Traditional Chinese medicine capsule for treating cold and wind-cold and preparation method thereof

Abstract

The invention provides a traditional Chinese medicine capsule for treating cold and wind-cold and a preparation method thereof, and relates to the technical field of medical treatment. The traditional Chinese medicine capsule for treating cold and wind-cold comprises an outer-layer quick-release micro-capsule, the outer-layer quick-release micro-capsule is a micro-capsule particle with the particle size of 0.3-0.5 mm, and the outer-layer quick-release micro-capsule is prepared by mixing perilla leaf oil, ginger volatile oil and ephedra extract with microcrystalline cellulose serving as a filler and a disintegrating agent and hydroxypropyl methylcellulose serving as an adhesive after being included by beta-cyclodextrin, and the outer-layer quick-release micro-capsule is a micro-capsule particle with the particle size of 0.3-0.5 mm. The content accounts for 30% of the mass of the total content, and the inner-layer sustained-release pellet is prepared from a kudzu vine root extract, a radix saposhnikoviae extract, a liquorice extract, hydroxypropyl methyl cellulose and an ethyl cellulose composite framework and has the particle size of 0.5-0.8 mm. According to the present invention, the volatile oil is included by the beta-cyclodextrin in the outer layer rapid-release micro-capsule, the volatile oil is rapidly disintegrated within 10-15 min in the stomach, the HPMC K100LV + EC composite skeleton is adopted in the inner layer sustained-release micro-pill, and the sustained-release micro-pill is continuously released within 6-8 h, such that different release paths and time tables are designed for the drug components with different properties;

Description

TECHNICAL FIELD

[0001] The present application relates to the medical field, in particular to a traditional Chinese medicine capsule for treating cold and wind and a preparation method thereof. BACKGROUND

[0002] Cold and wind, also known as wind cold, is a classification of cold in traditional Chinese medicine, mainly caused by wind cold evil invading the human body, belonging to the category of external syndrome, traditional Chinese medicine is an important part of traditional Chinese medicine, which has a history of thousands of years, guided by traditional Chinese medicine theory, through syndrome differentiation and treatment, using natural medicine to prevent, treat diseases and health care, the traditional Chinese medicine capsule for treating cold and wind is a new type of traditional Chinese medicine preparation based on traditional Chinese medicine theory combined with modern pharmaceutical technology, which is mainly used for treating cold symptoms caused by wind cold evil, such as heavy chill, light fever, no sweat, nasal congestion, runny nose and cough with white sputum, which aims to quickly relieve cold symptoms through the combination of traditional Chinese medicine with the functions of dispelling wind cold, promoting lung and relieving cough, and providing sustained efficacy to promote patient recovery.

[0003] The existing traditional Chinese medicine capsule for treating cold and wind still has some problems, perilla leaf oil and ginger volatile oil are the key components for dispelling wind cold, but they are extremely unstable in chemical properties, which are easy to volatilize and oxidize during production and storage, resulting in rapid decline of drug efficacy, ordinary capsules release all components at the same time, and the relieving component needs to act quickly to dispel wind cold, while the radical component needs to act continuously to relieve muscle soreness and completely clear symptoms, so the single release mode cannot meet the requirements of quick-acting and long-acting, therefore, the technical personnel in the field provide a traditional Chinese medicine capsule for treating cold and wind and a preparation method thereof to solve the problems in the above background. SUMMARY

[0004] (I) Technical problems solved In view of the deficiencies in the prior art, the present application provides a traditional Chinese medicine capsule for treating cold and wind and a preparation method thereof, which solves the problems that perilla leaf oil and ginger volatile oil are the key components for dispelling wind cold, but they are extremely unstable in chemical properties, which are easy to volatilize and oxidize during production and storage, resulting in rapid decline of drug efficacy, ordinary capsules release all components at the same time, and the relieving component needs to act quickly to dispel wind cold, while the radical component needs to act continuously to relieve muscle soreness and completely clear symptoms, so the single release mode cannot meet the requirements of quick-acting and long-acting.

[0005] (II) Technical scheme In order to achieve the above purpose, the present application is realized by the following technical scheme: a traditional Chinese medicine capsule for treating cold and wind, comprising: The outer layer of immediate-release microcapsules consists of microcapsule particles with a particle size of 0.3 to 0.5 mm, made by encapsulating perilla leaf oil, ginger volatile oil, and ephedra extract with β-cyclodextrin, and mixing them with microcrystalline cellulose as a filler and disintegrant, and hydroxypropyl methylcellulose as a binder. These microcapsules account for 30% of the total content mass. The inner layer of sustained-release microspheres consists of microspheres with a particle size of 0.5 to 0.8 mm, made from a composite framework of kudzu root extract, saposhnikovia root extract, licorice extract, hydroxypropyl methylcellulose, and ethylcellulose, accounting for 70% of the total content mass. Capsule shell, wherein the capsule shell is made of hydroxypropyl methylcellulose plant capsule.

[0006] Preferably, the inner layer of sustained-release microspheres is coated with an ethyl cellulose isolation layer with a thickness of 10 to 20 μm, and the ethyl cellulose isolation layer is formed by an aqueous dispersion of ethyl acrylate to methyl methacrylate copolymer (2:1). The coating weight gain of the isolation layer is 4% to 6%. The EC isolation layer blocks moisture penetration, effectively preventing the sustained-release microspheres from absorbing moisture and clumping. Under storage conditions of 25°C / 75%RH, the stability is improved from 18 months for traditional formulations to 24 months without clumping, preventing degradation of the active ingredients due to moisture absorption.

[0007] Preferably, 0.5% of magnesium aluminum silicate anti-caking agent is added to the contents, wherein the specific surface area of ​​magnesium aluminum silicate is ≥200 m². 2 / g, particle size ≤5μm, using a specific surface area ≥200m² 2 / g of magnesium aluminum silicate, ordinary anti-caking agents only have 80 to 120 mg 2 / g significantly enhances the adsorption capacity for water molecules, preventing the contents from sticking together between particles in a humid environment.

[0008] Preferably, the ephedra extract is prepared by ultrasonic extraction with 60% ethanol at 40±5℃ and 200 to 400W power for 1.5 to 2 hours; the kudzu root extract is prepared by decoction twice with 10 times the amount of water, 1.5 hours each time, the decoctions are combined and concentrated to a relative density of 1.10 to 1.15 (60℃), ethanol is added to make the alcohol content reach 70%, the mixture is allowed to stand for 12 hours, filtered, the ethanol is recovered and dried. The use of 60% ethanol ultrasonic extraction (40±5℃, 200 to 400W, 1.5 to 2 hours) instead of traditional water extraction increases the ephedrine extraction rate by 35% and avoids the destruction of alkaloid components by high temperature. The water-to-solid ratio of water extraction to alcohol precipitation is 10:1, and the 70% ethanol precipitation combined with low-temperature concentration at 60℃ results in a puerarin content of ≥5.0% and reduces the loss of heat-sensitive components.

[0009] Preferably, the moisture content of the hydroxypropyl methylcellulose (HPMC) plant capsules is controlled between 4.5% and 6.5%. If the moisture content of HPMC capsules is too low (<4%), it will lead to increased brittleness and easy breakage during filling. Precisely controlling the moisture content between 4.5% and 6.5% ensures that the capsule shell maintains stable mechanical properties and disintegration characteristics during transportation and storage.

[0010] A method for preparing a traditional Chinese medicine capsule for treating colds and flu includes the following steps: S1. Preparation of outer layer fast-release microcapsules to achieve 95% retention of volatile components perilla leaf oil and ginger volatile oil, with a dissolution rate of ≥85% after 30 minutes; S1.1. Material preparation: 0.5g of perilla leaf oil, 0.3g of ginger volatile oil and β-cyclodextrin, with a molar ratio of 1:8; S1.2. Take 0.5g of perilla leaf oil and 0.3g of ginger volatile oil, mix them, and stir at 200r / min for 10 minutes under 40℃ water bath conditions to make them fully mixed; S1.3. Add β-cyclodextrin at a molar ratio of 1:8, maintain the temperature at 40℃, and sonicate at 200W power for 2 hours to obtain the inclusion complex; S1.4. Add 10g of microcrystalline cellulose and 5g of hydroxypropyl methylcellulose, and mix in a high-efficiency mixer at 300r / min for 15 minutes; S1.5. Transfer the mixture to a fluidized bed granulator, set the inlet air temperature to 40±2℃, the atomization pressure to 0.2MPa, and maintain the material temperature at 38 to 40℃ to carry out the granulation operation; S1.6. The obtained particles are sieved through a 0.3 to 0.5 mm sieve to obtain the outer layer of fast-release microcapsules; S2. Inner layer sustained-release microspheres are prepared, containing long-acting ingredients puerarin, cimicifugain glycoside and glycyrrhizic acid, and achieve sustained release for 6 to 8 hours through a hydroxypropyl methylcellulose and ethylcellulose composite framework. S2.1. Weigh 30g of kudzu root, 20g of saposhnikovia root, and 15g of licorice root. Add 10 times the amount of drinking water and soak for 30 minutes. Then heat to a gentle boil and maintain the temperature between 90 and 95°C. Continue to decoct at this temperature twice, each time for 1.5 hours. Stir slowly at a speed of 60 revolutions per minute during the decoction process. S2.2. Combine the two decoctions, filter them with a 200-mesh filter cloth, transfer the filtrate to a vacuum concentrator, and concentrate it to a relative density of 1.20 at 60°C and 0.08 MPa. S2.3. Add ethanol to the concentrate to make the alcohol content reach 70%, while stirring at a speed of 120 r / min. After the addition is complete, continue stirring for 15 minutes, place it in a refrigerator at 4℃ and let it stand for 12 hours. Take the supernatant and centrifuge (4000 r / min, 15 minutes) to collect the precipitate. S2.4. The precipitate is spray-dried with an inlet air temperature of 180±5℃, an outlet air temperature of 80±5℃, and an atomizer speed of 15000r / min to obtain a dried extract powder. S2.5. Mix the extract powder with 12g of hydroxypropyl methylcellulose and place it in a three-dimensional motion mixer. Mix at 25r / min for 30 minutes. Slowly add purified water, control the material temperature to not exceed 35℃, adjust the stirring speed to 200r / min and the chopping speed to 800r / min to obtain a soft material with a moisture content controlled at 25%. S2.6. Soft materials are processed using an extrusion rounding machine with a sieve plate aperture of 1.0 mm, an extrusion speed of 50 r / min, and a rounding speed of 800 r / min to obtain micro pellets with a particle size of 0.5 to 0.8 mm. S2.7. Place the microparticles in a fluidized bed coating machine and coat them with Eudragit® NE30D ethyl cellulose aqueous dispersion. Set the inlet air temperature to 50°C, the material temperature to 38 to 40°C, the spray rate to 5 mL / min, the atomization pressure to 0.8 Bar, and coat until the weight gain is 5%, forming an isolation layer with a thickness of 10 to 20 μm. S3. Total Mixing and Filling: Mix the outer layer of immediate-release microcapsules (30% of the total contents) with the inner layer of sustained-release microcapsules (70%), add 2g of magnesium aluminum silicate anti-caking agent, place in a V-type mixer, mix at 15r / min for 20 minutes until uniform, and use a fully automatic capsule filling machine to fill the mixture into No. 0 HPMC plant capsule shells, with each capsule containing 0.4g. After filling, polish the capsules and remove unqualified products. S4. Intermediate storage: After filling and polishing, the capsules should be temporarily stored in a sealed container in a Class D clean area. Use non-toxic polyethylene or stainless steel drums for storage. Place double-layered silica gel desiccant inside the drum. The ambient temperature should be controlled between 18 and 25°C, and the relative humidity (RH) should be controlled at <45%. The storage time should not exceed 24 hours. S5. Inner packaging: High-barrier aluminum foil or PVC / PVC composite rigid sheet should be used, with a water vapor transmission rate (WVTR) ≤ 0.5 g / m³. 2 • 24h, the back seal material is made of pharmaceutical aluminum foil with a thickness of 20 to 25 μm, and product information is printed on it. It is packaged using a fully automatic blister packaging machine. S6. Outer packaging: Place blister packs or medicine bottles into a pharmaceutical paper box and add the instruction manual. Bundle several small boxes into a medium pack or large tray using polyolefin heat shrink film. The heat shrink tunnel temperature is usually set to 160 to 180℃. After heat shrinking, the film should be flat and taut. Pack the medium packs or small boxes into a corrugated cardboard box. Place a moisture-proof pad inside the box. Print the product batch number, production date, and expiration date on the outside of the box. S7. Storage conditions: The final product should be stored in a cool, dry, and well-ventilated warehouse at a temperature not exceeding 25°C or refrigerated at 2 to 8°C, with a relative humidity of <60%. Avoid direct sunlight and keep away from heat sources. S8. Process Validation Requirements: To ensure packaging effectiveness, sealing tests are required. For blister packaging, a colorimetric leak test is performed; for bottled packaging, an airtightness test and stability tests are conducted. The final packaged product is placed under accelerated testing conditions (40±2℃, 75±5%RH) and long-term testing conditions (25±2℃, 60±5%RH) for evaluation. Key indicators such as appearance, moisture content, content, and dissolution rate are periodically tested to determine the shelf life. Preferably, the process parameters for the inner packaging described in step S5 are as follows: For PVC / PVDC rigid sheets, the heating plate temperature should be controlled at 120 to 140°C to ensure good heat sealing and prevent charring. The heat sealing roller temperature should be controlled at 150 to 170°C, and the pressure should be 0.3 to 0.5 MPa. A heat sealing strength test is required to ensure a tight seal and a peel strength ≥ 3.5 N / 15 mm. Before heat sealing, nitrogen or a nitrogen-to-carbon dioxide mixture can be injected into the blister cavity to replace the air inside and prevent oxidation of the contents.

[0011] Preferably, in steps S2 and S3 above, after filling and polishing, the capsules are immediately packaged in aluminum-plastic blister packs using PVDC-coated aluminum foil, with the heat sealing temperature controlled at 160±5℃ and the pressure at 0.4MPa, and nitrogen protection is applied. Subsequently, the capsules are boxed, shucked, and packed. The finished products are stored in a cool, dry place at a temperature ≤25℃ and a relative humidity <60%.

[0012] (III) Beneficial Effects This invention provides a traditional Chinese medicine capsule for treating colds and flu, and its preparation method. It has the following beneficial effects: 1. In this invention, the outer layer of immediate-release microcapsules uses β-cyclodextrin to encapsulate volatile oil, which rapidly disintegrates in the stomach within 10 to 15 minutes, while the inner layer of sustained-release microspheres uses an HPMC K100LV+EC composite framework, which continuously releases for 6 to 8 hours. Different release pathways and timelines are designed for drug components with different properties.

[0013] 2. In this invention, perilla leaf oil, ginger volatile oil and β-cyclodextrin are included in a 1:8 molar ratio, under nitrogen protection throughout the process. The volatile oil retention rate is increased from the traditional 60% to 70% to ≥95%. The surface of the sustained-release microspheres is coated with an EC isolation layer with a thickness of 10 to 20 μm, forming a dual drug release mechanism from sustained release to controlled release, prolonging the drug residence time in the intestine and improving bioavailability.

[0014] 3. In this invention, the surface of the sustained-release microspheres is coated with an EC isolation layer to prevent water penetration. The contents contain 0.5% nano-grade aluminum magnesium silicate, which increases the adsorption efficiency by 3 times. The capsule shell is made of HPMC plant capsules, and there is no clumping when stored at 25℃ / 75%RH for a long time under the triple protection system. Attached Figure Description

[0015] Fig. 1 This is a flowchart of the preparation process of the present invention; Fig. 2 This is a schematic diagram of the quality inspection standard of the present invention. Detailed Implementation

[0016] The technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0017] Example 1: like Figs. 1-2 As shown in the figure, this embodiment of the invention provides a traditional Chinese medicine capsule for treating colds and flu, comprising: The outer layer of immediate-release microcapsules consists of microcapsule particles with a particle size of 0.3 to 0.5 mm, made by encapsulating perilla leaf oil, ginger volatile oil, and ephedra extract with β-cyclodextrin, and mixing them with microcrystalline cellulose as a filler and disintegrant, and hydroxypropyl methylcellulose as a binder. These microcapsules account for 30% of the total content mass. The inner layer of sustained-release microspheres consists of microspheres with a particle size of 0.5 to 0.8 mm, made from a composite framework of kudzu root extract, saposhnikovia root extract, licorice extract, hydroxypropyl methylcellulose, and ethylcellulose, accounting for 70% of the total content mass. Capsule shell, the capsule shell is made of hydroxypropyl methylcellulose plant capsule.

[0018] The inner layer of sustained-release microcapsules is coated with an ethyl cellulose isolation layer with a thickness of 10 to 20 μm. The ethyl cellulose isolation layer may be formed by an aqueous dispersion of ethyl acrylate to methyl methacrylate copolymer (2:1). The coating weight gain of the isolation layer is 4% to 6%. The EC isolation layer blocks moisture penetration and effectively prevents the sustained-release microcapsules from absorbing moisture and clumping. Under storage conditions of 25℃ / 75%RH, the stability is improved from 18 months for traditional formulations to 24 months without clumping, preventing degradation of the active ingredients due to moisture absorption.

[0019] 0.5% magnesium aluminum silicate anti-caking agent is added to the contents, wherein the specific surface area of ​​magnesium aluminum silicate is ≥200m². 2 / g, particle size ≤5μm, using a specific surface area ≥200m²2 / g of magnesium aluminum silicate, ordinary anti-caking agents only have 80 to 120 mg 2 / g significantly enhances the adsorption capacity for water molecules, preventing the contents from sticking together between particles in a humid environment.

[0020] Ephedra extract was prepared by ultrasonic extraction with 60% ethanol at 40±5℃ and 200 to 400W for 1.5 to 2 hours. Pueraria extract was prepared by decoction twice with 10 times the amount of water, 1.5 hours each time, the decoctions were combined and concentrated to a relative density of 1.10 to 1.15 (60℃), ethanol was added to make the alcohol content reach 70%, and after standing for 12 hours, it was filtered, the ethanol was recovered and dried. The use of 60% ethanol ultrasonic extraction (40±5℃, 200 to 400W, 1.5 to 2 hours) instead of traditional water extraction increased the ephedrine extraction rate by 35% and avoided the destruction of alkaloid components by high temperature. The water-to-solid ratio of water extraction to alcohol precipitation was 10:1, and the 70% ethanol precipitation combined with low temperature concentration at 60℃ resulted in a puerarin content of ≥5.0% and reduced the loss of heat-sensitive components.

[0021] The moisture content of hydroxypropyl methylcellulose (HPMC) plant capsules is controlled between 4.5% and 6.5%. If the moisture content of HPMC capsules is too low (<4%), it will lead to increased brittleness and easy breakage during filling. Precisely controlling the moisture content between 4.5% and 6.5% ensures that the capsule shell maintains stable mechanical properties and disintegration characteristics during transportation and storage.

[0022] A method for preparing a traditional Chinese medicine capsule for treating colds and flu includes the following steps: S1. Preparation of outer layer fast-release microcapsules to achieve 95% retention of volatile components perilla leaf oil and ginger volatile oil, with a dissolution rate of ≥85% after 30 minutes; S1.1. Material preparation: 0.5g of perilla leaf oil, 0.3g of ginger volatile oil and β-cyclodextrin, with a molar ratio of 1:8; S1.2. Take 0.5g of perilla leaf oil and 0.3g of ginger volatile oil, mix them, and stir at 200r / min for 10 minutes under 40℃ water bath conditions to make them fully mixed; S1.3. Add β-cyclodextrin at a molar ratio of 1:8, maintain the temperature at 40℃, and sonicate at 200W power for 2 hours to obtain the inclusion complex; S1.4. Add 10g of microcrystalline cellulose and 5g of hydroxypropyl methylcellulose, and mix in a high-efficiency mixer at 300r / min for 15 minutes; S1.5. Transfer the mixture to a fluidized bed granulator, set the inlet air temperature to 40±2℃, the atomization pressure to 0.2MPa, and maintain the material temperature at 38 to 40℃ to carry out the granulation operation; S1.6. The obtained particles are sieved through a 0.3 to 0.5 mm sieve to obtain the outer layer of fast-release microcapsules; S2. Inner layer sustained-release microspheres are prepared, containing long-acting ingredients puerarin, cimicifugain glycoside and glycyrrhizic acid, and achieve sustained release for 6 to 8 hours through a hydroxypropyl methylcellulose and ethylcellulose composite framework. S2.1. Weigh 30g of kudzu root, 20g of saposhnikovia root, and 15g of licorice root. Add 10 times the amount of drinking water and soak for 30 minutes. Then heat to a gentle boil and maintain the temperature between 90 and 95°C. Continue to decoct at this temperature twice, each time for 1.5 hours. Stir slowly at a speed of 60 revolutions per minute during the decoction process. S2.2. Combine the two decoctions, filter them with a 200-mesh filter cloth, transfer the filtrate to a vacuum concentrator, and concentrate it to a relative density of 1.20 at 60°C and 0.08 MPa. S2.3. Add ethanol to the concentrate to make the alcohol content reach 70%, while stirring at a speed of 120 r / min. After the addition is complete, continue stirring for 15 minutes, place it in a refrigerator at 4℃ and let it stand for 12 hours. Take the supernatant and centrifuge (4000 r / min, 15 minutes) to collect the precipitate. S2.4. The precipitate is spray-dried with an inlet air temperature of 180±5℃, an outlet air temperature of 80±5℃, and an atomizer speed of 15000r / min to obtain a dried extract powder. S2.5. Mix the extract powder with 12g of hydroxypropyl methylcellulose and place it in a three-dimensional motion mixer. Mix at 25r / min for 30 minutes. Slowly add purified water, control the material temperature to not exceed 35℃, adjust the stirring speed to 200r / min and the chopping speed to 800r / min to obtain a soft material with a moisture content controlled at 25%. S2.6. Soft materials are processed using an extrusion rounding machine with a sieve plate aperture of 1.0 mm, an extrusion speed of 50 r / min, and a rounding speed of 800 r / min to obtain micro pellets with a particle size of 0.5 to 0.8 mm. S2.7. Place the microparticles in a fluidized bed coating machine and coat them with Eudragit® NE30D ethyl cellulose aqueous dispersion. Set the inlet air temperature to 50°C, the material temperature to 38 to 40°C, the spray rate to 5 mL / min, the atomization pressure to 0.8 Bar, and coat until the weight gain is 5%, forming an isolation layer with a thickness of 10 to 20 μm. S3. Total Mixing and Filling: Mix the outer layer of immediate-release microcapsules (30% of the total contents) with the inner layer of sustained-release microcapsules (70%), add 2g of magnesium aluminum silicate anti-caking agent, place in a V-type mixer, mix at 15r / min for 20 minutes until uniform, and use a fully automatic capsule filling machine to fill the mixture into No. 0 HPMC plant capsule shells, with each capsule containing 0.4g. After filling, polish the capsules and remove unqualified products. S4. Intermediate storage: After filling and polishing, the capsules should be temporarily stored in a sealed container in a Class D clean area. Use non-toxic polyethylene or stainless steel drums for storage. Place double-layered silica gel desiccant inside the drum. The ambient temperature should be controlled between 18 and 25°C, and the relative humidity (RH) should be controlled at <45%. The storage time should not exceed 24 hours. S5. Inner packaging: High-barrier aluminum foil or PVC / PVC composite rigid sheet should be used, with a water vapor transmission rate (WVTR) ≤ 0.5 g / m³. 2 • 24h, the back seal material is made of pharmaceutical aluminum foil with a thickness of 20 to 25 μm, and product information is printed on it. It is packaged using a fully automatic blister packaging machine. S6. Outer packaging: Place blister packs or medicine bottles into a pharmaceutical paper box and add the instruction manual. Bundle several small boxes into a medium pack or large tray using polyolefin heat shrink film. The heat shrink tunnel temperature is usually set to 160 to 180℃. After heat shrinking, the film should be flat and taut. Pack the medium packs or small boxes into a corrugated cardboard box. Place a moisture-proof pad inside the box. Print the product batch number, production date, and expiration date on the outside of the box. S7. Storage conditions: The final product should be stored in a cool, dry, and well-ventilated warehouse at a temperature not exceeding 25°C or refrigerated at 2 to 8°C, with a relative humidity of <60%. Avoid direct sunlight and keep away from heat sources. S8. Process Validation Requirements: To ensure packaging effectiveness, sealing tests are required. For blister packaging, a colorimetric leak test is performed; for bottled packaging, an airtightness test and stability tests are conducted. The final packaged product is placed under accelerated testing conditions (40±2℃, 75±5%RH) and long-term testing conditions (25±2℃, 60±5%RH) for evaluation. Key indicators such as appearance, moisture content, content, and dissolution rate are periodically tested to determine the shelf life. According to the process parameters of the inner packaging in step S5: For PVC / PVDC rigid sheets, the heating plate temperature should be controlled at 120 to 140°C to ensure good heat sealing and prevent charring. The heat sealing roller temperature should be controlled at 150 to 170°C, and the pressure should be 0.3 to 0.5 MPa. A heat sealing strength test is required to ensure a tight seal and a peel strength ≥ 3.5 N / 15 mm. Before heat sealing, nitrogen or a nitrogen-to-carbon dioxide mixture can be injected into the blister cavity to replace the air inside and prevent oxidation of the contents.

[0023] In steps S2 and S3 above, after filling and polishing, the capsules are immediately packaged in aluminum-plastic blister packs using PVDC-coated aluminum foil. The heat sealing temperature is controlled at 160±5℃ and the pressure is 0.4MPa. Nitrogen filling is also used for protection. Subsequently, the capsules are boxed, shucked, and packed. The finished products are stored in a cool, dry place at a temperature ≤25℃ and a relative humidity <60%.

[0024] Among them, pharmacodynamic and toxicological studies investigated the efficacy mechanism of this compound for colds and flu, such as viral colds and upper respiratory tract infections, including its relieving effects on symptoms such as fever, cough, nasal congestion, and headache; its anti-inflammatory and antiviral effects, such as those against influenza virus and rhinovirus; its antipyretic, analgesic, and immunomodulatory effects; and the synergistic or complementary relationship between the immediate-release components of perilla leaf oil, ginger volatile oil, and ephedra extract and the sustained-release components of kudzu root, saposhnikovia root, and licorice root.

[0025] Toxicological studies include acute toxicity and long-term toxicity, such as 28-day / 90-day feeding trials in rats, genotoxicity, safety pharmacology, safety assessment and maximum tolerated dose of each component, especially volatile oils and ephedrine, and irritant and allergenic properties of volatile components at high doses.

[0026] Preclinical pharmacokinetics, including the absorption, distribution, metabolism, and excretion characteristics of the main active ingredients such as ephedrine, puerarin, glycyrrhizic acid, and cimicifugain in vivo, the release characteristics of the immediate-release and sustained-release fractions in vivo, and whether there are drug interactions, such as ephedrine with certain antihypertensive drugs and monoamine oxidase inhibitors. This pharmacodynamics and toxicology are commonly used techniques in existing pharmaceutical technology and will not be elaborated on further here.

[0027] The properties were assessed based on the capsule appearance. Qualitative identification of the main ingredients, such as ephedra, kudzu root, licorice, perilla leaf oil, and ginger volatile oil, was performed using TLC, HPLC, or GC methods. Tests were conducted on moisture content (capsule contents and shell), disintegration time (especially for the immediate-release fraction, which should disintegrate within 30 minutes), microbial limits (total bacterial count, molds and yeasts, Escherichia coli, Salmonella, etc.), heavy metals and residual solvents (such as residual ethanol, ethylene oxide, etc.), content uniformity (especially for low-dose volatile oil components), and content determination of the main active ingredients. Quantitative methods (HPLC method recommended) and limits for substances such as puerarin, ephedrine (or pseudoephedrine), glycyrrhizic acid, and cimicifugain glycosides; content or characteristic chromatogram control of volatile components (perilla leaf oil, ginger volatile oil); dissolution / release testing: immediate release portion: ≥85% dissolution within 30 minutes; sustained release portion: it is recommended to develop cumulative release curves at different time points (e.g., 1h, 3h, 6h, 8h), with a target of sustained release over 6 to 8 hours. This identification technique belongs to existing pharmaceutical identification techniques and will not be elaborated upon further here.

[0028] Although embodiments of the invention have been shown and described, it will be understood by those skilled in the art that various changes, modifications, substitutions and alterations can be made to these embodiments without departing from the principles and spirit of the invention, the scope of which is defined by the appended claims and their equivalents.

Claims

1. A traditional Chinese medicine capsule for treating colds and flu, characterized in that: include: The outer layer of immediate-release microcapsules consists of microcapsule particles with a particle size of 0.3 to 0.5 mm, made by encapsulating perilla leaf oil, ginger volatile oil, and ephedra extract with β-cyclodextrin, and mixing them with microcrystalline cellulose as a filler and disintegrant, and hydroxypropyl methylcellulose as a binder. These microcapsules account for 30% of the total content mass. The inner layer of sustained-release microspheres consists of microspheres with a particle size of 0.5 to 0.8 mm, made from a composite framework of kudzu root extract, saposhnikovia root extract, licorice extract, hydroxypropyl methylcellulose, and ethylcellulose, accounting for 70% of the total content mass. Capsule shell, wherein the capsule shell is made of hydroxypropyl methylcellulose plant capsule.

2. The traditional Chinese medicine capsule for treating colds and flu according to claim 1, characterized in that: The inner layer of sustained-release microspheres is coated with an ethyl cellulose isolation layer with a thickness of 10 to 20 μm, and the ethyl cellulose isolation layer is formed by an aqueous dispersion of ethyl acrylate to methyl methacrylate copolymer (2:1), and the coating weight gain of the isolation layer is 4% to 6%.

3. The traditional Chinese medicine capsule for treating colds and flu according to claim 1, characterized in that: The contents contain 0.5% magnesium aluminum silicate anti-caking agent, wherein the specific surface area of ​​magnesium aluminum silicate is ≥200m². 2 / g, particle size ≤5μm.

4. A traditional Chinese medicine capsule for treating colds and flu according to claim 1, characterized in that: The ephedra extract was prepared by ultrasonic extraction with 60% ethanol at 40±5℃ and 200 to 400W power for 1.5 to 2 hours; the kudzu root extract was prepared by decoction twice with 10 times the amount of water, 1.5 hours each time, the decoctions were combined and concentrated to a relative density of 1.10 to 1.15 (60℃), ethanol was added to make the alcohol content reach 70%, the mixture was allowed to stand for 12 hours, filtered, the ethanol was recovered and dried.

5. A traditional Chinese medicine capsule for treating colds and flu according to claim 1, characterized in that: The water content of the hydroxypropyl methylcellulose plant capsules is controlled between 4.5% and 6.5%.

6. A method for preparing a traditional Chinese medicine capsule for treating colds and flu, comprising using a traditional Chinese medicine capsule for treating colds and flu as described in any one of claims 1 to 5, characterized in that: Includes the following steps: S1. Preparation of outer layer fast-release microcapsules to achieve 95% retention of volatile components perilla leaf oil and ginger volatile oil, with a dissolution rate of ≥85% after 30 minutes; S1.

1. Material preparation: 0.5g of perilla leaf oil, 0.3g of ginger volatile oil and β-cyclodextrin, with a molar ratio of 1:8; S1.

2. Take 0.5g of perilla leaf oil and 0.3g of ginger volatile oil, mix them, and stir at 200r / min for 10 minutes under 40℃ water bath conditions to make them fully mixed; S1.

3. Add β-cyclodextrin at a molar ratio of 1:8, maintain the temperature at 40℃, and sonicate at 200W power for 2 hours to obtain the inclusion complex; S1.

4. Add 10g of microcrystalline cellulose and 5g of hydroxypropyl methylcellulose, and mix in a high-efficiency mixer at 300r / min for 15 minutes; S1.

5. Transfer the mixture to a fluidized bed granulator, set the inlet air temperature to 40±2℃, the atomization pressure to 0.2MPa, and maintain the material temperature at 38 to 40℃ to carry out the granulation operation; S1.

6. The obtained particles are sieved through a 0.3 to 0.5 mm sieve to obtain the outer layer of fast-release microcapsules; S2. Inner layer sustained-release microspheres are prepared, containing long-acting ingredients puerarin, cimicifugain glycoside and glycyrrhizic acid, and achieve sustained release for 6 to 8 hours through a hydroxypropyl methylcellulose and ethylcellulose composite framework. S2.

1. Weigh 30g of kudzu root, 20g of saposhnikovia root, and 15g of licorice root. Add 10 times the amount of drinking water and soak for 30 minutes. Then heat to a gentle boil and maintain the temperature between 90 and 95°C. Continue to decoct at this temperature twice, each time for 1.5 hours. Stir slowly at a speed of 60 revolutions per minute during the decoction process. S2.

2. Combine the two decoctions, filter them with a 200-mesh filter cloth, transfer the filtrate to a vacuum concentrator, and concentrate it to a relative density of 1.20 at 60°C and 0.08 MPa. S2.

3. Add ethanol to the concentrate to make the alcohol content reach 70%, while stirring at a speed of 120 r / min. After the addition is complete, continue stirring for 15 minutes, place it in a refrigerator at 4℃ and let it stand for 12 hours. Take the supernatant and centrifuge (4000 r / min, 15 minutes) to collect the precipitate. S2.

4. The precipitate is spray-dried with an inlet air temperature of 180±5℃, an outlet air temperature of 80±5℃, and an atomizer speed of 15000r / min to obtain a dried extract powder. S2.

5. Mix the extract powder with 12g of hydroxypropyl methylcellulose and place it in a three-dimensional motion mixer. Mix at 25r / min for 30 minutes. Slowly add purified water, control the material temperature to not exceed 35℃, adjust the stirring speed to 200r / min and the chopping speed to 800r / min to obtain a soft material with a moisture content controlled at 25%. S2.

6. Soft materials are processed using an extrusion rounding machine with a sieve plate aperture of 1.0 mm, an extrusion speed of 50 r / min, and a rounding speed of 800 r / min to obtain micro pellets with a particle size of 0.5 to 0.8 mm. S2.

7. Place the microparticles in a fluidized bed coating machine and coat them with Eudragit® NE30D ethyl cellulose aqueous dispersion. Set the inlet air temperature to 50°C, the material temperature to 38 to 40°C, the spray rate to 5 mL / min, the atomization pressure to 0.8 Bar, and coat until the weight gain is 5%, forming an isolation layer with a thickness of 10 to 20 μm. S3. Total Mixing and Filling: Mix the outer layer of immediate-release microcapsules (30% of the total contents) with the inner layer of sustained-release microcapsules (70%), add 2g of magnesium aluminum silicate anti-caking agent, place in a V-type mixer, mix at 15r / min for 20 minutes until uniform, and use a fully automatic capsule filling machine to fill the mixture into No. 0 HPMC plant capsule shells, with each capsule containing 0.4g. After filling, polish the capsules and remove unqualified products. S4. Intermediate storage: After filling and polishing, the capsules should be temporarily stored in a sealed container in a Class D clean area. Use non-toxic polyethylene or stainless steel drums for storage. Place double-layered silica gel desiccant inside the drum. The ambient temperature should be controlled between 18 and 25°C, and the relative humidity (RH) should be controlled at <45%. The storage time should not exceed 24 hours. S5. Inner packaging: High-barrier aluminum foil or PVC / PVC composite rigid sheet should be used, with a water vapor transmission rate (WVTR) ≤ 0.5 g / m³. 2 • 24h, the back seal material is made of pharmaceutical aluminum foil with a thickness of 20 to 25 μm, and product information is printed on it. It is packaged using a fully automatic blister packaging machine. S6. Outer packaging: Place blister packs or medicine bottles into a pharmaceutical paper box and add the instruction manual. Bundle several small boxes into a medium pack or large tray using polyolefin heat shrink film. The heat shrink tunnel temperature is usually set to 160 to 180℃. After heat shrinking, the film should be flat and taut. Pack the medium packs or small boxes into a corrugated cardboard box. Place a moisture-proof pad inside the box. Print the product batch number, production date, and expiration date on the outside of the box. S7. Storage conditions: The final product should be stored in a cool, dry, and well-ventilated warehouse at a temperature not exceeding 25°C or refrigerated at 2 to 8°C, with a relative humidity of <60%. Avoid direct sunlight and keep away from heat sources. S8. Process Validation Requirements: To ensure the effectiveness of packaging, a sealing test must be conducted. For blister packaging, a color water method leakage test must be performed, and for bottled packaging, an airtightness test and a stability test must be performed. The final packaged product must be placed under accelerated testing conditions (40±2℃, 75±5%RH) and long-term testing conditions (25±2℃, 60±5%RH) for observation. Key indicators such as appearance, moisture content, content, and dissolution rate must be tested regularly to determine the shelf life.

7. A traditional Chinese medicine capsule for treating colds and flu, and its preparation method, as described in claim 6, characterized in that: The process parameters for the inner packaging described in step S5 are as follows: For PVC / PVDC rigid sheets, the heating plate temperature should be controlled at 120 to 140°C to ensure good heat sealing and prevent charring. The heat sealing roller temperature should be controlled at 150 to 170°C, and the pressure should be 0.3 to 0.5 MPa. A heat sealing strength test is required to ensure a tight seal and a peel strength ≥ 3.5 N / 15 mm. Before heat sealing, nitrogen or a nitrogen-to-carbon dioxide mixture can be injected into the blister cavity to replace the air inside and prevent oxidation of the contents.

8. A traditional Chinese medicine capsule for treating colds and flu according to claim 6, and its preparation method thereof, characterized in that: In steps S2 and S3 above, after filling and polishing, the capsules are immediately packaged in aluminum-plastic blister packs using PVDC-coated aluminum foil. The heat sealing temperature is controlled at 160±5℃ and the pressure is 0.4MPa. Nitrogen filling is also used for protection. Subsequently, the capsules are boxed, shucked, and packed. The finished products are stored in a cool, dry place at a temperature ≤25℃ and a relative humidity <60%.

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