Pharmaceutical composition for treating glomerular disease and method for preparing the same

Abstract

The application discloses a kind of pharmaceutical composition for treating glomerular disease and preparation method thereof, belong to medical technology field.The technology aims at solving the problems that pharmaceutical composition containing heat-sensitive active ingredient is easily degraded by heat in the process of micronization preparation, and low content active ingredient is difficult to uniformly disperse, which affects the uniformity of preparation quality.The key points of technical scheme are as follows: the pharmaceutical composition contains daidzein, calycosin and formononetin, and the weight ratio of the three is 1:(0.8-1.5):(1.5-3).The preparation method includes pre-mixing the three, co-milling and grading under low temperature and inert atmosphere, monitoring the outlet temperature and performing multi-stage regulation operation to control the temperature during the process, and finally mixing the obtained composite active ingredient powder with excipients to granulate.The application is mainly used for preparing drugs for treating glomerular disease.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology. More specifically, this invention relates to a pharmaceutical composition for treating glomerular diseases and a method for preparing the same. Background Technology

[0002] In the development of drugs for the treatment of glomerular diseases, flavonoids such as daidzein, verrucoside, and gentiopicrin have shown potential therapeutic value. Formulating these active ingredients into solid dosage forms suitable for oral administration is a common approach in modern drug development. However, this transformation process, from raw material processing to formulation, presents a series of inherent technological challenges that directly affect the quality, efficacy, and production stability of the final product.

[0003] First, in the micronization process of active pharmaceutical ingredients (APIs), there is a risk of degradation of active ingredients due to heat. To achieve ideal dissolution rates and bioavailability, active ingredients typically need to be pulverized to micron-sized particles. While commonly used air jet milling technology is highly efficient, the high-speed collisions between materials and between materials and equipment during the milling process generate significant heat. Components such as daidzein, verrucoside, and gentianin are particularly sensitive to heat; localized or overall temperature increases may lead to changes in their chemical structure, resulting in a loss of efficacy. Existing technologies attempt to control temperature by introducing low-temperature gas into the milling chamber or by externally cooling the equipment, but these methods are often slow and uneven in controlling temperature during continuous heat generation. When the throughput or material properties change, simple cooling methods cannot accurately and quickly respond to temperature fluctuations, posing a challenge to the stability of heat-sensitive components. The fundamental difficulty lies in how to achieve efficient mechanical milling while simultaneously implementing real-time, precise closed-loop control of the process temperature to maintain a stable low-temperature microenvironment throughout the entire process of micron-sized particle preparation.

[0004] Secondly, achieving uniform dispersion of low-proportion active ingredients (APIs) has long been a challenge in the mixing process of pharmaceutical formulations. In solid dosage forms, the proportion of APIs is typically low, while excipients (such as fillers and disintegrants) constitute the majority. Mixing a small amount of micronized active ingredient with a large amount of excipients with different physical properties (such as density, particle size, and flowability) easily leads to uneven mixing. Micronized active ingredient powders are prone to agglomeration or separation within the mixer due to differences in properties with the excipients, resulting in an uneven distribution of APIs in the final mixture. This unevenness directly impacts subsequent granulation processes, ultimately causing the API content in individual dosage units (such as tablets or capsules) to exceed the pharmacopoeia-specified limits, affecting the safety and efficacy of the medication. Traditional solutions involve extending mixing time or increasing mixing intensity, but this can lead to overmixing, causing fine powders to re-agglomerate or generate static electricity, exacerbating the unevenness or damaging the fragile structure of the micronized particles. Therefore, designing a mixing process that can ensure highly uniform physical dispersion of low-content, easily agglomerated active ingredient micropowders in a large amount of excipients, while maintaining process stability and repeatability, is a key challenge in ensuring the uniformity of formulation quality.

[0005] Furthermore, at the level of automated control in the production process, there is a problem that process parameters are difficult to automatically recover to their optimal state after disturbances occur. In temperature-sensitive continuous or semi-continuous production units such as micronization and drying, when key parameters such as temperature are detected to deviate from the set range, the control system will perform adjustment operations (such as reducing the feed rate and increasing the cooling intensity) to restore the parameters to normal. However, common control strategies, after intervention, often keep the system operating at relatively conservative "safe" parameters set to cope with deviations, such as a low feed rate. While these parameters can ensure process stability in the short term, they are not the optimal process point for balancing efficiency and quality as initially designed. Long-term operation under such non-optimal parameters will lead to efficiency losses such as decreased equipment capacity utilization, increased energy consumption, and extended production cycles. Relying on manual judgment and gradually restoring parameters to the optimal setting poses risks of slow response, inconsistent operation, and potential human error. The core challenge lies in how to enable the production system to automatically, smoothly, and reliably identify recovery conditions after undergoing necessary intervention and adjustment, and safely guide the operating parameters back to the efficient and optimal set range, thereby achieving a balance between production efficiency and process stability.

[0006] In summary, three interconnected and pressing technical bottlenecks exist in the development of specific flavonoid compositions into solid dosage forms: effectively protecting heat-sensitive active ingredients from thermal degradation during the micronization stage; achieving high uniformity dispersion of low-content active ingredients during the mixing stage; and enabling adaptive parameter recovery in key process units to maintain overall efficiency. These issues hinder the high-quality, high-efficiency, and stable controllable preparation of such pharmaceutical compositions in industrial-scale production. Summary of the Invention

[0007] One object of the present invention is to solve at least the above-mentioned problems and to provide at least the advantages that will be described later.

[0008] To achieve these objectives and other advantages according to the present invention, the present invention provides a method for preparing a pharmaceutical composition for treating glomerular diseases, comprising the following steps: S1. Weigh and premix soybean glycoside, verrucoside, and gentianin according to a weight ratio of 1:(0.8-1.5):(1.5-3) for 10-20 min to obtain the premixed active ingredients. S2. The premixed active ingredients are placed in a low-temperature environment below 10°C and an inert atmosphere, and then co-pulverized and classified using a disc-type airflow pulverizer containing a classifying wheel. During the co-crushing and classification process, the outlet air temperature of the crushing chamber is monitored in real time, and multi-level adjustment operations are triggered and executed sequentially based on the comparison results of the outlet air temperature with at least two incremental temperature thresholds, so as to control the outlet air temperature below 32°C. The multi-stage adjustment operation includes at least one of the following parameters: nitrogen flow rate, material feed rate, classifier rotation frequency, and temperature of the medium in contact with the crushing chamber. S3. Collect the composite active ingredient micro powder obtained after grading, mix the composite active ingredient micro powder with filler and disintegrant, granulate, dry and granulate to obtain drug composition particles.

[0009] The aforementioned technical solution establishes a core process route of "premixing—co-pulverization and classification—formulation," particularly proposing the concept of "co-pulverizing and classification" of the three components under low temperature and an inert atmosphere. This ensures the uniformity of the final composite active ingredient micropowder in terms of material morphology and distribution, laying the physical foundation for the subsequent preparation of a uniform solid formulation. Simultaneously, this method introduces the overall concept of process regulation based on real-time temperature monitoring, providing direction for process control.

[0010] Preferably, the multi-level adjustment operation specifically includes: The first temperature threshold is set to T1=26°C, the second temperature threshold is set to T2=28°C, and the third temperature threshold is set to T3=32°C. When the outlet air temperature is monitored to exceed T1 for more than 30 seconds, the first-level adjustment operation is executed, increasing the nitrogen flow rate by 10%-20% based on the initial flow rate; After performing the first-level adjustment operation, continue monitoring for 60-120 seconds; if the average outlet air temperature is still higher than T2 during this period, then perform the second-level adjustment operation, reduce the material feeding rate by 10-25% based on the initial feeding rate, and reduce the operating frequency of the classifier wheel by 5-15 Hz based on the initial frequency. After performing the second-level adjustment operation, continue monitoring for 60-120 seconds; if the outlet air temperature remains higher than T3 during this period, then perform the third-level adjustment operation, reducing the material feed rate by 10-20% from the current rate, increasing the nitrogen flow rate by 10-20% from the current flow rate, and reducing the temperature of the crushing chamber in contact with the medium by 2-4°C.

[0011] The above technical solution addresses the challenge of easily degrading heat-sensitive components under the heat-generating environment of pulverization by proposing a preventative dynamic temperature management strategy. A multi-level, progressive temperature feedback control system is established. Specifically, it sets three increasing thresholds and specifies corresponding adjustment operations with progressively increasing intervention intensity. The first level only increases the cooling nitrogen flow rate, minimizing interference; if ineffective, the second level reduces the heat source (feed rate) and slightly adjusts the stage parameters; if the temperature is still out of control, the third level initiates the most intense comprehensive cooling measures. This design achieves a smooth transition from "early warning regulation" to "strong intervention," aiming to maximize the protection of active ingredients with minimal process disturbance.

[0012] Preferably, during the multi-level adjustment operation, if the operating parameters are changed due to the execution of the second-level adjustment operation or the third-level adjustment operation, the parameter recovery process is initiated. The triggering condition for the parameter recovery process is: the outlet air temperature drops and remains below 25°C for 60-120 seconds; when the triggering condition is met, this moment is recorded as the recovery reference moment, and the real-time values ​​of the classifier wheel's operating frequency, material feed rate, and nitrogen flow rate at the recovery reference moment are obtained as the recovery reference parameters; subsequently, the following recovery operations are executed sequentially: S201. Based on the frequency of the recovery reference time, increase the operating frequency of the grading wheel by 3-8 Hz; S202. After completing the frequency adjustment in S201, continue to monitor the outlet air temperature. If the outlet air temperature does not exceed 26°C within the following 60-120 seconds, increase the material feeding rate by 5-15% based on the rate at the recovery reference time. S203. After completing the feed rate adjustment in S202, continue to monitor the outlet air temperature. If the outlet air temperature does not exceed 26°C within the following 60-120 seconds, reduce the nitrogen flow rate by 5-15% based on the flow rate at the recovery reference time, and increase the temperature of the crushing chamber in contact with the medium by 1-2°C. After each step of the parameter recovery process is executed, it must be confirmed that the outlet air temperature does not exceed 26°C within a specified time before proceeding to the next step or ending the parameter recovery process; if the outlet air temperature exceeds 26°C during the execution process or confirmation period of any step, the parameter recovery process is immediately interrupted.

[0013] To address the issue of long-term deviations from optimal process parameters caused by cooling adjustments, this technical solution constructs a "parameter recovery process" corresponding to the cooling adjustment. By introducing the concept of a "recovery reference moment," the real-time values ​​of each parameter are locked at this moment as the sole reference for all subsequent recovery operations. This solves the logical challenge of the recovery reference potentially changing or becoming invalid over time during dynamic processes. The recovery operations follow a sequence: first restoring the grading wheel frequency, which affects product quality; then restoring the feed rate, which affects production capacity; and finally adjusting the cooling parameters, ensuring the orderly and stable nature of the recovery process itself.

[0014] Preferably, the operation of interrupting the parameter recovery process includes: Immediately stop the currently executing parameter adjustment; The current operating parameters of the system, including the operating frequency of the stager wheel, the material feeding rate, and the nitrogen flow rate, are fixed and switched to an interruption hold state. During the interruption hold state, the fixed parameters are maintained and the outlet air temperature is continuously monitored; If the outlet air temperature does not exceed 28°C within 60-180 seconds of the interruption hold state, the current state will be used as a new starting point to recalculate and start a new round of parameter recovery process; if the outlet air temperature exceeds 28°C, the interruption hold state will be exited immediately, and the corresponding second-level or third-level adjustment operation will be triggered or executed according to the rules of the multi-level adjustment operation.

[0015] The parameter recovery process may be interrupted by unexpected temperature rises, requiring explicit handling rules to prevent the system from falling into an undefined chaotic state. This technical solution proposes the concept of "interruption-held state" and its corresponding dual-path exit mechanism. When an interruption occurs, the system does not stagnate but instead solidifies the current parameter combination into a valid temporary operating condition. Subsequently, the system monitors the temperature in this state: if the temperature remains stable within a specified time, recovery restarts from this state; if the temperature rises again above the safety threshold, it seamlessly reverts to the main control logic. This endows the process system with robustness for autonomous recovery from disturbances.

[0016] Preferably, in step S203, the operations of reducing the nitrogen flow rate by 5-15% and increasing the temperature of the medium in contact with the pulverizing chamber by 1-2°C are achieved through multiple alternating fine-tuning sub-steps. Each fine-tuning step includes: first, reducing the nitrogen flow rate by 2-4% from the current flow rate, and then monitoring the outlet air temperature within 60-120 seconds; if the outlet air temperature does not exceed 26°C, then increasing the temperature of the medium in contact with the pulverizing chamber by 0.5-1°C from the current temperature, and then monitoring the outlet air temperature within 60-120 seconds. Repeat the fine-tuning steps until the nitrogen flow rate decreases by a cumulative 5-15% and the temperature of the pulverizing chamber in contact with the medium increases by a cumulative 1-2°C. If the outlet air temperature exceeds 26°C during the monitoring period after any fine-tuning step, the subsequent fine-tuning steps are paused, and the current parameters are maintained for 120-180 seconds. If the outlet air temperature drops below 26°C within the 120-180 seconds, the subsequent fine-tuning steps are executed. Otherwise, the parameter recovery process is terminated.

[0017] To address the risk of a stepwise decrease in cooling capacity and temperature rebound due to simultaneously reducing two cooling parameters at the end of the recovery process, this technical solution proposes a "step-by-step alternating fine-tuning method." This method decouples the adjustment of nitrogen flow rate and chamber temperature, breaking it down into a series of alternating, small-amplitude adjustment sub-steps, with an observation period after each adjustment to confirm temperature stability. This gradual operation effectively avoids drastic fluctuations in cooling intensity, ensures a smooth transition in process temperature when partially removing cooling protection, and prevents system oscillations near the recovery endpoint.

[0018] Preferably, in step S3, the composite active ingredient micro powder, filler, and disintegrant are wet-granulated; wherein the filler is lactose, the disintegrant is crospovidone, and the weight ratio of the composite active ingredient micro powder, lactose, and crospovidone is 1:(2-4):(0.3-0.8); the binder used for granulation is a 5-15% aqueous solution of hydroxypropyl methylcellulose, and its amount is 8-12% of the total weight of the composite active ingredient micro powder, lactose, and crospovidone; after granulation, the wet granules are dried and granulated; the drying conditions for the wet granules are a temperature of 40-45°C and a vacuum degree of 0.07-0.09 MPa, and drying until the moisture content of the granules is 1.5-3.0%; the granulation is carried out using an 18-24 mesh sieve, and the particle size distribution of the granulated particles is controlled between 100-250 μm.

[0019] To reliably and stably convert the active ingredient micronized powder obtained from previous processes into solid pharmaceutical granules that meet quality standards, this technical solution provides a specific and synergistic formulation and process parameters. Of particular note is its explicit limitation of the drying temperature of the wet granules to a lower range of 40-45°C. This limitation is not a conventional choice, but rather a continuation and reinforcement of the core principle of protecting heat-sensitive components throughout the entire process. It extends low-temperature protection measures from the pulverization stage to the drying stage, ensuring that the active ingredient remains in a mild environment during the final heat treatment stage before final formulation.

[0020] Preferably, the mixing of the composite active ingredient micro powder with lactose and crospovidone is carried out using a stepwise incremental mixing method, specifically: S301. Mix all the composite active ingredient micro powders with lactose accounting for 30%-50% of the total weight of the filler. The first mixing speed is 15-25 rpm and the first mixing time is 5-10 min. S302. Add all remaining lactose and all cross-linked polyvinylpyrrolidone to the mixture obtained in S301 for a second mixing. The second mixing speed is 20-30 rpm and the second mixing time is 10-15 min.

[0021] Addressing the common technical challenge of uniform dispersion of low-content active ingredient micropowders when mixed with large amounts of excipients, this technical solution proposes a "stepwise incremental mixing method." This method breaks with the conventional practice of mixing all ingredients at once. First, a portion of the filler is mixed with all the active ingredient micropowders for a preliminary "pre-dispersion" mixture, forming an intermediate with a higher concentration of active ingredient. The second step involves a final "distribution" mixture with the remaining excipients. This method cleverly applies the principle of concentration gradient, significantly improving the uniformity and efficiency of the distribution of trace active ingredients in the final mixture by reducing volume differences in the initial mixing, fundamentally ensuring the content uniformity of the formulation product.

[0022] The present invention also provides a pharmaceutical composition for treating glomerular diseases, comprising an active ingredient and pharmaceutically acceptable excipients; the active ingredient is composed of daidzein, verrucoside, and gentiopicrin; the total mass percentage of the active ingredient in the pharmaceutical composition is 50%-90%; the weight ratio of daidzein, verrucoside, and gentiopicrin is in the range of 1:(0.8-1.5):(1.5-3).

[0023] The present invention includes at least the following beneficial effects: The pharmaceutical composition for treating glomerular diseases and its preparation method, as described in this invention, firstly, provide a synergistic therapeutic effect on glomerular diseases through a combination of daidzein, verrucoside, and gentianin in a specific ratio, offering a new treatment option for clinical use. Secondly, the preparation method ensures uniform mixing at the microscopic scale by co-pulverizing and classifying the three active ingredients, laying a physical foundation for the quality uniformity of the final formulation. Thirdly, the multi-stage temperature regulation mechanism designed in this method effectively prevents the degradation of heat-sensitive components caused by heat accumulation during the pulverization process, minimizing production disturbances while protecting activity. A further parameter recovery process allows the system to automatically and orderly return to a highly efficient operating state after temperature regulation, thereby ensuring production efficiency and process stability. Fourthly, a dedicated interruption handling mechanism guides the system into a well-defined transient state and autonomously decides the subsequent path when an interruption occurs, significantly enhancing the robustness of continuous production. Finally, a step-by-step alternating fine-tuning method is used to adjust cooling parameters, avoiding temperature rebound and system oscillation caused by sudden changes in cooling intensity. In the subsequent formulation stage, the specific formulation and lower drying temperature extend the principle of heat protection to the final step, ensuring the stability of the active ingredient throughout the process. Finally, the stepwise incremental mixing strategy effectively solves the problem of uneven dispersion of low-content active ingredients in a large number of excipients, fundamentally ensuring the high uniformity of content among the units of the final drug, thereby systematically improving the product's safety, efficacy, and quality controllability.

[0024] Other advantages, objectives and features of the present invention will become apparent in part from the following description, and in part from those skilled in the art through study and practice of the invention. Attached Figure Description

[0025] Figure 1 A comparison image of PAS staining. Detailed Implementation

[0026] The present invention will now be described in further detail with reference to specific embodiments, so that those skilled in the art can implement it based on the description.

[0027] It should be understood that terms such as “having,” “comprising,” and “including” as used herein do not exclude the presence or addition of one or more other elements or combinations thereof.

[0028] It should be noted that, unless otherwise specified, the experimental methods described in the following implementation plan are all conventional methods, and the reagents and materials described are all commercially available unless otherwise specified.

[0029] Example 1 S1. Raw materials and premixing: Weigh 100 g of soybean stigmataside, 100 g of verrucoside isoflavone glycoside, and 200 g of gentianin, put them into a mixer and mix for 15 minutes to obtain premixed active ingredients.

[0030] S2. Initial Setting and Temperature Control of Co-pulverization: The premixed active ingredients are fed into the disc-type air jet mill. The initial feed rate is set to 40% of the rated throughput (10 kg / h) (i.e., 4 kg / h), the initial frequency of the classifying wheel is 40 Hz, the initial nitrogen flow rate is 0.9 times the chamber volume (50 L) / min (45 L / min), the contact temperature of the pulverizing chamber with the medium is 5°C, and 5°C nitrogen is introduced. The outlet air temperature is monitored in real time.

[0031] If the outlet air temperature remains above 26°C (T1) for more than 30 seconds, perform the first-stage adjustment: increase the nitrogen flow rate by 15% to approximately 52 L / min. After monitoring for another 90 seconds, if the average outlet air temperature is still above 28°C (T2), perform the second-stage adjustment: decrease the feed rate by 17.5% to approximately 3.3 kg / h and decrease the classifier frequency by 9 Hz to 31 Hz.

[0032] Parameter recovery procedure: After the outlet air temperature drops and remains below 25°C for 90 seconds, the parameter recovery procedure is initiated. Record this moment as the recovery baseline time (frequency 31 Hz, feed rate 3.3 kg / h, nitrogen flow rate 52 L / min).

[0033] Perform S201: Based on the restored reference frequency (31 Hz), increase the grading wheel frequency by 5 Hz to 36 Hz.

[0034] After completing S201 and stabilizing for 90 seconds, if the outlet air temperature does not exceed 26°C, proceed with S202: based on the restored baseline rate (3.3 kg / h), increase the feed rate by 10% to approximately 3.6 kg / h.

[0035] After completing S202 and stabilizing for 90 seconds, if the outlet air temperature does not exceed 26°C, proceed to S203: Based on restoring the baseline flow rate (52 L / min), reduce the nitrogen flow rate by 10%. This operation is performed according to the fine-tuning steps: first, reduce the nitrogen flow rate by 3% to approximately 50.4 L / min, and after monitoring the temperature for 90 seconds and finding it does not exceed 26°C, increase the temperature of the cavity contact medium by 0.8°C to 5.8°C; after monitoring the temperature for another 90 seconds and finding it does not exceed 26°C, continue to reduce the nitrogen flow rate by 3% to approximately 48.9 L / min, and after monitoring for 90 seconds, increase the cavity temperature by 0.7°C to 6.5°C. The cumulative flow rate reduction is approximately 6%, and the cumulative temperature increase is 1.5°C.

[0036] If the outlet air temperature exceeds 26°C during any monitoring period in S203, the adjustment will be stopped immediately, and the current parameter will be fixed to enter the interruption hold state. If the temperature does not exceed 28°C within 150 seconds of operation in this state, the recovery process will restart from the current state.

[0037] S3. Formulation Process: Collect the obtained composite active ingredient micro powder. Take 150g of this micro powder and mix it with 120g of lactose and 30g of crospovidone (ratio 1:0.8:0.2). Use a stepwise incremental mixing method: first, mix all the micro powder with 48g of lactose (accounting for 40% of the total weight of lactose) at 20 rpm for 7.5 minutes; then add the remaining 72g of lactose and all of the crospovidone, and mix at 25 rpm for 12.5 minutes. Add 30g of 10% hydroxypropyl methylcellulose aqueous solution to the mixture for granulation. Dry the wet granules at 42.5°C and 0.08 MPa until the moisture content is 2.25%, and finally granulate them through a 21-mesh sieve.

[0038] Example 2 S1. Raw materials and premixing: Weigh 100g of soybean stigmataside, 80g of verrucoside isoflavone glycoside, and 150g of gentianin (ratio 1:0.8:1.5), mix for 10 minutes to obtain the premixed active ingredients.

[0039] S2. Initial setting and temperature control of co-crushing: Set the initial feed rate to 30% of the rated processing capacity (5 kg / h) (1.5 kg / h), the initial frequency of the classifier wheel to 35 Hz, the initial flow rate of nitrogen to 0.8 times the volume of the chamber (30 L) per minute (24 L / min), the temperature of the medium in contact with the chamber to 2°C, and introduce nitrogen at 2°C.

[0040] If the outlet air temperature remains above 26°C (T1) for more than 30 seconds, perform the first-stage adjustment: increase the nitrogen flow rate by 10% to 26.4 L / min. After performing the first-stage adjustment, continue monitoring for 60 seconds; if the average outlet air temperature remains above 28°C (T2) during this period, perform the second-stage adjustment: decrease the feed rate by 10% to 1.35 kg / h and decrease the classifier frequency by 5 Hz to 30 Hz.

[0041] Parameter recovery procedure: After the outlet air temperature drops and remains below 25°C for 60 seconds, the parameter recovery procedure is initiated. Record the parameters at the baseline recovery time (frequency 30 Hz, feed 1.35 kg / h, flow rate 26.4 L / min).

[0042] S201: Increase the frequency by 3 Hz to 33 Hz.

[0043] After stabilizing for 60 seconds, if the outlet air temperature does not exceed 26°C, execute S202: increase the feed rate by 5% to approximately 1.42 kg / h.

[0044] After stabilizing for 60 seconds, if the outlet air temperature does not exceed 26°C, execute S203: reduce the nitrogen flow rate by 5% to approximately 25.1 L / min, and simultaneously increase the chamber temperature by 1°C to 3°C (perform fine-tuning: first reduce the flow rate by 2%, monitor for 60 seconds, then increase the temperature by 0.5°C; monitor for another 60 seconds, then reduce the flow rate by 2%, then increase the temperature by 0.5°C).

[0045] S3. Formulation Process: Take 200g of micronized powder and mix it with 150g of lactose and 50g of crospovidone (ratio 1:0.75:0.25). Mix in steps: First, mix the micronized powder with 60g of lactose at 15 rpm for 5 minutes; then add the remaining 90g of lactose and all of the crospovidone, and mix at 20 rpm for 10 minutes. Add 40g of 5% hydroxypropyl methylcellulose solution to granulate. Dry the wet granules at 40°C and 0.07 MPa until the moisture content is 1.5%, and then granulate using an 18-mesh sieve.

[0046] Example 3 S1. Raw materials and premixing: Weigh 100g of soybean stigmataside, 150g of verrucoside isoflavone glycoside, and 300g of gentianin (ratio 1:1.5:3), mix for 20 minutes to obtain the premixed active ingredients.

[0047] S2. Initial setting and temperature control adjustment of co-crushing: Set the initial feed rate to 50% of the rated processing capacity (20 kg / h) (10 kg / h), the initial frequency of the classifier wheel to 45 Hz, the initial flow rate of nitrogen to 1.0 times the volume of the chamber (60 L) per minute (60 L / min), the temperature of the medium in contact with the chamber to 8°C, and introduce nitrogen at 8°C.

[0048] If the outlet air temperature remains above 26°C (T1) for more than 30 seconds, perform the first-stage adjustment: increase the nitrogen flow rate by 20% to 72 L / min. After performing the first-stage adjustment, continue monitoring for 120 seconds; if the average outlet air temperature is still above 28°C (T2) during this period, perform the second-stage adjustment: reduce the feed rate by 25% to 7.5 kg / h and reduce the classifier frequency by 15 Hz to 30 Hz.

[0049] Parameter recovery procedure: After the outlet air temperature drops and remains below 25°C for 120 seconds, the parameter recovery procedure is initiated. Record the parameters at the baseline recovery time (frequency 30 Hz, feed 7.5 kg / h, flow rate 72 L / min).

[0050] S201: Increase the frequency by 8 Hz to 38 Hz.

[0051] After completing S201 and stabilizing for 120 seconds, if the outlet air temperature does not exceed 26°C, proceed with S202: increase the feed rate by 15% to approximately 8.6 kg / h.

[0052] After completing S202 and stabilizing for 120 seconds, if the outlet air temperature does not exceed 26°C, proceed to S203: reduce the nitrogen flow rate by 15%. This operation is performed according to the fine-tuning steps: first, reduce the nitrogen flow rate by 4% to approximately 69.1 L / min, monitor for 120 seconds. If the temperature does not exceed 26°C, increase the temperature of the cavity contact medium by 1°C to 9°C; monitor again for 120 seconds. If the temperature does not exceed 26°C, continue to reduce the nitrogen flow rate by 4% to approximately 66.3 L / min; repeat this alternating fine-tuning step until the nitrogen flow rate has cumulatively decreased by 15% (to approximately 61.2 L / min) and the cavity temperature has cumulatively increased by 2°C (to 10°C).

[0053] If the outlet air temperature exceeds 26°C during any monitoring period in S203, the adjustment will be stopped immediately, and the current parameter will be fixed to enter the interruption hold state. If the temperature does not exceed 28°C within 180 seconds of operation in this state, the recovery process will restart from the current state. If the temperature exceeds 28°C, the interruption hold state will be exited immediately, and the corresponding adjustment operation will be performed according to the rules.

[0054] S3. Formulation Process: Take 120g of micronized powder and mix it with 80g of lactose and 20g of crospovidone (ratio 1:0.67:0.17). Mix in steps: First, mix the micronized powder with 32g of lactose at 25 rpm for 10 minutes; then add the remaining 48g of lactose and all of the crospovidone, and mix at 30 rpm for 15 minutes. Add 22g of 15% hydroxypropyl methylcellulose solution to granulate. Dry the wet granules at 45°C and 0.09MPa until the moisture content is 3.0%, and then granulate using a 24-mesh sieve.

[0055] Comparative Example 1: Traditional airflow pulverization process (without multi-stage temperature control) S1. Raw Materials and Initial Settings Same as Example 1.

[0056] S2, Co-crushing and Classification Process Start the equipment and add the premixed active ingredients. The difference is that the pulverization process relies solely on the initially set cooling conditions, does not monitor the outlet air temperature, and does not perform any multi-stage adjustment operations or parameter recovery procedures.

[0057] S3, Formulation Process Same as Example 1.

[0058] Comparative Example 2: Fixed-parameter operation process (parameterless recovery process) S1. Raw Materials and Initial Settings Same as Example 1.

[0059] S2, Co-crushing and Classification Process Start the equipment and add the premixed active ingredients. After stable operation, the outlet air temperature gradually rises. When the outlet air temperature reaches 25.5°C, the system automatically increases the nitrogen flow rate by 15%, to approximately 52 L / min (corresponding to the first-level adjustment). 45 seconds after this operation, if the outlet air temperature remains at 26.5°C, the system automatically reduces the feed rate by 17.5% to approximately 3.3 kg / h, while simultaneously reducing the classifier frequency by 9 Hz to 31 Hz (corresponding to the second-level adjustment). The difference is that thereafter, even if the outlet air temperature drops and remains below 25°C, reaching the trigger condition, the system does not initiate the parameter recovery process but continues to operate at the adjusted parameters until the batch is finished.

[0060] S3, Formulation Process Same as Example 1.

[0061] Comparative Example 3: Conventional one-time total mixing process (without stepwise incremental mixing) S1. Raw Materials and Initial Settings Same as Example 1.

[0062] S2, Co-crushing and Classification Process Same as Example 1.

[0063] S3, Formulation Process Collect the obtained composite active ingredient micro powder. Take 150g of this micro powder and mix it with 120g of lactose and 30g of crospovidone (ratio 1:3:0.55). The difference is that the mixing step does not use a step-by-step incremental mixing method, but a conventional one-time total mixing method. All materials (all micro powder, all lactose, and all crospovidone) are added to the mixer at once, the mixer speed is set to 25 rpm, and the mixing time is 20 minutes (the total time is equivalent to the sum of the two mixing times in Example 1, which is 20 minutes). The subsequent granulation, drying, and granulation steps are the same as in Example 1.

[0064] Stability testing of active ingredients: High-performance liquid chromatography (HPLC) was used to detect the composite active ingredient micropowders prepared in the examples and comparative examples. The percentage of total degradation products of the three active ingredients was calculated by comparing with the raw material reference standard.

[0065] Pulverization process efficiency and particle size test: The total processing time of step S2 in the examples and comparative examples was recorded, and the average production capacity was calculated. The D90 particle size of the obtained composite active ingredient micro powder was determined using a laser particle size analyzer.

[0066] Content uniformity test of the formulation: The content uniformity of the final drug composition particles obtained in the examples and comparative examples was checked according to the methods in the Chinese Pharmacopoeia. Ten units were randomly sampled, and the relative standard deviation of the content was calculated using gentianin as the indicator component.

[0067] The test results are shown in Table 1.

[0068] Table 1 Example 1 Example 2 Example 3 Comparative Example 1 Comparative Example 2 Comparative Example 3 Total degradation products 0.5% 0.7% 0.6% 4.2% 0.5% 0.5% Average production capacity (kg / h) 3.6 1.45 8.5 4.0 3.3 3.6 Micronized powder D90 (μm) 22 19 25 25 28 22 Content uniformity RSD 2.8% 3.0% 3.2% 4.5% 2.9% 8.7% Results Analysis and Conclusions Protection of heat-sensitive active ingredients: The degradation products of Examples 1-3 were all below 1%, significantly better than Comparative Example 1 (4.2%). This proves that the multi-stage temperature control operation of the present invention effectively prevents thermal degradation during the pulverization process. Comparative Example 1, due to the lack of temperature control, suffered severe degradation.

[0069] Improved process efficiency and particle size control: Example 1 achieved the best protection effect while having a higher production capacity (3.6 kg / h) than Comparative Example 2 (3.3 kg / h) and a better particle size (22 μm) than Comparative Example 2 (28 μm). This indicates that the parameter recovery process of the present invention successfully restored the system from the "adjusted state" to a better operating condition, avoiding production capacity loss and particle size coarsening caused by long-term low-frequency operation.

[0070] Ensuring the uniformity of formulation quality: The content uniformity RSD of Examples 1-3 is all below 3.5%, meeting high standards. Comparative Example 3, using a single total mixing, has an RSD as high as 8.7%, demonstrating that the stepwise incremental mixing method of this invention plays a crucial role in solving the dispersion problem of low-content active ingredients.

[0071] Optimal overall performance: Example 1 showed excellent performance in all key indicators (lowest degradation, optimal particle size, and best uniformity) and high efficiency, fully demonstrating the synergistic benefits of the present invention: while maximizing the protection of active ingredients, it simultaneously achieved efficient process operation and excellent final product quality.

[0072] To demonstrate the beneficial effects of the compounds in the drug of this invention in treating glomerular diseases, a systematic pharmacodynamic, mechanistic, and safety study was conducted based on a mouse model of nephropathy induced by anti-GBM nephrotoxic serum from rats. Specific experimental methods and results are as follows.

[0073] I. Experimental Materials and Methods 1. Laboratory animals and grouping Animals: 64 healthy male C57BL / 6 mice, weighing 18-22g.

[0074] Modeling: A nephrotoxic serum nephritis model was prepared by means of the following method: Seven days after pre-immunization, mice were injected via tail vein with sheep anti-rat GBM nephrotoxic serum at a dose of 0.1 mL per 20 g body weight.

[0075] Grouping: Mice were randomly divided into 8 groups, with 8 mice in each group.

[0076] A. Model control group: After modeling, the model was administered an equal volume of solvent (0.5% sodium carboxymethyl cellulose solution) by gavage.

[0077] B. Strigol group: After modeling, strigol (100 mg / kg / day) was administered by gavage.

[0078] C. Soybean glycoside group: After modeling, soybean glycoside (50 mg / kg / day) was administered by gavage.

[0079] D. Versicolor isoflavone group: After modeling, versicolor isoflavone (50 mg / kg / day) was administered by gavage.

[0080] E. Glycine + Versiflavonoids group: A mixture of gyptin (50 mg / kg / day) and versiflavonoids (50 mg / kg / day) was administered by gavage.

[0081] F. Glycine + Arganin group: A mixture of gyptin (25 mg / kg / day) and arganin (75 mg / kg / day) was administered by gavage.

[0082] G. Versicolor isoflavone glycoside + argentin group: A mixture of versicolor isoflavone glycoside (25 mg / kg / day) and argentin (75 mg / kg / day) was administered by gavage.

[0083] H. The ternary combination of the present invention: a mixture of daidzein, verrucoside and gentianin in a weight ratio of 1:1:2 is administered by gavage, with doses of 25 mg / kg / day, 25 mg / kg / day and 50 mg / kg / day, and a total dose of 100 mg / kg / day.

[0084] Cycle: Mice were pre-immunized for 7 days before modeling, and drug intervention was started at the same time, once a day for 7 consecutive days.

[0085] 2. Main detection indicators and methods Sample Collection: During the experiment, random urine samples (greater than 500 μL) were collected from mice during the pre-immunization period (1 day) and on days 1, 3, 5, and 7 after modeling for the detection of urine biochemical indicators. At the end of the experiment, blood was collected from the heart of the mice after anesthesia, and serum was separated for biochemical analysis; the kidneys were removed, a portion of which was flash-frozen in liquid nitrogen for molecular biological detection, and another portion was fixed in 4% paraformaldehyde or glutaraldehyde for pathological examination.

[0086] Indicator 1: Urine protein / creatinine ratio Methods: Total protein in urine was determined by the Coomassie brilliant blue method, and creatinine in urine was determined by the sarcosine oxidase method. The urine protein / creatinine ratio was calculated.

[0087] Indicator 2: Serum albumin Methods: Serum albumin (ALB) levels were determined using the bromocresol green method.

[0088] Indicator 3: Kidney function indicators Methods: Serum creatinine (CRE) and blood urea nitrogen (BUN) levels were measured using a fully automated biochemical analyzer.

[0089] Indicator 4: Expression of key proteins in podocytes Methods: Total protein was extracted from renal cortex tissue. The expression levels of podocyte marker proteins Nephrin and Podocin were detected by Western blotting, with GAPDH used as an internal control.

[0090] Indicator 5: Kidney pathological morphology Light microscopy (PAS staining): assess the degree of glomerular mesangial matrix proliferation, sclerosis, and crescent formation, and perform semi-quantitative scoring; Indicator Six: Safety Indicators Methods: Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were detected using a fully automated biochemical analyzer.

[0091] II. Experimental Results and Comparative Analysis Indicator 1: The effect on improving proteinuria, the results are shown in Table 2.

[0092] Table 2 Group Urine protein / creatinine ratio (g / g) A. Model control group 51.19±7.51 B. Acanthophyte group 28.74±9.76 C. Soybean glycoside group 36.36±9.8 D. Versicolor isoflavone group 38.02±5.01 E. Soybean glycosides + Verbascosides 32.15 ± 6.22 F. Soybean glycosides + gentiopicrosides 26.84 ± 7.33 G. Versicolor isoflavone glycoside + stigmosiderin 24.91 ± 5.67 H. The ternary combination of the present invention 18.43 ± 4.85 Conclusion: Compared with the model control group, all treatment groups significantly reduced the urine protein / creatinine ratio. The reduction rate (64.0%) of the ternary combination (Group H) of this invention was significantly higher than that of any single component group (Groups B, C, and D) and any pairwise combination group (Groups E, F, and G). The pairwise combination groups (E, F, and G) were more effective than their corresponding single component groups, but none were as effective as the ternary combination of this invention. This indicates that the ternary combination of this invention has a synergistic effect in reducing proteinuria.

[0093] Indicator 2: Effect on the recovery of serum albumin, the results are shown in Table 3.

[0094] Table 3 Group Serum ALB (g / L) A. Model control group 24.81±6.36 B. Acanthophyte group 33.15±2.8 C. Soybean glycoside group 34.42±0.58 D. Versicolor isoflavone group 32.08±4.14 E. Soybean glycosides + Verbascosides 36.89 ± 3.12 F. Soybean glycosides + gentiopicrosides 37.74 ± 2.45 G. Versicolor isoflavone glycoside + stigmosiderin 36.22 ± 3.67 H. The ternary combination of the present invention 40.87 ± 3.05 Conclusion: Compared with the model control group, the ALB levels in mice in the gentianin group, daidzein group, and verrucoside group were significantly increased. These results indicate that these three compounds can improve the hypoalbuminemia state in nephrotic model mice to some extent. Furthermore, the ternary combination (group H) of this invention showed the best effect, significantly superior to any single component group (B, C, D) and any pairwise combination groups (E, F, G), indicating that the albumin synthesis or protective effect is synergistically enhanced when the three compounds are used in combination.

[0095] Indicator 3: The effect on improving kidney function, the results are shown in Table 4.

[0096] Table 4 Group Serum CRE (μmol / L) Serum BUN (mmol / L) A. Model control group 39.00±7.21 30.03±7.79 B. Acanthophyte group 28.00±4.24 22.30±1.48 C. Soybean glycoside group 27.00±4.24 20.90±4.14 D. Versicolor isoflavone group 29.33±4.53 24.93±3.46 E. Soybean glycosides + Verbascosides 24.50 ± 3.11 19.05 ± 2.11 F. Soybean glycosides + gentiopicrosides 23.80 ± 3.67 18.20 ± 2.45 G. Versicolor isoflavone glycoside + stigmosiderin 22.90 ± 2.85 17.90 ± 2.67 H. The ternary combination of the present invention 19.20 ± 2.44 16.10 ± 2.20 Conclusion: Compared with the model control group, the levels of CRE and BUN in mice in the three treatment groups treated with traditional Chinese medicine were significantly reduced, indicating that gentianin, daidzein, and verrucoside can effectively improve renal function indicators and have a clear protective effect on renal function. Furthermore, the ternary combination (Group H) of this invention showed the most significant reduction effect, superior to all single-component groups and pairwise combinations, directly demonstrating the synergistic advantage of the ternary combination in improving glomerular filtration function.

[0097] Indicator 4: Protective effect on key proteins of podocytes, the results are shown in Table 5.

[0098] Table 5 Group Relative expression level of Nephrin protein Relative expression level of Podocin protein A. Model control group 0.23 ± 0.06 0.19 ± 0.05 B. Acanthophyte group 0.64 ± 0.06 0.59 ± 0.05 C. Soybean glycoside group 0.81 ± 0.06 0.79 ± 0.08 D. Versicolor isoflavone group 0.56 ± 0.08 0.46 ± 0.06 E. Soybean glycosides + Verbascosides 0.92 ± 0.07 0.88 ± 0.06 F. Soybean glycosides + gentiopicrosides 1.05 ± 0.08 1.02 ± 0.07 G. Versicolor isoflavone glycoside + stigmosiderin 0.98 ± 0.07 0.94 ± 0.06 H. The ternary combination of the present invention 1.38 ± 0.10 1.35 ± 0.09 Conclusion: Compared with the model control group, all treatment groups significantly upregulated the expression of podocyte key proteins Nephrin and Podocin. The ternary combination (group H) of this invention showed the most significant upregulation effect, which was superior to any single component group (B, C, D) and any pairwise combination group (E, F, G). This directly proves at the molecular mechanism level that the composition of this invention, through synergistic action, most effectively protects and repairs the core structure of the glomerular filtration barrier.

[0099] Indicator 5: Improvement of kidney pathological damage PAS staining comparison image as follows Figure 1 As shown, the effects of different dosing regimens on glomerular pathological damage in model animals are illustrated. The single-component group (BD) improved glomerular structure to some extent and reduced basement membrane thickening and mesangial proliferation compared to the model control group (A); the binary combination group (EG) further alleviated glomerular sclerosis and crescent formation; the ternary combination group (H) of this invention showed the best effect in maintaining glomerular structural integrity, reducing basement membrane thickening, mesangial proliferation, and crescent formation.

[0100] The glomerular sclerosis score in the model control group was (0.32±0.25). Under the intervention of traditional Chinese medicine, the glomerular structure of the three single-agent groups remained basically intact, and the sclerosis scores were significantly reduced, namely: (genistein group: 0.12±0.05), (daidzein group: 0.17±0.09), and (verrucoside group: 0.20±0.02). The sclerosis scores of the three binary drug combination groups also showed a certain degree of improvement, in the following order: (daidzein + verrucoside group: 0.11±0.04), (daidzein + genistein group: 0.14±0.06), and (verrucoside + genistein group: 0.08±0.03). The sclerosis score of the ternary combination group was (0.07±0.01), showing the most significant improvement and the lowest sclerosis score, further verifying that the combined use of the three drugs had the most obvious efficacy.

[0101] The glomerular crescent score in the model control group was (0.33±0.09). Under the intervention of traditional Chinese medicine, the glomerular structure of the three single-agent groups was basically intact, and the crescent score was significantly reduced, namely: (genistein group: 0.14±0.1), (daidzein group: 0.2±0.03), and (verrucoside group: 0.29±0.13), all of which were better than the model control group. In the three binary drug combination groups, the sclerosis scores were as follows: (daidzein + verrucoside group: 0.12±0.04), (daidzein + genistein group: 0.16±0.07), and (verrucoside + genistein group: 0.18±0.09). The sclerosis score of the ternary combination group was (0.08±0.02), showing the most significant improvement and the lowest sclerosis score, further verifying that the combined use of the three drugs had the most obvious efficacy.

[0102] This study demonstrates that the present invention can effectively alleviate glomerular sclerosis and crescent formation, and significantly improve kidney damage. Its protective effect on the kidneys is verified from a histomorphological perspective.

[0103] Indicator 6: Safety comparison, the results are shown in Table 6.

[0104] Table 6 Group Body weight at the end of the experiment (g) Serum ALT (U / L) Serum AST (U / L) A. Model control group 26.4 ± 1.1 35±7.21 180.03±6.79 B. Acanthophyte group 22.3 ± 1.6 34±4.24 122.3±9.48 C. Soybean glycoside group 20.9 ± 1.5 44±4.24 165.9±5.14 D. Versicolor isoflavone group 24.4 ± 1.3 47.33±3.53 170.93±5.46 E. Soybean glycosides + Verbascosides 23.5 ± 1.4 42 ± 3.61 155.2 ± 6.22 F. Soybean glycosides + gentiopicrosides 22.8 ± 1.5 38 ± 3.77 140.5 ± 7.33 G. Versicolor isoflavone glycoside + stigmosiderin 24.0 ± 1.4 40 ± 3.85 145.1 ± 8.45 H. The ternary combination of the present invention 25.2 ± 1.2 36 ± 3.05 118.5 ± 6.50 Conclusion: During the experiment, compared with the model control group, the body weight of mice in all treatment groups decreased (possibly related to the disease model and the gavage procedure), but the body weight decrease was the smallest in the ternary combination of the present invention (Group H). Regarding liver function indicators, serum ALT and AST levels in all treatment groups were not statistically significantly increased compared with the model control group, and the ALT and AST values ​​in the ternary combination (Group H) were at a lower level than in all treatment groups. These results indicate that the pharmaceutical composition of the present invention has good safety at the experimental dose, and the ternary combination exhibits a better safety trend while achieving optimal efficacy.

[0105] The different monomeric compounds of this invention exhibited clear renal protective effects in a nephropathy model: 1) significantly reduced proteinuria; 2) significantly increased serum albumin levels; 3) effectively improved renal function; 4) the core mechanism was the upregulation of key podocyte proteins, directly protecting the filtration barrier; 5) effectively improved renal pathological damage; and 6) while achieving the above-mentioned therapeutic effects, possessed significantly higher safety. These data collectively confirm that this invention provides a novel therapeutic strategy for glomerular diseases with definite efficacy, a novel mechanism, and superior safety.

[0106] The number of devices and processing scale described herein are for the purpose of simplifying the description of the invention. Applications, modifications, and variations of the invention will be readily apparent to those skilled in the art.

[0107] Although the embodiments of the present invention have been disclosed above, they are not limited to the applications listed in the specification and embodiments. They can be applied to various fields suitable for the present invention. For those skilled in the art, other modifications can be easily made. Therefore, without departing from the general concept defined by the claims and their equivalents, the present invention is not limited to the specific details.

Claims

1. A method for preparing a pharmaceutical composition for treating glomerular diseases, characterized in that, Includes the following steps: S1. Weigh and premix soybean glycoside, verrucoside, and gentianin according to a weight ratio of 1:(0.8-1.5):(1.5-3) for 10-20 min to obtain the premixed active ingredients. S2. The premixed active ingredients are placed in a low-temperature environment below 10°C and an inert atmosphere, and then co-pulverized and classified using a disc-type airflow pulverizer containing a classifying wheel. During the co-crushing and classification process, the outlet air temperature of the crushing chamber is monitored in real time, and multi-level adjustment operations are triggered and executed sequentially based on the comparison results of the outlet air temperature with at least two incremental temperature thresholds, so as to control the outlet air temperature below 32°C. The multi-stage adjustment operation includes at least one of the following parameters: nitrogen flow rate, material feed rate, classifier rotation frequency, and temperature of the medium in contact with the crushing chamber. S3. Collect the composite active ingredient micro powder obtained after grading, mix the composite active ingredient micro powder with filler and disintegrant, granulate, dry and granulate to obtain drug composition particles.

2. The preparation method according to claim 1, characterized in that, The multi-level adjustment operation specifically includes: The first temperature threshold is set to T1=26°C, the second temperature threshold is set to T2=28°C, and the third temperature threshold is set to T3=32°C. When the outlet air temperature is monitored to exceed T1 for more than 30 seconds, the first-level adjustment operation is executed, increasing the nitrogen flow rate by 10%-20% based on the initial flow rate; After performing the first-level adjustment operation, continue monitoring for 60-120 seconds; if the average outlet air temperature is still higher than T2 during this period, then perform the second-level adjustment operation, reduce the material feeding rate by 10%-25% based on the initial feeding rate, and reduce the operating frequency of the classifier wheel by 5-15 Hz based on the initial frequency. After performing the second-level adjustment operation, continue monitoring for 60-120 seconds; if the outlet air temperature remains higher than T3 during this period, then perform the third-level adjustment operation, reducing the material feed rate by 10-20% from the current rate, increasing the nitrogen flow rate by 10-20% from the current flow rate, and reducing the temperature of the crushing chamber in contact with the medium by 2-4°C.

3. The preparation method according to claim 2, characterized in that, During the multi-level adjustment operation, if the operating parameters are changed due to the execution of the second-level adjustment operation or the third-level adjustment operation, the parameter recovery process is initiated. The triggering condition for the parameter recovery process is: the outlet air temperature drops and remains below 25°C for 60-120 seconds; when the triggering condition is met, this moment is recorded as the recovery reference moment, and the real-time values ​​of the classifier wheel's operating frequency, material feed rate, and nitrogen flow rate at the recovery reference moment are obtained as the recovery reference parameters. Then, perform the following recovery operations in sequence: S201. Based on the frequency of the recovery reference time, increase the operating frequency of the grading wheel by 3-8 Hz; S202. After completing the frequency adjustment in S201, continue to monitor the outlet air temperature. If the outlet air temperature does not exceed 26°C within the following 60-120 seconds, increase the material feeding rate by 5-15% based on the rate at the recovery reference time. S203. After completing the feed rate adjustment in S202, continue to monitor the outlet air temperature. If the outlet air temperature does not exceed 26°C within the following 60-120 seconds, reduce the nitrogen flow rate by 5-15% based on the flow rate at the recovery reference time, and increase the temperature of the crushing chamber in contact with the medium by 1-2°C. After each step of the parameter recovery process is executed, it must be confirmed that the outlet air temperature does not exceed 26°C within a specified time before proceeding to the next step or ending the parameter recovery process. If the outlet air temperature exceeds 26°C during the execution process or confirmation period of any step, the parameter recovery process shall be immediately interrupted.

4. The preparation method according to claim 3, characterized in that, The operation of interrupting the parameter recovery process includes: Immediately stop the currently executing parameter adjustment; The current operating parameters of the system, including the operating frequency of the classifier wheel, the material feeding rate, and the nitrogen flow rate, are fixed and switched to an interruption hold state. During the interruption hold state, the fixed parameters are maintained and the outlet air temperature is continuously monitored; If the outlet air temperature does not exceed 28°C within 60-180 seconds of the interruption hold state, the current state will be used as a new starting point to recalculate and start a new round of parameter recovery process; if the outlet air temperature exceeds 28°C, the interruption hold state will be exited immediately, and the corresponding second-level or third-level adjustment operation will be triggered or executed according to the rules of the multi-level adjustment operation.

5. The preparation method according to claim 3, characterized in that, In step S203, the operations of reducing the nitrogen flow rate by 5-15% and increasing the temperature of the medium in contact with the pulverizing chamber by 1-2°C are achieved through multiple alternating fine-tuning sub-steps. Each fine-tuning step includes: first, reducing the nitrogen flow rate by 2-4% from the current flow rate, and then monitoring the outlet air temperature within 60-120 seconds; if the outlet air temperature does not exceed 26°C, then increasing the temperature of the medium in contact with the pulverizing chamber by 0.5-1°C from the current temperature, and then monitoring the outlet air temperature within 60-120 seconds. Repeat the fine-tuning steps until the nitrogen flow rate decreases by a cumulative 5-15% and the temperature of the pulverizing chamber in contact with the medium increases by a cumulative 1-2°C. If the outlet air temperature exceeds 26°C during the monitoring period after any fine-tuning step, the subsequent fine-tuning steps are paused, and the current parameters are maintained for 120-180 seconds. If the outlet air temperature drops below 26°C within the 120-180 seconds, the subsequent fine-tuning steps are executed. Otherwise, the parameter recovery process is terminated.

6. The preparation method according to claim 1, characterized in that, In step S3, the composite active ingredient micro powder, filler, and disintegrant are wet-granulated; wherein the filler is lactose, the disintegrant is crospovidone, and the weight ratio of the composite active ingredient micro powder, lactose, and crospovidone is 1:(2-4):(0.3-0.8); the binder used for granulation is a 5-15% aqueous solution of hydroxypropyl methylcellulose, and its amount is 8-12% of the total weight of the composite active ingredient micro powder, lactose, and crospovidone; after granulation, the wet granules are dried and granulated; the drying conditions for the wet granules are a temperature of 40-45°C and a vacuum degree of 0.07-0.09 MPa, and drying is carried out until the moisture content of the granules is 1.5-3.0%; the granulation is carried out using an 18-24 mesh sieve, and the particle size distribution of the granulated particles is controlled between 100-250 μm.

7. The preparation method according to claim 6, characterized in that, The mixing of the composite active ingredient micro powder with lactose and crospovidone adopts a stepwise incremental mixing method, specifically: S301. Mix all the composite active ingredient micro powders with lactose accounting for 30%-50% of the total weight of the filler. The first mixing speed is 15-25 rpm and the first mixing time is 5-10 min. S302. Add all remaining lactose and all cross-linked polyvinylpyrrolidone to the mixture obtained in S301 for a second mixing. The second mixing speed is 20-30 rpm and the second mixing time is 10-15 min.

8. A pharmaceutical composition for treating glomerular diseases, characterized in that, The pharmaceutical composition contains an active ingredient and pharmaceutically acceptable excipients; the active ingredient is composed of daidzein, verrucoside, and gentiopicrin; the total mass percentage of the active ingredient in the pharmaceutical composition is 50%-90%; the weight ratio of daidzein, verrucoside, and gentiopicrin is in the range of 1:(0.8-1.5):(1.5-3).

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