Preparation method of infantile cough and asthma treating granules

Abstract

The preparation method comprises the following steps: (1) carrying out water extraction on trichosanthes kirilowii maxim, gypsum, semen armeniacae amarae, liquorice and radix isatidis to obtain medicine residues and a first extracting solution; (2) mixing herba ephedrae, honeysuckle flowers and the medicine residues in the step (1), performing water extraction to obtain a second extracting solution, mixing the first extracting solution and the second extracting solution, and performing concentration to obtain a fluid extract; (3) carrying out alcohol precipitation, filtration and concentration on the fluid extract to obtain a thick extract; in the extraction process, by controlling the relative density of a fluid extract and a thick extract in the extraction process, controlling the amount of added ethanol in alcohol precipitation and filtering the thick extract while the thick extract is hot in the last step, the content of ephedrine and chlorogenic acid can be effectively increased, the content of impurities is reduced, and the side effects of the impurities are reduced; and the safety of the product is improved. Meanwhile, the traditional Chinese medicine composition provided by the invention can be effectively used for resisting new coronavirus.

Description

Technical Field

[0001] The invention relates to the field of traditional Chinese medicine preparations, and in particular to a method for preparing pediatric Kechuanling granules. Background Art

[0002] Pediatric cough is a common and frequent lung disease in pediatrics. It can occur in all seasons, but is more common in winter and spring. Due to the physiological and pathological characteristics of children, Western medicine focuses on the use of antiviral drugs, but there are many adverse reactions. Traditional Chinese medicine is widely used in the treatment and prevention of various diseases due to its advantages of few side effects, significant efficacy, low price, and easy availability.

[0003] Xiaoer Kechuanling Granule is a traditional Chinese medicine compound preparation. Its main ingredients are seven traditional Chinese medicines: ephedra, honeysuckle, bitter almond, isatis root, gypsum, licorice, and trichosanthes. It tastes sweet, spicy, and slightly bitter. It can clear lung heat, relieve cough and expectorant. It is mostly used for cough caused by upper respiratory tract infection and can effectively improve the lung function and clinical symptoms of children with bronchitis, pneumonia, and asthma. In the prescription, ephedra can diaphoretically relieve the exterior, relieve lung heat and relieve asthma; gypsum is good at clearing heat from the lungs and stomach, and can be used together with ephedra to clear heat in the qi; bitter almond can lower qi, relieve cough and asthma; trichosanthes can clear heat and remove phlegm, widen the chest and disperse knots; isatis root and honeysuckle can clear heat and detoxify, and also have anti-inflammatory and immunomodulatory effects; licorice can relieve cough and expectorant, and has hormone-like effects, which can reduce inflammatory reactions. The whole prescription treats both the symptoms and the root causes, and plays a role in clearing lung heat, relieving cough and relieving asthma.

[0004] A study of the formula of Xiaoer Kechuanling found that ephedra and honeysuckle are the main drugs, and ephedrine is one of the ingredients with clear efficacy, with good quantitative control. The main ingredient in honeysuckle is chlorogenic acid, which has a wide range of life activities. If the content of these two ingredients can be effectively increased in the process, it can provide better therapeutic effects.

[0005] In the process of extracting medicinal materials, the relative density of the extract is a relatively important indicator. If the relative density is large, then in addition to the active ingredients, there will be other impurities such as polysaccharides, proteins, tannins, etc. in the extract. A large amount of impurities will remain in the extract, which will bring side effects to the application of the drug, thereby limiting the efficacy of the drug; at the same time, it is not suitable to mix evenly with the excipients during granulation. If the relative density is small, the content of the active ingredient is low, and the efficacy of the drug is also affected.

[0006] In patent CN115252683A, when the density of the thick extract is 1.10-1.14, the particle size index of the prepared particles is better; when the relative density of the extract is 1.10, the particle size index is the best; in patent CN100477984C, the relative density of the fluid extract is 1.09, and the density of the thick extract is 1.22; in patent CN101249161B, the relative density of the fluid extract is 1.32-1.35, and the relative density of the thick extract is 1.33; in patent CN110292597A, the relative density of the fluid extract is 1.06, and the relative density of the thick extract is 1.24-1.29 or 1.32-1.36.

[0007] Therefore, controlling the relative density of the extract can play a better role in the quality and efficacy of the drug. Summary of the invention

[0008] In order to solve the above problems, the present invention provides a kind of pediatric Kechuanling granules and a preparation method and application thereof.

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

[0010] In a first aspect, the present invention provides a method for preparing pediatric Kechuanling granules, which comprises the following steps:

[0011] (1) extracting the root of Trichosanthes kirilowii, gypsum, bitter almond, liquorice and isatis root with water to obtain a residue and a first extract;

[0012] (2) extracting the residues of ephedra and honeysuckle together with the residues of step (1) with water to obtain a second extract, combining the first extract and the second extract, and concentrating to obtain a fluid extract;

[0013] (3) alcohol precipitation of the fluid extract, filtering, and concentrating to obtain a thick extract;

[0014] (4) Preparation, granulation and granulation selection;

[0015] (5) Add the selected granules into the main mixing barrel and mix them.

[0016] In step (2), the mixture is concentrated to a relative density of 1.12-1.44; and / or, in step (3), the mixture is concentrated to a relative density of 1.20-1.48.

[0017] In a second aspect, the present invention provides a Chinese medicine composition, which is prepared by the following method, comprising the following steps:

[0018] (1) extracting Trichosanthes kirilowii, gypsum, bitter almond, liquorice and isatis root with water to obtain medicinal residues and a first extract;

[0019] (2) extracting the residues of ephedra and honeysuckle together with the residues of step (1) with water to obtain a second extract, combining the first extract and the second extract, and concentrating to obtain a fluid extract;

[0020] (3) alcohol precipitation of the fluid extract, filtering, and concentrating to obtain a thick extract;

[0021] (4) Preparation, granulation and granulation selection;

[0022] (5) Add the selected granules into the main mixing barrel and mix them.

[0023] In step (2), the mixture is concentrated to a relative density of 1.12-1.44; and / or, in step (3), the mixture is concentrated to a relative density of 1.20-1.48.

[0024] The dosage form of the Chinese medicine composition includes granules, capsules and the like.

[0025] In the first and second aspects above, the specific parameter steps are as follows:

[0026] In some embodiments, the mass ratio of Trichosanthes kirilowii, gypsum, bitter almond, licorice, indigo plant, ephedra, and honeysuckle is 1:1.8-9:0.6-3:1.2-3.6:0.12-0.36:1.2-3.6, preferably 1:2.4-6:0.8-2:1.6-2.4:0.16-0.24:1.6-2.4, and further preferably 1:3:1:2:0.2:2.

[0027] In step (1), the mass of water added is 4-20 times, preferably 5-15 times, and more preferably 6-10 times the total mass of Trichosanthes kirilowii, gypsum, bitter almond, liquorice and Radix Isatidis.

[0028] In step (1), the water extraction temperature is 80°C.

[0029] In step (1), the water extraction time is 0.1-4h, preferably 0.3-3h, and more preferably 0.5-2h.

[0030] In step (2), the mass of water added is 3.5-10.5 times, preferably 4-9 times, and more preferably 4.5-7.5 times, of the total mass of ephedra, honeysuckle and the residue after water extraction in step (1).

[0031] In step (2), the water extraction time is 0.1-4h, preferably 0.3-3h, and more preferably 0.5-2h.

[0032] In step (2), the water extraction temperature is 80°C.

[0033] In step (2), the relative density is concentrated to 1.15-1.33, preferably 1.18-1.22; preferably, the relative density is concentrated to 1.12-1.44 at 60°C, preferably 1.15-1.33, and more preferably 1.18-1.22.

[0034] In step (3), the amount of alcohol used for alcohol precipitation is 0.6-1.8 times the mass of the fluid extract, preferably 0.7-1.5 times, and more preferably 0.8-1.2 times.

[0035] In step (3), ethanol precipitation is performed with ethanol;

[0036] In step (3), the relative density is concentrated to 1.20-1.48, preferably 1.24-1.40, and more preferably 1.28-1.32; preferably, the relative density is concentrated to 1.20-1.48, preferably 1.24-1.40, and more preferably 1.28-1.32 at 60-70°C.

[0037] In step (3), step (3) is to precipitate the fluid extract with alcohol, stir, refrigerate and stand, filter, concentrate, and filter while hot to obtain a thick extract;

[0038] The refrigerated standing time is 8-52 hours, preferably 10-50 hours, and more preferably 12-48 hours;

[0039] The refrigerated storage temperature is -4 to 12°C, preferably -2 to 10°C, and more preferably 0 to 8°C.

[0040] The hot filtration is hot screening, preferably hot filtration through a 170-250 mesh sieve, more preferably hot filtration through a 175-240 mesh sieve, and even more preferably hot filtration through a 180-230 mesh sieve; after hot screening, the obtained permeate is a thick extract.

[0041] The concentration method described in the present invention includes concentration under reduced pressure.

[0042] The filtering method described in the present invention includes plate and frame filtration.

[0043] In some embodiments, in step (4), the preparation, granulation and granulation are specifically carried out in the following manner: the thick extract is mixed with sucrose and dextrin, granulated, sieved and granulated, and granulated.

[0044] In some embodiments, the mixing of the thick extract with sucrose and dextrin, granulation, sieving and selecting the granules specifically comprises the following steps: primary granulation: in a granulator, part of the thick extract is mixed with sucrose, dextrin and alcohol, granulated, dried to obtain dry granules; secondary granulation: the obtained dry granules are mixed with alcohol and the remaining thick extract, granulated, dried, sieved and selected; in some embodiments, the alcohol is ethanol.

[0045] In the primary granulation, the mass ratio of dextrin to sucrose is 1:0.6-9, preferably 1:0.8-6, and more preferably 1:1-3; preferably, the mass ratio of alcohol to dextrin is 1:180-720, preferably 1:210-600, and more preferably 1:240-480; preferably, the mass of the added part of the thick extract is 30-90% of the total mass of the thick extract, preferably 40-80%, and more preferably 50-70%.

[0046] In the primary granulation, the obtained dry granules are crushed into 40-80 meshes before use.

[0047] In the secondary granulation, the mass ratio of alcohol to dextrin is 1:25.6-192, preferably 1:32-128, and more preferably 1:38.4-64.

[0048] In some embodiments, the sucrose is crushed into 60-120 mesh before use.

[0049] In step (5), the mixing time is 3-15 min, preferably 4-10 min, and more preferably 5 min.

[0050] In some embodiments, the preparation method of the pediatric Kechuanling granules specifically comprises the following steps:

[0051] (1) adding 6-10 times the amount of water to Trichosanthes kirilowii, gypsum, bitter almond, liquorice, and Radix Isatidis, extracting at 80° C. for 0.5-2 hours, filtering, and obtaining a residue and a first extract;

[0052] (2) combining ephedra, honeysuckle and the residues of step (1), adding 4.5-7.5 times the amount of water, extracting at 80° C. for 0.5-2 hours, filtering to obtain a second extract, combining the first extract and the second extract, and concentrating under reduced pressure to a relative density of 1.18-1.22 at 60° C. to obtain a fluid extract;

[0053] (3) Add 0.8-1.2 times the amount of ethanol to the fluid extract, stir, refrigerate at 0-8°C for 12-48 hours, filter, concentrate to a relative density of 1.28-1.32 at 60-70°C, filter through a 180-230 mesh sieve while hot to obtain a thick extract;

[0054] (4) primary granulation: pour sucrose powder and dextrin into a wet mixing granulator, add ethanol, stir and mix for 30-60 seconds, add 50-70% of the total weight of the thick extract, mix for 2-12 seconds to obtain wet granules, and dry to obtain dry granules;

[0055] Secondary granulation: the above dry granules are crushed and added to a wet mixing granulator, ethanol is added, and the mixture is stirred for 25-70 seconds, the remaining thick extract is evenly added, and the mixture is mixed for 4-16 seconds. The obtained wet granules are granulated through a 12-20 mesh sieve, and dried to obtain dry granules; the dry granules are sized through a 10-14 mesh sieve, and then granulated through a 10-14 mesh sieve. The granules that do not pass through are sized and granulated through a 40-60 mesh sieve to obtain granules after granulation;

[0056] (5) adding the selected granules into the main mixing barrel and mixing them to obtain Xiaoer Kechuanling granules;

[0057] In the third aspect, the present invention also provides the use of the above-mentioned Xiaoer Kechuanling granules in the preparation of drugs for treating lung-clearing, heat-clearing, cough-relieving and expectorant, or in the preparation of anti-new coronavirus drugs.

[0058] In a fourth aspect, the present invention provides an application of a traditional Chinese medicine composition in the preparation of anti-new coronavirus drugs; preferably, the virus is a wild-type new coronavirus; preferably, the traditional Chinese medicine composition is made of Trichosanthes kirilowii, gypsum, bitter almond, licorice, isatis root, ephedra, and honeysuckle; preferably, the mass ratio of Trichosanthes kirilowii, gypsum, bitter almond, licorice, isatis root, ephedra, and honeysuckle is 1:1.8-9:0.6-3:1.2-3.6:0.12-0.36:1.2-3.6, preferably 1:2.4-6:0.8-2:1.6-2.4:0.16-0.24:1.6-2.4, and further preferably 1:3:1:2:0.2:2.

[0059] In some embodiments, the Chinese medicine composition is prepared by extraction according to conventional techniques in the art, or prepared according to the preparation method of the first aspect above, and the preparation method comprises the following steps:

[0060] (1) extracting Trichosanthes kirilowii, gypsum, bitter almond, liquorice and isatis root with water to obtain medicinal residues and a first extract;

[0061] (2) extracting the residues of ephedra and honeysuckle together with the residues of step (1) with water to obtain a second extract, combining the first extract and the second extract, and concentrating to obtain a fluid extract;

[0062] (3) alcohol precipitation of the fluid extract, filtering, and concentrating to obtain a thick extract;

[0063] In step (2), the mixture is concentrated to a relative density of 1.12-1.44;

[0064] And / or, in step (3), the mixture is concentrated to a relative density of 1.20-1.48.

[0065] In some embodiments, the parameters and steps in the above method are the same as those in the preparation methods of the first and second aspects described above.

[0066] In some embodiments, the dosage form of the Chinese medicine composition includes granules, capsules, etc.

[0067] The beneficial effects of the present invention are:

[0068] 1. In the extraction process of the present invention, by controlling the relative density of the fluid extract and the thick extract during the extraction process, controlling the amount of ethanol added during the alcohol precipitation, and filtering the thick extract while hot in the last step, the impurity content is reduced while ensuring that the content of ephedrine and chlorogenic acid can be effectively increased, the side effects of impurities are reduced, and the safety of the product is improved.

[0069] 2. Two-step granulation is adopted in the granulation process to ensure the forming rate of the particles during the granulation process, and the whole process improves the stability of the product.

[0070] 3. The Chinese medicine composition provided by the present invention can be effectively used to fight against the new coronavirus. DETAILED DESCRIPTION

[0071] The experimental methods described in the following examples are conventional methods unless otherwise specified; the reagents and materials described are commercially available unless otherwise specified.

[0072] In the following examples, all Chinese medicinal materials were purchased from Anhui Shengantang Pharmaceutical Co., Ltd.

[0073] Example 1 Preparation method of Xiaoer Kechuanling granules

[0074] (1) adding 8 times the amount of water to 125 kg of Trichosanthes kirilowii, 375 kg of gypsum, 125 kg of bitter almond, 125 kg of liquorice, and 250 kg of Radix Isatidis, and extracting at 80° C. for 1 hour to obtain a medicinal residue and a first extract;

[0075] (2) combining 25 kg of Ephedra sinica and 250 kg of Honeysuckle with the residues of step (1), adding 6 times the amount of water, extracting at 80° C. for 1 hour, combining the filtrates, and concentrating the extract under reduced pressure to a relative density of 1.18-1.22 (measured at 60° C.), to obtain 564 kg of a fluid extract;

[0076] (3) Add 1 times the amount of ethanol to the fluid extract, stir, refrigerate at 0-8°C for 30 hours, filter on a plate and frame, concentrate to a relative density of 1.28-1.32 (measured at 60-70°C), filter through a 200-mesh sieve while hot, and obtain 180 kg of thick extract;

[0077] (4) primary granulation: 90 mesh sucrose is crushed, 192 kg sucrose powder and 96 kg dextrin are poured into a wet mixing granulator, 0.2-0.4 kg ethanol is added, and the mixture is stirred for 45-50 seconds, 60% of the total weight of the thick extract is evenly added, and the mixture is mixed for 4-8 seconds to obtain wet granules, and the wet granules are dried by hot air circulation at 60-70° C. for 6 hours to obtain dry granules;

[0078] Secondary granulation: the above dry granules are crushed into 50 mesh, the crushed materials are added into a wet mixing granulator, 1.5-2.5 kg of ethanol is added, the stirring mixing time is 45-50 seconds, the remaining thick extract is evenly added, and mixed for 8-12 seconds. The obtained wet granules are granulated with 16 mesh, and then dried by hot air circulation at 60-70°C for 15 hours to obtain dry granules; the dry granules are sieved with a 12 mesh sieve, and then sieved with a 12 mesh / 60 mesh sieve, and the granules that do not pass the 12 mesh sieve are sieved and selected to obtain the selected granules;

[0079] (5) Add the selected granules into the main mixing barrel and mix for 5 minutes to obtain the Children's Kechuanling Granules.

[0080] Example 2 Preparation method of children's Kechuanling granules

[0081] (1) adding 6 times the amount of water to 125 kg of Trichosanthes kirilowii, 375 kg of gypsum, 125 kg of bitter almond, 125 kg of liquorice, and 250 kg of Radix Isatidis, and extracting at 80° C. for 2 hours to obtain a medicinal residue and a first extract;

[0082] (2) combining 25 kg of Ephedra sinica and 250 kg of Honeysuckle with the residues of step (1), adding 7.5 times the amount of water, extracting at 80° C. for 2 hours, combining the filtrates, and concentrating the extract under reduced pressure to a relative density of 1.18-1.22 (measured at 60° C.), to obtain 487 kg of a fluid extract;

[0083] (3) Add 0.8 times the amount of ethanol to the fluid extract, stir, refrigerate at 0-8°C for 12 hours, filter on a plate and frame, concentrate to a relative density of 1.28-1.32 (measured at 60-70°C), filter through a 180-mesh sieve while hot, and obtain 145 kg of thick extract;

[0084] (4) primary granulation: crush sucrose into 60 mesh size, pour 96 kg sucrose powder and 96 kg dextrin into a wet mixing granulator, add 0.2-0.4 kg ethanol, stir and mix for 30-45 seconds, add 50% of the total weight of the thick extract evenly, mix for 2-4 seconds to obtain wet granules, dry the wet granules by hot air circulation at 60-70° C. for 8 hours to obtain dry granules;

[0085] Secondary granulation: the dry granules are crushed into 40 mesh, the crushed materials are added into a wet mixing granulator, 1.5-2.5 kg of ethanol is added, the stirring mixing time is 25-45 seconds, the remaining thick extract is evenly added, and the mixture is mixed for 4-8 seconds. The obtained wet granules are granulated with 12 mesh, and then dried by hot air circulation at 70-80°C for 20 hours to obtain dry granules; the dry granules are sized with a 14 mesh sieve, and then sieved with 14 mesh / 40 mesh, and the granules that do not pass through the 14 mesh sieve are sized and selected to obtain the selected granules;

[0086] (5) Add the selected granules into the main mixing barrel and mix for 5 minutes to obtain the Children's Kechuanling Granules.

[0087] Example 3 Preparation method of Xiaoer Kechuanling granules

[0088] (1) adding 10 times the amount of water to 125 kg of Trichosanthes kirilowii, 375 kg of gypsum, 125 kg of bitter almond, 125 kg of liquorice, and 250 kg of Radix Isatidis, and extracting at 80° C. for 0.5 hour to obtain a medicinal residue and a first extract;

[0089] (2) combining 25 kg of Ephedra sinica and 250 kg of Honeysuckle with the residues of step (1), adding 4.5 times the amount of water, extracting at 80° C. for 0.5 hour, combining the filtrates, and concentrating the extract under reduced pressure to a relative density of 1.18-1.22 (measured at 60° C.), to obtain 548 kg of a fluid extract;

[0090] (3) Add 1.2 times the amount of ethanol to the fluid extract, stir, refrigerate at 0-8°C for 48 hours, filter on a plate and frame, concentrate to a relative density of 1.28-1.32 (measured at 60-70°C), filter through a 230-mesh sieve while hot, and obtain 165 kg of thick extract;

[0091] (4) primary granulation: 120 mesh sucrose is crushed, 288 kg sucrose powder and 96 kg dextrin are poured into a wet mixing granulator, 0.2-0.4 kg ethanol is added, and the mixture is stirred for 40-60 seconds, 70% of the total weight of the thick extract is evenly added, and the mixture is mixed for 8-12 seconds to obtain wet granules, and the wet granules are dried by hot air circulation at 60-70° C. for 4 hours to obtain dry granules;

[0092] Secondary granulation: the above dry granules are crushed into 80 mesh, the crushed materials are added to a wet mixing granulator, 1.5-2.5 kg of ethanol is added, the stirring mixing time is 50-70 seconds, the remaining thick extract is evenly added, and mixed for 12-16 seconds, the obtained wet granules are granulated with 20 mesh, and then dried by hot air circulation at 50-60°C for 10 hours to obtain dry granules; the dry granules are sieved with a 10 mesh sieve, and then sieved with a 10 mesh / 80 mesh sieve, and the granules that do not pass through the 10 mesh sieve are sieved and selected to obtain the selected granules;

[0093] (5) Add the selected granules into the main mixing barrel and mix for 5 minutes to obtain the Children's Kechuanling Granules.

[0094] Comparative Example 1 Preparation method of Xiaoer Kechuanling granules (density of extract and extraction process in CN 110292597 A)

[0095] Extraction step, take gypsum 3.75kg, bitter almond 1.25kg, licorice 1.25kg, isatis root 2.5kg and trichosanthes 1.25kg five flavors of medicinal materials, put them into a multifunctional extraction tank, add 10 times the amount of water, boil for 1 hour, filter, and obtain the residue and the first filtrate;

[0096] Then, the extraction step is performed, and then 0.25 kg of Ephedra sinica and 2.5 kg of Honeysuckle are added to the residue, 9 times the amount of water is added, and the mixture is boiled at 80° C. for 1 hour, filtered, and a second filtrate is obtained;

[0097] The mixing and thick paste preparation step comprises mixing and stirring the first filtrate and the second filtrate, standing for 2 hours, taking the supernatant, placing the obtained supernatant in a ZN-C1000 type vacuum concentration tank and concentrating it into a fluid extract with a relative density of 1.06 (85-90° C. thermal measurement), placing the fluid extract and one times the amount of ethanol with a mass fraction of 95% in an alcohol precipitation tank, stirring evenly, refrigerating and standing for 36 hours at 2-10° C., taking the supernatant, recovering the ethanol, and concentrating it into a thick paste with a relative density of 1.36-1.40 (75-80° C. thermal measurement relative density);

[0098] Primary granulation: crush sucrose into 90 meshes, pour 1.92 kg sucrose powder and 0.96 kg dextrin into a wet mixing granulator, add 0.002-0.004 kg ethanol, stir and mix for 45-50 seconds, add 60% of the total weight of the thick extract evenly, mix for 4-8 seconds to obtain wet granules, dry the wet granules by hot air circulation at 60-70°C for 10 hours to obtain dry granules;

[0099] Secondary granulation: the dry granules are crushed into 60 mesh, the crushed materials are added into a wet mixing granulator, 0.015-0.025 kg of ethanol is added, the stirring mixing time is 45-50 seconds, the remaining thick extract is evenly added, and the mixture is mixed for 8-12 seconds. The obtained wet granules are granulated with 16 mesh, and then dried by hot air circulation at 60-70° C. for 15 hours to obtain dry granules; the dry granules are sized with a 12 mesh sieve, and then sieved with 12 mesh / 60 mesh, and the granules that do not pass through the 12 mesh sieve are sized and selected to obtain the selected granules;

[0100] Add the selected granules into the main mixing barrel and mix for 5 minutes to obtain the Children's Kechuanling Granules.

[0101] Comparative Example 2 Preparation method of Xiaoer Kechuanling granules (density of extract and extraction process in CN 110292597 A)

[0102] Extraction step, take gypsum 3.75kg, bitter almond 1.25kg, licorice 1.25kg, isatis root 2.5kg and trichosanthes 1.25kg five flavors of medicinal materials, put them into a multifunctional extraction tank, add 10 times the amount of water, boil for 1 hour, filter, and obtain the residue and the first filtrate;

[0103] Then, the extraction step is performed, and then 0.25 kg of ephedra and 2.5 kg of honeysuckle are added to the residue, 9 times the amount of water is added, and the mixture is boiled for 1 hour, filtered, and a second filtrate is obtained;

[0104] The mixing and thick paste preparation step comprises mixing and stirring the first filtrate and the second filtrate, standing for 2 hours, taking the supernatant, placing the obtained supernatant in a ZN-C1000 type vacuum concentration tank and concentrating it into a fluid extract with a relative density of 1.06 (85-90° C. thermal measurement), placing the fluid extract and one times the amount of ethanol with a mass fraction of 95% in an alcohol precipitation tank, stirring evenly, refrigerating and standing for 36 hours at 2-10° C., taking the supernatant, recovering the ethanol, and concentrating it into a thick paste with a relative density of 1.24-1.29 (75-80° C. thermal measurement relative density);

[0105] Primary granulation: crush sucrose into 90 meshes, pour 1.92 kg sucrose powder and 0.96 kg dextrin into a wet mixing granulator, add 0.002-0.004 kg ethanol, stir and mix for 45-50 seconds, add 60% of the total weight of the thick extract evenly, mix for 4-8 seconds to obtain wet granules, dry the wet granules by hot air circulation at 60-70°C for 10 hours to obtain dry granules;

[0106] Secondary granulation: the dry granules are crushed into 60 mesh, the crushed materials are added into a wet mixing granulator, 0.15-0.25 kg of ethanol is added, the stirring mixing time is 45-50 seconds, the remaining thick extract is evenly added, and the mixture is mixed for 8-12 seconds. The obtained wet granules are granulated with 16 mesh, and then dried by hot air circulation at 60-70°C for 15 hours to obtain dry granules; the dry granules are sieved with a 12 mesh sieve, and then sieved with a 12 mesh / 60 mesh sieve, and the granules that do not pass the 12 mesh sieve are sieved and selected to obtain the selected granules;

[0107] Add the selected granules into the main mixing barrel and mix for 5 minutes to obtain the Children's Kechuanling Granules.

[0108] Comparative Example 3 Preparation method of pediatric Kechuanling granules (preparation method of pediatric Kechuanling granules in CN 115252683 A)

[0109] (1) Add 3.75 kg of gypsum, 1.25 kg of bitter almonds, 1.25 kg of liquorice, 2.5 kg of isatis root, and 1.25 kg of trichosanthes to 12 times the amount of water and boil for 1 hour, then filter;

[0110] (2) boiling the residue from step (1), 0.25 kg of ephedra, and 2.5 kg of honeysuckle with 8 times the amount of water for 1 hour, and filtering;

[0111] (3) combining the filtrates from step (1) and step (2), allowing the mixture to stand, taking the supernatant, and concentrating the supernatant to obtain a fluid extract;

[0112] (4) Add one times the amount of ethanol, stir well, refrigerate for 12-48 hours, filter out the supernatant, recover the ethanol, and concentrate at 55-65°C to a relative density of 1.10 (55-65°C);

[0113] (5) Add sucrose powder and dextrin in a weight ratio of 2:1 for one-step granulation. The granulation process parameters are as follows:

[0114] Material temperature: 55-65℃;

[0115] Atomization pressure: 0.05-0.08MPa;

[0116] Feed speed: 12-16rpm;

[0117] Air intake frequency: 25-45HZ;

[0118] The bag shaking time is set to 60S and the number of times is set to 3 times;

[0119] (6) Drying, controlling the moisture content below 3%, passing through a No. 1 sieve, mixing for 10 minutes, and packaging, 2 g / bag.

[0120] Example 4 Determination of the content of chlorogenic acid and ephedrine in the prepared Xiaoer Kechuanling granules

[0121] The content determination was carried out by high performance liquid chromatography (HPLC) in the literature "Optimization of Quality Standards for Xiaoer Kechuanling Granules" to simultaneously determine the contents of ephedrine hydrochloride and chlorogenic acid.

[0122] The contents of chlorogenic acid and ephedrine hydrochloride in Examples 1-3 and Comparative Examples 1-2 were measured and are shown in the following table.

[0123] Table 1 Chlorogenic acid and ephedrine hydrochloride content in samples

[0124]

[0125] Example 5 Antiviral test of the Xiaoer Kechuanling granules prepared

[0126] This experiment is commissioned to other qualified units for testing

[0127] 1. Test materials

[0128] 1.1 Drugs

[0129] The Xiaoer Kechuanling granules prepared in Example 1 of the present invention, the concentration of the drug solution of the present invention is: 12 mg / mL (1 mL DMSO dissolves 120 mg of the drug, and then 9 mL DMEM culture medium is added) (containing 100 U / mL double antibody (penicillin and streptomycin) and 2% FBS, vortexed for 5 minutes, placed in a 4°C refrigerator for 12 hours, vortexed for another 5 minutes, and filtered through a 0.22 μM filter).

[0130] 1.2 Cells: African green monkey kidney cells (Vero-E6)

[0131] 1.3. Virus: Wild-type novel coronavirus [2019-nCoV, Wild-type (Wt)] (commercially available)

[0132] 1.4 Reagents

[0133] Virus diluent: DMEM medium, containing double antibodies (penicillin and streptomycin) at a final concentration of 100 U / mL, without serum;

[0134] Drug diluent: DMEM medium, containing double antibodies (penicillin and streptomycin) at a final concentration of 100 U / mL, without serum;

[0135] Cell culture medium: DMEM medium, containing double antibodies (penicillin and streptomycin) at a final concentration of 100 U / mL and 10% FBS;

[0136] Fetal bovine serum (FBS);

[0137] DMEM medium;

[0138] 1×PBS (pH 7.4);

[0139] 0.25% trypsin-EDTA (Trypsin 2.5 g, EDTA-Na2 0.34 g dissolved in 1×PBS 1000 mL, filtered through a 0.22uM filter);

[0140] DMSO.

[0141] 2. Experimental Methods

[0142] 2.1 Cells: VERO-E6 cells, after spreading into a monolayer, the antiviral test of the drug of the present invention was carried out

[0143] Virus: SARS-CoV-2 (Wt), 100 TCID50 / well virus inoculated cells.

[0144] Drug: The drug of the present invention was tested at 200, 100, 50, 25, 12.5, 6.25, 3.12, 1.57, 0.78, and 0.39 μg / mL; the virus and the drug were incubated at 37° C. for 1 h before inoculation into the cells, and a normal cell control and a positive virus control were set up.

[0145] Observation: CPE was observed 72 hours after virus infection.

[0146] 3. Results

[0147] CPE observation: 72 hours after virus infection, there was no CPE in the normal cell control group; CPE was obvious in the virus control group; different drug concentrations showed different inhibitory effects on CPE, as shown in Table 2. According to the EC50 calculation formula for the half effective concentration of the drug to inhibit the virus, EC50 = 78.85 μg / mL was obtained.

[0148] 4. Conclusion

[0149] A certain concentration of the drug of the present invention can inhibit the formation of CRE by wild-type new coronavirus on Vero E6 cells.

[0150] Table 2 The results of the present invention inhibiting the formation of CPE by Wt virus on Vero E6 cells ("+" has CPE, representing negative antiviral infection, "-" has no CPE, representing positive antiviral infection)

[0151]

[0152] Example 6 The yield of the Xiaoer Kechuanling granules

[0153] Weigh 5 bags of the product on an analytical balance, place them in the specified sieve, keep them horizontal and sieve them back and forth, tapping them for 3 minutes. Collect the particles and powder that cannot pass through the No. 1 sieve and can pass through the No. 5 sieve, weigh them, and calculate their proportion (%). Yield = 1-the proportion of particles and powder that cannot pass through the No. 1 sieve and can pass through the No. 5 sieve.

[0154] Table 3 Yield rate measured in samples

[0155] sample Yield rate (%) Example 1 98.3 Example 2 97.2 Example 3 97.7 Comparative Example 1 96.2 Comparative Example 2 96.8 Comparative Example 3 89.7

[0156] It can be seen from the above data that while ensuring the yield, the content of chlorogenic acid and ephedrine in the sample prepared by the preparation method of the present invention is higher, and it can also be effectively used to fight against the new coronavirus.

[0157] The above-mentioned embodiments only express several implementation methods of the present invention, and the description thereof is relatively specific and detailed, but it cannot be understood as limiting the scope of the patent of the present invention. It should be pointed out that, for ordinary technicians in this field, several variations and improvements can be made without departing from the concept of the present invention, which all belong to the protection scope of the present invention. Therefore, the protection scope of the patent of the present invention shall be subject to the attached claims.

Claims

1. A method for preparing pediatric Kechuanling granules, characterized in that: The following steps are involved: (1) extracting Trichosanthes kirilowii, gypsum, bitter almond, liquorice and isatis root with water to obtain medicinal residues and a first extract; (2) extracting the residues of ephedra and honeysuckle together with the residues of step (1) with water to obtain a second extract, combining the first extract and the second extract, and concentrating to obtain a fluid extract; (3) alcohol precipitation of the fluid extract, filtering, and concentrating to obtain a thick extract; In step (2), the mixture is concentrated to a relative density of 1.12-1.44; And / or, in step (3), the mixture is concentrated to a relative density of 1.20-1.

48.

2. A Chinese medicine composition, characterized in that: The method is as follows: (1) extracting the root of Trichosanthes kirilowii, gypsum, bitter almond, liquorice and isatis root with water to obtain a residue and a first extract; (2) extracting the residues of ephedra and honeysuckle together with the residues of step (1) with water to obtain a second extract, combining the first extract and the second extract, and concentrating to obtain a fluid extract; (3) alcohol precipitation of the fluid extract, filtering, and concentrating to obtain a thick extract; In step (2), the mixture is concentrated to a relative density of 1.12-1.44; And / or, in step (3), the mixture is concentrated to a relative density of 1.20-1.

48.

3. The preparation method according to claim 1 or the Chinese medicine composition according to claim 2, characterized in that: In step (1), the mass of water added is 4-20 times, preferably 5-15 times, and more preferably 6-10 times the total mass of Trichosanthes kirilowii, gypsum, bitter almond, liquorice, and Radix Isatidis; Preferably, the water extraction time is 0.1-4 h, preferably 0.3-3 h, and more preferably 0.5-2 h.

4. The preparation method according to claim 1 or the Chinese medicine composition according to claim 2, characterized in that: In step (2), the mass of water added is 3.5-10.5 times, preferably 4-9 times, and more preferably 4.5-7.5 times, of the total mass of ephedra, honeysuckle and the residue after water extraction in step (1); Preferably, the water extraction time is 0.1-4h, preferably 0.3-3h, and more preferably 0.5-2h; Preferably, the relative density is concentrated to 1.15-1.33, preferably 1.18-1.22; preferably, the relative density is concentrated to 1.12-1.44 at 60°C, preferably 1.15-1.33, and more preferably 1.18-1.

22.

5. The preparation method according to claim 1 or the Chinese medicine composition according to claim 2, characterized in that: In step (3), the amount of alcohol used for alcohol precipitation is 0.6-1.8 times the mass of the fluid extract, preferably 0.7-1.5 times, and more preferably 0.8-1.2 times; Preferably, ethanol is used for alcohol precipitation; Preferably, the relative density is concentrated to 1.20-1.48, preferably 1.24-1.40, and more preferably 1.28-1.32; preferably, the relative density is concentrated to 60-70°C, preferably 1.20-1.48, preferably 1.24-1.40, and more preferably 1.28-1.

32.

6. The preparation method according to claim 1 or the Chinese medicine composition according to claim 2, characterized in that: Step (3) is to precipitate the fluid extract with alcohol, stir, refrigerate and stand, filter, concentrate, and filter while hot to obtain a thick extract; Preferably, the refrigerated standing time is 8-52h, preferably 10-50h, and more preferably 12-48h; Preferably, the refrigerated storage temperature is -4 to 12°C, preferably -2 to 10°C, and more preferably 0 to 8°C; Preferably, the hot filtration is hot filtration through a 170-250 mesh sieve, preferably hot filtration through a 175-240 mesh sieve, and preferably hot filtration through a 180-230 mesh sieve.

7. The preparation method according to claim 1 or the Chinese medicine composition according to claim 2, characterized in that: The following steps are also included: (4) mixing the thick extract with sucrose and dextrin, granulating, sieving and selecting the granules; Preferably, the mixing of the thick extract with sucrose and dextrin, granulation, sieving and granulation, and granulation selection are specifically as follows: primary granulation: in a granulator, part of the thick extract is mixed with sucrose, dextrin and alcohol, granulated, dried, and dry granules are obtained; secondary granulation: the obtained dry granules are mixed with alcohol and the remaining thick extract, granulated, dried, sieved and granulated, and granules are selected; Preferably, in one granulation, the mass ratio of dextrin to sucrose is 1:0.6-9, preferably 1:0.8-6, and more preferably 1:1-3; preferably, the mass ratio of alcohol to dextrin is 1:180-720, preferably 1:210-600, and more preferably 1:240-480; preferably, the mass of the added part of the thick extract is 30-90% of the total mass of the thick extract, preferably 40-80%, and more preferably 50-70%; Preferably, in the secondary granulation, the mass ratio of alcohol to dextrin is 1:25.6-192, preferably 1:32-128, and more preferably 1:38.4-64.

8. The preparation method or Chinese medicine composition according to claim 7, characterized in that: The following steps are also included: (5) Add the selected particles into the main mixing barrel and mix them; Preferably, the mixing time is 3-15 min, preferably 4-10 min, and more preferably 5 min.

9. The preparation method according to claim 1 or the Chinese medicine composition according to claim 2, characterized in that: The steps include: (1) adding 6-10 times the amount of water to Trichosanthes kirilowii, gypsum, bitter almond, liquorice, and isatis indigo, extracting at 80° C. for 0.5-2 hours, filtering, and obtaining a residue and a first extract; (2) combining ephedra, honeysuckle and the residues of step (1), adding 4.5-7.5 times the amount of water, extracting at 80° C. for 0.5-2 hours, filtering to obtain a second extract, combining the first extract and the second extract, and concentrating under reduced pressure to a relative density of 1.18-1.22 at 60° C. to obtain a fluid extract; (3) Add 0.8-1.2 times the amount of ethanol to the fluid extract, stir, refrigerate at 0-8°C for 12-48 hours, filter, concentrate to a relative density of 1.28-1.32 at 60-70°C, filter through a 180-230 mesh sieve while hot to obtain a thick extract; (4) primary granulation: pour sucrose powder and dextrin into a wet mixing granulator, add ethanol, stir and mix for 30-60 seconds, add 50-70% of the total weight of the thick extract, mix for 2-12 seconds to obtain wet granules, and dry to obtain dry granules; Secondary granulation: the above dry granules are crushed and added to a wet mixing granulator, ethanol is added, and the mixture is stirred for 25-70 seconds, the remaining thick extract is evenly added, and the mixture is mixed for 4-16 seconds. The obtained wet granules are granulated through a 12-20 mesh sieve, and dried to obtain dry granules; the dry granules are sized through a 10-14 mesh sieve, and then granulated through a 10-14 mesh sieve. The granules that do not pass through are sized and granulated through a 40-60 mesh sieve to obtain granules after granulation; (5) adding the selected granules into the main mixing barrel and mixing them to obtain Xiaoer Kechuanling granules; Preferably, the mass ratio of the Trichosanthes kirilowii, gypsum, bitter almond, liquorice, isatis root, ephedra and honeysuckle is 1:1.8-9:0.6-3:1.2-3.6:0.12-0.36:1.2-3.6, preferably 1:2.4-6:0.8-2:1.6-2.4:0.16-0.24:1.6-2.4, and further preferably 1:3:1:2:0.2:

2.

10. Use of the Xiaoer Kechuanling Granules prepared by the method of claim 1 or the Chinese medicine composition of claim 2 in the preparation of drugs for treating lung-clearing, heat-clearing, cough-relieving and expectorant, or in the preparation of drugs against the new coronavirus.

11. Use of a traditional Chinese medicine composition in the preparation of an anti-new coronavirus drug; preferably, the virus is a wild-type new coronavirus; preferably, the traditional Chinese medicine composition is made of Trichosanthes kirilowii, gypsum, bitter almond, licorice, isatis root, ephedra, and honeysuckle; preferably, the mass ratio of the Trichosanthes kirilowii, gypsum, bitter almond, licorice, isatis root, ephedra, and honeysuckle is 1:1.8-9:0.6-3:1.2-3.6:0.12-0.36:1.2-3.6, preferably 1:2.4-6:0.8-2:1.6-2.4:0.16-0.24:1.6-2.4, and further preferably 1:3:1:2:0.2:2; preferably, the preparation method of the traditional Chinese medicine composition comprises the following steps: (1) extracting the root of Trichosanthes kirilowii, gypsum, bitter almond, liquorice and isatis root with water to obtain a residue and a first extract; (2) extracting the residues of ephedra and honeysuckle together with the residues of step (1) with water to obtain a second extract, combining the first extract and the second extract, and concentrating to obtain a fluid extract; (3) alcohol precipitation of the fluid extract, filtering, and concentrating to obtain a thick extract; In step (2), the mixture is concentrated to a relative density of 1.12-1.44; And / or, in step (3), the mixture is concentrated to a relative density of 1.20-1.48.

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