Preparation method of Ganmaoqing capsule

Abstract

The invention belongs to the technical field of medicine preparation, and provides a preparation method of a Ganmaoqing capsule. The preparation method comprises the following steps: preparing a Ganmaoqing extract; then totally mixing the cold clearing dry extract, acetaminophen, herba andrographitis leaf powder, moroxydine hydrochloride, chlorpheniramine maleate and talcum powder to obtain medicinal powder; and filling the medicine powder into hollow capsules to obtain the traditional Chinese medicine composition. According to the preparation method disclosed by the invention, sterilization is carried out for 15-20 minutes at 121 DEG C when the raw medicinal powder, namely the andrographis paniculata leaf powder is prepared, so that the microbial limit of the andrographis paniculata leaf powder meets the requirement, and the microbial limit of the Ganmaoqing capsules meets the requirement when the andrographis paniculata leaf powder is used for preparing the Meanwhile, the Ganmaoqing dry extract, the acetaminophen, the common andrographis herb leaf powder, the moroxydine hydrochloride, the chlorpheniramine maleate and the talcum powder are totally mixed for 25-35 min in a three-dimensional motion mixer under the condition of 6.5 r / min, the uniformity of the chlorpheniramine maleate in the Ganmaoqing capsule is improved, and the quality stability of the Ganmaoqing capsule is improved.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical preparation technology, and in particular to a method for preparing a cold relief capsule. Background Technology

[0002] The main ingredients of Ganmaoling Capsules include Isatis tinctoria leaf, Isatis root, Calendula officinalis, acetaminophen, Andrographis paniculata, chlorpheniramine maleate, and moroxydine hydrochloride, among other medications. This is a compound preparation containing both traditional Chinese medicine ingredients and various Western medicines. It primarily functions to dispel wind and release the exterior, clear heat and detoxify, and also has antipyretic and antiviral effects. It can be used for symptoms such as fever, headache, nasal congestion, runny nose, sneezing, sore throat, and general muscle aches caused by wind-heat colds.

[0003] Currently, cold relief capsules can be mass-produced. However, during mass production, there are still issues such as uneven chlorpheniramine maleate content and excessive microbial limits in cold relief capsules. Summary of the Invention

[0004] In view of this, the purpose of this invention is to provide a method for preparing cold relief capsules. The cold relief capsules prepared by the method of this invention have a uniform content of chlorpheniramine maleate and stable quality; the microbial limits meet the requirements.

[0005] To achieve the above-mentioned objectives, the present invention provides the following technical solution: This invention provides a method for preparing cold relief capsules, comprising the following steps: The extract was obtained by mixing Isatis root, Isatis leaf, Calendula officinalis, Ilex chinensis, Sesamum indicum, and water. The extract was concentrated to obtain a thick paste; The thick paste was subjected to alcohol precipitation, filtration, collection, drying and pulverization in sequence to obtain a cold-relieving dry extract. The cold-clearing extract, acetaminophen, andrographis paniculata leaf powder, morpholine guanidine hydrochloride, chlorpheniramine maleate and talc are mixed together to obtain a medicinal powder; The powder is filled into an empty capsule to obtain the cold relief capsule; The preparation method of Andrographis paniculata leaf powder is as follows: Andrographis paniculata leaves are successively cleaned, washed, dried, sterilized, crushed and sieved to obtain Andrographis paniculata leaf powder; the sterilization temperature is 121℃ and the time is 15~20min. The equipment used for the overall mixing is a three-dimensional motion mixer, and the mixing speed is 5~10 revolutions per minute, and the time is 25~35 minutes.

[0006] Preferably, the cold relief capsules comprise the following components in prescribed amounts: 940 parts by weight of Isatis indigotica root, 400 parts by weight of Isatis tinctoria leaf, 660 parts by weight of Calendula officinalis and Dioscorea opposita, 860 parts by weight of Ilex chinensis, 460 parts by weight of Sesame aralia elata, 40 parts by weight of Andrographis paniculata leaf, 24 parts by weight of acetaminophen, 24 parts by weight of morpholine guanidine hydrochloride, 1 part by weight of chlorpheniramine maleate, and 300 parts by weight of talc.

[0007] Preferably, before the extraction of Isatis root, Isatis leaf, Calendula officinalis, Ilex chinensis, and Sesame officinalis with water, a pretreatment is also included, which includes one or more of the following: cleaning, cutting, washing, and drying.

[0008] Preferably, the mass ratio of the total mass of Isatis root, Isatis leaf, Calendula officinalis, Ilex chinensis and Sesame officinalis to water is 1:3~5; The extraction was carried out under boiling conditions; The extraction is performed 1 to 3 times, with each extraction lasting 1 to 2 hours.

[0009] Preferably, the equipment used for concentration is a double-effect concentrator. During the concentration process, the temperature of the first-effect evaporation chamber of the double-effect concentrator is 50~90℃ and the vacuum degree is 0.01~0.06MPa; the temperature of the second-effect evaporation chamber is 40~80℃ and the vacuum degree is 0.02~0.08MPa. The relative density of the paste at 60°C is 1.15 g / mL.

[0010] Preferably, the alcohol used for alcohol precipitation is ethanol, and the volume content of ethanol in the system during the alcohol precipitation process is 50-55%. The alcohol precipitation includes sequential stirring and settling, with the stirring time being 30 minutes and the settling time being 24 hours.

[0011] Preferably, the equipment used for collecting the paste is a single-effect concentrator, and the temperature of the evaporation chamber of the single-effect concentrator is 30~70℃, and the vacuum degree is 0.01~0.09MPa; The density of the paste obtained after the extraction is 1.25~1.30 g / mL at 60~65℃.

[0012] Preferably, in the process of preparing the cold-clearing dry extract, the drying equipment used is a hot air circulating oven, the drying temperature is 70~80℃, the drying time is 45~48h, and the moisture content of the material obtained after drying is ≤5.0%; the pulverization is carried out in a sieve with an 80-mesh aperture.

[0013] Preferably, before use, the cold-clearing extract, acetaminophen, andrographis paniculata leaf powder, morpholine guanidine hydrochloride, and talc powder are further subjected to pulverization and sieving in sequence; the pulverization equipment is a pulverizer, and the sieving screen has an aperture of 80 mesh. Before use, the chlorpheniramine maleate is also sieved manually using an 80-mesh sieve.

[0014] Preferably, in the process of preparing Andrographis paniculata leaf powder, the equipment used for pulverizing is a pulverizer, and the aperture of the sieve used for sieving is preferably 80 mesh.

[0015] This invention provides a method for preparing cold relief capsules.

[0016] The preparation method of this invention involves sterilizing the Andrographis paniculata leaf powder at 121°C for 15-20 minutes to ensure that the microbial limits of the Andrographis paniculata leaf powder meet the requirements. When used to prepare Ganmaoling capsules, this ensures that the microbial limits of Ganmaoling capsules also meet the requirements. Simultaneously, Ganmaoling dry extract, acetaminophen, Andrographis paniculata leaf powder, morpholine guanidine hydrochloride, chlorpheniramine maleate, and talc are mixed in a three-dimensional motion mixer at 5-10 rpm for 25-35 minutes, which improves the uniformity of chlorpheniramine maleate in Ganmaoling capsules and enhances the quality stability of Ganmaoling capsules. Attached Figure Description

[0017] Figure 1 The flowchart for preparing the cold relief capsules of this invention is shown below; Figure 1 In the diagram, the gray area represents an area that needs to be cleaned at a level D. Figure 2 This is a schematic diagram of the sampling points in the three-dimensional motion mixer during the total mixing process of this invention. Detailed Implementation

[0018] Figure 1 The following is a flowchart illustrating the preparation process of the cold relief capsules according to the present invention. Figure 1 The preparation method provided by the present invention will be described.

[0019] This invention provides a method for preparing cold relief capsules, comprising the following steps: The extract was obtained by mixing Isatis root, Isatis leaf, Calendula officinalis, Ilex chinensis, Sesamum indicum, and water. The extract was concentrated to obtain a thick paste; The thick paste was subjected to alcohol precipitation, filtration, collection, drying and pulverization in sequence to obtain a cold-relieving dry extract. The cold-clearing extract, acetaminophen, andrographis paniculata leaf powder, morpholine guanidine hydrochloride, chlorpheniramine maleate and talc are mixed together to obtain a medicinal powder; The powder is filled into an empty capsule to obtain the cold relief capsule; The preparation method of Andrographis paniculata leaf powder is as follows: Andrographis paniculata leaves are successively cleaned, washed, dried, sterilized, crushed and sieved to obtain Andrographis paniculata leaf powder; the sterilization temperature is 121℃ and the time is 15~20min. The equipment used for the overall mixing is a three-dimensional motion mixer, and the mixing speed is 5~10 revolutions per minute, and the time is 25~35 minutes.

[0020] Unless otherwise specified, the raw materials used in this invention are preferably commercially available products.

[0021] This invention involves mixing and extracting a mixture of Isatis indigotica root, Isatis tinctoria leaf, Calendula officinalis, Ilex chinensis, Sesamum indicum, and water to obtain an extract.

[0022] In this invention, before the extraction of Isatis root, Isatis leaf, Calendula officinalis, Ilex chinensis, and Sesame officinalis with water, pretreatment is preferably included. The pretreatment preferably includes one or more of the following: cleaning, cutting, washing, and drying.

[0023] In one specific embodiment of the present invention, when the medicinal materials are Isatis indigotica root and Sesame aralia, the pretreatment preferably includes sequentially performing cleaning, cutting, washing, and drying. The present invention does not specifically limit the cleaning operation. In the present invention, the cleaning is preferably performed on a sorting table. After cleaning, the amount of medicinal debris and impurities in the obtained medicinal materials preferably should not exceed 3%. In the present invention, the cutting is preferably performed by cutting the medicinal materials into segments or pieces no longer than 8 cm; the cutting is preferably performed on a WQY300 reciprocating medicine cutter. In the present invention, the reagent used for washing is preferably water. The present invention does not specifically limit the amount and number of times the reagent is used for washing, as long as the mud and impurities on the surface of the medicinal materials are cleaned. In the present invention, the washing is preferably performed in a washing tank. In the present invention, the drying temperature is preferably 70~80℃, and after drying, the moisture content in the medicinal materials is preferably ≤10.0%; the drying is preferably performed in a hot air circulating oven.

[0024] In one specific embodiment of the present invention, when the medicinal material is Isatis tinctoria leaf, the pretreatment preferably includes sequentially performing cleaning, washing, and drying. In the present invention, the cleaning, washing, and drying operations are preferably consistent with the above-described technical solution, and will not be repeated here.

[0025] In one specific embodiment of the present invention, when the medicinal materials are *Cephalotaxus fortunei* and *Ilex chinensis*, the pretreatment preferably includes sequential cleaning and cutting. In the present invention, the cleaning and cutting operations are preferably consistent with the above-described technical solution, and will not be repeated here.

[0026] In this invention, the preferred mass ratio of the total mass of Isatis root, Isatis leaf, Calendula officinalis, Ilex chinensis, and Sesame aralia to water is 1:3 to 5, specifically 1:3, 1:4, or 1:5. In this invention, the extraction is preferably carried out under boiling conditions. In this invention, the extraction is preferably performed 1 to 3 times, more preferably 2 times; the extraction time for each extraction is preferably 1 to 2 hours, specifically 1 hour or 2 hours.

[0027] In one specific embodiment of the present invention, the extraction is preferably performed twice, namely a first extraction and a second extraction; during the first extraction, the mass ratio of the total mass of Isatis indigotica root, Isatis tinctoria leaf, Dioscorea opposita, Ilex chinensis and Sesame officinalis to water is 1:4, and the extraction time is 2 hours; during the second extraction, the mass ratio of the total mass of the total mass of Isatis indigotica root, Isatis tinctoria leaf, Dioscorea opposita, Ilex chinensis and Sesame officinalis to water is 1:3, and the extraction time is 1 hour.

[0028] In this invention, the extraction is preferably carried out in an extraction tank.

[0029] After obtaining the extract, the present invention concentrates the extract to obtain a thick paste.

[0030] In this invention, the equipment used for concentration is preferably a double-effect concentrator. During the concentration process, the temperature of the first-effect evaporation chamber of the double-effect concentrator is preferably 50-90°C, specifically 70°C, 80°C, or 90°C; the vacuum degree is preferably 0.01-0.06 MPa, specifically 0.04 MPa, 0.05 MPa, or 0.06 MPa; the temperature of the second-effect evaporation chamber is preferably 40-80°C, specifically 60°C, 70°C, or 80°C; the vacuum degree is preferably 0.02-0.08 MPa, specifically 0.06 MPa, 0.07 MPa, or 0.08 MPa. In this invention, the relative density of the thick paste at 60°C is preferably 1.15 g / mL.

[0031] After obtaining the thick paste, the present invention sequentially performs alcohol precipitation, filtration, collection, drying and pulverization on the thick paste to obtain cold-clearing dry extract.

[0032] In this invention, the alcohol used for alcohol precipitation is preferably ethanol. In this invention, during the alcohol precipitation process, the volume content of ethanol in the system is preferably 50-55%, specifically preferably 52%, 53%, or 54%. In this invention, the alcohol precipitation preferably includes sequential stirring and settling, the stirring time is preferably 30 minutes, the settling time is preferably 24 hours, and the temperature is preferably 10-30°C. In this invention, the alcohol precipitation is preferably carried out in an alcohol precipitation tank.

[0033] This invention does not specifically limit the filtering method described herein.

[0034] In this invention, the equipment used for collecting the paste is preferably a single-effect concentrator. The temperature of the evaporation chamber of the single-effect concentrator is preferably 30~70℃, specifically 30℃, 40℃, 50℃, 60℃, or 70℃; the vacuum degree is preferably 0.01~0.09MPa, specifically 0.05MPa, 0.06MPa, 0.07MPa, 0.08MPa, or 0.09MPa. In this invention, the density of the paste obtained after collection at 60~65℃ is preferably 1.25~1.30g / mL.

[0035] In this invention, the drying equipment used is a hot air circulating oven, the drying temperature is preferably 70~80℃, the drying time is preferably 45~48h, and the moisture content of the material obtained after drying is preferably ≤5.0%. In a specific embodiment of this invention, the drying process is preferably as follows: the thick paste is evenly spread on a drying tray with a thickness ≤2cm, placed on a material cart, each cart is filled, and then pushed into the hot air circulating oven for drying.

[0036] In this invention, the pulverization is preferably carried out in a sieve, and the sieve aperture is preferably 80 mesh.

[0037] In this invention, the collection, drying, and pulverization are preferably carried out in an area with a cleanliness level of D.

[0038] In this invention, it is preferable to perform quality control on the cold-clearing extract, and the quality control indicators preferably include appearance, moisture content, identification and microbial limits; the quality control standards are shown in Table 1.

[0039] Table 1. Quality Control Standards for Cold Relief Extract

[0040] After obtaining the Cold Relief Extract, the present invention further mixes the Cold Relief Extract, acetaminophen, andrographis paniculata leaf powder, morpholine guanidine hydrochloride, chlorpheniramine maleate, and talc to obtain a medicinal powder.

[0041] In this invention, the cold-relieving extract, acetaminophen, andrographis paniculata leaf powder, morpholine guanidine hydrochloride, and talc powder are preferably further subjected to pulverization and sieving sequentially before use. In this invention, the pulverization equipment is preferably a pulverizer, specifically a 30BV dust-collecting pulverizer unit; the sieve used for sieving is preferably 80 mesh. In this invention, the chlorpheniramine maleate is preferably further subjected to sieving before use, preferably manually sieving using an 80-mesh pharmaceutical sieve.

[0042] In this invention, the process of sequentially pulverizing and sieving the cold-clearing extract, acetaminophen, andrographis paniculata leaf powder, morpholine guanidine hydrochloride, and talc before use is preferably carried out in a purification level D area. In this invention, the process of sieving the chlorpheniramine maleate before use is preferably carried out in a purification level D area.

[0043] In this invention, the preparation method of Andrographis paniculata leaf powder is as follows: Andrographis paniculata leaves are sequentially cleaned, washed, dried, sterilized, pulverized, and sieved to obtain the Andrographis paniculata leaf powder. In this invention, the cleaning, washing, and drying operations are preferably the same as those performed on Isatis indigotica leaves in the above-mentioned technical solution, and will not be repeated here. In this invention, the sterilization temperature is 121℃, and the time is 15-20 minutes, more preferably 15 minutes; the sterilization is preferably carried out in a multi-functional traditional Chinese medicine sterilization cabinet. In this invention, the pulverizing equipment is preferably a pulverizer, specifically a 30BVI dust-collecting pulverizer unit, and the sieve used for sieving is preferably 80 mesh. In this invention, the sterilization temperature is 121℃, and the time is 15-20 minutes, ensuring that the microbial indicators of the Andrographis paniculata leaf powder are qualified, and the content of effective components (andrographolide, neoandrographolide, 14-deoxyandrographolide, and dehydratedandrographolide) also meets the requirements after sterilization. In this invention, the sterilization and pulverization processes during the preparation of the Andrographis paniculata leaf powder are preferably carried out in an area with a purification level of D.

[0044] In this invention, the Andrographis paniculata leaf powder is preferably subject to quality control, and the quality control standards are shown in Table 2.

[0045] Table 2 Quality Control Standards for Andrographis paniculata Leaf Powder

[0046] In this invention, the mixing equipment used is a three-dimensional motion mixer, and the mixing speed is 5-10 rpm, preferably 5 rpm, 6 rpm, 6.5 rpm, 7 rpm, 8 rpm, 9 rpm, or 10 rpm, with a mixing time preferably 25-35 minutes, more preferably 30 minutes. In this invention, the mixing is preferably carried out in a cleanroom of grade D. By controlling the above mixing conditions, the chlorpheniramine maleate content in the powder is made uniform and stable, improving the quality stability of the cold relief capsules.

[0047] In this invention, the cold relief capsules preferably comprise the following components in prescribed amounts: 940 parts by weight of Isatis indigotica root, 400 parts by weight of Isatis tinctoria leaf, 660 parts by weight of Calendula officinalis and Dioscorea opposita, 860 parts by weight of Ilex chinensis, 460 parts by weight of Sesame aralia elata, 40 parts by weight of Andrographis paniculata leaf, 24 parts by weight of acetaminophen, 24 parts by weight of morpholine guanidine hydrochloride, 1 part by weight of chlorpheniramine maleate, and 300 parts by weight of talc.

[0048] After obtaining the powder, the present invention fills the powder into an empty capsule to obtain the cold relief capsule.

[0049] In this invention, the hollow capsule is preferably a gelatin hollow capsule.

[0050] In this invention, the filling is preferably performed in a fully automated capsule filling machine. Furthermore, the filling is preferably performed in an area with a cleanliness level of D.

[0051] After filling, the present invention preferably also includes capsule polishing, inner packaging, inkjet printing, and packaging.

[0052] In this invention, the capsule polishing is preferably performed in a capsule polishing machine. Furthermore, the capsule polishing is preferably performed in an area with a cleanliness level of D. After capsule polishing and before inner packaging, quality control is preferably performed, and the standards for this quality control are shown in Table 3.

[0053] Table 3 Quality control standards for the intermediate product of Ganmaoling capsules obtained after capsule polishing

[0054] In this invention, the inner packaging is preferably aluminum-plastic inner packaging, and the inner packaging is preferably carried out in an intelligent flat-panel aluminum-plastic blister packaging machine. In this invention, the inner packaging is preferably carried out in an area with a cleanliness level of D.

[0055] After inner packaging and before coding, the present invention preferably includes quality control, which preferably includes the quality of PVC solid pharmaceutical rigid sheets / pharmaceutical aluminum foil and post-packaging quality. In this invention, the preferred standard for the PVC solid pharmaceutical rigid sheets / pharmaceutical aluminum foil is that the outer packaging is intact and the content is correct, clear, and complete. In this invention, the preferred standard for the post-packaging quality is that the seal is tight, the seal is flat, and the printed content is clear and accurate.

[0056] In this invention, the inkjet printing is preferably performed on paper boxes. The specific process of paper box inkjet printing preferably includes the following steps: after verifying that the paper box to be printed contains the content specified in the production instruction, inkjet printing is performed. The process after inkjet printing and before packaging preferably includes quality control, which preferably includes both the paper box and the inkjet printing. In this invention, the standard for the paper box is preferably that the content is correct, clear, and complete. In this invention, the standard for the inkjet printing is preferably that the production date, product batch number, expiration date, and other information are accurate and clear.

[0057] The present invention does not impose specific limitations on the packaging; it can be set according to actual needs.

[0058] After obtaining the cold relief capsules, the present invention preferably performs quality control, and the quality control standards are shown in Table 4.

[0059] Table 4 Quality Control Standards for Cold Relief Capsules

[0060] The following detailed description of the preparation method of the cold relief capsules provided by the present invention, in conjunction with the embodiments, should not be construed as limiting the scope of protection of the present invention.

[0061] Example 1 1.1 Validation of Andrographis paniculata leaves under different processing conditions Objective: To determine under what sterilization conditions Andrographis paniculata leaves meet the microbial standards.

[0062] Methods: Take 200g×6 leaves of Andrographis paniculata and clean, wash and dry them according to the requirements of the "Standard Operating Procedures for Cleaning and Removing Cold Relief Capsules", "Standard Operating Procedures for Washing and Removing Cold Relief Capsules", and "Standard Operating Procedures for Drying Chinese Herbal Medicines in Cold Relief Capsules". Then sterilize them at 121℃ for 10min, 15min, 20min and 115℃ for 10min, 20min, 30min. The microbial indicators of Andrographis paniculata leaves after sterilization are investigated.

[0063] Acceptable standards: ① Total aerobic bacteria count: not more than 16,000 CFU per 1g; ② Total mold and yeast count: not more than 160 CFU per 1g; ③ Escherichia coli: not detectable per 1g; ④ Bili salt-resistant Gram-negative bacteria: less than 10 per 1g. 2 CFU; ⑤ Salmonella: Not detectable per 10g.

[0064] The results are shown in Table 5.

[0065] Table 5. Validation results of Andrographis paniculata leaves under different sterilization process conditions

[0066] Table 5 shows that: at 121℃ for 15 min and 121℃ for 20 min, the total number of aerobic bacteria, molds, yeasts, Escherichia coli, bile salt-resistant Gram-negative bacteria, and Salmonella all met the requirements. At 121℃ for 10 min, bile salt-resistant Gram-negative bacteria did not meet the requirements; at 115℃ for 10 min, the total number of molds and yeasts, and bile salt-resistant Gram-negative bacteria did not meet the requirements; at 115℃ for 20 min and 115℃ for 30 min, bile salt-resistant Gram-negative bacteria did not meet the requirements.

[0067] 1.2 Validation of Andrographis paniculata leaves under suitable sterilization conditions and investigation of effective components in samples with qualified microbiological indicators Based on the production batch (250,000 seeds), take the batch amount of Andrographis paniculata leaves, sterilize them under the selected suitable process conditions, and examine their effective components and microbial indicators. Perform continuous validation on 3 batches.

[0068] Objective: To verify the content and microbiological indicators of the effective components (andrographolide, neoandrographolide, 14-deoxyandrographolide, and dehydratedandrographolide) under screened sterilization conditions.

[0069] Methods: Andrographis paniculata leaves were collected and cleaned, washed, and dried according to the "Standard Operating Procedures for Cleaning, Washing, and Drying of Cold and Flu Capsules" and the "Standard Operating Procedures for Drying Chinese Herbal Medicines in Cold and Flu Capsules." Approximately 10 kg × 3 batches of Andrographis paniculata leaves were obtained. Three batches were sterilized consecutively under the selected sterilization conditions. The content of effective components (andrographolide, neoandrographolide, 14-deoxyandrographolide, and dehydratedandrographolide) and microbial indicators of the sterilized leaves were investigated. Three consecutive batches were validated.

[0070] Meanwhile, the changes in the content of effective components (andrographolide, neoandrographolide, 14-deoxyandrographolide, and dehydratedandrographolide) in Andrographis paniculata leaf medicinal materials and microbial index qualified samples before and after sterilization were investigated.

[0071] Acceptable standards: ① The total amount of active ingredients (andrographolide, neoandrographolide, 14-deoxyandrographolide, and dehydratedandrographolide) after sterilization shall not be less than 1.5%; ② Total aerobic bacteria count: not more than 16,000 CFU per 1g; ③ Total mold and yeast count: not more than 160 CFU per 1g; ④ Escherichia coli: not detectable per 1g; ⑤ Bile salt-resistant Gram-negative bacteria: less than 10² CFU per 1g; ⑥ Salmonella: not detectable per 10g.

[0072] The results are shown in Table 6.

[0073] Table 6. Results of validation and investigation of effective components of Andrographis paniculata leaves under suitable sterilization conditions and in samples with qualified microbial indicators.

[0074] In summary, after six batches of process screening and confirmation, the microbial indicators of Andrographis paniculata leaves were all unqualified under sterilization conditions of 115℃ for 10 min, 20 min, and 30 min, and 121℃ for 10 min. Under sterilization conditions of 121℃ for 15 min and 20 min, the microbial indicators were qualified, and the content of effective components met the requirements after sterilization. Considering factors such as production time and energy consumption, 121℃ for 15 min was selected as the sterilization condition for Andrographis paniculata leaves. Under this sterilization condition, through three consecutive batches (order numbers: D2404001, D240402, and D2404003) of Andrographis paniculata leaves production verification, it was confirmed that the microbial indicators were qualified, and the content of effective components remained basically unchanged before and after sterilization and met the requirements. This proves that 121℃ for 15 min can be used as the sterilization process parameter for Andrographis paniculata leaves. Evaluation: Under the aseptic process condition of 121℃ for 15 min, the quality of Andrographis paniculata leaves can be effectively guaranteed to meet the requirements for medicinal use.

[0075] Example 2 The medicinal materials were weighed according to the prescription of 250,000 pills, as shown in Table 7.

[0076] Table 7. Prescription Quantity of 250,000 Tablets

[0077] The steps are as follows: Cleaning and Selection: Collect the medicinal materials including Isatis root, Isatis leaf, Calendula officinalis, Ilex chinensis, Sesame aralia, and Andrographis paniculata leaf. Verify that the weight and label information match the actual items. Clean the materials according to the standard operating procedures for this position. After cleaning, the amount of debris and impurities should not exceed 3%. Place the cleaned medicinal materials in a container and label it promptly for later use.

[0078] Preparation: Cut the cleaned and selected Isatis indigotica, Dioscorea opposita, Ilex chinensis, and Sesame officinalis into sections or pieces no longer than 8cm, place them in a clean container and label them promptly for later use.

[0079] Washing: Isatis root: Place the herb in a suitable container, add water and slowly let it seep into the herb to clean the mud and impurities on the surface. Place it in a transfer container and label it promptly for later use. Isatis leaf, mountain sesame, and Andrographis leaf: Place the herb in a suitable container in a washing pool, rinse it quickly with water to clean the mud and impurities on the surface. Place it in a transfer container and label it promptly for later use.

[0080] Drying: The washed and cleaned medicinal materials, including Isatis root, Isatis leaf, Andrographis paniculata leaf, and Sesamum indicum, are dried separately at a temperature range of 70-80℃. The moisture content after drying is ≤10.0%. After drying, the medicinal materials are placed in clean, reusable containers and labeled promptly for later use.

[0081] Sterilization and pulverization: Sterilize the dried Andrographis paniculata leaves at 121℃ for 15 minutes, pulverize them through an 80-mesh sieve, place them in a clean bag, and label them for later use.

[0082] Extraction: Place the sliced ​​herbs of Isatis root, Isatis leaf, Calendula officinalis, Ilex chinensis, and Sesame in an extraction tank, add about 4 times the amount of drinking water (3240-3400L), heat and hold at boiling for 2 hours to extract the liquid, then add about 3 times the amount of drinking water (2410-2570L), hold at boiling for 1 hour, and extract the liquid, yielding a total of 4600-4800L of medicinal liquid.

[0083] Concentration: Pump the above-mentioned drug solution into a double-effect concentrator and concentrate it to a thick paste with a relative density of 1.15 g / mL (60℃), with a volume of approximately 200~250 L. Label the paste and set aside. The temperature of the first-effect evaporation chamber of the double-effect concentrator should be controlled at 50~90℃, and the vacuum degree should be maintained at 0.01~0.06 MPa; the temperature of the second-effect evaporation chamber should be controlled at 40~80℃, and the vacuum degree should be maintained at 0.02~0.08 MPa.

[0084] Alcohol precipitation: After the concentrate is cooled to below 40°C, add ethanol to adjust the alcohol content to 50-55%. After adding ethanol, stir for 30 minutes and pump into the alcohol precipitation tank. Let stand at room temperature (10-30°C) for 24 hours.

[0085] Extraction: Take the ethanol-precipitated liquid, filter it, and use a single-effect concentrator to recover ethanol until there is no ethanol odor. The filtrate has a relative density of 1.25~1.30 g / mL (60~65℃) and a weight of 85.0~105.0 kg. The temperature of the evaporation chamber of the single-effect concentrator is controlled at 30~70℃ and the vacuum degree is maintained at 0.01~0.09 MPa. Transfer it to a sterilized transfer container, weigh it, and affix the material label.

[0086] Drying and pulverizing the extract: Spread the thick extract evenly on a drying tray, with a thickness of ≤2cm, and place it on a material cart. Fill each cart completely and push it into a hot air circulating oven. Adjust the temperature controller to the range of 70~80℃ for drying. The drying time is 45.0~48.0h, and the moisture content is controlled to ≤5.0%. Place the dried extract in a transfer container, weigh it, affix a material label, pulverize it through an 80-mesh sieve, place it in a clean bag, affix a label, and keep it for later use.

[0087] Prepare the following ingredients according to batch quantities: Cold Relief Extract, Acetaminophen, Andrographis paniculata Leaf Powder, Moroxydine Hydrochloride, Chlorpheniramine Maleate, and Talc. Weigh and label each ingredient individually for later use.

[0088] Grinding: The weighed chlorpheniramine maleate is manually sieved through an 80-mesh sieve. Other raw and auxiliary materials are pulverized and sieved in the following order: acetaminophen → moroxydine hydrochloride → talc → andrographis paniculata leaf powder → cold and flu clearing extract. The sieves are 80 mesh, labeled, and ready for use.

[0089] Ingredients: Weigh and label the pulverized cold medicine extract, acetaminophen, andrographis paniculata leaf powder, morpholine guanidine hydrochloride, chlorpheniramine maleate, and talc powder according to the batch feeding amount, and set aside for later use.

[0090] General mixing: The prepared raw and auxiliary materials are put into a three-dimensional motion mixer for general mixing at a frequency of 50Hz (6.5 rpm). During the general mixing process, according to... Figure 2 The sampling points shown were taken at 25 min, 30 min and 35 min respectively. Chlorpheniramine maleate in the powder was detected by high performance liquid chromatography (Agilent 1260 / 04121) to evaluate the mixing uniformity. Three batches were tested, and the results are shown in Tables 8 to 10.

[0091] Table 8. Test results for batch number 2308001

[0092] Table 9. Test results for batch number 2308002

[0093] Table 10 Test results for batch number 2308003

[0094] As can be seen from Tables 8 to 10, the chlorpheniramine maleate powder is mixed evenly and the RSD value meets the requirements.

[0095] Example 3 According to Example 2, the following steps were performed: weighing, cleaning, cutting, washing, drying, sterilizing, pulverizing, extracting, concentrating, alcohol precipitation, collecting the paste, pulverizing again, and mixing.

[0096] The prepared raw and auxiliary materials are put into a three-dimensional motion mixer for total mixing at a frequency of 50Hz (6.5 rpm) for 30 minutes. The powder is then placed in a clean bag, sealed, weighed, and labeled for later use. Filling and polishing can only be carried out after the inspection is qualified.

[0097] The medicine powder is used to fill capsules at a rate of 0.455g to 0.545g and then polished. The powder generated in the equipment during the filling process is disposed of as a non-recyclable product.

[0098] The qualified capsules are packaged in aluminum-plastic packaging using polyvinyl chloride solid pharmaceutical hard sheets and pharmaceutical aluminum foil, with 12 capsules per blister pack.

[0099] Paper box printing: After verifying that the paper boxes to be printed are correct according to the printing content in the production order, printing is carried out. Packaging: Packaging specifications: 0.5g / capsule × 12 capsules / blister × 2 blisters / box × 400 boxes / carton; 0.5g / capsule × 12 capsules / blister × 3 blisters / box × 300 boxes / carton; 0.5g / capsule × 12 capsules / blister × 4 blisters / box × 300 boxes / carton; 0.5g / capsule × 12 capsules / blister × 5 blisters / box × 240 boxes / carton.

[0100] Material preparation: Obtain instruction manuals, outer boxes for the cold relief capsules, product certificates, sealing tape, and packing straps according to the production instructions. Obtain qualified printing boxes from the inkjet printing station. Stamp the outer boxes and product certificates, ensuring the stamped content is accurate, clear, uniform, and free of stains.

[0101] Packaging: Inspect the quality of the medicine after blister packing (including appearance, imprinted information, etc.). Pack according to the specific packaging specifications. Place the pre-packaged small boxes into cardboard boxes printed with the corresponding product batch number, production date, and expiration date, and add a product certificate. Seal the top and bottom lids with packing tape, pack neatly, and store in the warehouse for inspection.

[0102] The obtained cold relief capsules were tested, and the results showed that all test items met the quality requirements.

[0103] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A method for preparing a cold relief capsule, characterized in that, Includes the following steps: The extract was obtained by mixing Isatis root, Isatis leaf, Calendula officinalis, Ilex chinensis, Sesamum indicum, and water. The extract was concentrated to obtain a thick paste; The thick paste was subjected to alcohol precipitation, filtration, collection, drying and pulverization in sequence to obtain a cold-relieving dry extract. The cold-clearing extract, acetaminophen, andrographis paniculata leaf powder, morpholine guanidine hydrochloride, chlorpheniramine maleate and talc are mixed together to obtain a medicinal powder; The powder is filled into an empty capsule to obtain the cold relief capsule; The preparation method of Andrographis paniculata leaf powder is as follows: Andrographis paniculata leaves are successively cleaned, washed, dried, sterilized, crushed and sieved to obtain Andrographis paniculata leaf powder; the sterilization temperature is 121℃ and the time is 15~20min. The equipment used for the overall mixing is a three-dimensional motion mixer, and the mixing speed is 5~10 revolutions per minute, and the time is 25~35 minutes.

2. The preparation method according to claim 1, characterized in that, The Cold Relief Capsules comprise the following ingredients in prescribed amounts: 940 parts by weight of Isatis indigotica root, 400 parts by weight of Isatis tinctoria leaf, 660 parts by weight of Calendula officinalis and Dioscorea opposita, 860 parts by weight of Ilex chinensis, 460 parts by weight of Sesame aralia elata, 40 parts by weight of Andrographis paniculata leaf, 24 parts by weight of acetaminophen, 24 parts by weight of morpholine guanidine hydrochloride, 1 part by weight of chlorpheniramine maleate, and 300 parts by weight of talc.

3. The preparation method according to claim 1, characterized in that, Before the extraction of Isatis root, Isatis leaf, Calendula officinalis, Ilex chinensis, and Sesame officinalis with water, a pretreatment process is also included, which includes one or more of the following: cleaning, cutting, washing, and drying.

4. The preparation method according to claim 1, 2, or 3, characterized in that, The mass ratio of the total mass of Isatis root, Isatis leaf, Calendula officinalis, Ilex chinensis and Sesame in the South China region to water is 1:3~5. The extraction was carried out under boiling conditions; The extraction is performed 1 to 3 times, with each extraction lasting 1 to 2 hours.

5. The preparation method according to claim 1, characterized in that, The equipment used for concentration is a double-effect concentrator. During the concentration process, the temperature of the first-effect evaporation chamber of the double-effect concentrator is 50~90℃ and the vacuum degree is 0.01~0.06MPa; the temperature of the second-effect evaporation chamber is 40~80℃ and the vacuum degree is 0.02~0.08MPa. The relative density of the paste at 60°C is 1.15 g / mL.

6. The preparation method according to claim 1, characterized in that, The alcohol used in the alcohol precipitation is ethanol. During the alcohol precipitation process, the volume content of ethanol in the system is 50-55%. The alcohol precipitation includes stirring and settling in sequence. The stirring time is 30 minutes and the settling time is 24 hours.

7. The preparation method according to claim 1, characterized in that, The equipment used for collecting the paste is a single-effect concentrator, and the temperature of the evaporation chamber of the single-effect concentrator is 30~70℃, and the vacuum degree is 0.01~0.09MPa; The density of the paste obtained after the extraction is 1.25~1.30 g / mL at 60~65℃.

8. The preparation method according to claim 1, characterized in that, In the process of preparing the cold-clearing dry extract, the drying equipment used is a hot air circulating oven, the drying temperature is 70~80℃, the drying time is 45~48h, and the moisture content of the material obtained after drying is ≤5.0%; the pulverization is carried out in a sieve with an 80-mesh aperture.

9. The preparation method according to claim 1, characterized in that, Before use, the cold-clearing extract, acetaminophen, andrographis paniculata leaf powder, morpholine guanidine hydrochloride, and talc powder are further subjected to pulverization and sieving in sequence; the pulverization equipment is a pulverizer, and the sieving screen has an aperture of 80 mesh. Before use, the chlorpheniramine maleate is also sieved manually using an 80-mesh sieve.

10. The preparation method according to claim 1, characterized in that, In the process of preparing Andrographis paniculata leaf powder, the equipment used for pulverizing is a pulverizer, and the sieve used for sieving has an aperture of 80 mesh.

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