Traditional chinese medicine ultrafine granules as well as preparation method therefor and application thereof

Abstract

Traditional Chinese medicine ultrafine granules, a preparation method therefor, and an application thereof. The granules are obtained through the steps of medicinal material processing, crushing, sterilization, ultrafine crushing, mixing, water balancing, granulation, screening, etc., and have the advantages of moderate tightness, good compressibility, and high yield, and the raw material components and amounts of the traditional Chinese medicinal materials have been preserved to a greater extent. During preparation, there is no residual solvents, no excipients are added, the granules are highly safe, there is good granule uniformity, the granules quickly dissolve, and the granules meet the standards set out in a pharmacopoeia; and the technical problem where traditional Chinese medicinal materials with high sugar content and which readily absorb moisture are unable to undergo wet granulation is solved. For the present ultrafine granules, processing is simple, production costs are low, and granule yield is high; continuous and amplified production of dry-granulated granules is achieved, and the present invention has broad application prospects.

Description

A kind of Chinese medicinal material wall-broken granules and its preparation method and application Technical Field

[0001] The present invention belongs to the technical field of traditional Chinese medicine preparations, and particularly relates to a traditional Chinese medicine wall-broken granule and a preparation method and application thereof. Background Art

[0002] Ultrafine grinding technology is a new technology that has developed rapidly in recent years. It is to grind Chinese herbal medicine pieces to about 300 meshes, and the cell wall breaking rate will reach 86.7%, which improves the dissolution of effective ingredients in medicinal materials, and the utilization rate of effective ingredients is above 90%, thereby enhancing its efficacy. At the same time, it is beneficial to reduce the use of Chinese medicinal materials and protect Chinese medicinal materials resources. However, as the cell wall breaking rate of ultrafine powder increases, the specific surface area of ​​the broken powder increases, the fluidity and dispersibility are poor, it is easy to absorb moisture, and the stability is poor. Therefore, the current solution is to granulate the ultrafine broken powder to improve the stability of the product. Among them, wet granulation is often used for granule preparation. However, the problems of the wet granulation process are as follows: (1) The granulation process involves the use of a certain concentration of ethanol as a processing aid to make soft materials, and the amount used is relatively large, which increases production costs and production safety risks; (2) A drying process is required to remove the added processing aid-ethanol, and to remove the untreated ethanol. It is easy to cause the residual solvent to exceed the standard; the drying efficiency is not high, and the varieties generally have high drying temperature and long drying time; (3) Most varieties of broken wall full powder wet granules are loose and have a high water content. Drying will cause a lot of fine powder and the yield of one granule is low; (4) After drying, the appearance and solubility of the granules will generally deteriorate; (5) Some sticky or non-sticky varieties have poor adaptability to wet granulation, resulting in difficulties in the production process or unstable production process, low granule yield and poor production efficiency; (6) Wet heat drying treatment causes component loss and damage to some varieties with volatile components and varieties easily destroyed by heat.

[0003] Compared to wet granulation, dry granulation offers several advantages. It requires no additives or binders, directly utilizing the viscosity of the material itself. Relying on mechanical extrusion, dry granulation processes the raw powder through compression, molding, crushing, and granulation. This allows for continuous granulation, resulting in energy savings, simple and convenient operation, low production costs, and a favorable environment for industrial production. However, dry granulation currently faces several challenges. Since the vast majority of Chinese medicinal materials are naturally derived from plants and animals, the medicinal parts of botanicals alone are complex, including leaves, flowers, fruits, roots, stems, and even the entire plant. These parts exhibit significant variations in properties, driven by differences in composition and proportion. This is reflected in the wide variation in compressibility of dry granules. Most varieties exhibit poor compressibility without the addition of excipients, resulting in low granule yields and high granule friability. Many varieties with poor compressibility are unsuitable for dry granulation and cannot meet the requirements of large-scale dry granulation production. The solution to poor compressibility is to add a certain amount of excipients. For example, Chinese patent CN113952306A discloses a method for improving the dry granulation formability of Chinese medicine formula granules by using a powder wetting agent. This method uses purified water instead of high-concentration ethanol, eliminating the safety hazards of high-concentration ethanol, and improves the dry granulation formability of the dry paste powder by directly and evenly spraying purified water into the excipient powder. However, this process still adds a large amount of non-water-soluble excipients such as substituted hydroxypropyl cellulose, colloidal silicon dioxide, magnesium aluminum silicate, silicon dioxide and ethyl cellulose. For example, patent CN110384760A discloses a Chinese medicine wall-breaking composition for intervening in blood stasis constitution, which adopts dry granulation. The Chinese medicine composition, filler, and flavoring agent are pulverized and granulated together to obtain an ultrafine powder, which can quickly disintegrate the Chinese medicinal ingredients and improve the drug's absorbability. However, the above dry granulation technical solutions still do not solve how to make the Chinese medicinal material powder particles have good molding and granulation properties without adding related auxiliary materials. CN103417582A discloses a Cordyceps sinensis pure powder tablet and its preparation method. This preparation method adopts a low-temperature, low-pressure, low-moisture dry granulation process to achieve, reducing the damage to the active ingredients of Cordyceps sinensis caused by the high-temperature and high-pressure tableting process. This technical solution only improves the tableting process that easily inactivates the active ingredients, but does not study the granulation process. On the other hand, some Chinese medicinal materials with high sugar content, although they have good compressibility, are prone to moisture absorption and cannot be produced by continuous dry granulation. Therefore, at present, the existing technology lacks a dry granulation process with wide applicability, which will limit the development and application of various Chinese medicinal preparations. Summary of the Invention

[0004] In response to the problems existing in the above-mentioned prior art, the present invention provides a new dry method for preparing Chinese medicinal material wall-broken granules. The preparation method does not cause loss or damage to the raw material components of the Chinese medicinal materials, has good compressibility, high granule yield, and wide applicability. It can be applied to a variety of Chinese medicinal materials, especially Chinese medicinal materials with poor compressibility or high sugar content and easy moisture absorption. In addition, the preparation process does not require the addition of processing aids such as ethanol and any other auxiliary materials, has high safety, and is suitable for large-scale industrial production.

[0005] In a first aspect, the present invention provides a method for preparing wall-broken granules of traditional Chinese medicine, the method comprising the following steps:

[0006] S1. Preparation of medicinal materials: Chinese medicinal materials are sorted, cleaned, cut and dried to obtain pure medicinal materials;

[0007] S2. Medicinal material crushing: clean medicinal materials are taken and crushed by a crusher to obtain coarse medicinal material powder;

[0008] S3. Sterilization of medicinal materials: The crude powder of medicinal materials is sterilized by superheated steam and then cooled;

[0009] S4, wall-breaking and pulverizing: the coarse powder of the medicinal material sterilized in step S3 is subjected to wall-breaking and pulverizing to obtain wall-broken powder;

[0010] S5. Mixing and moisture balance: The broken wall powder obtained in step S4 is placed in a mixing tank, and the total weight of the broken wall powder is weighed M (kg). The moisture content ω0 (%) is detected by online sampling. Then, the vacuum valve is opened to evacuate the tank, and compressed nitrogen is introduced in batches and in a quantitative manner. The initial relative humidity of the nitrogen is Φ0 (%) determined by online detection. The pressure of the compressed nitrogen is P (MPa) determined by online pressure detection. The broken wall powder is repeatedly mixed multiple times until the mixture is uniform. After the mixing is completed and maintained for 0.5 to 8 hours, the final moisture content of the broken wall powder is detected by online sampling to be ω1 (%). The equilibrium relative humidity of the nitrogen is determined by online detection to be Φ1 (%). The compressed nitrogen is then evacuated to a vacuum state to obtain a uniform broken wall powder with optimal compressibility.

[0011] S6. Granulation: In the granulation chamber, the uniform, optimally compressible, wall-broken powder obtained in step S5 is transferred into the hopper of a dry granulator and pressed into granules;

[0012] S7, screening: screening the particles in step S6 to prepare Chinese medicinal material wall-broken particles.

[0013] Furthermore, the moisture content of the Chinese medicinal materials in step S1 after drying is maintained at ≤10%;

[0014] Furthermore, the medicinal material coarse powder in step S2 is 80-120 mesh;

[0015] Furthermore, in step S3, the superheated steam is at a temperature of 150°C to 170°C, a pressure of 0.1 to 0.3 MPa, and a sterilization time of 3 to 10 seconds;

[0016] Furthermore, the broken powder in step S4 is 300-1000 mesh, D 90 <45μm;

[0017] Furthermore, in step S5, the vacuum valve is opened to evacuate the tank, and the vacuum degree is -0.05 to -0.09 MPa;

[0018] Furthermore, in step S5, the pressure of the compressed nitrogen gas introduced in batches and quantitatively is 0.3-0.8 MPa, and the relative humidity is 0-100% (wherein the high relative humidity value is 80%-100%, which is suitable for materials with poor compressibility; the low relative humidity value is 0%-20%, which is suitable for materials with high sugar content; and the medium relative humidity value is 45%-65%, which is suitable for general materials).

[0019] Furthermore, in step S5, the compressed nitrogen is exhausted to a vacuum degree of -0.05 to -0.09 MPa.

[0020] Furthermore, in step S5, the volume V1 (m 3 The relationship between ) and the number n can be obtained by the calculation method of formula (1):

[0021] Where: P sb is the saturated water vapor partial pressure, Pa, which can be found through the corresponding physical parameter table;

[0022] ρ is the density of compressed nitrogen, g / m 3 , can be found through the corresponding physical parameter table;

[0023] Q1 is the correction coefficient of the material, 0.1 to 10;

[0024] n is the number of times nitrogen is introduced, 5 to 20 times;

[0025] ω1(%) is the final moisture content of the broken powder, 8.5-12.3%;

[0026] Furthermore, the granulation process in step S6 is as follows: setting the screw feed speed to 20-80 rpm, the roller speed to 6-18 rpm, the roller oil pressure to 7-160 bar, the roller gap to 0.8-1.5 mm, the cooling circulation water temperature to 5-30° C., the granulation screen aperture to 1.0 mm-2.0 mm, and the granulation speed to 100-150 rpm;

[0027] Preferably, in step S6, the temperature of the granulation chamber is controlled not to exceed 25° C. and the relative humidity is controlled to be below 10%.

[0028] Furthermore, the Chinese medicinal material wall-broken particles in step S7 are 14 to 60 meshes;

[0029] Furthermore, the Chinese medicinal materials in the preparation method include but are not limited to salvia miltiorrhiza, angelica sinensis, wolfberry, astragalus, momordica grosvenori, Scrophularia ningpoensis, jujube, mulberry, polygonatum, tangerine peel, bergamot and / or ganoderma lucidum.

[0030] In a second aspect, the present invention provides a Chinese medicinal material wall-broken granules obtained by the preparation method.

[0031] Furthermore, the Chinese medicinal materials are selected from salvia miltiorrhiza, angelica, wolfberry, astragalus, momordica grosvenori, Scrophularia ningpoensis, jujube, mulberry, polygonatum, tangerine peel, bergamot and / or ganoderma lucidum, etc., and the Chinese medicinal materials are not limited to the above-mentioned Chinese medicinal materials.

[0032] In a third aspect, the present invention further provides the use of the Chinese herbal medicine wall-broken granules in pharmaceutical preparations, wherein the pharmaceutical preparations include but are not limited to tablets, capsules, suspensions, patches, and the like.

[0033] In the method for preparing Chinese medicinal material wall-broken granules of the present invention, the wall-broken powder is subjected to mixing and moisture balance treatment in step S5, wherein compressed nitrogen is used to prevent the Chinese medicinal material wall-broken powder with a large specific surface area from contacting with air, thereby preventing the medicinal ingredients from being oxidized by oxygen in the air and protecting the medicinal ingredients. The compressed nitrogen is introduced at a fixed volume, fixed pressure, and fixed relative humidity calculated based on the difference between the online detected moisture value and the optimal compressible moisture value, so as to achieve the effects of fully mixing the materials and balancing the moisture. By introducing the compressed nitrogen in a quantitative manner in batches, the wall-broken powder is repeatedly mixed multiple times until it is evenly mixed, thereby obtaining a wall-broken powder with good uniformity and compressibility, thereby ensuring smooth production and improving the quality of the medicine.

[0034] Compared with the prior art, the present invention has the following beneficial effects:

[0035] (1) The present invention realizes a method for preparing wall-broken granules of Chinese medicinal materials without adding processing aids and / or auxiliary materials, thereby solving the problem that some varieties with high sugar content and easy moisture absorption cannot be wet granulated, and dry granulation is also difficult to be continuously and scaled up.

[0036] (2) The method for preparing the wall-broken granules of Chinese medicinal materials of the present invention solves the problem that most Chinese medicinal materials have poor compressibility, low granule yield, and high granule friability without adding auxiliary materials, which makes it difficult to dry granulate. The processing process is simple, the cost is low, the granule yield is high, the granule hardness is good, and the friability meets the standard.

[0037] (3) The preparation process of the Chinese herbal medicine wall-broken granules of the present invention does not use organic solvents such as ethanol as processing aids, and there is no solvent residue, which is highly safe.

[0038] (4) The preparation process of the Chinese herbal medicine wall-broken granules of the present invention does not undergo wet and heat processing, so the granule components are more completely retained, and the prepared granules have better solubility and disintegrate more quickly. BRIEF DESCRIPTION OF THE DRAWINGS

[0039] Figure 1 is the fingerprint of the mixed reference substance (peak 1: ferulic acid, peak 2: ligustilide, peak 4: coniferyl ferulate, peak 7: ligustilide, peak 8: butenylphthalide).

[0040] Figure 2 is the fingerprints of Example 2, Comparative Example 2 and dry medicinal materials (S1: dry medicinal materials in the medicinal material processing stage, S2: Example 2, S3: Comparative Example 2). DETAILED DESCRIPTION

[0041] The experimental methods in the following examples of the present invention, where specific conditions are not specified, are generally carried out under conventional conditions or conditions recommended by the manufacturers. The various commonly used chemical reagents used in the examples are all commercially available products.

[0042] Unless otherwise defined, all technical and scientific terms used in the present invention have the same meaning as those commonly understood by those skilled in the art. The terms used in the specification of the present invention are only for the purpose of describing specific embodiments and are not intended to limit the present invention.

[0043] In order to make the purpose, technical solutions and advantages of the present invention more clear, the present invention is further described in detail below in conjunction with specific embodiments. It should be understood that these descriptions are merely exemplary and are not intended to limit the scope of the present invention. In addition, in the following description, descriptions of well-known structures and technologies are omitted to avoid unnecessary confusion of the concept of the present invention.

[0044] Example 1 Preparation of Danshen Broken Wall Granules

[0045] This example uses the Chinese medicinal material Danshen to prepare broken-wall granules, and the specific preparation steps are as follows:

[0046] S1. Preparation of medicinal materials: Take the medicinal materials of Danshen, wash them immediately after harvesting, sort them to remove impurities and foreign matter, non-medicinal parts, etc., cut them into pieces of about 1.0 cm in length using a medicinal cutting machine, transfer them to a hot air circulation oven, set the drying temperature at 60°C, dry them for 3-4 hours, and then continue drying at 50°C until the moisture content is ≤6.0%, to obtain the clean medicinal materials;

[0047] S2. Medicinal material grinding: pre-install a 120-mesh screen in the coarse grinder, set the machine chamber temperature to ≤35°C, the discharge temperature to ≤40°C, the cold air inlet temperature to 5°C, and the fan frequency to 50Hz, then place the dried clean medicinal materials in the coarse grinder and grind them into a coarse medicinal material powder of about 120 mesh;

[0048] S3. Sterilization of medicinal materials: The crude powder of medicinal materials is transported to the superheated steam instant sterilization system through a pipeline. The sterilization steam temperature is set to 160°C, the pressure is set to 0.19 MPa, and the sterilization time is set to 5 seconds to sterilize the materials. After sterilization, the materials quickly enter the cooling section. The air inlet temperature of the cooling section is set to 5°C to quickly cool the sterilized materials to room temperature.

[0049] S4. Wall-breaking and pulverizing: The sterilized medicinal material coarse powder is transferred to the supersonic airflow pulverizing and classifying system, and the classifier forward frequency is set to 35.0Hz, the air hammer starting frequency is 10s, the inlet pressure is 0.7MPa~0.8MPa, the inlet temperature is 10℃, the feeder frequency is 0~15Hz (when the classifier current is lower than 3.0A, the feed rate is 15Hz; when 3.0A≤classifier current≤3.5A, the feed rate is 10Hz; when 3.5A<classifier current≤4.0A, the feed rate is 5Hz; when the classifier current is greater than 4.0A, the feed rate is 0Hz), and the pulse electromagnetic valve starting time interval is 20s (duration 1s), and the powder is pulverized into 300-mesh broken-wall powder (D 90 <45μm);

[0050] S5, mixing and moisture balance: the broken wall powder of Danshen obtained in step S4 is transferred to the mixing tank by vacuum conveying, and the total weight M of the broken wall powder is 3125.6 kg by the automatic weighing device of the tank body. The moisture content ω0 of the powder is measured by the online moisture meter to be 5.62%. Then, the vacuum valve is opened, and the mixing tank is slowly evacuated to a vacuum degree of -0.09 MPa. According to the formula (2), the compressed nitrogen with a pressure P of 0.3 MPa and a relative humidity Φ0 of 95% is divided into 15 equal parts and passed through The powder was mixed in the mixing tank (the interval of each introduction of compressed nitrogen was 2 to 10 seconds). After the broken wall powder was evenly mixed, the mixing tank was kept at a pressure of 0.3 MPa for 8 hours. At the same time, the moisture content was detected online to have reached the optimal compressible moisture content. At this time, the equilibrium relative humidity Φ1 of the nitrogen was 85%, and the compressed nitrogen pressure P was 0.3 MPa. At this time, the final moisture content ω1 of the broken wall powder measured by the online moisture meter was 12.3%. The volume V1 (m 3 ):

[0051] Where: P sb is the saturated water vapor partial pressure. According to the saturated water vapor pressure temperature comparison table, the saturated water vapor partial pressure P at 24°C is sb 3000Pa;

[0052] ρ is the density of compressed nitrogen. At 24°C, the density of 0.3 MPa compressed nitrogen is approximately 3400 g / m 3 ;

[0053] Q1 is the correction factor of the material, 0.8;

[0054] n is the number of times nitrogen is introduced, 15 times;

[0055] Substituting the above data into formula (2), the calculation is as follows: 3125.6×(12.3%-5.62%)×1000=622×[(95%×3000)÷(300000-95%×3000)-(85%×3000)÷(300000-85%×3000)]×3400×0.8×15×V1

[0056] Calculated V1 = 8.066m 3 ;

[0057] Then, the compressed nitrogen in the mixing tank is slowly evacuated again until the pressure in the mixing tank reaches a vacuum state of -0.09 MPa, thereby obtaining a uniform, wall-broken powder with optimal compressibility.

[0058] S6. Granulation: The compressible wall-broken powder obtained in step S5 is transferred to the hopper of a dry granulator. The screw feed speed is set at 25 rpm, the roller speed is 10 rpm, the roller oil pressure is 135 bar, the roller gap is 1.3 mm, the cooling circulating water temperature is 30°C, the granulation screen aperture is 1.0 mm, and the granulation speed is 100 rpm. Granulation is then performed.

[0059] S7, screening: the granules pressed in step S6 are screened through a vibrating screening machine with an upper 20-mesh and a lower 60-mesh sieve to produce granules with a mesh size of 20 to 60. The unqualified fine powder is vacuum-fed again into the hopper of the dry granulator for secondary granulation to finally obtain Danshen wall-broken granules.

[0060] Example 2 Preparation of Angelica wall-broken granules

[0061] This example uses Chinese medicinal material Angelica sinensis to prepare broken-wall granules, and the specific preparation steps are as follows:

[0062] S1. Preparation of medicinal materials: Take Chinese angelica medicinal materials, spread them out to dry in the sun for 2-3 days after harvesting (avoid direct exposure to the sun), shake off the residual soil on the roots, pick out impurities such as residual petioles, rinse with drinking water until there is no soil on the surface of the medicinal materials, straighten the lateral roots, remove the residual petioles, tie them into small bundles, select a dry and ventilated room or a special fumigation shed, and slowly heat and dry them with firewood (avoid coal fire). The indoor temperature is controlled at 30-70°C. After about 8-20 days, when the total dryness reaches 70%-80%, the fire can be stopped, and then cut into thick slices with a thickness of 1-2 mm using a medicinal cutting machine, transfer them to a hot air circulation oven, set the drying temperature to 50°C and dry them to a moisture content of ≤8.0%, to obtain clean medicinal materials;

[0063] S2. Medicinal material grinding: pre-install a 120-mesh screen in the coarse grinder, set the machine chamber temperature to ≤32°C, the discharge temperature to ≤35°C, the cold air inlet temperature to 3°C, and the fan frequency to 50Hz, then place the dried clean medicinal materials in the coarse grinder and grind them into a coarse medicinal material powder of about 120 mesh;

[0064] S3. Sterilization of medicinal materials: The crude powder of medicinal materials is transported to the superheated steam instant sterilization system through a pipeline. The sterilization steam temperature is set to 150°C, the pressure is set to 0.17 MPa, and the sterilization time is set to 3 seconds to sterilize the materials. After sterilization, the materials quickly enter the cooling section. The inlet air temperature of the cooling section is set to 1°C to quickly cool the sterilized materials to room temperature.

[0065] S4. Wall-breaking and pulverizing: The sterilized coarse powder of the medicinal material is transferred to the supersonic airflow pulverizing and classifying system, and the classifier forward frequency is set to 30.0 Hz, the air hammer starting frequency is 10s, the air intake pressure is 0.7MPa-0.8MPa, the air intake temperature is 5°C, the feeder frequency is 0-20Hz (when the classifier current is lower than 3.0A, the feed rate is 20Hz; when 3.0A≤classifier current≤3.5A, the feed rate is 15Hz; when 3.5A<classifier current≤4.0A, the feed rate is 10Hz; when the classifier current is greater than 4.0A, the feed rate is 0Hz), and the pulse electromagnetic valve starting time interval is 20s (duration 1s), and the powder is pulverized into 300-mesh Angelica wall-breaking powder (D 90 <45μm);

[0066] S5, mixing and moisture balance: The angelica root wall-broken powder obtained in step S4 is transferred to the mixing tank via vacuum conveying, and the total weight M of the wall-broken powder is weighed by the automatic weighing device of the tank body to be 2500.5 kg. The moisture content ω0 of the powder is measured by the online moisture meter to be 7.01%. Then, the vacuum valve is opened, and the mixing tank is slowly evacuated to a vacuum degree of -0.09 MPa. According to the formula (3), the compressed nitrogen gas with a pressure P of 0.5 MPa and a relative humidity Φ0 of 50% is divided into 5 equal parts and passed through the mixing tank. The powder was mixed in the mixing tank (the interval of each compressed nitrogen introduction was 2 to 10 seconds). After the broken wall powder was mixed evenly, it was kept at a pressure of 0.5 MPa for 0.5 h. At the same time, the moisture content was detected online to have reached the optimal compressible moisture content. At this time, the equilibrium relative humidity Φ1 of the nitrogen was 45%, and the compressed nitrogen pressure P was 0.5 MPa. At this time, the final moisture content ω1 of the broken wall powder measured by the online moisture meter was 8.51%. The volume V1 (m 3 ):

[0067] Where: P sb is the saturated water vapor partial pressure. According to the saturated water vapor pressure temperature comparison table, the saturated water vapor partial pressure P at 24°C is sb 3000Pa;

[0068] ρ is the density of compressed nitrogen. At 24°C, the density of 0.5 MPa compressed nitrogen is approximately 5700 g / m 3 ;

[0069] Q1 is the correction factor of the material, 1.0;

[0070] n is the number of times nitrogen is introduced, 5 times;

[0071] Substituting the above data into formula (3), the calculation is as follows: 2500.5×(8.51%-7.01%)×1000=622×[(50%×3000)÷(500000-50%×3000)-(45%×3000)÷(500000-45%×3000)]×5700×1.0×5×V1

[0072] Calculation: V1 = 7.053m 3 ;

[0073] The compressed nitrogen in the mixing tank is slowly evacuated to a vacuum state of -0.09 MPa to obtain a uniform, wall-broken powder with optimal compressibility;

[0074] S6. Granulation: The compressible wall-broken powder obtained in step S5 is transferred to the hopper of a dry granulator. The screw feed speed is set to 75 rpm, the roller speed is 15 rpm, the roller oil pressure is 70 bar, the roller gap is 1.0 mm, the cooling circulating water temperature is 17° C., the granulation screen aperture is 1.5 mm, and the granulation speed is 140 rpm. Granulation is then performed.

[0075] S7, screening: the granules pressed in step S6 are screened through a vibrating screening machine with an upper 20-mesh and a lower 60-mesh sieve to produce granules with a mesh size of 20 to 60. The unqualified fine powder is vacuum-fed again into the hopper of the dry granulator for secondary granulation to finally obtain the Angelica sinensis wall-broken granules.

[0076] Example 3 Preparation of Lycium barbarum wall-broken granules

[0077] This example uses the Chinese medicinal material wolfberry to prepare broken-wall granules, and the specific preparation steps are as follows:

[0078] S1. Preparation of medicinal materials: Take wolfberry medicinal materials, select the obviously cracked and immature fresh fruits after harvesting, and remove other impurities. Then transfer them to a hot air circulation oven, set the drying temperature at 45°C for 4 hours in the first stage, set the drying temperature at 55°C for 10 hours in the second stage, and set the drying temperature at 60°C for 10 hours in the third stage until the moisture content is ≤10%, to obtain pure medicinal materials;

[0079] S2. Medicinal material crushing: In this embodiment, the wolfberry does not need to be crushed;

[0080] S3. Sterilization of medicinal materials: The clean medicinal materials are sterilized by the superheated steam instant sterilization system, where the sterilization steam temperature is set to 155°C, the pressure is set to 0.2MPa, and the sterilization time is set to 3 seconds to sterilize the materials. After sterilization, the materials quickly enter the cooling section, and the cooling section inlet temperature is set to 3°C to quickly cool the sterilized materials to room temperature;

[0081] S4. Wall-breaking and pulverizing: After sterilization, the clean medicinal materials were transferred to a deep freezer and refrigerated at -20°C for more than 12 hours. Then, they were transferred to a vibration-type pharmaceutical ultrafine pulverizer. The relative humidity of the vibration-milling chamber was controlled below 10%. The vibration frequency was set to 30 times / s and the vibration amplitude was 10mm. The refrigeration temperature of the refrigerator was -20°C to -25°C. After 10 minutes of vibration-milling, the material was discharged. The particle size of the obtained wolfberry wall-breaking powder was above 300 mesh (D 90 <45μm);

[0082] S5, mixing and moisture balance: The wall-broken wolfberry powder obtained in step S4 is transferred to the mixing tank via vacuum conveying, and the total weight M of the wall-broken powder is weighed by the automatic weighing device of the tank body to be 2002.5 kg. The moisture content ω0 of the powder is measured by the online moisture meter to be 12.25%. Then, the vacuum valve is opened, and the mixing tank is slowly evacuated to a vacuum degree of -0.09 MPa. According to the formula (4), the pressure P is 0.8 MPa, the relative humidity Φ0 is 0%, and the compressed nitrogen is divided into 20 equal parts. The powder was introduced into the mixing tank for mixing (the interval between each introduction of compressed nitrogen was 2 to 10 seconds). After the broken wall powder was evenly mixed, it was kept at a pressure of 0.8 MPa for 5 hours. At the same time, the moisture content was detected online to have reached the optimal compressible moisture content. At this time, the equilibrium relative humidity Φ1 of the nitrogen was 25%, and the compressed nitrogen pressure P was 0.8 MPa. At this time, the final moisture content ω1 of the broken wall powder measured by the online moisture meter was 10.20%. The volume V1 (m 3 ):

[0083] Where: P sb is the saturated water vapor partial pressure. According to the saturated water vapor pressure temperature comparison table, the saturated water vapor partial pressure P at 24°C is sb 3000Pa;

[0084] ρ is the density of compressed nitrogen. At 24°C and 0.8 MPa, the density of compressed nitrogen ρ is about 9120 g / m 3 ;

[0085] Q1 is the correction factor of the material, 1.5;

[0086] n is the number of times nitrogen is introduced, 20 times;

[0087] Substituting the above data into formula (4), the calculation is as follows: 2002.5×(10.20%-12.25%)×1000=622×[(0%×3000)÷(800000-0%×3000)-(25%×3000)÷(800000-25%×3000)]×9120×1.5×20×V1

[0088] Calculation: V1 = 0.257m 3 ;

[0089] The compressed nitrogen in the mixing tank is slowly evacuated to a vacuum state of -0.09 MPa to obtain a uniform, wall-broken powder with optimal compressibility;

[0090] S6. Granulation: The temperature of the granulation chamber was controlled at 18° C. and the relative humidity was below 10%. The compressible wall-broken powder obtained in step S5 was transferred to the hopper of the dry granulator. The screw feed speed was set to 50 rpm, the roller speed was 11 rpm, the roller oil pressure was 10 bar, the roller gap was 0.8 mm, the cooling circulating water temperature was 5° C., the granulation screen aperture was 2.0 mm, and the granulation speed was 115 rpm. The granules were pressed into granules.

[0091] S7, screening: the granules pressed in step S6 are screened through a vibrating screening machine with an upper 14-mesh and a lower 60-mesh sieve to produce granules with a mesh size of 14 to 60. The unqualified fine powder is vacuum-fed again into the hopper of the dry granulator for secondary granulation to finally obtain wolfberry wall-broken granules.

[0092] Experimental Example 1: Effects of different granulation methods on granulation efficiency, granulation energy consumption, granule yield, and residual ethanol in finished products

[0093] This test example tested the Danshen wall-broken granules, Angelica wall-broken granules, and Lycium barbarum wall-broken granules prepared in Examples 1 to 3. The specific test method is as follows:

[0094] 1) Particle properties: Place an appropriate amount of sample in a 50 mL beaker or white porcelain dish and observe its color and appearance under natural light;

[0095] 2) Particle yield: After the dry granules obtained in the granulation process are sieved through a 20-60 mesh sieve, those that cannot pass through a 20-mesh sieve or a 60-mesh sieve are classified as unqualified granules, and those between 20 and 60 mesh are qualified granules. The weights of the granules are respectively weighed and the granule yield (%) is calculated according to formula (5):

[0096] Particle yield % = qualified particle weight ÷ (qualified particles + total weight of unqualified particles) × 100% (5)

[0097] 3) Particle dissolution: Weigh 2 g of particles and add them to 300 mL of 60°C water. Stir at 40 rpm for 1 minute and observe the dissolution of the particles.

[0098] 4) Particle friability: Refer to the "0923 Tablet Friability Test Method" in Part IV of the Pharmacopoeia of the People's Republic of China 2020 Edition for testing;

[0099] 5) Granulation efficiency: refers to the number of qualified granules produced by the same operator in a normal 8-hour shift, in kg / shift;

[0100] 6) Residual ethanol content in granules: Determined according to the "0861 Residual Solvent Determination Method" in Part IV of the Pharmacopoeia of the People's Republic of China 2020 Edition.

[0101] The results obtained by the above test method are shown in Table 1:

[0102] Table 1: Performance test results of Chinese herbal medicine wall-broken granules of Examples 1 to 3

[0103] From the process of preparing the wall-broken granules of Chinese medicinal materials in Examples 1 to 3, it can be seen that the amount of compressed nitrogen introduced in the mixing and moisture balance step of step S5 of different Chinese medicinal materials varies greatly. The key step is to introduce compressed nitrogen in batches and repeatedly mix the wall-broken powder until it is evenly mixed and balanced to the optimal compressibility value. To achieve 3125.6 kg of Danshen wall-broken powder, it is necessary to divide it into 15 equal parts and introduce a total of 120.99 m 3 Compressed nitrogen gas is used to inject 35.26 m3 of compressed nitrogen into 2500.5 kg of Angelica sinensis wall-broken powder in 5 equal portions. 3 2002.5kg of wolfberry powder needs to be divided into 20 equal parts and introduced into the container with a total volume of 5.14m 3 of compressed nitrogen, it can be seen that Angelica sinensis wall-broken powder is a Chinese medicinal material with good compressibility, Salvia miltiorrhiza wall-broken powder is a Chinese medicinal material with poor compressibility, and although Lycium barbarum wall-broken powder has good compressibility, it cannot be carried out continuously due to its high sugar content and easy moisture absorption. However, the preparation method of Chinese medicinal material wall-broken granules developed by the present invention enables Chinese medicinal materials with different compressibility to be converted into good compressibility materials, which is suitable for large-scale continuous production, and the production process is efficient, the particle yield is good, the energy consumption is low, and the particle quality is further improved.

[0104] Test Example 2

[0105] Take appropriate amounts of the Chinese herbal medicine wall-broken granules prepared in Examples 1 to 3 for component testing:

[0106] Danshen Broken Wall Granules: Follow the Chinese Pharmacopoeia 2020 edition Danshen [Content Assay];

[0107] Angelica Broken Wall Granules:

[0108] 1) Volatile Oil: Determined according to the volatile oil determination method of Part IV of the Pharmacopoeia of the People's Republic of China 2020 Edition (General Chapter 2204B Method).

[0109] 2) Determination of the content of the main components of the remaining parts: Determined according to the method in Luo Zheng, Deng Wen, Zhang Qianliang, et al. Research on quality evaluation of Angelica sinensis wall-broken powder based on the QBD concept of traditional Chinese medicine [J]. China Journal of Traditional Chinese Medicine, 2020, 45(5:): 1105-1113.

[0110] Lycium barbarum wall-broken granules: follow the Chinese Pharmacopoeia 2020 edition Lycium barbarum [Content Determination] item.

[0111] The experimental results obtained by the above-mentioned determination method are shown in Tables 2 to 4;

[0112] Table 2: Test results of ingredients of Danshen wall-broken granules prepared in Example 1

[0113] Table 3: Test results of ingredients of the Angelica wall-broken granules prepared in Example 2

[0114] Table 4: Test results of ingredients of wolfberry wall-broken granules prepared in Example 3

[0115] The above test results show that the effective active ingredients of the wall-broken granules obtained by the granulation method of the present invention are well retained, with almost no loss of ingredients.

[0116] Comparative Example 1

[0117] According to the preparation method of Example 2 in patent CN108310056A: after preparing Danshen wall-broken powder through steps (1) to (6), using ethanol aqueous solution with volume fractions of 75% and 30% (the volume ratio of the two is 2:1), the total amount of ethanol aqueous solution added is 0.3 times the amount of wall-broken powder, using a 40-mesh sieve for extrusion granulation, setting a boiling granulator at 80°C to obtain wet granules, setting the upper layer 20 mesh and the lower layer 60 mesh sieve to a vibrating sieving machine to prepare granules with 20-60 mesh.

[0118] Comparative Example 2

[0119] Reference is made to the preparation method of Example 1 in CN101147746A: After preparing the angelica wall-broken powder through steps (1) to (3), the powder is placed in a mixer, and a soft material is prepared with an appropriate amount of ethanol aqueous solution with a volume fraction of 70%. The soft material is granulated by a swing granulator pre-installed with a 30-mesh sieve to obtain wet granules, which are placed in a hot air circulation oven with a set temperature of 60°C to 65°C and dried to a moisture content of ≤6.5%. The wet granules are then sieved using a vibrating sieve with an upper layer of 20 mesh and a lower layer of 60 mesh sieves to obtain 20-60 mesh granules.

[0120] Comparative Example 3

[0121] Reference is made to the preparation method of Example 3 in CN108310056A: wolfberry wall-broken powder is prepared by steps (1) to (6), and at the same time, the concentration and amount of the wetting agent are increased according to the material property of wolfberry being more sticky to reduce the viscosity of the soft material, and in step (7), ethanol aqueous solution with a volume fraction of 95% and 30% (the volume ratio of the two is 2:1) is used, and the total amount of ethanol aqueous solution added is 0.1 times the weight of the wall-broken powder, and granulated by a swing granulator pre-loaded with a 20-mesh sieve, dried at 60°C to 65°C, and sieved to prepare 14-60 mesh granules.

[0122] Comparative Example 4

[0123] The difference between this comparative example and Example 1 is that the method for preparing the Danshen Chinese medicinal material wall-broken granules does not include step S5 of the mixing and moisture balance process, and the remaining steps are consistent with those in Example 1.

[0124] Comparative Example 5

[0125] The difference between this comparative example and Example 3 is that the preparation method of the wolfberry Chinese medicinal material broken wall granules omits step S5 of the mixing and moisture balance process, and the remaining steps are consistent with Example 3.

[0126] Experimental Example 3: Effects of different granulation methods on granulation efficiency, granulation energy consumption, granule yield, and residual ethanol in finished products

[0127] This test example tests the Danshen wall-broken granules prepared by different granulation methods in Example 1, Comparative Example 1, and Comparative Example 4. The specific test method is as follows:

[0128] 1) The processing aid, the amount of the processing aid added, the drying temperature, the drying time, the granulation efficiency, and the granulation energy consumption are statistically obtained from the granulation preparation process (steps S6 and S7) based on actual conditions;

[0129] 2) The particle properties, particle yield, particle dissolution, particle friability, and particle ethanol residue were all measured according to the test method of Test Example 1.

[0130] The results obtained by the above test method are shown in Table 5:

[0131] Table 5: Performance test results of Danshen wall-broken granules

[0132] From the comparison results in Table 5, it can be seen that compared with Comparative Example 1, Example 1 and Comparative Example 4 adopt a dry granulation method, so there is no processing aid ethanol solvent and the addition of multiple excipients. Therefore, there is no need to dry the granulation process of the Chinese medicinal materials, which saves a lot of additional energy consumption due to the input and drying of excipients. At the same time, it will not cause the residual auxiliary ethanol in the finished granules. The ethanol residues in the finished granules in Example 1 and Comparative Example 4 meet the limit requirement of no more than 0.5% of ethanol residues in the "Pharmacopoeia of the People's Republic of China 2020 Edition".

[0133] Compared with Comparative Example 1, the granulation efficiency of Example 1 is significantly improved, and the granulation energy consumption is significantly reduced; while Comparative Example 4 has low efficiency and greatly increased energy consumption due to poor compressibility. In terms of granule properties, there is little difference between Example 1 and Comparative Example 4, and there are certain colored granules in Comparative Example 1, indicating that the uniformity of Comparative Example 1 during the granulation process is poor. In terms of granule yield, the yield of Example 1 is high, reaching 85.7%, while the yield of Comparative Example 1 decreases to 65.4%, and the yield of Comparative Example 4 decreases significantly, only 28.8%. It can be seen that the mixing and moisture balance process in step S5 of the granule preparation process of the present invention has a greater impact on the yield of granule granulation. In terms of granule dissolution, since Comparative Example 1 undergoes a longer period of fluidized drying during the drying process, the granules gradually become compacted during the drying process, so the granule dissolution of Example 1 and Comparative Example 4 is better than that of Comparative Example 1. In terms of granule friability, the dry granulation of the present invention significantly improves the compressibility of the granules during the dry granulation process after the material is subjected to compressed nitrogen mixing balance, and significantly reduces the friability of the granules. Although it is higher than that of Comparative Example 1, it is still at a very low level and meets the requirements of the "Pharmacopoeia of the People's Republic of China 2020 Edition".

[0134] In summary, combined with the comparative experimental results of Example 1, Comparative Example 1 and Comparative Example 4, it can be seen that different granulation methods have a significant impact on granulation efficiency, granulation energy consumption, granule yield, and residual ethanol in the finished product.

[0135] Test Example 4: Effects of different granulation methods on the composition of finished granules

[0136] Appropriate amounts of the Angelica wall-broken granules prepared in Example 2 and Comparative Example 2 were taken for component testing:

[0137] 1) Volatile Oil: Determined according to the Volatile Oil Determination Method of Part IV of the Pharmacopoeia of the People's Republic of China 2020 Edition (General Chapter 2204B Method), and compared with the dry medicinal materials at the preparation stage.

[0138] 2) Determination of the content of the main components of the remaining parts: Determined according to the method in Luo Zheng, Deng Wen, Zhang Qianliang, et al. Research on quality evaluation of Angelica sinensis wall-broken powder based on the QBD concept of traditional Chinese medicine [J]. China Journal of Traditional Chinese Medicine, 2020, 45(5:): 1105-1113.

[0139] Chromatographic conditions: chromatographic column is CAPCELL PAK C 18 MG III column (4.6 mm × 250 mm, 5 μm), mobile phase: 0.1% phosphoric acid (A)-acetonitrile containing 10% tetrahydrofuran (B), gradient elution (0–15 min, 85%–70% A; 15–29 min, 70%–44% A; 29–32 min, 44% A; 32–35 min, 44%–38% A; 35–43 min, 38%–35% A; 43–48 min, 35%–85% A; 48–58 min, 85% A); flow rate: 1.2 mL min -1 , column temperature 30 °C, injection volume 10 μL, detection wavelength 350 nm from 29 to 31 min and 270 nm for the rest of the time.

[0140] Preparation of test solution: Grind the particles in Example 2 and Comparative Example 2 into a powder that passes through a No. 3 sieve. Pulverize the dried medicinal materials into a powder that passes through a No. 3 sieve using a grinder. Accurately weigh 1.0 g of each, add 50 mL of a formic acid-methanol (5:95) solution, weigh the mixture, filter through a 0.45 μm filter, and collect the filtrate.

[0141] Preparation of mixed reference solution: Accurately weigh appropriate amounts of ferulic acid, ligustilide I, coniferyl ferulate, ligustilide, and butenylphthalide reference substances, and add formic acid-methanol (5:95) solution to prepare mass solubilities of 0.0984, 0.0455, 0.2193, 1.3400, and 0.0799 mg mL, respectively. -1 The mixed reference substance mother solution was stored in the dark at 4°C. Accurately pipette 1 mL of the reference substance mother solution into a 10 μL brown volumetric flask, make up to volume, and shake well to obtain the product.

[0142] 3) Fingerprint comparison: The fingerprints of Example 2, Comparative Example 2 and the dry medicinal materials in the medicinal material processing stage were compared at the same time.

[0143] The results obtained by the above method are shown in Table 6 and Figures 1 and 2:

[0144] Table 6: Determination results of the content of ingredients in Danggui Broken Wall Granules

[0145] From the comparative experimental results in Table 6, it can be seen that in terms of volatile oil components, the volatile oil yield of Example 2 is significantly increased compared with the dry medicinal materials and Comparative Example 2, which may be related to the fact that the plant oil chambers are broken after the wall breaking process, making the volatile oil easier to extract. After wet granulation and drying, the volatile oil in Comparative Example 2 is almost undetectable (unable to read). In terms of other components, Example 2 is similar to the dry medicinal materials, and the composition and content do not change much. In Comparative Example 2, due to the long drying time during the wet heat drying process, the composition loss and change are very large. It can be seen that dry granulation can retain the effective ingredients in the Chinese medicinal materials to a greater extent. In the granulation process of the present invention, compressed nitrogen is used for material mixing and moisture balance, without causing loss or change in the content of the Chinese medicinal materials, which has obvious advantages over wet granulation.

[0146] As can be seen from the fingerprint results, Figures 1 and 2 show that the similarity between Example 2 and the dry medicinal materials is as high as over 99%, while the similarity between Comparative Example 2 and the dry medicinal materials is significantly reduced by about 80%, and even some component peaks are clearly missing.

[0147] Test Example 5: Comparison of production processes under different granulation methods

[0148] The granulation process and yield of the wolfberry wall-broken granules prepared in Example 3, Comparative Example 3, and Comparative Example 5 were compared. The granule yield was calculated according to formula (5) in Experimental Example 1. The results are shown in Table 7:

[0149] Table 7: Results of determination of yield of wolfberry wall-broken particles

[0150] As can be seen from the experimental results in Table 7, the addition of ethanol aqueous solution is required during the granulation process of Comparative Example 3, and the viscosity of the material during the granulation process is very high. Therefore, the wet granulation process of Comparative Example 3 is completely unsuitable for the granulation production of Chinese medicinal materials with high sugar content and easy moisture absorption. In contrast, dry granulation has significant advantages in granulating such varieties, but also requires strict control of conditions. Among them, the moisture balance process is a critical process to ensure the smooth progress of production. As can be seen from the comparison of the results of Example 3 and Comparative Example 5 in Table 7, the omission of step S5 in the dry granulation process will gradually increase the degree of adhesion of the material, thereby making the granulation process difficult and further making production impossible.

[0151] Obviously, the above embodiments are merely examples for clarity of explanation and are not intended to limit the implementation methods. Those skilled in the art will readily appreciate that other variations or modifications based on the above descriptions are possible. It is not necessary and impossible to enumerate all implementation methods here. Obvious variations or modifications arising therefrom remain within the scope of protection of the present invention.

Claims

1. A method for preparing Chinese medicinal material wall-broken granules, the method comprising the following steps: S1. Preparation of medicinal materials: Chinese medicinal materials are sorted, cleaned, cut and dried to obtain clean medicinal materials; S2. Medicinal material crushing: Take clean medicinal materials and crush them in a crusher to obtain coarse medicinal material powder; S3, medicinal material sterilization: the crude powder of medicinal materials is sterilized by superheated steam and then cooled; S4, wall-breaking and pulverizing: the sterilized crude powder of the medicinal material in step S3 is subjected to wall-breaking and pulverizing to obtain wall-broken powder; S5, mixing and moisture balance: placing the broken wall powder obtained in step S4 in a total mixing tank, weighing it, calculating the total weight of the broken wall powder, taking samples online to detect the moisture, then opening the vacuum valve to evacuate the tank, then introducing compressed nitrogen in batches and quantitatively, mixing the broken wall powder evenly, and then evacuating the compressed nitrogen to a vacuum to obtain compressible broken wall powder; S6, granulation: the compressible wall-broken powder obtained in step S5 is transferred into the hopper of a dry granulator and pressed into granules; S7, screening: screening the particles in step S6 to prepare Chinese medicinal material wall-broken particles.

2. The method for preparing the Chinese herbal medicine wall-broken granules according to claim 1, characterized in that: In step S5, the vacuum valve is opened to evacuate the inside of the tank, and the vacuum degree is -0.05 to -0.09 MPa.

3. The method for preparing the Chinese herbal medicine wall-broken granules according to claim 1, characterized in that: The pressure of the compressed nitrogen gas introduced quantitatively in batches is 0..3-0.8MPa, and the relative humidity is 0-100%.

4. The method for preparing the Chinese herbal medicine wall-broken granules according to claim 1, characterized in that: In the step S5, the compressed nitrogen is evacuated to a vacuum degree of -0.05 to -0.09 MPa.

5. The method for preparing the Chinese herbal medicine wall-broken granules according to claim 1, characterized in that: The method for calculating the volume V1 and the number n of times the compressed nitrogen is quantitatively introduced in batches in step S5 is: Where: V1 is the volume of compressed nitrogen introduced quantitatively in batches, m 3 ; M is the weight of the broken powder obtained in step S4, kg; ω0 is the initial moisture content, %, measured by an online moisture meter; ω1 is the final moisture content of the broken powder, %, 8.5-12.3%; Φ0 is the initial relative humidity of nitrogen, %, known through online detection; Φ1 is the equilibrium relative humidity of nitrogen, %, known through online detection; P sb is the saturated water vapor partial pressure, Pa, which can be found through the corresponding physical parameter table; P is the compressed nitrogen pressure, Pa, known by online pressure detection; ρ is the density of compressed nitrogen, g / m 3 , check the corresponding physical parameter table; Q1 is the correction coefficient of the material, 0.1 to 10; n is the number of times nitrogen is introduced, ranging from 5 to 20 times.

6. The method for preparing the Chinese herbal medicine wall-broken granules according to claim 1, characterized in that: The granulation process in step S6 is as follows: setting the screw feed speed to 20-80 rpm, the roller speed to 6-18 rpm, the roller oil pressure to 7-160 bar, the roller gap to 0.8-1.5 mm, the cooling circulation water temperature to 5-30° C., the granulation screen aperture to 1.0 mm-2.0 mm, and the granulation speed to 100-150 rpm.

7. The method for preparing the Chinese herbal medicine wall-broken granules according to claim 1, characterized in that: In the step S7, the Chinese medicinal material wall-broken particles have a size of 14 to 60 meshes.

8. A Chinese medicinal material wall-broken granule obtained by the preparation method according to any one of claims 1 to 7.

9. The Chinese medicinal material wall-broken granules according to claim 8, characterized in that: The Chinese medicinal materials are selected from one or more of salvia miltiorrhiza, angelica, wolfberry, astragalus, momordica grosvenori, Scrophularia ningpoensis, jujube, mulberry, polygonatum odoratum, tangerine peel, bergamot or ganoderma.

10. The use of the Chinese herbal medicine wall-broken granules according to claim 8 in pharmaceutical preparations, characterized in that: Pharmaceutical preparations include tablets, capsules, suspensions, powders and patches.

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