Composite Chinese herbal medicine micronized additive and preparation process thereof

Abstract

The invention relates to the technical field of traditional Chinese medicine preparation processing, and discloses a composite Chinese herbal medicine micronized additive and a preparation process thereof, the formula comprises Fe3O4 at cellulase, Fe3O4 at pectinase and a phosphate buffer solution; the preparation method comprises the following steps: coarsely crushing traditional Chinese medicinal materials, soaking the coarsely crushed traditional Chinese medicinal materials in a composite enzymatic hydrolysate, and activating enzyme activity under the assistance of an alternating magnetic field; then crushing by adopting a bipolar ionization aerosol fluidized bed combined with a supercritical CO2-ethanol cosolvent droplet phase change technology, and triggering the surface nanostructuring of the particles through sudden pressure drop and temperature change; in the process, a dynamic feedback system based on Raman spectrum and laser granularity data optimizes a magnetic field, air pressure and droplet parameters in real time; and finally performing low-temperature freeze drying and packaging. Through integration of magnetic immobilized enzyme, alternating magnetic field-supercritical phase change modification, intelligent regulation and asymmetric fluidization technologies, the problem of collaborative optimization of component retention, structural functionalization, production stability and crushing energy efficiency in traditional Chinese medicine micronization is solved.

Description

Technical Field

[0001] The present invention relates to the technical field of traditional Chinese medicine preparation processing, in particular to a composite Chinese herbal medicine micronized additive and a preparation process thereof. Background Art

[0002] Traditional Chinese medicine micronization technology is a key process for improving the dissolution rate and bioavailability of active ingredients and is widely used in the development of modern Chinese medicine formulations. By crushing medicinal materials to the micron or nanometer scale, the particle surface area can be significantly increased, promoting the release of active ingredients while improving the uniformity and stability of the formulation. Current mainstream technologies rely primarily on physical methods such as mechanical pulverization and airflow milling, supplemented by biochemical methods such as enzymatic hydrolysis or supercritical fluid processing. However, significant bottlenecks remain in process efficiency, functional modification, and product quality control.

[0003] Existing technologies often suffer from high costs due to the inactivation of free enzymes and difficulty in recovering them. Furthermore, traditional pulverization processes struggle to simultaneously control particle size and achieve targeted functionalization of the particle surface. Furthermore, fluctuations in raw material composition and equipment parameter drift during production can easily lead to batch-to-batch quality variations, while the energy consumption of key equipment like fluidized beds and the resulting inconsistency in particle dispersion uniformity remain unresolved. These shortcomings not only limit the performance consistency of micronized products but also lead to a series of problems, such as the loss of heat-sensitive components and insufficient formulation stability, making it difficult to meet the demands of developing high-value-added traditional Chinese medicine products.

[0004] In response to the above-mentioned systemic problems, the present invention provides a composite Chinese herbal medicine micronized additive and a preparation process thereof. Summary of the Invention

[0005] In response to the shortcomings of the existing technology, the present invention provides a composite Chinese herbal medicine micronized additive and its preparation process, which solves the problems of low enzymatic hydrolysis efficiency, easy loss of heat-sensitive active ingredients, poor pulverization uniformity and high energy consumption in traditional Chinese medicine micronization technology.

[0006] To achieve the above objectives, the present invention is implemented through the following technical solutions:

[0007] The first aspect of the present invention provides a composite Chinese herbal medicine micronized additive, which is composed of the following components in percentage by weight:

[0008] Fe3O4@cellulase 0.5-1.5%;

[0009] Fe3O4@pectinase 0.3-0.8%;

[0010] Phosphate buffer balance;

[0011] The Fe3O4 nanoparticles of the Fe3O4@cellulase and Fe3O4@pectinase have a particle size of 20-50 nm, a cellulase loading capacity of ≥120 U / mgFe3O4, and a pectinase loading capacity of ≥80 U / mgFe3O4.

[0012] The present invention uses magnetic nanoparticles (Fe3O4) as carriers to fix the composite additive of cellulase and pectinase. Its core innovation lies in the surface modification of nanomagnetic carriers and the directional loading technology of enzyme molecules, which realizes the maximum exposure of enzyme active sites and magnetic responsiveness control. The particle size (20-50nm) of Fe3O4 nanoparticles has been optimized, which can not only ensure efficient diffusion through plant cell walls under magnetic drive, but also avoid the decrease in enzyme loading due to too small particle size. The loading amount of cellulase and pectinase is limited to ≥120U / mg and ≥80U / mg respectively. This threshold is determined based on the monolayer saturated adsorption experiment of enzyme molecules on the Fe3O4 surface, ensuring that the enzyme molecules are arranged in an orderly manner in a monolayer on the carrier surface, avoiding the active site shielding problem caused by multi-layer stacking. The selection of phosphate buffer (pH5.5) not only provides the optimal pH environment for the enzymatic hydrolysis reaction, but also further stabilizes the nanoparticle dispersion system through the coordination effect of phosphate ions and the Fe3O4 surface.

[0013] Preferably, the phosphate buffer is prepared from sodium dihydrogen phosphate and disodium hydrogen phosphate in a molar ratio of 1:1.5 to 1:2.

[0014] The second aspect of the present invention provides a preparation process of a composite Chinese herbal medicine micronized additive, which is prepared using the composite Chinese herbal medicine micronized additive, comprising the following steps:

[0015] S1. Coarsely grind the Chinese medicinal materials into 1.0-3.0 mm, and soak them in the composite Chinese herbal medicine micronized additive solution with a liquid-to-solid ratio of 4:1 to 6:1;

[0016] S2. Treat in an alternating magnetic field for 30-60 min, with a magnetic field frequency of 10-50 kHz, a magnetic field intensity of 0.5-1.2 T, and a temperature of 35-45°C;

[0017] S3. The enzymatically hydrolyzed material is fed into a bipolar ionization aerosol fluidized bed, subjected to a 5-10 kV electric field gradient pulverization, and simultaneously injected with supercritical CO2-ethanol co-solvent droplets. The supercritical fluid pressure is instantaneously released through a pressure drop device, while the temperature is controlled to drop suddenly, triggering the droplet liquid-gas phase transition and forming a nano-pit array on the particle surface;

[0018] S4, dynamically controlling the magnetic field frequency, crushing pressure, and droplet injection rate through Raman spectroscopy and laser particle size data;

[0019] S5. Vacuum freeze-drying and packaging.

[0020] Alternating magnetic field pretreatment (S2) and bipolar ionization aerosol fluidized bed pulverization (S3) form a synergistic effect. The alternating magnetic field induces periodic vibration of cellulose microfibrils in the cell wall of the medicinal material through the magnetostrictive effect, causing local breakage of its crystal structure, thereby significantly reducing the energy consumption of subsequent enzymatic hydrolysis and pulverization. The dynamic matching of the magnetic field frequency is based on the difference in dielectric properties of cellulose crystal types (α type / β type), and targeted destruction is achieved through frequency tuning. For example, β-type cellulose requires a higher frequency (25-50kHz) to stimulate the resonance effect due to its higher crystallinity. The asymmetric electrode configuration in the bipolar ionization aerosol fluidized bed forms a non-uniform ionization field in the pulverization area through the gradient electric field of the positive and negative electrodes and the honeycomb electric field distribution, so that alternating polarization charges are generated on the surface of the medicinal material particles, and the particles are self-dispersed through electrostatic repulsion, thereby avoiding the problem of thermal aggregation in traditional mechanical pulverization.

[0021] Preferably, the frequency of the alternating magnetic field in step S2 is dynamically matched according to the crystal structure of the medicinal material cellulose, and the matching rule is:

[0022] β-cellulose crystals correspond to 25-50kHz;

[0023] α-cellulose crystals correspond to 10-24kHz.

[0024] Preferably, the asymmetric electrode spacing of the aerosol fluidized bed in step S3 is configured as follows:

[0025] The positive electrode array has a spacing of 5-8 mm and a parallel plate gradient arrangement;

[0026] The negative electrode array has a spacing of 15-20 mm and is arranged in a honeycomb hexagonal pattern.

[0027] Preferably, the conditions for generating supercritical CO2-ethanol co-solvent droplets in step S3 are:

[0028] Supercritical CO2 is in a supercritical state with a pressure of 15.0-25.0 MPa and a temperature of 38-42°C;

[0029] CO2 and ethanol are mixed in a volume ratio of 8.0:1.0 to 12.0:1.0;

[0030] The droplet size is 50-100nm.

[0031] Preferably, in step S3, the pressure sudden drop device releases the supercritical fluid pressure from 15.0-25.0 MPa to 0.1-0.5 MPa instantaneously, the pressure change rate is 250-500 MPa / s, the response time is less than 0.05 s, the temperature is controlled to drop suddenly from 35-45°C to 10-25°C, the depth of the nano-pit array is 50-100 nm, the diameter is 100-200 nm, and the distribution density is ≥1×104 Pieces / mm 2 .

[0032] When the pressure of supercritical CO2 drops suddenly, it undergoes adiabatic expansion and rapidly changes from a supercritical state to a gaseous state. During this process, a violent cavitation effect occurs inside the droplets. The microjets generated by the collapse of the gas-liquid interface impact the surface of the particles, forming nano-pits of controllable size (50-100nm depth). The role of ethanol as a co-solvent is to adjust the polarity of CO2 so that it can penetrate into the hydrophobic components of the medicinal materials and enhance the dissolution efficiency of the active ingredients during the phase change process. The design of a sudden temperature drop (35-45℃→10-25℃) induces liquid-gas phase separation inside the droplets through rapid thermodynamic state switching across the critical point, thereby forming a nano-scale rough structure on the inner wall of the pit, increasing the specific surface area of ​​the particles to improve the subsequent drying efficiency.

[0033] Preferably, the dynamic control in step S4 adopts a topology optimization algorithm, and the input parameters include:

[0034] Crushing air pressure 0.5-2.0MPa;

[0035] Electric field strength 5-10kV / cm;

[0036] Enzyme activity data 80-150U / mg;

[0037] Real-time particle size distribution D50: 1-10μm, D90≤25μm.

[0038] Preferably, the vacuum freeze-drying conditions in step S5 are:

[0039] Pre-freezing temperature -40~-50℃, rate 4-6℃ / min;

[0040] Sublimation drying -30℃ / 10Pa, keep for 6-8h;

[0041] Desorption drying at 25℃ / <10Pa, maintain for 2-3h.

[0042] Preferably, the purity of nitrogen filled in the packaging in step S5 is ≥99.99%, and the oxygen permeability of the aluminum-plastic composite film is ≤0.01cm 3 / m 2 d. Sealing strength ≥50N / 15mm.

[0043] The present invention provides a composite Chinese herbal medicine micronized additive and its preparation process. It has the following beneficial effects:

[0044] 1. The present invention achieves directional loading and magnetically controlled positioning of enzyme molecules through the size and surface functionalization design of magnetic nanoparticles, solving the problem of easy inactivation and difficult recovery of traditional free enzymes. The magnetic response characteristics enable the enzyme-carrier complex to be quickly enriched at the reaction interface and recycled, significantly shortening the enzymatic hydrolysis time while avoiding the loss of enzyme activity caused by mechanical stirring, providing reliable technical support for continuous production.

[0045] 2. Based on the synergistic effect of alternating magnetic field pre-activation and supercritical phase change, the present invention constructs a nanoscale pit array on the surface of micronized particles, significantly improving the dissolution rate of active ingredients and the anti-hygroscopic and caking performance of the preparation. This structure achieves the goal of physical modification by regulating the interaction force between particles and the interfacial wetting behavior, breaking through the limitations of the single function of traditional pulverization technology.

[0046] 3. The present invention automatically optimizes energy input parameters by real-time monitoring of multi-dimensional data on raw material composition and particle size distribution, effectively suppressing the impact of raw material batch differences and equipment status drift on product quality, ensuring that the chemical and physical properties of the micronized particles are highly consistent, and meeting the stringent requirements of large-scale production.

[0047] 4. The asymmetric electrode fluidized bed design of the present invention regulates the particle suspension state through a gradient electric field, enhances the turbulent mixing effect of the gas-solid two-phase flow, and achieves narrow distribution control of micronized particles while reducing energy consumption per unit output, laying a physical foundation for the dissolution consistency of subsequent formulation processes. BRIEF DESCRIPTION OF THE DRAWINGS

[0048] Figure 1 Flow chart of the preparation process of the present invention. DETAILED DESCRIPTION

[0049] The following will clearly and completely describe the technical solutions in the embodiments of the present invention in conjunction with the drawings in the present specification. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative efforts are within the scope of protection of the present invention.

[0050] Example 1-3:

[0051] Please see the attached Figure 1 The present invention provides a composite Chinese herbal medicine micronized additive and a preparation process thereof through three embodiments, the specific contents of which are as follows:

[0052] Example 1:

[0053] Step 1: Compound additive preparation

[0054] Take Fe3O4@cellulase 1.0wt% (cellulase loading 120U / mgFe3O4, Fe3O4 particle size 35nm)

[0055] Fe3O4@pectinase 0.55wt% (pectinase loading 80U / mgFe3O4, Fe3O4 particle size 35nm)

[0056] The balance of phosphate buffer (pH 5.5) was prepared by sodium dihydrogen phosphate: sodium hydrogen phosphate = 1:1.75 (molar ratio).

[0057] Step 2: Enzymatic pretreatment

[0058] The medicinal material (Astragalus) was coarsely ground to 2.0 mm and soaked in the additive solution with a liquid-to-solid ratio of 5:1.

[0059] Alternating magnetic field treatment for 45 min: frequency 30 kHz, intensity 0.85 T, temperature 40°C.

[0060] Step 3: Aerosol fluidized powder

[0061] Asymmetric electrode configuration: positive electrode spacing 6.5mm (gradient arrangement), negative electrode spacing 17.5mm (honeycomb).

[0062] Supercritical CO2-ethanol co-solvent: pressure 20.0 MPa, temperature 40°C, CO2:ethanol volume ratio 10:1, droplet size 75 nm.

[0063] Pressure drop: 20.0MPa→0.3MPa, pressure change rate 375MPa / s, response time 0.03s; temperature drop 40℃→17.5℃.

[0064] Nanopit parameters: depth 75nm, diameter 150nm, distribution density 3×10 4 Pieces / mm 2 .

[0065] Step 4: Dynamic Control

[0066] Input parameters: crushing pressure 1.25 MPa, electric field strength 7.5 kV / cm, enzyme activity 115 U / mg;

[0067] Real-time particle size control:

[0068] D50: 5.5μm;

[0069] D90: 20μm.

[0070] Step 5: Freeze Drying and Packaging

[0071] Pre-freezing: -45°C, cooling rate 5°C / min;

[0072] Sublimation drying: -30℃ / 10Pa, keep for 7h;

[0073] Desorption drying: 25℃ / <10Pa, maintain for 2.5h;

[0074] Packaging: Nitrogen purity 99.99%, aluminum plastic film oxygen permeability 0.005cm 3 / m 2 d, sealing strength 60N / 15mm.

[0075] Example 2:

[0076] Step 1: Compound additive preparation

[0077] Fe3O4@cellulase 0.5wt% (loading 120U / mg, particle size 20nm)

[0078] Fe3O4@pectinase 0.3wt% (loading 80U / mg, particle size 20nm)

[0079] Phosphate buffer (pH 5.5): phosphate molar ratio 1:1.5.

[0080] Step 2: Enzymatic pretreatment

[0081] The medicinal materials were crushed to 1.0 mm, with a liquid-to-solid ratio of 4:1;

[0082] Alternating magnetic field treatment for 30 min: frequency 10 kHz, intensity 0.5 T, temperature 35 °C.

[0083] Step 3: Aerosol fluidized powder

[0084] Electrode distance: positive electrode 5mm, negative electrode 15mm;

[0085] Supercritical parameters: pressure 15.0 MPa, temperature 38°C, CO2:ethanol 8:1, droplet size 50 nm;

[0086] Pressure drop: 15.0MPa→0.1MPa, rate 250MPa / s, response time 0.05s; temperature drop 35℃→10℃;

[0087] Pit parameters: depth 50nm, diameter 100nm, density 1×10 4 Pieces / mm 2 .

[0088] Step 4: Dynamic Control

[0089] Input parameters: crushing pressure 0.5 MPa, electric field strength 5 kV / cm, enzyme activity 80 U / mg;

[0090] Real-time particle size:

[0091] D50: 1μm;

[0092] D90: 15μm.

[0093] Step 5: Freeze Drying and Packaging

[0094] Prefreezing: -40°C, rate 4°C / min;

[0095] Sublimation drying: -30℃ / 10Pa, keep for 6h;

[0096] Packaging: Oxygen permeability 0.01cm 3 / m 2 d, sealing strength 50N / 15mm.

[0097] Example 3:

[0098] Step 1: Compound additive preparation

[0099] Fe3O4@cellulase 1.5wt% (loading 150U / mg, particle size 50nm)

[0100] Fe3O4@pectinase 0.8wt% (loading 100U / mg, particle size 50nm)

[0101] Phosphate buffer (pH 5.5): phosphate molar ratio 1:2.

[0102] Step 2: Enzymatic pretreatment

[0103] The medicinal materials were crushed to 3.0 mm, with a liquid-to-solid ratio of 6:1;

[0104] Alternating magnetic field treatment for 60 min: frequency 50 kHz, intensity 1.2 T, temperature 45°C.

[0105] Step 3: Aerosol fluidized powder

[0106] Electrode distance: positive electrode 8mm, negative electrode 20mm;

[0107] Supercritical parameters: pressure 25.0 MPa, temperature 42°C, CO2:ethanol 12:1, droplet size 100 nm;

[0108] Pressure drop: 25.0MPa→0.5MPa, rate 500MPa / s, response time 0.01s; temperature drop 45℃→25℃;

[0109] Pit parameters: depth 100nm, diameter 200nm, density 5×10 4 Pieces / mm 2 .

[0110] Step 4: Dynamic Control

[0111] Input parameters: crushing pressure 2.0 MPa, electric field strength 10 kV / cm, enzyme activity 150 U / mg;

[0112] Real-time particle size:

[0113] D50: 10 μm;

[0114] D90: 25μm.

[0115] Step 5: Freeze Drying and Packaging

[0116] Pre-freezing: -50°C, rate 6°C / min;

[0117] Sublimation drying: -30℃ / 10Pa, keep for 8h;

[0118] Packaging: Oxygen permeability 0.008cm 3 / m 2 d, sealing strength 70N / 15mm.

[0119] Comparative Examples 1-8:

[0120] Comparative Example 1:

[0121] Compared with Example 1, the difference is:

[0122] Instead of using Fe3O4@cellulase and Fe3O4@pectinase, free cellulase (1.0 wt%) and free pectinase (0.55 wt%) were directly added, and the rest of the steps and parameters were the same.

[0123] Comparative Example 2:

[0124] Compared with Example 1, the difference is:

[0125] The particle size of the Fe3O4 nanoparticles is 10 nm (exceeding the range of 20-50 nm in claim 1), and the other components and parameters are the same.

[0126] Comparative Example 3:

[0127] Compared with Example 1, the difference is:

[0128] The alternating magnetic field treatment in step S2 is omitted, and the medicinal materials are directly subjected to aerosol fluidization pulverization after being soaked. The remaining steps and parameters are the same.

[0129] Comparative Example 4:

[0130] Compared with Example 1, the difference is:

[0131] During the pressure drop process, the temperature drop was not controlled (the temperature was kept constant at 40° C.), and only pressure release was implemented. The remaining steps and parameters were the same.

[0132] Comparative Example 5:

[0133] Compared with Example 1, the difference is:

[0134] In step S4, the topology optimization algorithm was not used for dynamic control. The magnetic field frequency was fixed at 30 kHz, the crushing pressure was 1.25 MPa, and the droplet injection rate was constant. The remaining steps and parameters were the same.

[0135] Comparative Example 6:

[0136] Compared with Example 1, the difference is:

[0137] During the packaging in step S5, nitrogen is not filled and packaging is performed in an air environment instead. The remaining steps and parameters are the same.

[0138] Comparative Example 7:

[0139] Compared with Example 1, the difference is:

[0140] The pH value of the phosphate buffer was adjusted to 7.0 (outside the pH range of 5.5 of claim 1), and the remaining components and parameters were the same.

[0141] Comparative Example 8:

[0142] Compared with Example 1, the difference is:

[0143] The aerosol fluidized bed adopted a symmetrical electrode configuration (the distance between the positive and negative electrodes was 10 mm), and the other steps and parameters were the same.

[0144] Test Example 1-5:

[0145] Test Example 1: Experimental description of enzymatic hydrolysis efficiency and magnetic recovery rate test

[0146] Purpose of the experiment:

[0147] Verify the technical advantages of the magnetic nanoenzyme composite system (Fe3O4@cellulase / pectinase) compared with the free enzyme system in terms of enzymatic hydrolysis efficiency, magnetic recovery rate and enzyme activity retention, and clarify the influence of the Fe3O4 nanoparticle size range (20-50nm) on the penetration effect.

[0148] Experimental materials and equipment:

[0149] Test samples: enzymatic hydrolysis solutions of Examples 1-3, Comparative Example 1 (free enzyme), and Comparative Example 2 (Fe3O4 particle size 10 nm);

[0150] instrument:

[0151] Conductivity meter (to measure the degree of cell wall disruption);

[0152] Magnetic separation device (500 mT permanent magnet, 50 mm diameter);

[0153] Centrifuge (6000 rpm, 10 mL centrifuge tube);

[0154] UV spectrophotometer (DNS method for measuring reducing sugar).

[0155] Experimental steps:

[0156] Determination of enzymatic hydrolysis time:

[0157] 50 mL of the enzymatic hydrolysate of each example and comparative example was taken, and the conductivity change was monitored in real time.

[0158] The time when the conductivity suddenly increased to a stable value (a sign of complete cell wall destruction) was recorded, and the average value was obtained by repeating 3 times.

[0159] Magnetic recovery test:

[0160] The enzymatically hydrolyzed solution was transferred to a glass beaker, placed on the side wall of the magnetic separation device, and allowed to stand for 10 min.

[0161] The unadsorbed solution was collected and centrifuged (6000 rpm, 10 min) to separate the residual Fe3O4 particles.

[0162] Calculate the magnetic recovery rate:

[0163]

[0164] Enzyme activity retention test:

[0165] The Fe3O4@enzyme particles after magnetic recovery were redispersed in pH 5.5 buffer and the cellulase activity was determined (glucose production was measured by DNS method).

[0166] Calculation of enzyme activity retention rate:

[0167]

[0168] Experimental data:

[0169] Table 1 Enzymatic hydrolysis efficiency and magnetic recovery test results

[0170] Test Group Enzymatic hydrolysis time (min) Magnetic recovery rate (%) Enzyme activity retention rate (%) Example 1 42.3 92.3 88.7 Example 2 58.1 89.5 85.2 Example 3 37.6 94.8 91.4 Comparative Example 1 73.5 34.8 62.1 Comparative Example 2 68.9 81.6 73.5

[0171] Data Analysis:

[0172] Enzymatic hydrolysis time:

[0173] The enzymatic hydrolysis time of Example 1-3 was significantly shorter than that of Comparative Example 1-2, indicating that the magnetically driven penetration of the magnetic nanozyme significantly improved the enzymatic hydrolysis efficiency;

[0174] In comparative example 2 (Fe3O4 particle size 10 nm), the penetration efficiency decreased and the enzymatic hydrolysis time was prolonged due to particle agglomeration.

[0175] Magnetic recovery rate:

[0176] The magnetic recovery rates of Examples 1-3 were all >89%, while the recovery rate of Comparative Example 1 (free enzyme) was only 34.8% due to the inability to magnetically separate;

[0177] In Comparative Example 2, part of the particles were not captured by the magnetic field due to the small particle size, and the recovery rate was lower than that of the embodiment group.

[0178] Enzyme activity retention rate:

[0179] The magnetic nanozymes (Examples 1-3) had an activity retention rate of >85% due to carrier immobilization protection, while the comparative example 1 (free enzyme) was inactivated due to the solution environment, with a retention rate of only 62.1%.

[0180] Experimental summary: The magnetic nanoenzyme composite system significantly improves the enzymatic efficiency and operational stability through the size effect and surface functionalization design of Fe3O4 nanoparticles. The particle size of Fe3O4 particles is controlled in the range of 20-50nm, which enables it to penetrate the pore structure of the plant cell wall (typical pore size 100-200nm) under the drive of an external magnetic field, while avoiding the decrease in magnetic responsiveness caused by too small particles. The surface of the nanoparticles is modified by carboxylation to directionally load cellulase and pectinase, so that the enzyme molecules are arranged in an orderly monolayer, reducing the problem of active site shielding. Compared with the free enzyme system (Comparative Example 1), the magnetically controlled positioning characteristics of the immobilized enzyme enable it to be more efficiently enriched on the surface of the medicinal cell wall, shortening the enzymatic hydrolysis time by about 40%; while Fe3O4 with too small a particle size (Comparative Example 2) has insufficient magnetic moment and easy agglomeration problems, resulting in a decrease in magnetic field driving efficiency, which confirms the necessity of limiting the particle size range.

[0181] The specific pH (5.5) of the phosphate buffer and its ion coordination further enhance the stability of the enzyme-carrier complex. Experimental data show that the magnetic recovery rate of the magnetic nanozyme exceeds 89%, and the enzyme activity retention rate after recovery is >85%, indicating that the synergistic effect of the carrier and the buffer effectively avoids the loss and inactivation of the enzyme molecules during recycling. In contrast, the free enzyme is susceptible to shear force and ionic strength fluctuations in the solution due to the lack of carrier protection, with an activity retention rate of only 62.1%, and is difficult to recycle and reuse.

[0182] Furthermore, the magnetic response of Fe₃O₄ nanoparticles provides a foundation for multi-step process integration. The magnetic separation operation can be completed rapidly within 1-2 minutes, avoiding material loss associated with traditional centrifugation or filtration, and seamlessly integrating with the subsequent aerosol fluidized pulverization step. This design not only simplifies the process flow but also reduces the exposure of the active ingredient to the external environment through the continuous enzymatic hydrolysis-pulverization process, providing technical support for a complete, low-damage process.

[0183] Test Example 2: Experimental description of the nano-pit structure generation effect test

[0184] Purpose of the experiment:

[0185] Verify the effect of alternating magnetic field pretreatment and supercritical fluid pressure-temperature synergistic sudden drop process on the formation of nano-pit structure on the particle surface, and its effect on improving the dissolution rate and anti-caking performance.

[0186] Experimental materials and equipment:

[0187] Test samples: micronized particles of Examples 1-3, Comparative Example 3 (without magnetic field pretreatment), and Comparative Example 4 (without temperature drop);

[0188] instrument:

[0189] Laser confocal microscopy (measurement of surface roughness Ra value, scanning accuracy 0.1nm);

[0190] UV-visible spectrophotometer (for dissolution rate determination, wavelength 254 nm);

[0191] Constant temperature and humidity chamber (RH75%, temperature 25℃).

[0192] Experimental steps:

[0193] Surface roughness test:

[0194] The particles of each sample were evenly dispersed on a glass slide, and 10 areas were randomly selected for scanning using a laser confocal microscope to calculate the average Ra value (arithmetic mean roughness).

[0195] Dissolution rate test:

[0196] 50 mg of micronized particles were weighed and dispersed in 500 mL of simulated gastric fluid (pH 1.2, 37°C) with magnetic stirring (200 rpm);

[0197] Samples were taken at 5, 15, 30, and 60 min, and the concentration of astragaloside IV in the supernatant was determined after centrifugation (UV-Vis method, calculated by standard curve method).

[0198] Anti-caking rate test:

[0199] Take 10 g of micronized particles and spread them on a culture dish, and place it in a constant temperature and humidity chamber (RH75%, 25°C) for 48 h;

[0200] After sieving (100 mesh sieve), weigh the mass of the unagglomerated particles and calculate the anti-agglomeration rate:

[0201]

[0202] Experimental data:

[0203] Table 2 Test results of nano-pit structure generation effect

[0204] Test Group Surface roughness Ra (nm) 30min dissolution rate (%) Anti-caking rate (%) Example 1 68.3 82.7 94.5 Example 2 53.9 76.4 89.2 Example 3 74.8 86.9 96.1 Comparative Example 3 21.5 43.2 73.8 Comparative Example 4 39.7 57.6 81.4

[0205] Data Analysis:

[0206] Surface roughness:

[0207] The Ra value of the Example group is significantly higher than that of Comparative Examples 3-4, indicating that the synergistic effect of alternating magnetic field pretreatment (destruction of cellulose crystals) and supercritical phase transition (pressure-temperature drop) can effectively construct nano-pits;

[0208] In Comparative Example 3 (without magnetic field pretreatment), the cell wall was not pre-destroyed, and the phase change impact energy was absorbed by the dense structure, resulting in an Ra value of only 21.5 nm.

[0209] Dissolution rate:

[0210] The dissolution rates of Examples 1-3 were >76% at 30 min, while the dissolution of Comparative Examples 3-4 was delayed due to their smooth surfaces (low Ra values), verifying the contribution of the nano-pits to the solubilization effect.

[0211] Anti-caking rate:

[0212] The nano-pits increase the repulsive force at the contact points between particles (surface roughness effect), and the anti-caking rate of the embodiment group is greater than 89%, while the agglomeration rate of the comparative examples 3-4 increases due to the smooth surface of the particles that easily absorb moisture.

[0213] Experimental summary: Alternating magnetic field pretreatment induces high-frequency vibration of cellulose microfibrils in the cell walls of medicinal materials through the magnetostrictive effect, causing directional fracture of the crystal structure and forming a micron-scale crack network. This pre-destruction mechanism provides an energy release channel for the subsequent supercritical fluid phase change impact, so that the cavitation microjets generated during the pressure drop can act in a directional manner on the weak areas of the cell wall, significantly improving the efficiency of nano-pit generation. Experimental data show that the comparative example 3, which has not been pretreated with a magnetic field, has an intact cell wall structure, and the supercritical phase change energy is absorbed by the dense cellulose layer. The surface roughness (Ra value) is only 30%-40% of that of the embodiment group, which confirms the necessity of multi-step coordinated treatment.

[0214] The synergistic pressure-temperature drop process of the supercritical CO2-ethanol co-solvent induces a dramatic gas-liquid interface collapse within the droplets through a rapid phase transition across the critical point. The adiabatic expansion effect generated by the sudden pressure drop and the liquid-gas phase separation caused by the sudden temperature drop synergize to cause the cavitation bubbles to collapse directionally on the particle surface, forming nano-pits with controllable depth and diameter. In Comparative Example 4, the pressure release under constant temperature conditions lacked a phase transition driving force, resulting in dispersed microjet impact energy, insufficient pit depth, and a dissolution rate approximately 30% lower than that of the embodiment group, revealing the key regulatory role of temperature drop on phase transition dynamics.

[0215] The nano-pit array significantly improves the interfacial wettability and dispersion stability of micronized particles by increasing the surface roughness and specific surface area of ​​the particles. The nanoscale wrinkled structure on the inner wall of the pit forms a physical barrier layer, reducing the van der Waals force between particles, thereby inhibiting the agglomeration phenomenon caused by capillary force in a hot and humid environment. The anti-agglomeration rate of the embodiment group (>89%) is significantly improved compared with that of comparative examples 3-4 (73.8%-81.4%), which verifies the core value of surface nanostructured design in functional modification and provides an innovative solution for high active ingredient retention and formulation processing adaptability.

[0216] Test Example 3: Particle Size Distribution Control Stability Test Experiment Description

[0217] Purpose of the experiment:

[0218] Verify the dynamic feedback control system's ability to control the stability of the particle size distribution (D50, D90) of micronized particles, as well as its adaptability to differences in raw material batches.

[0219] Experimental materials and equipment:

[0220] Test samples: 5 consecutive batches of micronized particles of Examples 1-3 and Comparative Example 5 (fixed parameter control);

[0221] instrument:

[0222] Laser particle size analyzer (measure D50 and D90, repeat 3 times and take the average value);

[0223] Raw material simulation device (can adjust the particle size of medicinal materials before crushing by ±20%);

[0224] Experimental steps:

[0225] Batch-to-batch particle size variation test:

[0226] Continuously produce 5 batches of micronized particles, with an interval of 2 hours between each batch (simulating the actual production interval);

[0227] Random sampling was performed three times in each batch, and the D50 and D90 values ​​were measured. The standard deviation (SD) of the data from the five batches was calculated.

[0228] Abnormal working conditions adaptability test:

[0229] Simulate raw material particle size fluctuations: the initial particle size of the first group of raw materials is +20% (coarse particles), and the second group is -20% (fine particles);

[0230] The time (min) required for the system to output D50 and D90 from feeding to reaching the target range (D50: 1-10μm, D90 ≤ 25μm) was recorded.

[0231] Experimental data:

[0232] Table 3 Particle size distribution control stability test results

[0233]

[0234] Data Analysis:

[0235] Batch stability:

[0236] The D50 batch standard deviations (SD) of Examples 1-3 were all <1.15 μm, and the D90 SD was <2.34 μm, indicating that the dynamic control system effectively suppressed production fluctuations;

[0237] Comparative Example 5 (fixed parameters) cannot adapt to the equipment state drift, and the D50 batch SD is as high as 3.42μm.

[0238] Adaptability to abnormal working conditions:

[0239] In the embodiment group, the adjustment time was less than 19 minutes when the raw material particle size fluctuated by ±20%. However, in the comparative example 5, the adjustment time was extended by 2-3 times due to the fixed parameters, and the D90 exceeded the standard (>25 μm).

[0240] Experimental summary: The dynamic feedback control system constructs a two-dimensional data matrix of chemical composition and particle size distribution of micronized particles through real-time monitoring of Raman spectroscopy and laser particle size analyzer. Based on the particle swarm optimization algorithm, the system dynamically associates the fluctuation of medicinal material components (such as changes in the cellulose / pectin ratio) with the pulverization energy input, and realizes cross-scale (microscopic composition-macroscopic particle size) process closed-loop control through the coordinated adjustment of multiple parameters such as droplet injection rate, pulverization pressure and magnetic field frequency. Experimental data show that the inter-batch particle size standard deviation (D50SD<1.15μm) of the embodiment group is reduced by 60%-80% compared with the fixed parameter mode (Comparative Example 5), verifying the strong robustness of dynamic control to differences in raw material batches.

[0241] Under abnormal operating conditions (raw material particle size fluctuations of ±20%), the system's rapid response capability stems from a multi-parameter adjustment priority strategy. When it is detected that the raw material particle size has increased, the droplet injection rate is prioritized to increase the shear force of the supercritical solvent, while the pulverization pressure is reduced to avoid excessive crushing; conversely, when the raw material particle size decreases, the magnetic field frequency is prioritized to improve the uniformity of particle fluidization. This hierarchical control strategy based on energy consumption sensitivity shortens the adjustment time of the embodiment group under coarse / fine material fluctuations to less than 1 / 3 of the fixed parameter mode, solving the problem of over- or insufficient pulverization caused by parameter solidification in traditional processes.

[0242] Improved process stability is directly related to the functional consistency of micronized products. Narrow range control of particle size distribution (D90 ≤ 25 μm) ensures uniform release of active ingredients and repeatability of formulation processing by optimizing particle specific surface area and porosity. The stable output of the embodiment group in continuous production (adjustment time < 19 min) provides core technical guarantee for quality controllability in large-scale production, breaking through the efficiency bottleneck of traditional intermittent process.

[0243] Test Example 4: Active Ingredient Retention Rate Test Experiment Description

[0244] Purpose of the experiment:

[0245] Verify the effects of nitrogen encapsulation process and specific pH value of phosphate buffer on the retention effect and oxidative stability of heat-sensitive active ingredients (such as astragaloside IV and polysaccharides).

[0246] Experimental materials and equipment:

[0247] Test sample:

[0248] the freeze-dried micronized particles of Examples 1-3;

[0249] Freeze-dried micronized particles of Comparative Example 6 (air encapsulation) and Comparative Example 7 (pH 7.0 buffer);

[0250] instrument:

[0251] High performance liquid chromatography (HPLC, determination of astragaloside IV content);

[0252] UV spectrophotometer (phenol-sulfuric acid method to measure polysaccharide content);

[0253] Accelerated oxidation test chamber (40℃ / RH75%).

[0254] Experimental steps:

[0255] Heat-sensitive component retention rate test:

[0256] 100 mg of each sample before and after freeze-drying was extracted with methanol-water (70:30) for 30 min by ultrasonication, and the supernatant was collected by centrifugation;

[0257] Astragaloside IV: HPLC detection (C18 column, mobile phase acetonitrile-water, detection wavelength 203 nm), calculation of retention rate:

[0258]

[0259] Polysaccharide: color development was performed using the phenol-sulfuric acid method (absorbance was measured at a wavelength of 490 nm), and retention was calculated using the standard curve method.

[0260] Oxidation stability test:

[0261] Take 10g of sample, seal it in a transparent bag, and place it in an accelerated oxidation test chamber for 30 days;

[0262] Take samples every 10 days to determine the peroxide value of the fat-soluble component (astragalone) (GB5009.227-2016 method):

[0263]

[0264] (V: sample titration volume; V0: blank titration volume; C: sodium thiosulfate concentration; m: sample mass).

[0265] Experimental data:

[0266] Table 4 Active ingredient retention rate and oxidation stability test results

[0267]

[0268] Data Analysis:

[0269] Retention rate of heat-sensitive components:

[0270] Due to the staged freeze-drying (to inhibit ice crystal coarsening) and nitrogen packaging, the retention rate of astragaloside IV in the Example group was >89%, which was significantly higher than that in Comparative Example 6 (degradation caused by air oxidation);

[0271] In Comparative Example 7 (pH 7.0 buffer), the enzymatic hydrolysis efficiency decreased due to the deviation from the optimal pH of the enzyme activity, and the cell walls of the medicinal materials were not fully broken, resulting in a lower extraction rate.

[0272] Oxidation stability:

[0273] The peroxide value of the example group was <5 meq / kg, while the peroxide value of comparative example 6 (air encapsulation) was as high as 18.9 meq / kg due to lipid oxidation induced by oxygen permeation;

[0274] Although the pH 7.0 buffer in Comparative Example 7 reduced the potential impact of the acidic environment on lipids, the incomplete enzymatic hydrolysis resulted in residual cell walls and accelerated oxidative side reactions.

[0275] Experimental summary: The nitrogen packaging process constructs a full-chain low-oxygen protection system for active ingredients through a phased gradient freezing and low oxygen permeability membrane composite barrier design. During the freeze-drying stage, the magnetically controlled gradient freezing technology inhibits the mechanical damage to the cell microstructure through directional ice crystal growth, reducing the loss of heat-sensitive components (such as astragaloside IV) due to ice crystal extrusion; during the packaging stage, nitrogen is filled and sealed with an aluminum-plastic composite film to keep the residual oxygen content inside the package below 0.5%, effectively blocking the auto-oxidation chain reaction of fat-soluble components (such as astragaloside ketone). Experimental data show that the retention rate of astragaloside IV in the embodiment group exceeds 89%, and the peroxide value is less than 5meq / kg after 30 days of accelerated oxidation, while the peroxide value of comparative example 6 (air packaging) increases to 18.9meq / kg due to the free radical reaction triggered by oxygen penetration, confirming the decisive role of the low-oxygen environment in the stability of the ingredients.

[0276] The pH value of phosphate buffer (5.5) achieves the synergistic optimization of enzymatic efficiency and component stability by precisely regulating the enzyme-substrate binding energy barrier and ion coordination balance. Under weakly acidic conditions, the carboxyl group of the active center of cellulase forms a hydrogen bond network with the hydroxyl group on the Fe3O4 surface, enhancing the conformational stability of the enzyme-carrier complex; at the same time, pH 5.5 inhibits the activity of polyphenol oxidase in medicinal materials and reduces the damage to heat-sensitive components caused by the formation of quinones. Comparative Example 7 (pH 7.0) deviates from the optimal activity pH of the enzyme, resulting in incomplete cell wall fragmentation and a polysaccharide extraction rate reduced to 68.4%. The neutral environment accelerates metal ion catalytic oxidation, and the peroxide value increases by 2-3 times compared with the embodiment group, revealing the criticality of pH value to the coordinated regulation of multiple targets.

[0277] The synergistic effect of the encapsulation process and the buffer system is further reflected in the interface modification effect of the micronized particles. The nano-hydrophobic coating on the surface of the low oxygen permeability membrane reduces the water vapor permeability (<0.1g / m 2 ·day), inhibiting capillary adsorption on the particle surface in hot and humid environments; while the phosphate ions in the buffer complex with the hydroxyl groups on the particle surface, forming a dense passivation layer that blocks oxidative catalysis triggered by metal ion migration. This multi-level protection mechanism enables the Example group to maintain ingredient stability even under complex storage conditions, breaking through the technical bottleneck of easy degradation of active ingredients in traditional processes and providing a new path for the development of high-value-added Chinese medicine preparations.

[0278] Test Example 5: Particle Dispersion Uniformity Test Experiment Description

[0279] Purpose of the experiment:

[0280] Verify the effect of asymmetric electrode fluidized bed design on improving the dispersion uniformity of micronized particles and optimizing the crushing energy consumption.

[0281] Experimental materials and equipment:

[0282] Test samples: fluidized bed treated particles of Examples 1-3 and Comparative Example 8 (symmetrical electrode);

[0283] instrument:

[0284] High-speed camera system (2000 frames / second, capturing particle motion in the fluidized bed);

[0285] Image analysis software (calculate the coefficient of variation CV value of particle distribution);

[0286] Power quality analyzer (measures real-time power during the crushing process).

[0287] Experimental steps:

[0288] Dispersion index test:

[0289] The fluidized bed was started without load until it reached a stable state (air flow velocity 2 m / s), 50 g of micronized particles were injected, and the fluidized bed was run for 5 min;

[0290] Shoot a 10-second dynamic image in the middle of the fluidized bed and capture 100 frames of images;

[0291] Use the software to divide the grid (10×10 area), count the number of particles in each grid, and calculate the coefficient of variation (CV):

[0292]

[0293] Crushing energy consumption test:

[0294] Weigh 500 g of the original medicinal material and record the total energy consumption (kWh) of fluidized bed pulverization to the target particle size (D90 ≤ 25 μm);

[0295] The experiment was repeated 3 times and the average value was taken.

[0296] Experimental data:

[0297] Table 5 Particle dispersion and crushing energy consumption test results

[0298]

[0299]

[0300] Data Analysis:

[0301] Dispersion uniformity:

[0302] The CV value of the example group was <15.7%, while that of comparative example 8 (symmetrical electrode) reached 28.4% due to particle agglomeration caused by uneven electric field distribution;

[0303] Example 3 uses a high-frequency pulse electric field, the particle suspension trajectory is more stable, and the CV value is optimal (9.8%).

[0304] Crushing energy consumption:

[0305] The asymmetric electrode design enhances the particle collision efficiency, and the energy consumption of the embodiment group is reduced by 50%-60% compared with the comparative example 8;

[0306] The target particle size achievement rate is negatively correlated with the dispersion degree. The high dispersion of Example 3 increases the pulverization efficiency to 99.2%.

[0307] Experimental summary: The asymmetric electrode fluidized bed forms a gradient-distributed dynamic electric field in the fluidization chamber through the heterogeneous structure design of serrated copper plates and porous carbon fiber meshes. The local high electric field intensity (>5kV / m) generated by the positive electrode serrated structure induces rapid polarization of the surface charge of the particles, while the diffuse discharge characteristics of the negative electrode porous carbon mesh form a space charge compensation effect. The synergistic effect of the two breaks the uniform electric field limitation of the traditional symmetrical electrode. Experimental data show that the coefficient of variation of the particle dispersion of the embodiment group (CV<15.7%) is reduced by 45%-65% compared with that of Comparative Example 8 (symmetric electrode), indicating that the asymmetric electric field effectively suppresses the agglomeration tendency of the micronized particles by enhancing the electrostatic repulsion and turbulent mixing effect between the particles.

[0308] The composite electric field control strategy of high-frequency pulses and low-frequency alternation further optimizes the crushing energy efficiency. In the initial stage, 10kHz high-frequency pulses quickly disaggregate particle clusters through the dielectrophoresis effect, reducing invalid collision energy consumption; in the steady-state stage, it switches to a 500Hz low-frequency alternating electric field, and uses periodic charge reversal to maintain the stability of particle suspension. This dynamic regulation reduces the crushing energy consumption of the embodiment group (0.72-1.02kWh / kg) by 38%-56% compared with the traditional fluidized bed (Comparative Example 8: 1.65kWh / kg), while the target particle size achievement rate is increased to >95%, verifying the core role of matching optimization of energy input mode and crushing process in improving energy efficiency.

[0309] The improvement of particle dispersion uniformity is directly related to the functional performance of micronized products. The low CV value (Example 3: 9.8%) indicates that the particles are distributed in a nearly monolayer state in the fluidized cavity. This high degree of dispersion enables the shear force of airflow milling to act evenly on the surface of each particle, avoiding thermal damage to the active ingredient caused by local over-milling. The significant improvement in the target particle size achievement rate (Example 1: 98.5%) not only reduces the waste of raw materials, but also provides a physical structure guarantee for the consistency of the dissolution rate of the subsequent formulation process through the optimization of the stacking pores of narrowly distributed particles, forming a closed-loop quality control chain from milling to dosage form.

[0310] While embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that various changes, modifications, substitutions, and variations may be made to these embodiments without departing from the principles and spirit of the invention, and that the scope of the invention is defined by the appended claims and their equivalents.

Claims

1. A composite Chinese herbal medicine micronized additive, characterized in that: It is composed of the following components in percentage by weight: Fe3O4@cellulase 0.5-1.5%; Fe3O4@pectinase 0.3-0.8%; Phosphate buffer balance; The Fe3O4 nanoparticles of the Fe3O4@cellulase and Fe3O4@pectinase have a particle size of 20-50 nm, a cellulase loading capacity of ≥120 U / mgFe3O4, and a pectinase loading capacity of ≥80 U / mgFe3O4.

2. The micronized composite Chinese herbal medicine additive according to claim 1, characterized in that: The phosphate buffer is prepared by mixing sodium dihydrogen phosphate and disodium hydrogen phosphate in a molar ratio of 1:1.5 to 1:

2.

3. The preparation process of the composite Chinese herbal medicine micronized additive is characterized in that: The preparation method is prepared by using the micronized composite Chinese herbal medicine additive according to any one of claims 1 to 2, comprising the following steps: S1. Coarsely grind the Chinese medicinal materials into 1.0-3.0 mm, and soak them in the composite Chinese herbal medicine micronized additive solution with a liquid-to-solid ratio of 4:1 to 6:1; S2. Treat in an alternating magnetic field for 30-60 min, with a magnetic field frequency of 10-50 kHz, a magnetic field intensity of 0.5-1.2 T, and a temperature of 35-45°C; S3. The enzymatically hydrolyzed material is fed into a bipolar ionization aerosol fluidized bed, subjected to a 5-10 kV electric field gradient pulverization, and simultaneously injected with supercritical CO2-ethanol co-solvent droplets. The supercritical fluid pressure is instantaneously released through a pressure drop device, while the temperature is controlled to drop suddenly, triggering the droplet liquid-gas phase transition and forming a nano-pit array on the particle surface; S4, dynamically controlling the magnetic field frequency, crushing pressure, and droplet injection rate through Raman spectroscopy and laser particle size data; S5. Vacuum freeze-drying and packaging.

4. The preparation process of the composite Chinese herbal medicine micronized additive according to claim 3, characterized in that: In step S2, the frequency of the alternating magnetic field is dynamically matched according to the crystal structure of the medicinal material cellulose, and the matching rule is: β-cellulose crystals correspond to 25-50kHz; α-cellulose crystals correspond to 10-24kHz.

5. The preparation process of the composite Chinese herbal medicine micronized additive according to claim 3, characterized in that: The asymmetric electrode spacing configuration of the aerosol fluidized bed in step S3 is: The positive electrode array has a spacing of 5-8 mm and a parallel plate gradient arrangement; The negative electrode array has a spacing of 15-20 mm and is arranged in a honeycomb hexagonal pattern.

6. The preparation process of the composite Chinese herbal medicine micronized additive according to claim 3, characterized in that: The conditions for generating supercritical CO2-ethanol co-solvent droplets in step S3 are: Supercritical CO2 is in a supercritical state with a pressure of 15.0-25.0 MPa and a temperature of 38-42°C; CO2 and ethanol are mixed in a volume ratio of 8.0:1.0 to 12.0:1.0; The droplet size is 50-100nm.

7. The preparation process of the composite Chinese herbal medicine micronized additive according to claim 3, characterized in that: In step S3, the pressure sudden drop device releases the supercritical fluid pressure from 15.0-25.0 MPa to 0.1-0.5 MPa instantaneously, with a pressure change rate of 250-500 MPa / s and a response time of <0.05 s. The temperature is controlled to drop sharply from 35-45°C to 10-25°C. The depth of the nano-pit array is 50-100 nm, the diameter is 100-200 nm, and the distribution density is ≥1×10 4 Pieces / mm 2 .

8. The preparation process of the composite Chinese herbal medicine micronized additive according to claim 3, characterized in that: The dynamic control in step S4 adopts a topology optimization algorithm, and the input parameters include: Crushing air pressure 0.5-2.0MPa; Electric field strength 5-10kV / cm; Enzyme activity data 80-150U / mg; Real-time particle size distribution D50: 1-10μm, D90≤25μm.

9. The preparation process of the composite Chinese herbal medicine micronized additive according to claim 3, characterized in that: The vacuum freeze-drying conditions in step S5 are: Pre-freezing temperature -40~-50℃, rate 4-6℃ / min; Sublimation drying -30℃ / 10Pa, keep for 6-8h; Desorption drying at 25℃ / <10Pa, maintain for 2-3h.

10. The preparation process of the composite Chinese herbal medicine micronized additive according to claim 3, characterized in that: The purity of nitrogen filled in the packaging step S5 is ≥99.99%, and the oxygen permeability of the aluminum-plastic composite film is ≤0.01cm 3 / m 2 d. Sealing strength ≥50N / 15mm.

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