A kind of high stability cough relieving tangerine peel granules and preparation method thereof

Abstract

The invention provides a high-stability cough-relieving tangerine peel granule and a preparation method thereof. The cough-relieving tangerine peel granule is composed of an active composition, an auxiliary material and a carrier. The active composition is composed of gypsum, tangerine peel, dried orange peel, coltsfoot flower, French pinellia, tuckahoe, platycodon, bitter almond, aster, perilla seed, trichosanthes peel, rhizoma anemarrhenae, ophiopogon, rehmannia root and liquorice. The auxiliary material is composed of β-glucan, kudzu root polysaccharide, β-carotene and dipalmitoyl phosphatidylethanolamine, and the carrier is modified sodium carboxymethyl cellulose. β-glucan is used as a stabilizer to improve the stability of the drug particles, kudzu root polysaccharide and β-carotene are used as antioxidants to prevent oxidation, dipalmitoyl phosphatidylethanolamine is a synthetic phospholipid, has a single component, is wrapped on the surface of the active composition, improves stability, improves taste, and improves bioavailability, and the modified sodium carboxymethyl cellulose helps to evenly distribute the drug, improves drug loading capacity and biocompatibility, and enhances the dissolution and absorption of the drug.

Description

Technical Field

[0001] The invention relates to the technical field of medicines, and in particular to a high-stability cough-relieving tangerine peel granule and a preparation method thereof. Background Art

[0002] Cough-clearing tangerine peel granules can clear the lungs, relieve coughs, and resolve phlegm. They are mainly suitable for recurrent coughs caused by phlegm-damp coughs, heavy coughs, phlegm and wheezing. Its main ingredients are tangerine peel, baibu, tuckahoe, pinellia, white grass, licorice, almonds, schisandra, etc.

[0003] Patent CN111632105A discloses a cough-relieving tangerine peel granule and a preparation method thereof, which mainly provides a simple preparation method and sugar-free tangerine peel granule with good taste. The preparation method is as follows: the raw material drug extract and the auxiliary materials are evenly stirred, poured into dextrin for granulation, dried, granulated, and mixed. At present, the stability of drug granules is generally improved by controlling pH, controlling temperature, shading, controlling moisture, or adding antioxidants (sodium sulfite, sodium thiosulfate, butylated p-hydroxyanisole BHA) and metal ion complexing agents (disodium edetate), but the production conditions need to be strictly controlled, the cost becomes high, the bioavailability is low, and the safety of drug granules is affected. Summary of the invention

[0004] In view of this, the present invention proposes a highly stable cough-relieving tangerine peel granule and a preparation method thereof to solve the above-mentioned problems, and provides a highly stable cough-relieving tangerine peel granule with good stability, biocompatibility and controlled release, thereby improving bioavailability and safety.

[0005] The technical solution of the present invention is achieved in this way:

[0006] A highly stable cough-relieving tangerine peel granule, comprising an active composition, an auxiliary material and a carrier;

[0007] The active composition is composed of gypsum, tangerine peel, coltsfoot flower, pinellia tuber, tuckahoe, platycodon grandiflorum, bitter almond, aster, perilla seed, trichosanthes peel, anemarrhena, ophiopogon japonicus, rehmannia root and liquorice;

[0008] The auxiliary materials are composed of β-glucan, kudzu root polysaccharide, β-carotene and dipalmitoylphosphatidylethanolamine;

[0009] The carrier is modified sodium carboxymethyl cellulose.

[0010] Furthermore, the active composition is composed, by weight, of 1-3 parts of gypsum, 3-5 parts of tangerine peel, 3-5 parts of coltsfoot flower, 1-3 parts of pinellia tuber, 1-3 parts of tuckahoe, 1-2 parts of platycodon, 0.5-1.0 parts of bitter almond, 1-2 parts of aster, 0.5-1.5 parts of perilla seed, 1-2 parts of trichosanthes peel, 0.5-1.0 parts of anemarrhena, 0.5-1.5 parts of ophiopogon, 1-2 parts of rehmannia and 1-3 parts of liquorice.

[0011] Furthermore, the auxiliary materials are composed of 1-2 parts of β-glucan, 1-3 parts of kudzu root polysaccharide, 0.5-0.8 parts of β-carotene and 3-5 parts of dipalmitoyl phosphatidylethanolamine in parts by weight.

[0012] Furthermore, the mass ratio of the carrier to the active composition is 0.1-0.3:1.

[0013] Furthermore, the preparation method of the modified sodium carboxymethyl cellulose comprises: grinding the sodium carboxymethyl cellulose into powder, adding it into water, adding allylamine, subjecting it to electron beam radiation treatment for the first time, adding polyethylene glycol, subjecting it to electron beam radiation treatment for the second time, filtering it through a reverse osmosis membrane, and obtaining the modified sodium carboxymethyl cellulose.

[0014] Furthermore, the solid-liquid ratio of sodium carboxymethyl cellulose to water is 1:5-9 g / mL; the mass ratio of allylamine to sodium carboxymethyl cellulose to polyethylene glycol is 0.1-0.5:1:0.1-0.5; the dose of the first electron beam radiation is 10-50 kGy, and the time is 20-30 min; the dose of the second electron beam radiation is 10-30 kGy, and the time is 30-60 min; the pore size of the reverse osmosis membrane is 0.1-0.3 μm.

[0015] Furthermore, the preparation method of the active composition comprises:

[0016] (1) crushing Citrus aurantium, gypsum, Platycodon grandiflorum, Licorice root and Aster tataricus, adding them into an ethanol-potassium carbonate aqueous two-phase system, performing ultrasonic extraction, and collecting extract A;

[0017] (2) Crush coltsfoot flower, pinellia ternata, poria cocos and rhizoma anemarrhenae, add them into an isopropanol-ammonium sulfate aqueous two-phase system, perform microwave extraction, and collect extract B;

[0018] (3) Crush dried orange peel, bitter almond, perilla seed, Trichosanthes peel, Ophiopogon japonicus and Rehmannia glutinosa, add to ethanol-ammonium sulfate-sodium dodecyl sulfate aqueous two-phase system, perform ultrasonic extraction, and collect extract C;

[0019] (4) Combine the extracts A, B and C, add 60%-70% v / v ethanol for alcohol precipitation, and concentrate under reduced pressure to obtain an active composition.

[0020] Furthermore, in step (1), the solid-liquid ratio of the tangerine peel, gypsum, platycodon, liquorice and aster to the ethanol-potassium carbonate two-phase aqueous system is 1:8-10 g / mL; the concentration of the ethanol-potassium carbonate two-phase aqueous system is 30-50% v / v, wherein the volume of ethanol to potassium carbonate is 1:1-3; the ultrasonic extraction is performed at 150-250W and 50-60°C for 20-30 min;

[0021] In step (2), the solid-liquid ratio of the coltsfoot flower, pinellia tuber, poria cocos and rhizoma anemarrhenae to the isopropanol-ammonium sulfate two-phase aqueous system is 1:6-8 g / mL; the concentration of the isopropanol-ammonium sulfate two-phase aqueous system is 20-40% v / v, wherein the volume of isopropanol and ammonium sulfate is 1:3-5; the microwave extraction is performed at 350-450 W and 40-50° C. for 5-10 min;

[0022] In step (3), the solid-liquid ratio of the dried tangerine peel, bitter almond, perilla seed, trichosanthes peel, ophiopogon japonicus and rehmannia root to the ethanol-ammonium sulfate-sodium dodecyl sulfate two-phase aqueous system is 1:10-20 g / mL; the concentration of the ethanol-ammonium sulfate-sodium dodecyl sulfate two-phase aqueous system is 40-50% v / v, wherein the volume of ethanol to ammonium sulfate and sodium dodecyl sulfate is 1:2-4:0.1-0.3; and the ultrasonic extraction is performed at 200-300 W and 50-60° C. for 40-60 min.

[0023] A method for preparing high-stability cough-relieving tangerine peel granules, the specific steps comprising:

[0024] (1) adding modified sodium carboxymethyl cellulose to water, and then adding the active composition and auxiliary materials in sequence, stirring evenly to obtain a material;

[0025] (2) freeze-drying the material to obtain granules, crushing and sieving to obtain the target cough-relieving tangerine peel granules.

[0026] Furthermore, in step (1), the solid-liquid ratio of the modified sodium carboxymethyl cellulose to water is 1:10-20 g / mL; the stirring time is 30-60 min, the temperature is 50-60° C., and the rotation speed is 300-500 rpm.

[0027] Compared with the prior art, the present invention has the following beneficial effects:

[0028] 1. The β-glucan in the auxiliary materials of the present invention acts as a stabilizer to improve the stability of the cough-relieving tangerine peel granules; kudzu root polysaccharide and β-carotene act as antioxidants to prevent oxidation of the active composition, further enhance the stability of the cough-relieving tangerine peel granules, and extend the shelf life of the drug; dipalmitoylphosphatidylethanolamine is a synthetic phospholipid, which has a single component and higher purity compared to natural phospholipids, and is wrapped on the surface of the active composition to improve stability, while also improving taste and bioavailability.

[0029] 2. The use of modified sodium carboxymethyl cellulose as a carrier of the present invention helps to evenly distribute the drug, improve drug loading capacity and biocompatibility, enhance drug dissolution and absorption, improve bioavailability, and improve drug efficacy and safety.

[0030] 3. The extraction method of the present invention can extract the active composition more fully, with high extraction efficiency, and the extracted active composition is more stable and has higher purity. DETAILED DESCRIPTION

[0031] In order to better understand the technical content of the present invention, specific embodiments are provided below to further illustrate the present invention.

[0032] Unless otherwise specified, the experimental methods used in the embodiments of the present invention are all conventional methods.

[0033] Unless otherwise specified, the materials, reagents, etc. used in the embodiments of the present invention can be obtained from commercial sources.

[0034] Example 1

[0035] The high-stability cough-relieving tangerine peel granules of this embodiment are composed of an active composition, an auxiliary material and a carrier;

[0036] The active composition is composed of 2 parts of gypsum, 4 parts of tangerine peel, 4 parts of coltsfoot flower, 2 parts of pinellia tuber, 2 parts of tuckahoe, 1.5 parts of platycodon, 0.8 parts of bitter almond, 1.5 parts of aster, 1 part of perilla seed, 1.5 parts of trichosanthes peel, 0.7 parts of anemarrhena, 1 part of ophiopogon, 1.5 parts of rehmannia root and 2 parts of liquorice;

[0037] The excipients consist of 1.5 parts of β-glucan, 2 parts of kudzu root polysaccharide, 0.7 parts of β-carotene and 4 parts of dipalmitoylphosphatidylethanolamine;

[0038] The carrier is 5.86 parts of modified sodium carboxymethyl cellulose.

[0039] Preparation of modified sodium carboxymethyl cellulose: Grind sodium carboxymethyl cellulose into powder, add it to water at a solid-liquid ratio of 1:7 g / mL, add allylamine, the mass ratio of allylamine to sodium carboxymethyl cellulose is 0.3:1, perform the first electron beam irradiation for 25 min (dose of 30 kGy), add polyethylene glycol, the mass ratio of polyethylene glycol to sodium carboxymethyl cellulose is 0.3:1, perform the second electron beam irradiation for 45 min (dose of 20 kGy), filter through a reverse osmosis membrane with a pore size of 0.2 μm to obtain modified sodium carboxymethyl cellulose.

[0040] The preparation method of the active composition comprises: (1) crushing tangerine peel, gypsum, platycodon, liquorice and aster, adding them into a 40% v / v ethanol-potassium carbonate two-phase aqueous system (the volume of ethanol and potassium carbonate is 1:2) at a solid-liquid ratio of 1:9 g / mL, performing ultrasonic extraction at 200 W and 55° C. for 25 min, and collecting extract A;

[0041] (2) Crush coltsfoot flower, pinellia ternata, poria cocos and rhizoma anemarrhenae, add them into a 30% v / v isopropanol-ammonium sulfate aqueous two-phase system (the volume of isopropanol and ammonium sulfate is 1:4) at a solid-liquid ratio of 1:7 g / mL, and extract them under microwave at 400 W and 45 °C for 8 min, and collect extract B;

[0042] (3) Crush dried orange peel, bitter almond, perilla seed, Trichosanthes peel, Ophiopogon japonicus and Rehmannia glutinosa, add into a 45% v / v ethanol-ammonium sulfate-sodium dodecyl sulfate two-phase aqueous system (the volume of ethanol to ammonium sulfate and sodium dodecyl sulfate is 1:3:0.2) at a solid-liquid ratio of 1:15 g / mL, and extract under ultrasonic condition at 250 W and 55 °C for 50 min, and collect extract C;

[0043] (4) The extracts A, B and C were combined, 65% v / v ethanol was added for alcohol precipitation, and the mixture was concentrated under reduced pressure to obtain an active composition.

[0044] The preparation method of the above-mentioned high-stability cough-relieving tangerine peel granules specifically comprises the following steps:

[0045] (1) adding modified sodium carboxymethyl cellulose to water at a solid-liquid ratio of 1:15 g / mL, and then adding the active composition and the auxiliary materials in sequence, stirring at 55° C. and 400 rpm for 45 min to obtain a material;

[0046] (2) freeze-drying the material to obtain granules, crushing and sieving to obtain the target cough-relieving tangerine peel granules.

[0047] Example 2

[0048] The high-stability cough-relieving tangerine peel granules of this embodiment are composed of an active composition, an auxiliary material and a carrier;

[0049] The active composition is composed of 1 part of gypsum, 3 parts of tangerine peel, 3 parts of tangerine peel, 1 part of coltsfoot flower, 1 part of pinellia tuber, 1 part of tuckahoe, 1 part of platycodon grandiflorum, 0.5 part of bitter almond, 1 part of aster, 0.5 part of perilla seed, 1 part of trichosanthes peel, 0.5 part of anemarrhena, 0.5 part of ophiopogon, 1 part of rehmannia root and 1 part of liquorice;

[0050] The excipients consist of 1 part of β-glucan, 1 part of kudzu root polysaccharide, 0.5 part of β-carotene and 3 parts of dipalmitoylphosphatidylethanolamine;

[0051] The carrier is 1.8 parts of modified sodium carboxymethyl cellulose.

[0052] Preparation of modified sodium carboxymethyl cellulose: Grind sodium carboxymethyl cellulose into powder, add it to water at a solid-liquid ratio of 1:5 g / mL, add allylamine, the mass ratio of allylamine to sodium carboxymethyl cellulose is 0.1:1, perform the first electron beam irradiation for 20 min (dose of 10 kGy), add polyethylene glycol, the mass ratio of polyethylene glycol to sodium carboxymethyl cellulose is 0.1:1, perform the second electron beam irradiation for 30 min (dose of 10 kGy), filter through a reverse osmosis membrane with a pore size of 0.1 μm to obtain modified sodium carboxymethyl cellulose.

[0053] The preparation method of the active composition comprises: (1) crushing Citrus aurantium, gypsum, Platycodon grandiflorum, Licorice root and Aster tataricus, adding them into a 30% v / v ethanol-potassium carbonate two-phase aqueous system (the volume of ethanol and potassium carbonate is 1:1) at a solid-liquid ratio of 1:8 g / mL, performing ultrasonic extraction at 150W and 50°C for 20 minutes, and collecting an extract A;

[0054] (2) Crush coltsfoot flower, pinellia ternata, poria cocos and rhizoma anemarrhenae, add them into a 20% v / v isopropanol-ammonium sulfate aqueous two-phase system (the volume of isopropanol and ammonium sulfate is 1:3) at a solid-liquid ratio of 1:6 g / mL, and extract them under microwave at 350 W and 40 °C for 5 min, and collect extract B;

[0055] (3) Crush dried tangerine peel, bitter almond, perilla seed, Trichosanthes peel, Ophiopogon japonicus and Rehmannia glutinosa, add them into a 40% v / v ethanol-ammonium sulfate-sodium dodecyl sulfate two-phase aqueous system (the volume of ethanol to ammonium sulfate and sodium dodecyl sulfate is 1:2:0.1) at a solid-liquid ratio of 1:10 g / mL, and extract them by ultrasonic extraction at 200 W and 50° C. for 40 min, and collect the extract C;

[0056] (4) The extracts A, B and C were combined, 60% v / v ethanol was added for alcohol precipitation, and the mixture was concentrated under reduced pressure to obtain an active composition.

[0057] The preparation method of the above-mentioned high-stability cough-relieving tangerine peel granules specifically comprises the following steps:

[0058] (1) adding modified sodium carboxymethyl cellulose to water at a solid-liquid ratio of 1:10 g / mL, and then adding the active composition and the auxiliary materials in sequence, stirring at 50° C. and 300 rpm for 30 min to obtain a material;

[0059] (2) freeze-drying the material to obtain granules, crushing and sieving to obtain the target cough-relieving tangerine peel granules.

[0060] Example 3

[0061] The high-stability cough-relieving tangerine peel granules of this embodiment are composed of an active composition, an auxiliary material and a carrier;

[0062] The active composition is composed of 3 parts of gypsum, 5 parts of tangerine peel, 5 parts of coltsfoot flower, 3 parts of pinellia tuber, 3 parts of tuckahoe, 2 parts of platycodon, 1.0 part of bitter almond, 2 parts of aster, 1.5 parts of perilla seed, 2 parts of trichosanthes peel, 1.0 part of anemarrhena, 1.5 parts of ophiopogon, 2 parts of rehmannia root and 3 parts of liquorice;

[0063] The excipients consist of 2 parts of β-glucan, 3 parts of kudzu root polysaccharide, 0.8 parts of β-carotene and 5 parts of dipalmitoylphosphatidylethanolamine;

[0064] The carrier is 12.9 parts of modified sodium carboxymethyl cellulose.

[0065] Preparation of modified sodium carboxymethyl cellulose: Grind sodium carboxymethyl cellulose into powder, add it to water at a solid-liquid ratio of 1:9 g / mL, add allylamine, the mass ratio of allylamine to sodium carboxymethyl cellulose is 0.5:1, perform the first electron beam irradiation for 30 min (dose of 50 kGy), add polyethylene glycol, the mass ratio of polyethylene glycol to sodium carboxymethyl cellulose is 0.5:1, perform the second electron beam irradiation for 60 min (dose of 30 kGy), filter through a reverse osmosis membrane with a pore size of 0.3 μm to obtain modified sodium carboxymethyl cellulose.

[0066] The preparation method of the active composition comprises: (1) crushing tangerine peel, gypsum, platycodon, liquorice and aster, adding them into a 50% v / v ethanol-potassium carbonate two-phase aqueous system (the volume of ethanol and potassium carbonate is 1:3) at a solid-liquid ratio of 1:10 g / mL, performing ultrasonic extraction at 250W and 60°C for 30 minutes, and collecting extract A;

[0067] (2) Crush coltsfoot flower, pinellia ternata, poria cocos and rhizoma anemarrhenae, add them into a 40% v / v isopropanol-ammonium sulfate aqueous two-phase system (the volume of isopropanol and ammonium sulfate is 1:5) at a solid-liquid ratio of 1:8 g / mL, and extract them under microwave at 450 W and 50 °C for 10 min, and collect extract B;

[0068] (3) Crush dried orange peel, bitter almond, perilla seed, Trichosanthes peel, Ophiopogon japonicus and Rehmannia glutinosa, add into a 50% v / v ethanol-ammonium sulfate-sodium dodecyl sulfate two-phase aqueous system (the volume of ethanol to ammonium sulfate and sodium dodecyl sulfate is 1:4:0.3) at a solid-liquid ratio of 1:20 g / mL, and extract by ultrasonic extraction at 300 W and 60 ° C for 60 min, and collect extract C;

[0069] (4) The extracts A, B and C were combined, 70% v / v ethanol was added for alcohol precipitation, and the mixture was concentrated under reduced pressure to obtain an active composition.

[0070] The preparation method of the above-mentioned high-stability cough-relieving tangerine peel granules specifically comprises the following steps:

[0071] (1) adding modified sodium carboxymethyl cellulose to water at a solid-liquid ratio of 1:20 g / mL, and then adding the active composition and the auxiliary materials in sequence, stirring at 60° C. and 500 rpm for 60 min to obtain a material;

[0072] (2) freeze-drying the material to obtain granules, crushing and sieving to obtain the target cough-relieving tangerine peel granules.

[0073] Comparative Example 1

[0074] The difference between this comparative example and Example 1 is that the auxiliary material lacks β-glucan, and the missing weight is allocated to other components according to the ratio of pueraria polysaccharide, β-carotene and dipalmitoylphosphatidylethanolamine. The rest is consistent with Example 1.

[0075] Comparative Example 2

[0076] The difference between this comparative example and Example 1 is that the auxiliary material lacks pueraria polysaccharide, and the missing weight is allocated to other components according to the ratio of β-glucan, β-carotene and dipalmitoylphosphatidylethanolamine. The rest is consistent with Example 1.

[0077] Comparative Example 3

[0078] The difference between this comparative example and Example 1 is that the auxiliary material lacks β-carotene, and the missing weight is allocated to other components according to the ratio of β-glucan, kudzu polysaccharide and dipalmitoylphosphatidylethanolamine. The rest is consistent with Example 1.

[0079] Comparative Example 4

[0080] The difference between this comparative example and Example 1 is that the auxiliary material lacks dipalmitoylphosphatidylethanolamine, and the missing weight is allocated to other components according to the ratio of β-glucan, β-carotene and pueraria polysaccharide. The rest is consistent with Example 1.

[0081] Comparative Example 5

[0082] The difference between this comparative example and Example 1 is that the carrier is sodium carboxymethyl cellulose, and the rest is the same as Example 1.

[0083] The preparation method of the high-stability cough-relieving tangerine peel granules in this comparative example specifically comprises the following steps:

[0084] (1) adding sodium carboxymethyl cellulose to water at a solid-liquid ratio of 1:15 g / mL, and then adding the active composition and the excipients in sequence, stirring at 55° C. and 400 rpm for 45 min to obtain a material;

[0085] (2) freeze-drying the material to obtain granules, crushing and sieving to obtain the target cough-relieving tangerine peel granules.

[0086] Comparative Example 6

[0087] The difference between this comparative example and Example 1 is that the preparation method of the active composition is prepared according to the preparation method of patent CN111632105A, and the rest is consistent with Example 1.

[0088] The preparation method of the active composition of this comparative example comprises:

[0089] (1) decocting gypsum with water for 3 times, adding 10 times the amount of water for the first time and decocting for 1 hour, adding 8 times the amount of water for the second and third times and decocting for 1 hour, filtering, and concentrating the filtrate to obtain a concentrated solution for later use;

[0090] (2) The remaining 14 herbs were decocted twice, with 8 times the amount of water added for 2 hours for the first time and 8 times the amount of water added for the second time for 2 hours, filtered, and the filtrate was concentrated to a relative density of about 1.05, ethanol was added to make the alcohol content reach 60%, and the supernatant after alcohol precipitation for 24 hours was taken, filtered, and the filtrate was concentrated to recover ethanol until there was no alcohol taste;

[0091] (3) The gypsum concentrate and the alcohol concentrate are combined and concentrated to a relative density of about 1.35, and weighed to obtain an extract, i.e., the active composition.

[0092] Comparative Example 7

[0093] The difference between this comparative example and Example 1 is that the active composition is extracted by alcohol extraction, and the rest is consistent with Example 1.

[0094] The preparation method of the active composition of this comparative example comprises: grinding fifteen kinds of herbs including tangerine peel, gypsum, platycodon, liquorice, aster, coltsfoot flower, pinellia, tuckahoe, anemarrhena, tangerine peel, bitter almond, perilla seed, trichosanthes peel, ophiopogon and rehmannia, adding the powder to an ethanol solution with a concentration of 60% v / v at a solid-liquid ratio of 1:9 g / mL, performing ultrasonic extraction at 200 W and 55° C. for 60 min, collecting the extract, and concentrating under reduced pressure to obtain the active composition.

[0095] Test Example 1

[0096] The cough-relieving tangerine peel granules prepared in Examples 1-3 and Comparative Examples 1-7 were subjected to stability tests.

[0097] Test method: The cough-relieving tangerine peel granules prepared in Examples 1-3 and Comparative Examples 1-7 were placed in a watch dish, opened and placed under light (4500lux±500lux) and high temperature (60°C) for 30 days, and samples were taken at 0 day and 30 days respectively; the cough-relieving tangerine peel granules prepared in Examples 1-3 and Comparative Examples 1-7 were placed in an environment of temperature 45°C±2°C and relative humidity 80%±5% for 6 months for accelerated testing, and samples were taken for content detection and changes in total impurities.

[0098] Among them, the detection method for detecting the sample content of Examples 1-3 and Comparative Examples 1-7 is as follows: S1, preparing the test solution: grind the cough-relieving orange red granules, weigh 0.5 g, accurately weigh, place in a 100 mL conical flask, accurately add 50 mL of methanol solution, weigh, ultrasonically treat at 360 W, 40 KHz for 60 min, cool to room temperature, weigh, make up the lost weight with methanol solution, shake and filter, take the filtrate to obtain the test solution; S2, prepare the mixed reference solution: accurately weigh 11.24 mg of naringin reference substance, place in a 50 mL volumetric flask, add methanol solution to dissolve and dilute to the scale, shake well to obtain naringin reference substance solution; accurately weigh orange 10.33 g of naringin reference substance was placed in a 50 mL volumetric flask, and methanol solution was added to dissolve and diluted to the scale, and shaken to obtain hesperidin reference substance solution; 10 mL of naringin reference substance solution and 3 mL of hesperidin reference substance solution were accurately drawn and mixed, and methanol solution was added to dilute to 25 mL to obtain a mixed reference substance solution. S3. High performance liquid chromatography determination: 20 μL of the test solution and the mixed reference substance solution were accurately drawn and injected into a high performance liquid chromatograph (with octadecylsilane bonded silica gel as the filler, acetonitrile-phosphoric acid solution with a volume ratio of 14:84 as the mobile phase, the detection wavelength was 283 nm, the column temperature was 30°C, and the flow rate was 1.0 mL / min). The results are shown in Table 1.

[0099] Table 1

[0100]

[0101]

[0102]

[0103] It can be seen from the stability test in Table 1 that, relative to Comparative Examples 1-7, the cough-relieving tangerine peel granules prepared in Examples 1-3 are obtained by a specific extraction method to obtain an active composition, and add excipients and carriers of specific composition, and have high stability. Under the conditions of light (4500 lux ± 500 lux), high temperature (60° C.), and accelerated 6-month test, the stability is better than that of Comparative Examples 1-7, and there is no significant difference in the content of naringin and hesperidin, the quality is stable, and the application prospect is good.

[0104] Test Example 2

[0105] The cough-relieving tangerine peel granules prepared in Example 1 and the commercially available cough-relieving granules (purchased from Guangzhou Huacheng Pharmaceutical Factory) were tested for cough-relieving and expectorant effects;

[0106] Modeling method: buy 60 healthy mice (100g ± 10g), half male and half female, put mice into a beaker of 1000mL, the beaker mouth is sealed with preservative film and two mouths are opened, one of which is used to insert the ultrasonic atomizer outlet pipe (ultrasonic atomizer preheating, adding 50mL of 13wt% ammonia), and the other is a ventilation hole. Then the ultrasonic atomizer continues to pass into 60s ammonia with maximum spraying power, immediately closes and quickly opens the preservative film, and ammonia in the beaker is naturally diffused. While passing into ammonia, observe and record the number of coughs of mice in 3min, if the cough latency (time of starting cough for the first time) is 12s-50s, the number of coughs (mouse abdominal muscle contraction, open mouth at the same time, there is coughing) for 3min is 10-80 times, represents that modeling is successful, and the result is that all modelings of 60 mice are successful.

[0107] Drug administration and grouping method: 60 mice with successful modeling were randomly divided into 3 groups, namely (commercially available group, Example 1 group and blank group). The Example 1 group was gavaged with the cough-relieving tangerine red granules prepared in Example 1 (distilled water was added to make a 0.1 g / mL solution) for 5 days, with a dose of 10 mL / kg, twice a day. The commercially available group was gavaged with commercially available phlegm-relieving cough granules (distilled water was added to make a 0.1 g / mL solution) for 5 days, with a dose of 10 mL / kg, twice a day. The blank group was gavaged with the same volume of distilled water (10 mL / kg). The number of coughs and the cough latency time within 3 min were observed and recorded.

[0108] 30 minutes after the last administration, each mouse was intraperitoneally injected with 0.5% phenol red 10mL / kg. One hour later, the mice were killed by air embolism. The mice were fixed in a supine position on a frog board to separate the trachea. 0.5mL of 5% NaHCO3 solution was injected into the mouse trachea. The respiratory tract was repeatedly flushed back and forth 3 times. The flushing fluid was collected and repeated 2 more times according to the above method. The flushing fluid was combined and centrifuged (speed 1000rpm, 5min), and the absorbance of the supernatant was measured at 546nm. The concentration was calculated according to the regression equation of the phenol red standard curve.

[0109] The results are shown in Table 2.

[0110] Table 2

[0111] sample Cough latency time (s) Number of coughs in 3 minutes (times) Phenol red excretion (ug / kg) Blank Group 32.4 105 0.21 Example 1 Group 70.5 41 0.30 Commercially available group 54.7 68 0.24

[0112] As can be seen from Table 2, the cough-relieving tangerine peel granules prepared in Example 1 of the present invention are better at prolonging the cough latency time and reducing the number of coughs than the commercially available expectorant and cough-relieving granules and the blank group, have a good expectorant effect, and have a good market prospect.

[0113] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims

1. A highly stable cough-relieving tangerine peel granule, characterized in that: It consists of an active composition, excipients and a carrier; The active composition is composed of 1-3 parts of gypsum, 3-5 parts of tangerine peel, 3-5 parts of coltsfoot flower, 1-3 parts of pinellia tuber, 1-3 parts of tuckahoe, 1-2 parts of platycodon, 0.5-1.0 parts of bitter almond, 1-2 parts of aster, 0.5-1.5 parts of perilla seed, 1-2 parts of trichosanthes peel, 0.5-1.0 parts of anemarrhena, 0.5-1.5 parts of ophiopogon, 1-2 parts of rehmannia root and 1-3 parts of liquorice in parts by weight; The preparation method of the active composition comprises: (1) crushing Citrus aurantium, gypsum, Platycodon grandiflorum, Licorice root and Aster tataricus, adding them into an ethanol-potassium carbonate aqueous two-phase system, performing ultrasonic extraction, and collecting extract A; (2) Crush coltsfoot flower, pinellia ternata, poria cocos and rhizoma anemarrhenae, add them into an isopropanol-ammonium sulfate aqueous two-phase system, perform microwave extraction, and collect extract B; (3) Crush dried orange peel, bitter almond, perilla seed, Trichosanthes peel, Ophiopogon japonicus and Rehmannia glutinosa, add to ethanol-ammonium sulfate-sodium dodecyl sulfate aqueous two-phase system, perform ultrasonic extraction, and collect extract C; (4) combining extract A, extract B and extract C, adding 60%-70% v / v ethanol for alcohol precipitation, and concentrating under reduced pressure to obtain an active composition; The auxiliary material is composed of 1-2 parts of β-glucan, 1-3 parts of kudzu root polysaccharide, 0.5-0.8 parts of β-carotene and 3-5 parts of dipalmitoyl phosphatidylethanolamine in parts by weight; The carrier is modified sodium carboxymethyl cellulose, and the mass ratio of the carrier to the active composition is 0.1-0.3:1; The preparation method of the modified sodium carboxymethyl cellulose comprises: grinding the sodium carboxymethyl cellulose into powder, adding the powder into water, adding allylamine, performing electron beam radiation treatment for the first time, adding polyethylene glycol, performing electron beam radiation for the second time, filtering through a reverse osmosis membrane, and obtaining the modified sodium carboxymethyl cellulose.

2. The high-stability cough-relieving tangerine peel granules according to claim 1, characterized in that: In the preparation method of modified sodium carboxymethyl cellulose, the solid-liquid ratio of sodium carboxymethyl cellulose to water is 1:5-9 g / mL; the mass ratio of allylamine to sodium carboxymethyl cellulose to polyethylene glycol is 0.1-0.5:1:0.1-0.5; the dose of the first electron beam radiation is 10-50 kGy, and the time is 20-30 min; the dose of the second electron beam radiation is 10-30 kGy, and the time is 30-60 min; and the pore size of the reverse osmosis membrane is 0.1-0.3 μm.

3. The high-stability cough-relieving tangerine peel granules according to claim 1, characterized in that: In the preparation method of the active composition, in step (1), the solid-liquid ratio of the tangerine peel, gypsum, platycodon, liquorice and aster to the ethanol-potassium carbonate two-phase aqueous system is 1:8-10 g / mL; the concentration of the ethanol-potassium carbonate two-phase aqueous system is 30-50% v / v, wherein the volume of ethanol to potassium carbonate is 1:1-3; the ultrasonic extraction is performed at 150-250W and 50-60°C for 20-30min; In step (2), the solid-liquid ratio of the coltsfoot flower, pinellia tuber, poria cocos and rhizoma anemarrhenae to the isopropanol-ammonium sulfate two-phase aqueous system is 1:6-8 g / mL; the concentration of the isopropanol-ammonium sulfate two-phase aqueous system is 20-40% v / v, wherein the volume of isopropanol and ammonium sulfate is 1:3-5; the microwave extraction is performed at 350-450 W and 40-50° C. for 5-10 min; In step (3), the solid-liquid ratio of the dried tangerine peel, bitter almond, perilla seed, trichosanthes peel, ophiopogon japonicus and rehmannia root to the ethanol-ammonium sulfate-sodium dodecyl sulfate two-phase aqueous system is 1:10-20 g / mL; the concentration of the ethanol-ammonium sulfate-sodium dodecyl sulfate two-phase aqueous system is 40-50% v / v, wherein the volume of ethanol to ammonium sulfate and sodium dodecyl sulfate is 1:2-4:0.1-0.3; and the ultrasonic extraction is performed at 200-300 W and 50-60° C. for 40-60 min.

4. The method for preparing the cough-relieving tangerine peel granules with high stability as claimed in claim 1, characterized in that: The specific steps include: (1) adding modified sodium carboxymethyl cellulose to water, and then adding the active composition and auxiliary materials in sequence, stirring evenly to obtain a material; (2) freeze-drying the material to obtain granules, crushing and sieving to obtain the target cough-relieving tangerine peel granules.

5. The method for preparing the cough-relieving tangerine peel granules with high stability as claimed in claim 4, characterized in that: In step (1), the solid-liquid ratio of the modified sodium carboxymethyl cellulose to water is 1:10-20 g / mL; the stirring time is 30-60 min, the temperature is 50-60° C., and the rotation speed is 300-500 rpm.

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