracted twice for 1.4-1.6 hours each time, the two extraction solutions are combined and filtered through 100-200 mesh filter cloth to obtain an alcohol extraction filtrate, the alcohol extraction filtrate is concentrated under reduced pressure at a temperature of ≤60°C to recover the ethanol, and the concentration is continued until the extract residue has a relative density of 1.10-1.15, 2.0-2.5 times the volume of 95% ethanol solution is slowly added to the extract residue under stirring, the mixture is allowed to stand at 3-5°C for 20-30 hours, centrifuged, and the supernatant is collected, the supernatant is concentrated under reduced pressure at a temperature of ≤50°C to 15-25% of the original volume, then the pH value is adjusted to 2.0-3.0 with 1% hydrochloric acid solution under stirring, the mixture is allowed to stand at 3-5°C for 6-8 hours, centrifuged, and the precipitate is collected; the precipitate is washed once with purified water, then 3-5 times the mass of purified water is added to the precipitate, the pH value is adjusted to 9.0-10.0 with 10% ammonia water solution under stirring to obtain an alkaline water solution, the alkaline water solution is extracted with an equal volume of ethyl acetate, the extraction is repeated 3 times, the ethyl acetate extracts are combined, the combined ethyl acetate extract is concentrated under reduced pressure at a temperature of ≤40°C until no ethyl acetate is distilled off, an extract residue having a relative density of 1.15-1.25 is obtained, and then vacuum freeze-drying is performed, the extract is pre-frozen to ≤-40°C for 2 hours, then sublimation drying is performed at a cold trap temperature of ≤-50°C, a vacuum degree of ≤20 Pa, a temperature of -24~-26°C for 20-30 hours, and desorption drying is performed at 24~26°C for 7-9 hours to obtain the extract of Paederia scandens (Lour.) Meisn.

6. A cough suppressant expectorant composition as claimed in claim 2, wherein, The cough-relieving and phlegm-removing composition is prepared into tablets.

7. A cough suppressant expectorant composition as claimed in claim 6 wherein, The tablet is prepared by the following method: dissolving sodium benzoate in 8-10 times of its mass of purified water at a temperature of 50-60 DEG C, stirring until completely dissolved, then cooling to room temperature to obtain a sodium benzoate solution; dissolving trans-anethole and camphor in 3-5 times of its mass of 95% ethanol solution to obtain an essential oil ethanol solution; mixing the sodium benzoate solution and the essential oil ethanol solution, stirring until uniform, adding 15-25 mg of hydroxypropyl methyl cellulose, stirring until uniform to obtain a binder solution; taking 8-12 mg of microcrystalline cellulose into a mixer, adding anhydrous morphine and anhydrous codeine phosphate, three-dimensionally mixing for 15-20 min to obtain mixture A; then taking 3-5 times of the mass of mixture A of microcrystalline cellulose and mixing with mixture A, stirring until uniform to obtain mixture B; adding silk gourd vine extract, rhizome of Chinese patrinia extract, catclaw vine bark extract, glycyrrhizic acid, glycyrrhizin, glycyrrhizin, isoglycyrrhizin, glycyrrhetic acid, isoglycyrrhetic acid into a wet granulator, adding 150-250 mg of microcrystalline cellulose and 8-12 mg of croscarmellose sodium, dry mixing for 10-15 min to obtain mixture C; slowly and portion-wise adding mixture B into mixture C, stirring for 15-20 min, under stirring, adding the binder solution to form a soft mass, placing the soft mass into a granulator to granulate, passing through a 14-20 mesh screen, then drying at 50-60 DEG C until the water content is ≤5%, then transferring the granules into a three-dimensional motion mixer, adding 2-3 mg of magnesium stearate, mixing for 5-10 min, then using a rotary tablet press to compress into tablets, and the tablet hardness is 4-8 kp.

8. A cough suppressant expectorant composition as claimed in claim 7 wherein, The tablet is a one-time dosage, taken three times a day.

9. A process for the preparation of a cough suppressant expectorant composition as claimed in claim 6, wherein, The antitussive and expectorant composition can also be prepared into one of an oral liquid, granules, and orally disintegrating tablets.