A preparation method of children's Kechuanling granules

Abstract

The present invention provides a method for preparing pediatric cough and asthenia granatum granules, comprising the following steps: (1) taking gypsum, bitter almond, liquorice and trichosanthes, adding water, decocting, filtering, and obtaining liquid A and residue; (2) taking the residue, ephedra and isatis root of step (1), adding water, adjusting the pH to 6.5-7.5, maintaining at a temperature of 45-50°C for 20-30min, adding honeysuckle, decocting, filtering, and obtaining liquid B; (3) combining liquid A and liquid B, standing, taking supernatant, and obtaining liquid C; concentrating; (4) adding ethanol, refrigerating; (5) recovering ethanol, concentrating and collecting paste; (6) mixing sucrose powder, dextrin and extract; (7) drying; (8) granulating. The present invention improves the total amount of ephedrine hydrochloride and pseudoephedrine hydrochloride and the content of chlorogenic acid as a whole through process adjustment, shortens the processing time, effectively improves production efficiency, and can meet market demand faster.

Description

Technical Field

[0001] The invention relates to the technical field of pharmaceutical chemistry and provides a method for preparing pediatric Kechuanling granules. Background Art

[0002] Xiaoer Kechuanling Granules is a medicine made from Chinese medicines such as ephedra, honeysuckle, licorice, bitter almonds, and isatis root, and is often used to treat pediatric cough and asthma. The optimization of the preparation method of Xiaoer Kechuanling Granules is of great significance for improving drug quality, reducing costs, and meeting market demand. Chinese invention patent applications with application numbers 202310294107.0 and 202210976813.9 respectively disclose a method for preparing Xiaoer Kechuanling Granules, which have achieved certain results. However, there are still some shortcomings, including: ① It takes a long time: It takes a long time from the treatment of medicinal materials to the final preparation of the finished product. For example, after filtering, the extract needs to be left to stand and precipitate impurities. The standing time is as long as 48 hours, which seriously affects production efficiency. The reason for the need for long-term standing may be: due to the diverse sources of medicinal materials for Xiaoer Kechuanling Granules, there are many types of components in each medicinal material extract, and the solubility, stability and other properties of different components are different. In addition, chemical reactions may occur between different components, such as redox reactions, and the products of these reactions may also make the solution turbid, so a longer period of standing is required to allow the reaction to be complete and form a precipitate. ② Loss of active ingredients: During the preparation process, active ingredients such as ephedrine, pseudoephedrine, and chlorogenic acid are lost, resulting in an unsatisfactory content of active ingredients in the finished product. Although the Chinese invention patent with application number 202310294107.0 can solve this problem, the effect achieved is still unsatisfactory. Therefore, it is urgent to further optimize the preparation process of Pediatric Kechuanling Granules. It is necessary to comprehensively consider various factors, starting from the extraction of medicinal materials and other links, in order to increase the content of active ingredients in the product, shorten processing time, and reduce costs, so as to better meet the development requirements of the market. Summary of the invention

[0003] In view of the shortcomings of the prior art, the object of the present invention is to provide a method for preparing pediatric Kechuanling granules.

[0004] In order to achieve the above purpose, the scheme of the present invention is as follows:

[0005] A method for preparing pediatric Kechuanling granules comprises the following steps:

[0006] (1) Take gypsum, bitter almond, liquorice and Trichosanthes kirilowii, add water, decoct, filter, and obtain liquid A and residue;

[0007] (2) taking the residue, ephedra and isatis root of step (1), adding water, adjusting the pH to 6.5-7.5, maintaining the mixture at 45-50° C. for 20-30 min, adding honeysuckle, decocting, filtering, and obtaining liquid B;

[0008] (3) combining solution A and solution B, allowing them to stand, taking the supernatant to obtain solution C; and concentrating;

[0009] (4) Add ethanol and refrigerate;

[0010] (5) recovering ethanol and concentrating the paste;

[0011] (6) mixing sucrose powder, dextrin and extract;

[0012] (7) Drying;

[0013] (8) Whole grains.

[0014] In the extraction process of ephedra and honeysuckle, adjusting the pH to alkaline can improve the extraction rate of ephedrine, pseudoephedrine and other ingredients, but it is easy to reduce the extraction rate of chlorogenic acid. The study found that transferring the root of isatis to the extraction process of step 2 can effectively avoid this problem and improve the extraction rate of active ingredients such as ephedrine, pseudoephedrine and chlorogenic acid at the same time.

[0015] Preferably, the standing time in step (3) is at least 3 hours.

[0016] Preferably, the standing time in step (3) is 3 to 12 hours.

[0017] Preferably, the amount of water added in step (1) and step (2) is 6 times by weight respectively.

[0018] Preferably, the refrigeration time is at least 12 hours.

[0019] Preferably, in step (3), the solution is concentrated to a relative density of 1.16-1.21.

[0020] Preferably, in step (5), the mixture is concentrated to a relative density of 1.21-1.30.

[0021] Preferably, the mass ratio of sucrose powder to dextrin is 1:1.

[0022] Preferably, the mass ratio of the total amount of sucrose powder and dextrin to the extract is 1:10.

[0023] A kind of pediatric Kechuanling granules is prepared by the preparation method.

[0024] Compared with the prior art, the present invention has the following beneficial effects:

[0025] The present invention improves the total amount of ephedrine hydrochloride and pseudoephedrine hydrochloride and the content of chlorogenic acid as a whole through process adjustment, including the order of decoction of medicinal materials, pH adjustment, etc.

[0026] After the preparation method of the present invention is improved, impurities generated by changes in the conditions of the mixed solution are reduced, the precipitation time of impurities in the mixed filtrate is accelerated, and the standing time is shortened to 3 hours, thereby effectively improving production efficiency and being able to meet market demand more quickly. DETAILED DESCRIPTION

[0027] In order to better understand the technical content of the present invention, specific embodiments are provided below to further illustrate the present invention.

[0028] Unless otherwise specified, the experimental methods used in the embodiments of the present invention are all conventional methods.

[0029] Unless otherwise specified, the materials, reagents, etc. used in the embodiments of the present invention can be obtained from commercial sources.

[0030] Example 1: Preparation method of Xiaoer Kechuanling granules

[0031] Prescription medicine:

[0032]

[0033]

[0034] (1) Take gypsum, bitter almond, liquorice and Trichosanthes kirilowii, add 6 times the weight of water, boil for 1 hour, filter (filter membrane pore size 0.8 μm), and obtain liquid A and residue.

[0035] (2) Take the residue, ephedra and isatis root of step (1), add 6 times the weight of water, adjust the pH to 6.5-7.5 with hydrochloric acid or sodium hydroxide, keep at a temperature of 45-50°C for 20-30 minutes, then add honeysuckle, decoct for 1 hour, filter (filter membrane pore size 0.8 μm), and obtain liquid B.

[0036] (3) Combine solution A and solution B, let stand for 3 hours, take the supernatant to obtain solution C. Concentrate to a relative density of 1.16-1.21 (50°C)

[0037] (4) Add an equal volume of ethanol while stirring and refrigerate for 12 hours.

[0038] (5) Recovering ethanol and concentrating to obtain an extract: Under the conditions of a temperature of 80-90°C and a vacuum degree of 0.02-0.04 MPa, recover ethanol until there is no alcohol smell, and then turn on the vacuum pump to concentrate it to an extract with a relative density of 1.21-1.30 (80°C).

[0039] (6) First, mix equal amounts of sucrose powder and dextrin for 20 minutes, then add the extract at a mass ratio of 1:10 (sucrose powder and dextrin: extract) and mix for 20 minutes.

[0040] (7) Drying temperature: 65±5℃, drying time: 1.5±0.5 hours, moisture content of granules: ≤2.0%.

[0041] (8) After drying, the granules are screened with a 10-mesh sieve in a vibrating screen to remove coarse powder and a 60-mesh sieve to remove fine powder (the coarse powder and fine powder can be re-granulated and dried) to obtain the granules.

[0042] Example 2

[0043] The prescription of the Kechuanling granules for children is the same as that of Example 1. In the preparation method of the Kechuanling granules for children, the mixing and standing time in step 3 is 12 hours. Specifically:

[0044] (1) Take gypsum, bitter almond, liquorice and Trichosanthes kirilowii, add 6 times the weight of water, boil for 1 hour, filter (filter membrane pore size 0.8 μm), and obtain liquid A and residue.

[0045] (2) Take the residue, ephedra and isatis root of step (1), add 6 times the weight of water, adjust the pH to 6.5-7.5 with hydrochloric acid or sodium hydroxide, keep at a temperature of 45-50°C for 20-30 minutes, then add honeysuckle, decoct for 1 hour, filter (filter membrane pore size 0.8 μm), and obtain liquid B.

[0046] (3) Combine solution A and solution B, let stand for 12 hours, take the supernatant to obtain solution C. Concentrate to a relative density of 1.16-1.21 (50°C)

[0047] (4) Add an equal volume of ethanol while stirring and refrigerate for 12 hours.

[0048] (5) Recovering ethanol and concentrating to obtain an extract: Under the conditions of a temperature of 80-90°C and a vacuum degree of 0.02-0.04 MPa, recover ethanol until there is no alcohol smell, and then turn on the vacuum pump to concentrate it to an extract with a relative density of 1.21-1.30 (80°C).

[0049] (6) First, mix equal amounts of sucrose powder and dextrin for 20 minutes, then add the extract at a mass ratio of 1:10 (sucrose powder and dextrin: extract) and mix for 20 minutes.

[0050] (7) Drying temperature: 65±5℃, drying time: 1.5±0.5 hours, moisture content of granules: ≤2.0%.

[0051] (8) After drying, the granules are screened with a 10-mesh sieve in a vibrating screen to remove coarse powder and a 60-mesh sieve to remove fine powder (the coarse powder and fine powder can be re-granulated and dried) to obtain the granules.

[0052] Comparative Example 1:

[0053] The prescription of Xiaoer Kechuanling Granules is the same as that of Example 1. The preparation method of Xiaoer Kechuanling Granules is as follows:

[0054] (1) Take gypsum, bitter almond, liquorice, isatis root and trichosanthes, add 6 times the weight of water, boil for 1 hour, filter (filter membrane pore size 0.8 μm), and obtain liquid A and residue.

[0055] (2) Take the residue, ephedra and honeysuckle from step (1), add 6 times the weight of water, boil for 1 hour, filter (filter membrane pore size 0.8 μm), and obtain medicinal solution B.

[0056] (3) Combine solution A and solution B, let stand for 24 hours, take the supernatant to obtain solution C. Concentrate to a relative density of 1.16-1.21 (50°C);

[0057] (4) Add an equal volume of ethanol while stirring and refrigerate for 12 hours.

[0058] (5) Recovering ethanol and concentrating to obtain an extract: Under the conditions of a temperature of 80-90°C and a vacuum degree of 0.02-0.04 MPa, recover ethanol until there is no alcohol smell, and then turn on the vacuum pump to concentrate it to an extract with a relative density of 1.21-1.30 (80°C).

[0059] (6) First, mix equal amounts of sucrose powder and dextrin for 20 minutes, then add the extract at a mass ratio of 1:10 (sucrose powder and dextrin: extract) and mix for 20 minutes.

[0060] (7) Drying temperature: 65±5℃, drying time: 1.5±0.5 hours, moisture content of granules: ≤2.0%.

[0061] (8) After drying, the granules are screened with a 10-mesh sieve in a vibrating screen to remove coarse powder and a 60-mesh sieve to remove fine powder (the coarse powder and fine powder can be re-granulated and dried) to obtain the granules.

[0062] Comparative Example 2

[0063] The prescription of the Kechuanling granules for children is the same as that of Example 1. In the preparation method of the Kechuanling granules for children, the bitter almonds in step 1 and the isatis root in step 2 are interchanged, specifically:

[0064] (1) Take gypsum, isatis root, liquorice and trichosanthes, add 6 times the weight of water, boil for 1 hour, filter (filter membrane pore size 0.8 μm), and obtain liquid A and residue.

[0065] (2) Take the residue, ephedra and bitter almond from step (1), add 6 times the weight of water, adjust the pH to 6.5-7.5 with hydrochloric acid or sodium hydroxide, keep at 45-50°C for 20-30 minutes, then add honeysuckle, decoct for 1 hour, filter (filter membrane pore size 0.8 μm), and obtain liquid B.

[0066] (3) Combine solution A and solution B, let stand for 3 hours, take the supernatant to obtain solution C. Concentrate to a relative density of 1.16-1.21 (50°C)

[0067] (4) Add an equal volume of ethanol while stirring and refrigerate for 12 hours.

[0068] (5) Recovering ethanol and concentrating to obtain an extract: Under the conditions of a temperature of 80-90°C and a vacuum degree of 0.02-0.04 MPa, recover ethanol until there is no alcohol smell, and then turn on the vacuum pump to concentrate it to an extract with a relative density of 1.21-1.30 (80°C).

[0069] (6) First, mix equal amounts of sucrose powder and dextrin for 20 minutes, then add the extract at a mass ratio of 1:10 (sucrose powder and dextrin: extract) and mix for 20 minutes.

[0070] (7) Drying temperature: 65±5℃, drying time: 1.5±0.5 hours, moisture content of granules: ≤2.0%.

[0071] (8) After drying, the granules are screened with a 10-mesh sieve in a vibrating screen to remove coarse powder and a 60-mesh sieve to remove fine powder (the coarse powder and fine powder can be re-granulated and dried) to obtain the granules.

[0072] Comparative Example 3

[0073] The prescription of the Kechuanling granules for children is the same as that of Example 1. In the preparation method of the Kechuanling granules for children, the pH is not adjusted. Specifically:

[0074] (1) Take gypsum, bitter almond, liquorice and Trichosanthes kirilowii, add 6 times the weight of water, boil for 1 hour, filter (filter membrane pore size 0.8 μm), and obtain liquid A and residue.

[0075] (2) Take the residue, ephedra and isatis root of step (1), add 6 times the weight of water, keep at 45-50°C for 20-30 minutes, then add honeysuckle, decoct for 1 hour, filter (filter membrane pore size 0.8 μm), and obtain liquid B.

[0076] (3) Combine solution A and solution B, let stand for 3 hours, take the supernatant to obtain solution C. Concentrate to a relative density of 1.16-1.21 (50°C)

[0077] (4) Add an equal volume of ethanol while stirring and refrigerate for 12 hours.

[0078] (5) Recovering ethanol and concentrating to obtain an extract: Under the conditions of a temperature of 80-90°C and a vacuum degree of 0.02-0.04 MPa, recover ethanol until there is no alcohol smell, and then turn on the vacuum pump to concentrate it to an extract with a relative density of 1.21-1.30 (80°C).

[0079] (6) First, mix equal amounts of sucrose powder and dextrin for 20 minutes, then add the extract at a mass ratio of 1:10 (sucrose powder and dextrin: extract) and mix for 20 minutes.

[0080] (7) Drying temperature: 65±5℃, drying time: 1.5±0.5 hours, moisture content of granules: ≤2.0%.

[0081] (8) After drying, the granules are screened with a 10-mesh sieve in a vibrating screen to remove coarse powder and a 60-mesh sieve to remove fine powder (the coarse powder and fine powder can be re-granulated and dried) to obtain the granules.

[0082] Comparative Example 4

[0083] The prescription of Xiaoer Kechuanling Granules is the same as that of Example 1. In the preparation method of Xiaoer Kechuanling Granules, step 2 is to mix all the medicinal materials and directly decoct them for 1.5 hours.

[0084] (1) Take gypsum, bitter almond, liquorice and Trichosanthes kirilowii, add 6 times the weight of water, boil for 1 hour, filter (filter membrane pore size 0.8 μm), and obtain liquid A and residue.

[0085] (2) Take the residues, ephedra, isatis root, and honeysuckle from step (1), add 6 times the weight of water, boil for 1.5 hours, and filter (filter membrane pore size 0.8 μm) to obtain medicinal solution B.

[0086] (3) Combine solution A and solution B, let stand for 3 hours, take the supernatant to obtain solution C. Concentrate to a relative density of 1.16-1.21 (50°C)

[0087] (4) Add an equal volume of ethanol while stirring and refrigerate for 12 hours.

[0088] (5) Recovering ethanol and concentrating to obtain an extract: Under the conditions of a temperature of 80-90°C and a vacuum degree of 0.02-0.04 MPa, recover ethanol until there is no alcohol smell, and then turn on the vacuum pump to concentrate it to an extract with a relative density of 1.21-1.30 (80°C).

[0089] (6) First, mix equal amounts of sucrose powder and dextrin for 20 minutes, then add the extract at a mass ratio of 1:10 (sucrose powder and dextrin: extract) and mix for 20 minutes.

[0090] (7) Drying temperature: 65±5℃, drying time: 1.5±0.5 hours, moisture content of granules: ≤2.0%.

[0091] (8) After drying, the granules are screened with a 10-mesh sieve in a vibrating screen to remove coarse powder and a 60-mesh sieve to remove fine powder (the coarse powder and fine powder can be re-granulated and dried) to obtain the granules.

[0092] Ephedrine hydrochloride (C 10 H 15 NO·HCl) and pseudoephedrine hydrochloride (C10 H 15 The detection method of NO·HCl) is carried out according to the method under the content determination item of "Pediatric Kechuanling Oral Liquid" in the Part 1 of the Chinese Pharmacopoeia 2020.

[0093] Chlorogenic acid was detected by high performance liquid chromatography, which was improved with reference to relevant literature. The chromatographic conditions were:

[0094] Chromatographic column: Agilent ZORBAX XDB-C18 (250 mm × 4.6 mm, 5 μm); mobile phase: acetonitrile-0.2% phosphoric acid = 15:85; flow rate 1.0 ml min -1 ; Column temperature: 30℃; Measurement wavelength 325nm, injection volume 20μl.

[0095] The samples obtained from the examples and comparative examples were tested for the content of effective ingredients. The product test data are as follows:

[0096] Table 1

[0097]

[0098] The active ingredients of licorice, liquiritin and glycyrrhizic acid, the main ingredient of Radix Isatidis (R, S)-goitrin, and the main ingredient of bitter almond, amygdalin, were all detected at their maximum absorption wavelengths with reference to the detection method of chlorogenic acid. The results showed that the above main ingredients did not change significantly in the samples of the embodiments and comparative examples, indicating that the preparation methods of the embodiments and comparative examples had little effect on the content of the main ingredients such as liquiritin.

[0099] Analysis of the total amount of ephedrine hydrochloride and pseudoephedrine hydrochloride and the chlorogenic acid content of each sample in Table 1 shows that the preparation method of the embodiment is superior to the comparative example in terms of the total amount of ephedrine hydrochloride and pseudoephedrine hydrochloride and the chlorogenic acid content as a whole, and different process changes (such as the order of decoction of medicinal materials, pH adjustment, etc.) have different degrees of influence on the extraction and retention of the two active ingredients in the Children's Kechuanling Granules.

[0100] Compared with the embodiment, the content of ephedrine hydrochloride + pseudoephedrine hydrochloride and chlorogenic acid in comparative example 1 is significantly lower, and the extraction efficiency is lower. Comparative example 3 did not adjust the pH to 6.5-7.5, resulting in low contents of ephedrine hydrochloride + pseudoephedrine hydrochloride and chlorogenic acid. Comparative example 2 adjusted the pH, but did not add Radix Isatidis during extraction in step 2, resulting in an increase in the content of ephedrine hydrochloride and pseudoephedrine hydrochloride, but a decrease in the content of chlorogenic acid. While adjusting the pH in Example 1, Radix Isatidis was added to step 2, so that the contents of ephedra and chlorogenic acid were increased. The content of comparative example 4 is significantly lower than that of Example 1, and is equivalent to that of comparative example 1, indicating that simply extending the decoction time does not increase the content of effective ingredients such as ephedrine.

[0101] 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 method for preparing pediatric Kechuanling granules, characterized in that: The following steps are involved: (1) Take gypsum, bitter almond, liquorice and Trichosanthes kirilowii, add water, decoct, filter, and obtain liquid A and residue; (2) taking the residue, ephedra and isatis root of step (1), adding water, adjusting the pH to 6.5-7.5, maintaining the mixture at 45-50° C. for 20-30 min, adding honeysuckle, decocting, filtering, and obtaining liquid B; (3) combining solution A and solution B, allowing them to stand, taking the supernatant to obtain solution C; and concentrating; (4) Add ethanol and refrigerate; (5) recovering ethanol and concentrating the paste; (6) mixing sucrose powder, dextrin and extract; (7) Drying; (8) Whole grains.

2. The method for preparing the Xiaoer Kechuanling granules according to claim 1, characterized in that: The standing time in step (3) is at least 3 hours.

3. The method for preparing the Xiaoer Kechuanling granules according to claim 1, characterized in that: The standing time in step (3) is 3 to 12 hours.

4. The method for preparing the Xiaoer Kechuanling granules according to claim 1, characterized in that: The amount of water added in step (1) and step (2) is 6 times the weight respectively.

5. The method for preparing the Xiaoer Kechuanling granules according to claim 1, characterized in that: Refrigerate for at least 12 hours.

6. The method for preparing the Xiaoer Kechuanling granules according to claim 1, characterized in that: Step (3), concentrating to a relative density of 1.16-1.

21.

7. The method for preparing the Xiaoer Kechuanling granules according to claim 1, characterized in that: Step (5), concentrating to a relative density of 1.21-1.

30.

8. The method for preparing the Xiaoer Kechuanling granules according to claim 1, characterized in that: The mass ratio of sucrose powder to dextrin is 1:

1.

9. The method for preparing the Xiaoer Kechuanling granules according to claim 1, characterized in that: The mass ratio of the total amount of sucrose powder and dextrin to the extract is 1:

10.

10. A pediatric Kechuanling granule, characterized in that: The method is prepared according to any one of claims 1 to 9.

Images