Nano dispersed porous coated heat-clearing and detoxifying particle and preparation method thereof

Abstract

The invention relates to the technical field of traditional Chinese medicine preparations, in particular to nano dispersed porous coated heat-clearing and detoxifying granules and a preparation method thereof. The invention discloses a preparation method of nano dispersed porous coated heat-clearing and detoxifying granules, which comprises the following steps: by taking cornu bubali, coptis chinensis, radix scrophulariae and the like as raw materials, crushing, performing hot reflux extraction, decocting and concentrating to obtain clear paste, mixing, homogenizing and grinding to obtain submicron dispersed clear paste; granulating the porous auxiliary material mixture and cornu bubali micron powder, and spraying a diluent containing povidone K30 to obtain a porous particle intermediate; preparing modified calcium sulfate whisker as a main coating solution and ethyl cellulose aqueous dispersion as a water-based hydrophobic coating solution, sequentially coating, drying and sieving to obtain target particles. The dissolvability and the stability of the granules are improved through a porous coating and nano dispersion technology, and the preparation method is suitable for industrial production.

Description

Technical Field

[0001] This invention relates to the field of traditional Chinese medicine preparation technology, and in particular to a nano-dispersed porous coated heat-clearing and detoxifying granule and its preparation method. Background Technology

[0002] In the field of medical formulations, especially oral preparations containing active ingredients derived from animals, plants, and minerals, they are widely used in clinical symptomatic treatments such as clearing heat and detoxifying due to their convenient administration and wide applicability. Their efficacy, safety, and stability directly depend on core technological processes such as raw material processing, active ingredient extraction and dispersion, formulation shaping, and coating protection. However, existing technologies still have many key technical deficiencies in the preparation of these medical formulations, severely restricting the improvement of their medicinal value.

[0003] Chinese patent CN1215610A discloses a heat-clearing and detoxifying granule and its preparation method. The method involves extracting honeysuckle, scutellaria, gardenia, isatis root, rehmannia root, and scrophularia root by ethanol reflux, collecting the ethanol extract and residue; decocting the remaining six herbs containing gypsum with water, collecting the decoction; combining all the residue and decocting again with water, summarizing the three decoctions, filtering and concentrating, adding ethanol, stirring and letting stand, combining the supernatant with the ethanol extract, recovering the ethanol and concentrating to form a clear paste, adding water to the supernatant, further concentrating, adding sucrose powder and dextrin in proportion, mixing, granulating, drying, and sizing to produce the finished product. This patent lacks a differentiated processing strategy for different types of raw materials, adopting a simple "classified mixing processing" model. Plant-based medicinal materials are processed uniformly using only two methods: "ethanol extraction" or "water decoction," without designing specific processes based on the differences in cell wall structure and solubility of active ingredients among individual herbs. Mineral raw material gypsum is also conventionally decocted with plant-based medicinal materials without optimizing particle size through specialized pulverization processes, resulting in insufficient release of active ingredients and underutilization of the raw material's medicinal value. The extraction process is simplistic and lacks synergistic design, relying solely on traditional methods like ethanol reflux and water decoction without considering the characteristics of the raw materials to construct a synergistic extraction system, leading to low dissolution efficiency of different types of active ingredients. Post-extraction processing involves only simple concentration and settling, without efficient dispersion steps such as homogenization and grinding, causing active ingredients to easily aggregate and resulting in poor dispersion uniformity. This leads to uneven distribution of active ingredients in subsequent formulations, potentially causing unstable efficacy. The excipients were conventional inert types, using only sucrose powder and dextrin as excipients. No functional formulation matrix adapted to multiple active ingredients was constructed. The particles had a small specific surface area and insufficient dissolution channels, which restricted the dissolution rate and bioavailability of the active ingredients. No coating system was designed, and there was a lack of protection and controlled-release structure for the particles. As a result, the active ingredients were easily degraded and lost due to environmental factors such as temperature and humidity during storage and transportation. Furthermore, the precise controlled release of the drug could not be achieved, affecting the clinical application effect.

[0004] Chinese patent CN106620188B discloses a method for preparing heat-clearing and detoxifying granules. The method involves pounding buffalo horn into thin slices and dividing them into two parts. One part is ultra-finely pulverized for later use, while the other part is extracted by hydrothermal reflux. The residue is then boiled under pressure, and the reflux liquid and decoction are combined and concentrated into a paste. Gypsum is crushed into small pieces, Rehmannia glutinosa is sliced, and mixed with other medicinal materials such as Coptis chinensis, Scrophularia ningpoensis, and Forsythia suspensa. Hydrothermal reflux extraction is performed, and the filtrate is concentrated into a clear paste. The two clear pastes are combined, filtered, and concentrated. Ethanol is added, stirred, and allowed to stand. The supernatant is then concentrated, and excipients such as sucrose and dextrin, along with the prepared buffalo horn ultra-fine powder, are added. The mixture is granulated using a specialized granulator and boiled to obtain the finished product. The optimized process specifically improves the extraction methods of buffalo horn and other medicinal materials. However, this patent only designs a differentiated processing strategy of "partial ultra-fine pulverization and partial extraction" for buffalo horn; no specific processes are developed for the other raw materials. Plant-based medicinal materials were simply mixed without undergoing refined processing such as ultrafine grinding to account for differences in cell wall structure and the solubility of active ingredients. Gypsum, a mineral raw material, was merely crushed into small pieces without optimizing particle uniformity and specific surface area through specialized grinding processes. This resulted in insufficient release channels for the effective components from both types of raw materials, and their medicinal value was not fully realized. The extraction process lacked synergistic design for multiple types of raw materials. A single hot reflux extraction mode was used after mixing plant and mineral medicinal materials, without adjusting extraction conditions based on the dissolution characteristics of different components, leading to limited dissolution efficiency of some active ingredients. The dispersion process relied solely on conventional stirring, without incorporating efficient dispersion steps such as high-pressure homogenization and grinding. This resulted in active ingredients easily forming aggregates, making submicron-level dispersion difficult and leading to uneven distribution of effective components in the formulation, potentially affecting the stability of the drug's efficacy. The excipients used are only conventional inert excipients such as sucrose and dextrin. No functional matrix with high dispersibility and high dissolution potential has been constructed. The particles have a small specific surface area and insufficient dissolution channels, which restricts the dissolution rate and bioavailability of the active ingredients. No coating system design is involved, and there is a lack of dual protection and controlled release structure for the particles. As a result, the active ingredients are easily degraded and lost due to environmental factors such as temperature and humidity during storage and transportation. Furthermore, it is impossible to achieve precise controlled release of the drug efficacy, which makes it difficult to meet the clinical requirements for the stability and long-lasting effect of the formulation.

[0005] In summary, the aforementioned technical deficiencies result in low levels of performance in existing medical formulations in key indicators such as active ingredient extraction rate, dispersion uniformity, stability, and bioavailability. This prevents the full realization of the medicinal value of raw materials and fails to meet the core clinical requirements for medical formulations to be "precisely effective, safe and stable, and highly bioavailable." Therefore, it is urgent to optimize the preparation process of medical formulations, specifically address these deficiencies, and improve their medicinal performance and clinical application value. Summary of the Invention

[0006] To address the aforementioned problems, the present invention aims to provide a nano-dispersed porous coated heat-clearing and detoxifying granule and its preparation method. The preparation method of the nano-dispersed porous coated heat-clearing and detoxifying granule specifically includes the following steps: S001, buffalo horn is processed using a high-speed slicer to obtain buffalo horn slices, which are divided into two parts. One part is subjected to airflow pulverization and drying to obtain buffalo horn micron powder, and the other part is reserved. S002, take Coptis chinensis, Scrophularia ningpoensis, Lonicera japonica, Rehmannia glutinosa, Isatis indigotica, Forsythia suspensa, and Anemarrhena asphodeloides, pulverize them separately and mix them evenly to obtain ultrafine powder of plant medicinal materials, take gypsum and ball mill it, and after sieving, obtain gypsum powder. S003, take the prepared buffalo horn slices, add ultrapure water for hot reflux extraction, filter and collect the reflux liquid, collect the dregs, add ultrapure water for decoction, filter, collect the decoction, combine the reflux liquid and decoction for concentration treatment to obtain buffalo horn extract. S004, mix plant-based medicinal materials ultrafine powder and gypsum powder, add ultrapure water for hot reflux extraction, filter and collect the extract for concentration to obtain plant-based medicinal material extract, take the plant-based medicinal material extract, add buffalo horn extract and mix, add ultrapure water for homogenization, add polyethylene glycol 6000 and Tween 80, stir and then grind and vacuum concentrate to obtain submicron dispersed extract; S005, micronized sucrose, micronized dextrin, porous microcrystalline cellulose, and mannitol are subjected to three-dimensional mixing to obtain a porous excipient mixture. Submicron dispersion is diluted with ultrapure water, and povidone K30 is added and stirred to dissolve to obtain a spray. The porous excipient mixture is then granulated with buffalo horn micronized powder. During the granulation process, the spray is continuously sprayed in, and the wet particles are collected and dried to obtain a porous particle intermediate. S006, take calcium sulfate whiskers, add titanate coupling agent for pretreatment to obtain modified calcium sulfate whiskers, take hydroxypropyl methylcellulose and polyvinyl alcohol, add ultrapure water and stir to obtain a double network matrix solution, add modified calcium sulfate whiskers, povidone K30, polyethylene glycol 6000 and calcium chloride solution, stir and keep warm, then sieve to remove bubbles to obtain the main coating solution, take ethyl cellulose aqueous dispersion, add ultrapure water to dilute, stir evenly and let stand to remove bubbles to obtain an aqueous hydrophobic coating solution; S007, the porous particle intermediate is coated with a main coating layer. During the coating process, the main coating liquid is continuously sprayed in. After hot air drying, an aqueous hydrophobic coating liquid is sprayed in for coating. After hot air drying and cooling, the nano-dispersed porous coated heat-clearing and detoxifying particles are obtained.

[0007] The slices prepared in step S001 are 0.1~0.3 mm in size; the buffalo horn slices are divided into two parts, 0.2 parts and 0.8 parts respectively; the 0.2 parts of buffalo horn slices are subjected to air jet pulverization; the air jet pulverization conditions are 0.9 MPa, 30 ℃, air jet pulverization 3 times; the drying conditions are 40 ℃, -0.08 MPa, drying for 2 h.

[0008] In step S002, the mass ratio of Coptis chinensis, Scrophularia ningpoensis, Lonicera japonica, Rehmannia glutinosa, Isatis indigotica, Forsythia suspensa, and Anemarrhena asphodeloides is 1:5:5:10:10:5:5; the pulverization conditions are pulverization at 28000 r / min for 6 min; the ball milling conditions are adding zirconia balls with a ball-to-material ratio of 5:1 and pulverizing at 300 r / min for 1 h; and passing through a 200-mesh sieve.

[0009] In step S003, the mass-to-volume ratio of the buffalo horn slices to ultrapure water is 1:10; the conditions for hot reflux extraction are 0.2 m^3 / h, hot reflux extraction for 14 h at the 6th hour; the mass-to-volume ratio of the residue to ultrapure water is 1:6; the conditions for decoction are 1.8×10^5 Pa, 120 ℃, and decoction for 3 h; the conditions for concentration are 60 ℃, -0.09 MPa, and concentration for 2 h.

[0010] In step S004, the mass ratio of ultrafine plant medicinal material powder to gypsum powder is 41:20; the mass-to-volume ratio of the mixture to ultrapure water is 1:10; the hot reflux extraction conditions are 0.2 m^3 / h, hot reflux extraction for 150 min at the 30th min; the concentration treatment conditions are 60 ℃, -0.09 MPa concentration for 3 h; the mass ratio of plant medicinal material extract to buffalo horn extract is 4:1; the mass-to-volume ratio of the mixed extract to ultrapure water is 1:1; the homogenization treatment conditions are 80 MPa homogenization for 3 times; the amount of polyethylene glycol 6000 added is 0.2% of the weight of the homogenized liquid, and the amount of Tween 80 added is 0.1% of the weight of the homogenized liquid; the stirring conditions are 100 r / min, stirring for 15 min; the grinding treatment conditions are adding zirconia balls with a ball-to-material ratio of 8:1, grinding at 2500 r / min for 40 min; the vacuum concentration treatment conditions are 60 ℃, -0.09 MPa vacuum concentration for 2 h.

[0011] In step S005, the mass ratio of micronized sucrose, micronized dextrin, porous microcrystalline cellulose, and mannitol is 206:103:32:8, wherein the particle size of micronized sucrose and micronized dextrin is 50-100 μm, the particle size of porous microcrystalline cellulose is 20-50 μm, and the particle size of mannitol is 30-80 μm; the three-dimensional mixing conditions are 60 r / min for 20 min; the mass ratio of submicron dispersed extract to ultrapure water is 1:1; the amount of povidone K30 added is 0.5% of the weight of the diluent; the mass ratio of porous excipient mixture, buffalo horn micronized powder, and spray liquid is 109:1:52; the granulation conditions are inlet air temperature 95 ℃, outlet air temperature 53 ℃, atomization pressure 0.3 MPa, spray speed 12 mL / min, and compressed air flow rate 0.6 m^3 / min; the drying conditions are inlet air temperature 50 ℃ and air velocity 1.2 m^3 / min. Drying treatment at m / s for 30 min.

[0012] In step S006, the amount of titanate coupling agent added is 1.2% of the weight of calcium sulfate whiskers; the pretreatment conditions are 1000 r / min for 20 min; the mass ratio of hydroxypropyl methylcellulose to polyvinyl alcohol is 1:1; the mass-volume ratio of hydroxypropyl methylcellulose to ultrapure water is 1:16; the stirring conditions are 40 ℃ for 30 min; the volume-mass ratio of the dual-network matrix solution, modified calcium sulfate whiskers, povidone K30, polyethylene glycol 6000, and calcium chloride solution is 80:3:2:1:2, and the concentration of calcium chloride solution is 0.3%; the stirring and heat preservation conditions are 80 r / min and 40 ℃ for 20 min; degassing is performed by passing through a 100-mesh sieve; the mass-volume ratio of ethyl cellulose aqueous dispersion to ultrapure water is 1:1; after stirring evenly, the mixture is allowed to stand for 30 min to degas.

[0013] In step S007, the conditions for coating the main coating layer are: inlet air temperature 60 ℃, outlet air temperature 40 ℃, air velocity 0.8 m / s, atomization pressure 0.25 MPa, and spraying speed 8 mL / min; the mass-to-volume ratio of porous particle intermediate to main coating liquid is 7:2, and hot air drying is performed for 15 min; the mass-to-volume ratio of porous particle intermediate to aqueous hydrophobic coating liquid is 10:1; the conditions for coating the aqueous hydrophobic coating layer are: inlet air temperature 55 ℃, outlet air temperature 38 ℃, atomization pressure 0.3 MPa, spraying speed 6 mL / min, hot air drying for 20 min, and then cooling to room temperature; and passing through a 40-mesh sieve.

[0014] Compared with the prior art, the beneficial effects of the present invention are as follows: 1. This invention optimizes the raw material processing stage for medical formulations, laying a solid foundation for the pharmaceutical efficacy of the formulations. It breaks through the limitations of traditional "single-method processing" of medicinal materials, designing differentiated processing schemes for different raw materials to maximize their medicinal value. For buffalo horn, a graded processing strategy is adopted: one part is pulverized into micron-sized powder, retaining some of its original structure of active ingredients; the other part is extracted to obtain water-soluble active ingredients, achieving dual utilization of "solid-state retention and liquid-state extraction," avoiding component loss caused by single processing. For plant-based medicinal materials, ultra-micro pulverization technology is used to reduce particle size and increase specific surface area, allowing the cell walls of the medicinal materials to fully rupture, making it easier for the internal active ingredients to contact the extraction medium. For mineral medicinal materials such as gypsum, ball milling is used to ensure uniform and fine particle size while avoiding damage to the component structure caused by over-pulverization. This processing method solves the problem of insufficient release and low utilization rate of active ingredients caused by the "one-size-fits-all" approach in traditional raw material processing, laying a high-quality foundation for subsequent extraction and formulation. 2. This invention improves the utilization rate and uniformity of active ingredients in medical preparations through scientific extraction and component dispersion processes. By combining "synergistic extraction, efficient dispersion, and adjuvant regulation," the invention achieves full dissolution and uniform dispersion of active ingredients. First, ultrafine powder of plant-based medicinal materials and micro-powder of gypsum are synergistically extracted using hot reflux. The high specific surface area of ​​the ultrafine powder enhances extraction efficiency, while allowing the active ingredients from different types of raw materials to initially fuse during the extraction process. Subsequently, the clear extract of plant-based medicinal materials and clear extract of buffalo horn are mixed. Homogenization breaks up aggregated flocs or particles, and grinding further refines the dispersion system, achieving submicron-level dispersion of active ingredients. Furthermore, the addition of specific functional adjuvants optimizes the stability of the dispersion system, preventing the active ingredients from re-aggregating or precipitating in subsequent processes. Compared to traditional processes that simply mix ingredients after extraction, this technology not only improves the extraction rate of active ingredients but also solves the problems of uneven component dispersion and unstable efficacy in multi-component systems, ensuring that all active ingredients in the preparation can work synergistically. 3. This invention enhances the stability and bioavailability of medical preparations through rational excipient selection and innovative coating system design. It leverages the structural characteristics and composite combination of porous excipients to construct a particle matrix with high dispersibility and high dissolution potential. Excipients such as microcrystalline cellulose with porous structures are selected, and a three-dimensional mixing process ensures uniform compounding of the excipients, forming a well-developed porous excipient matrix. During granulation, a spray containing the active ingredient is uniformly sprayed onto a mixture of porous excipients and buffalo horn micron powder, allowing the active ingredient to adhere to the surface of the excipient particles and penetrate into the pores of the excipients. This porous structure design, on the one hand, increases the specific surface area of ​​the particles, providing ample channels for the subsequent dissolution of the active ingredient and solving the problem of slow dissolution rate in traditional particles; on the other hand, the porous structure buffers the influence of the external environment on the internal active ingredient, while creating favorable conditions for the uniform coating layer, improving the granulation stability and consistency. 4. This invention constructs a dual-protection and controlled-release structure consisting of a "main coating layer and an aqueous hydrophobic coating layer," while optimizing the coating layer performance through modified reinforcing materials. The main coating layer is based on a dual-network matrix solution, with the addition of calcium sulfate whiskers modified by a coupling agent. The modified calcium sulfate whiskers can form a strong composite structure with the dual-network matrix, improving the mechanical strength and stability of the main coating layer, effectively locking in the active ingredients inside the particles, and preventing loss or degradation due to humidity and temperature factors during storage and transportation. The aqueous hydrophobic coating layer is constructed using specific polymer materials, which can regulate the release rate of the active ingredients in vivo, avoiding fluctuations in blood drug concentration caused by rapid release of the active ingredients, and achieving a long-lasting and stable onset of action. Compared with traditional single coating layers, this composite coating system not only solves the problem of insufficient stability of the active ingredients, but also achieves precise control of drug release. At the same time, the aqueous coating system is more in line with environmental protection and drug safety requirements, overcoming the residual risks that may be caused by traditional organic solvent coatings. Detailed Implementation

[0015] The present invention will be further described below with reference to specific embodiments.

[0016] Example A method for preparing nano-dispersed porous coated heat-clearing and detoxifying granules specifically includes the following steps: S001, 200 g of buffalo horn was processed using a high-speed slicer to obtain buffalo horn slices, which were then divided into two parts. 40 g of the buffalo horn slices were subjected to airflow pulverization at 0.9 MPa and 30 ℃ three times, and then dried at 40 ℃ and -0.08 MPa for 2 h to obtain buffalo horn micron powder. 160 g of the buffalo horn slices were reserved for later use. S002, take 10 g of Coptis chinensis, 50 g of Scrophularia ningpoensis, 50 g of Lonicera japonica, 100 g of Rehmannia glutinosa, 100 g of Isatis indigotica, 50 g of Forsythia suspensa, and 50 g of Anemarrhena asphodeloides. Grind them separately at 28000 r / min for 6 min and mix them evenly to obtain ultrafine powder of plant medicinal materials. Take 200 g of gypsum and add 1000 g of zirconia balls. Grind at 300 r / min for 1 h and pass through a 200 mesh sieve to obtain gypsum powder. S003, take 160 g of prepared buffalo horn slices and add 1600 mL of ultrapure water, reflux extract for 14 h at 0.2 m^3 / h for 6 hours, filter and collect the reflux liquid, collect 160 g of the residue and add 960 mL of ultrapure water, decoct at 120 ℃ for 3 h at 1.8×10^5 Pa, filter and collect the decoction, combine the reflux liquid and the decoction, concentrate at 60 ℃ and -0.09 MPa for 2 h to obtain buffalo horn extract; S004, 410 g of ultrafine plant-based medicinal material powder and 200 g of gypsum powder were mixed, 6100 mL of ultrapure water was added, and the mixture was extracted by hot reflux for 150 min at 0.2 m^3 / h for 30 min. The extract was collected by filtration and concentrated at 60 ℃ and -0.09 MPa for 3 h to obtain a clear extract of plant-based medicinal material. 500 g of the clear extract of plant-based medicinal material was taken and mixed with 125 g of buffalo horn extract. 625 mL of ultrapure water was added, and the mixture was homogenized three times at 80 MPa. 2.5 g of polyethylene glycol 6000 and 1.25 g of Tween 80 were added, and the mixture was stirred at 100 r / min for 15 min. 10030 g of zirconia balls were added, and the mixture was ground at 2500 r / min for 40 min. The mixture was then concentrated under vacuum at 60 ℃ and -0.09 MPa for 2 h to obtain a submicron dispersed extract. S005, take 206 g of micronized sucrose, 103 g of micronized dextrin, 32 g of porous microcrystalline cellulose, and 8 g of mannitol, and mix them in three dimensions at 60 r / min for 20 min to obtain a porous excipient mixture. Take 700 g of submicron dispersion extract, add 700 g of ultrapure water to dilute, add 7 g of povidone K30 and stir to dissolve to obtain a spray. Take 327 g of the porous excipient mixture, add 3 g of buffalo horn micronized powder, and continuously spray 156 g of spray during the granulation process with an inlet air temperature of 95 ℃, an outlet air temperature of 53 ℃, an atomization pressure of 0.3 MPa, a spray speed of 12 mL / min, and a compressed air flow rate of 0.6 m^3 / min. Collect the wet granules, and dry them for 30 min with an inlet air temperature of 50 ℃ and a wind speed of 1.2 m / s to obtain a porous granule intermediate. S006, take 9 g of calcium sulfate whiskers, add 0.108 g of titanate coupling agent, pre-treat at 1000 r / min for 20 min to obtain modified calcium sulfate whiskers, take 15 g of hydroxypropyl methylcellulose and 15 g of polyvinyl alcohol, add 240 mL of ultrapure water, stir at 40℃ for 30 min to obtain a double network matrix solution, take 160 mL of the double network matrix solution, add 6 g of modified calcium sulfate whiskers, 4 g of povidone K30, 2 g of polyethylene glycol 6000 and 4 g of 0.3% calcium chloride solution, stir at 80 r / min and 40 ℃ for 20 min, pass through a 100 mesh sieve to remove bubbles to obtain the main coating solution, take 35 g of ethyl cellulose aqueous dispersion, add 35 mL of ultrapure water to dilute, stir evenly and let stand for 30 min to remove bubbles to obtain an aqueous hydrophobic coating solution; S007, 294 g of porous particle intermediate was sprayed with 84 mL of main coating liquid during the coating process, with an inlet air temperature of 60 ℃, an outlet air temperature of 40 ℃, an air velocity of 0.8 m / s, an atomization pressure of 0.25 MPa, and a spraying speed of 8 mL / min. After hot air drying for 15 min, 29.4 mL of aqueous hydrophobic coating liquid was sprayed with 55 ℃ inlet air temperature, an outlet air temperature of 38 ℃, an atomization pressure of 0.3 MPa, and a spraying speed of 6 mL / min. After hot air drying for 20 min, it was cooled to room temperature and passed through a 40-mesh sieve to obtain the coated particle intermediate, which was recorded as the test sample.

[0017] Comparative Example 1 A method for preparing nano-dispersed porous coated heat-clearing and detoxifying granules lacking raw material differentiation treatment specifically includes the following steps: The difference from the example is that, in S001, 200 g of buffalo horn is processed with a high-speed slicer to obtain buffalo horn slices, which are then pulverized three times with airflow at 0.9 MPa and 30 ℃, and dried at 40 ℃ and -0.08 MPa for 2 h to obtain buffalo horn micron powder; S002, take 10 g of Coptis chinensis, 50 g of Scrophularia ningpoensis, 50 g of Lonicera japonica, 100 g of Rehmannia glutinosa, 100 g of Isatis indigotica, 50 g of Forsythia suspensa, and 50 g of Anemarrhena asphodeloides, pulverize them separately at 10000 r / min for 5 min and mix them evenly to obtain plant medicinal powder. Take 200 g of gypsum, pulverize it for 1 h, and pass it through a 200 mesh sieve to obtain gypsum powder. Replace the buffalo horn slices in S003 with buffalo horn micron powder; replace the ultrafine plant medicine powder in S004 with plant medicine powder; replace the gypsum powder in S004 with gypsum powder; the remaining steps are the same as in the example, thus obtaining control product 1.

[0018] Comparative Example 2 A method for preparing nano-dispersed porous coated heat-clearing and detoxifying granules using traditional techniques includes the following steps: Take 200 g of buffalo horn, 10 g of Coptis chinensis, 50 g of Scrophularia ningpoensis, 50 g of Lonicera japonica, 100 g of Rehmannia glutinosa, 100 g of Isatis indigotica, 50 g of Forsythia suspensa, 50 g of Anemarrhena asphodeloides, and 200 g of gypsum. Mix them evenly and pulverize them at 10,000 r / min for 5 min. Pass the mixture through a 100-mesh sieve and collect the powder. Add 6480 mL of ultrapure water and soak for 30 min. Bring to a boil over high heat, then simmer over low heat for 1.5 h. While still hot, pass the mixture through a 200-mesh sieve and collect the first decoction. Add 4860 mL of ultrapure water to the dregs, bring to a boil over high heat, then simmer over low heat for 1.5 h. Filter and collect the second decoction. Combine the two decoctions and pass them through a 200-mesh sieve to obtain the total decoction. The total decoction was concentrated at 5℃ and -0.08 MPa for 4 h to obtain a clear extract. 300 g of sucrose and 150 g of dextrin were mixed evenly and stirred at 60 r / min for 15 min. Granulation was performed using a 16-mesh sieve. The wet granules were collected and dried at an inlet air temperature of 55 ℃ and a drying air velocity of 0.8 m / s for 60 min. After cooling, the granules were passed through a 16-mesh sieve to obtain reference standard 2.

[0019] Comparative Example 3 A method for preparing nano-dispersed porous coated heat-clearing and detoxifying granules lacking synergistic extraction and efficient dispersion processes specifically includes the following steps: The difference from the example is that, in S004, 410 g of ultrafine plant powder is added to 4100 mL of ultrapure water, and extracted by hot reflux for 150 min at 0.2 m^3 / h for 30 min. The plant extract is collected by filtration and concentrated at 60 ℃ and -0.09 MPa for 3 h to obtain plant extract. 200 g of gypsum powder is mixed and added to 200 mL of ultrapure water. The extract is extracted by hot reflux for 150 min at 0.2 m^3 / h for 30 min. The gypsum extract is collected by filtration and concentrated at 60 ℃ and -0.09 MPa for 3 h to obtain gypsum extract. All plant extracts are added and mixed to obtain plant-gypsum mixed extract. 500 g of plant-gypsum mixed extract is mixed with 125 g of buffalo horn extract, and 625 mL of ultrapure water is added. The mixture is stirred at 100 r / min for 15 min and then concentrated under vacuum at 60 ℃ and -0.09 MPa for 2 h to obtain extract. Replace the submicron-dispersed extract in S005 with the clear extract; the remaining steps are the same as in the example, and control product 3 is obtained.

[0020] Comparative Example 4 A method for preparing nano-dispersed porous coated heat-clearing and detoxifying granules lacking a porous excipient system specifically includes the following steps: The difference from the example is that, in S005, 206 g of micronized sucrose, 103 g of micronized dextrin, 32 g of microcrystalline cellulose, and 8 g of mannitol were mixed at 60 r / min for 10 min to obtain an excipient mixture. 700 g of submicron dispersed extract was diluted with 700 g of ultrapure water, and 7 g of povidone K30 was added and stirred to dissolve to obtain a spray. 327 g of the excipient mixture was taken, and 3 g of buffalo horn micronized powder was added. The inlet air temperature was 95 ℃, the outlet air temperature was 53 ℃, the atomization pressure was 0.3 MPa, the spraying speed was 12 mL / min, and the compressed air flow rate was 0.6 m^3 / min. During the granulation process, 156 g of spray was continuously sprayed, the wet granules were collected, and the inlet air temperature was 50 ℃ and the air velocity was 1.2 m / s for 30 min to obtain a granular intermediate. The remaining steps were the same as in the example, thus obtaining control product 4.

[0021] Comparative Example 5 A method for preparing nano-dispersed porous coated heat-clearing and detoxifying granules lacking a dual coating system specifically includes the following steps: The difference from the example is that, in S006, only the main coating liquid is prepared, and the aqueous hydrophobic coating liquid is not prepared; in S007, 294 g of porous particle intermediate is continuously sprayed with 84 mL of main coating liquid during the coating process of the main coating layer, with an inlet air temperature of 60 ℃, an outlet air temperature of 40 ℃, an air velocity of 0.8 m / s, an atomization pressure of 0.25 MPa, and a spraying speed of 8 mL / min. After hot air drying for 15 min, it is cooled to room temperature and passed through a 40-mesh sieve to obtain the coated particle intermediate; the remaining steps are the same as in the example, thus obtaining control product 5.

[0022] Experimental Example 1 This experimental example determines the extraction rate of active ingredients in the test sample of the example, control 1 of comparative example 1, and control 2 of comparative example 2, specifically including the following steps: 1. Preparation of stock solution Weigh 10 mg of chlorogenic acid standard, add 8 mL of methanol, sonicate at 30 ℃ and 500 W for 10 min, cool to room temperature, transfer the solution to a 10 mL brown volumetric flask, dilute to the mark with methanol, shake well, and filter through a 0.45 μm organic phase filter membrane to obtain chlorogenic acid stock solution. Weigh 10 mg of baicalin standard, add 1 mL of ethanol and 7 mL of methanol, heat in a 40 ℃ water bath for 5 min, sonicate at 30 ℃ and 500 W for 10 min, cool to room temperature, transfer the solution to a 10 mL brown volumetric flask, dilute to the mark with methanol, shake well, and filter through a 0.45 μm organic phase filter membrane to obtain baicalin stock solution; Weigh 10 mg of forsythoside standard, add 8 mL of methanol, sonicate at 30 ℃ and 500 W for 10 min, cool to room temperature, transfer the solution to a 10 mL brown volumetric flask, dilute to the mark with methanol, shake well, filter through a 0.45 μm organic phase filter membrane to obtain forsythoside stock solution. Weigh 10 mg of cholic acid standard, add 8 mL of methanol, sonicate at 30 ℃ and 500 W for 10 min, cool to room temperature, transfer the solution to a 10 mL brown volumetric flask, dilute to the mark with methanol, shake well, and filter through a 0.45 μm organic phase filter membrane to obtain cholic acid stock solution. Weigh 10 mg of deoxycholic acid standard, add 8 mL of methanol, sonicate at 30 ℃ and 500 W for 10 min, cool to room temperature, transfer the solution to a 10 mL brown volumetric flask, dilute to the mark with methanol, shake well, and filter through a 0.45 μm organic phase filter membrane to obtain deoxycholic acid stock solution. Transfer 0.05 mL, 0.1 mL, 0.2 mL, 0.3 mL, 0.5 mL, and 1 mL of chlorogenic acid stock solution, baicalin stock solution, forsythoside stock solution, cholic acid stock solution, and deoxycholic acid stock solution to 10 mL volumetric flasks, respectively, dilute to the mark with methanol, and shake well to obtain the mixed standard working solution. 2. Preparation of raw material mixed powder Weigh out 2 g of buffalo horn powder, 0.1 g of Coptis chinensis powder, 0.5 g of Scrophularia ningpoensis powder, 0.5 g of Lonicera japonica powder, 1 g of Rehmannia glutinosa powder, 1 g of Isatis indigotica powder, 0.5 g of Forsythia suspensa powder, 0.5 g of Anemarrhena asphodeloides powder, and 2 g of gypsum powder, and mix them evenly to obtain the raw material mixed powder. 3. Sample processing Weigh 2 g of raw material mixed powder, 2 g of test sample, 2 g of reference 1, and 2 g of reference 2 respectively, and place them in 100 mL stoppered conical flasks. Add 50 mL of methanol, weigh, and extract by ultrasonication at 30 ℃ and 500 W for 60 min. Cool to room temperature, weigh, and replenish the lost weight with methanol. Shake well, let stand for 30 min, take 10 mL of supernatant, centrifuge at 10000 r / min for 10 min, take the supernatant, filter through a 0.45 μm organic phase filter membrane, and collect the filtrate. The filtrate obtained from the raw material mixed powder is used as the raw material solution, and the filtrates obtained from the test sample, reference 1, and reference 2 are used as the formulation solution. 4. Measurement The instrumental conditions for chlorogenic acid and forsythoside were as follows: C18 column; mobile phase A: acetonitrile; mobile phase B: 0.1% phosphoric acid solution; flow rate: 1 mL / min; gradient elution: 0–10 min, 90%–80% of phase B; 10–20 min, 80%–70% of phase B; 20–30 min, 70%–60% of phase B; column temperature: 30 ℃; detection wavelength: 327 nm for chlorogenic acid; detection wavelength: 277 nm for forsythoside; injection volume: 20 μL. The instrumental conditions for baicalin were as follows: C18 column; mobile phase: methanol-0.1% phosphoric acid water (40:60 v / v); flow rate: 1 mL / min; run time: 20 min; column temperature: 30 ℃; detection wavelength: 280 nm; injection volume: 20 μL. The instrument conditions for cholic acid and deoxycholic acid were as follows: C18 column; mobile phase: methanol-water (75:25 v / v); flow rate: 1 mL / min; run time: 15 min; column temperature: 35 ℃; detection wavelength: 208 nm; injection volume: 20 μL.

[0023] A standard curve was plotted with the concentration of the mixed standard working solution on the x-axis and the corresponding peak area on the y-axis. The average value was taken to obtain the concentrations of chlorogenic acid, baicalin, forsythoside, cholic acid, and deoxycholic acid in the raw material solution and each formulation solution. The total content of each active ingredient in the raw material was calculated by multiplying the concentration of each component in the raw material solution by the final volume of the raw material solution and dividing by a conversion factor of 1000 units. The total content of each active ingredient in the raw material was calculated by multiplying the total amount of raw material used in the example by 810 g and dividing by the amount of raw material mixed powder sampled by 2 g. The total content of each active ingredient in the formulation was calculated by multiplying the concentration of each component in the formulation solution by the final volume of the formulation solution and dividing by a conversion factor of 1000 units and multiplying by the final actual total amount of each formulation (test sample, reference 1, and reference 2) and dividing by the amount of formulation sampled by 2 g. The total content of each active ingredient in the formulation was calculated by dividing the total content of each active ingredient in the raw material by the total content of each active ingredient in the formulation. The arithmetic mean of the extraction rates of each component was calculated to obtain the total extraction rate. The results are shown in Table 1.

[0024] Table 1 Results of total extraction rate

[0025] Table 1 shows that different preparation processes affect the total extraction rate of the effective components of the heat-clearing and detoxifying granules. The example using the optimized nano-dispersed porous coating process had the highest total extraction rate, reaching 54.7%; Comparative Example 1, using a simplified process lacking differentiated raw material treatment, had a total extraction rate of 41.8%, which was 12.9% lower than the example; Comparative Example 2, using the traditional decoction and granulation process, had the lowest total extraction rate, at only 31.7%, which was 23.0% lower than the example.

[0026] The embodiment employs a multi-dimensional optimization design, including differentiated raw material treatment (buffalo horn air-jet milling into micronized powder and hot reflux, decoction extraction, ultra-fine milling of plant-based medicinal materials, and fine milling assisted by gypsum and zirconia balls), submicron dispersion treatment (high-pressure homogenization and grinding), porous excipient mixing and granulation, double-network primary coating, and water-based hydrophobic coating, etc., to maximize the dissolution, retention and extraction of active ingredients (chlorogenic acid, baicalin, forsythoside, cholic acid, deoxycholic acid, etc.), thus achieving the highest total extraction rate.

[0027] Comparative Example 1 only lacked "differentiated raw material processing". All buffalo horn was air-jet pulverized, plant-based medicinal materials were conventionally pulverized, and gypsum was ordinaryly pulverized. No extraction scheme was designed for the characteristics of different raw materials, resulting in insufficient release of effective ingredients and a significantly lower extraction rate compared to the Example.

[0028] Comparative Example 2 uses traditional mixed decoction and conventional granulation processes, without modern optimization methods such as ultrafine grinding, targeted extraction, nano-dispersion, and porous coating. The effective ingredients are easily lost during the decoction process, and it is difficult to fully release them after the granules are formed. Therefore, the total extraction rate is the lowest and the difference from the example is the greatest.

[0029] In summary, the optimized nano-dispersed porous coating process of the embodiments, through improvements in core technologies such as raw material differentiation, ultrafine pulverization, and submicron dispersion, improved the total extraction rate of effective components in the heat-clearing and detoxifying granules. In contrast, Comparative Example 2, using a traditional process, and Comparative Example 1, which lacked key optimization steps, both failed to achieve efficient extraction of effective components. This indicates that process design, especially the application of raw material differentiation and modern dispersion and coating technologies, is crucial for improving the extraction rate of effective components in this type of granule.

[0030] Experiment Example 2 This experimental example determines the uniformity of the dispersion of the active ingredient in the test sample of Example 1, Comparative Example 2 (Reference 2), and Comparative Example 3 (Reference 3), specifically including the following steps: 1. Physical particle size distribution determination Take 600 mL of pH 6.8 phosphate buffer, add 0.3 mL of Tween 80, and degas by sonication at 300 W for 30 min to obtain the dispersion medium; Weigh 0.5 g of the test sample, 0.5 g of reference standard 2, and 0.5 g of reference standard 3 respectively, add 30 mL of dispersion medium, vortex for 1 min, sonicate at 300 W for 10 min, and take out and shake once every 2 min during the process. Transfer the solution to a 50 mL brown volumetric flask, dilute to the mark with dispersion medium, and shake well to obtain the test dispersion. Laser particle size analysis was performed with stirring at 2000 r / min and online ultrasonication at 100 W. Each sample was measured three times consecutively, with each measurement lasting 10 s. The particle refractive index was 1.53, and the refractive index of the dispersion medium was 1.33. Record the D10, D50, and D90 particle size distribution parameters of each dispersion to be tested. Calculate the span by the ratio of the difference between D90 and D10 to D50. The measurement results are shown in Table 2.

[0031] 2. Determination of chemical content uniformity Weigh 10 mg of chlorogenic acid standard, add 80 mL of methanol, sonicate at 30 ℃ and 500 W for 10 min, cool to room temperature, transfer the solution to a 100 mL brown volumetric flask, dilute to the mark with methanol, shake well, filter through a 0.45 μm organic phase filter membrane to obtain the stock solution, transfer 2 mL of the stock solution to a 10 mL brown volumetric flask, dilute to the mark with methanol, shake well to obtain the standard working solution; Ten portions of each of the following samples were randomly weighed from the same batch of particles: 0.5 g of the test sample, 0.5 g of reference standard 2, and 0.5 g of reference standard 3. Each sample was placed in a 50 mL stoppered conical flask, 25 mL of methanol was added, and the samples were weighed. The samples were then extracted by ultrasonication at 30 °C and 500 W for 30 min. After cooling to room temperature, the samples were weighed again. The weight loss was made up with methanol, and the samples were shaken well. 5 mL of the supernatant was taken and centrifuged at 10000 r / min for 10 min. The supernatant was then filtered through a 0.45 μm organic phase filter membrane, and the filtrate was collected as the test solution. The instrument conditions were as follows: a C18 column; mobile phase A was acetonitrile, and mobile phase B was 0.1% phosphoric acid solution; the flow rate was 1 mL / min; gradient elution was used: 0–10 min, 90%–80% of phase B; 10–20 min, 80%–70% of phase B; 20–30 min, 70%–60% of phase B; column temperature was 30 ℃; detection wavelength was 327 nm; and the injection volume was 20 μL. The chlorogenic acid content of the test sample, reference 2, and reference 3 was calculated by multiplying the peak area ratio of the test solution to the standard working solution by the concentration of the standard working solution (20 μg / mL), the extraction volume of the test sample (25 mL), dividing by the conversion factor of 1000 units, and dividing by the sample amount of the test solution (0.5 g). The relative standard deviation of the chlorogenic acid content in 10 test samples, reference 2, and reference 3 was also calculated. The results are shown in Table 2.

[0032] Table 2 Results of the determination of the dispersion uniformity of the active ingredients

[0033] As shown in Table 2, the physical particle size distribution uniformity of the example was the best, while that of the traditional process was the worst. The span of the example was only 1.13, the smallest among the three samples, indicating that its particle size distribution was highly concentrated and the nano-dispersion effect was the best. The span of Comparative Example 2, which uses the traditional process, reached 2.55, which is 2.26 times that of the example, indicating that the particle size difference of the particles prepared by the traditional mixing, pulverizing, and simple decoction process was large and the dispersibility was extremely poor. The span of Comparative Example 3, which lacked the synergistic extraction and efficient dispersion process, was 1.63, which was between that of the example and Comparative Example 2 and larger than that of the example. This indicates that the synergistic extraction of plant medicinal materials and gypsum by synergistic hot reflux extraction and the efficient dispersion of homogenization, grinding and other steps are the key processes to improve the particle size distribution uniformity. Without this process, the concentration of particle size distribution decreased significantly.

[0034] The uniformity and stability of the active ingredient content in the examples far exceeded that of the control samples. The relative standard deviation of the chlorogenic acid content in the examples was only 0.31%, demonstrating that the active ingredient was extremely uniformly distributed in the particles and the product quality was highly consistent. The relative standard deviation of the traditional process in Comparative Example 2 was as high as 1.38%, which was 4.45 times that of the examples, indicating that the traditional process could not guarantee the uniform distribution of the active ingredient in the particles and that the quality fluctuated greatly within batches. The relative standard deviation of Comparative Example 3, which lacked the key process, was 0.60%, which was better than that of Comparative Example 2 of the traditional process, but was still 1.94 times that of the examples. This verified that the synergistic extraction and efficient dispersion process can promote the full release and uniform mixing of the active ingredient and reduce the content difference.

[0035] The embodiment uses a step-by-step process of buffalo horn air-flow pulverization and hot reflux, decoction extraction, ultra-fine pulverization of plant-based medicinal materials, and synergistic hot reflux extraction. Homogenization and grinding introduce efficient dispersion steps, and the excipient compatibility is optimized. At the same time, it avoids the "one-pot cooking" of traditional processes and the key process deficiencies of Comparative Example 3. Ultimately, it achieves the dual advantages of "concentrated particle size distribution and uniform content of effective ingredients". In contrast, the traditional process of Comparative Example 2 and the process defects of Comparative Example 3 directly lead to a decrease in dispersion uniformity.

[0036] In summary, the stepwise extraction, synergistic dispersion, precise granulation, and coating pretreatment process of the embodiments can effectively improve the physical dispersion uniformity and the consistency of effective ingredient content of the heat-clearing and detoxifying granules. Its product quality stability is far superior to that of Comparative Example 2 with traditional process and Comparative Example 3 with missing key process.

[0037] Experimental Example 3 This experimental example conducts stability tests on the test sample of Example 1, Control 2 of Comparative Example 2, Control 4 of Comparative Example 4, and Control 5 of Comparative Example 5, specifically including the following steps: The test sample, reference 2, reference 4, and reference 5 were packaged into aluminum-plastic composite film bags at a rate of 20 g per bag and then heat-sealed. The packaged samples were placed in an environment of 40 ℃ and 75% RH, and samples were taken at 0 months, 1 month, 3 months and 6 months. Three bags of each sample were taken each time to accelerate the stability. The packaged samples were placed in an environment of 25 ℃ and 60% RH, and samples were taken at 0 months, 6 months and 12 months. Three bags of each sample were taken each time to determine the long-term stability. The extracted samples were immediately opened and mixed thoroughly. Following the methods described in "1. Preparation of the stock solution", "3. Sample processing", and "4. Determination" in Experiment Example 1, the accelerated stability and long-term stability samples were determined. The contents of chlorogenic acid, baicalin, and cholic acid in the samples at each time point were measured. The retention rate of the effective components was calculated by dividing the component content at a certain time point by the component content at 0 months. The arithmetic mean of the extraction rates of each component was calculated to obtain the total retention rate. The results are shown in Table 3.

[0038] Table 3 Results of stability tests

[0039] As can be seen from Table 3, for accelerated stability, the total retention rate of the Examples was the highest at all time points, reaching 95.44% at 1 month and still maintaining 87.82% at 6 months, with the smallest decrease. The Comparative Example 2 with the traditional process performed the worst, with a total retention rate of only 70.18% at 6 months, and the fastest decrease. The total retention rates of Comparative Example 4, which lacked the porous excipient system, and Comparative Example 5, which lacked the double coating system, were in between, at 80.53% and 77.90% respectively at 6 months, both lower than those of the Examples.

[0040] In terms of long-term stability, the example also maintained its lead, with a total retention rate of 89.52% over 12 months; Comparative Example 2 was still the lowest, with only 74.82% over 12 months; Comparative Examples 4 and 5 had total retention rates of 84.58% and 82.27% over 12 months, respectively, which were still lower than the example.

[0041] In summary, the embodiments improved the retention of active ingredients and achieved stability far exceeding that of Comparative Example 2, which uses a traditional process, through the optimization of the entire process including raw material differentiation treatment, submicron dispersion, porous excipient granulation, dual-network primary coating, and aqueous hydrophobic coating. In contrast, the processes of Comparative Example 4, which lacked a porous excipient system, or Comparative Example 5, which lacked a dual coating system, resulted in a decrease in the retention rate of active ingredients due to insufficient key stability assurance links. This demonstrates the crucial role of multi-dimensional process optimization in improving the stability of granules.

[0042] Experiment Example 4 This experimental example performs in vitro dissolution determination on the test sample of Example 1, Control 2 of Comparative Example 2, and Control 4 of Comparative Example 4, specifically including the following steps: Weigh 10 mg of chlorogenic acid standard, add 80 mL of methanol, sonicate at 30 ℃ and 500 W for 10 min, cool to room temperature, transfer the solution to a 100 mL brown volumetric flask, dilute to the mark with methanol, shake well, filter through a 0.45 μm organic phase filter membrane to obtain the stock solution. Transfer 0.01 mL, 0.05 mL, 0.1 mL, 0.5 mL, 1 mL, and 2 mL of the stock solution into 10 mL volumetric flasks, respectively, dilute to the mark with methanol, and shake well to obtain the standard working solution; Weigh 5 g of the test sample, 5 g of reference standard 2, and 5 g of reference standard 4 respectively, and place them in 200 mL stoppered conical flasks. Add 100 mL of methanol, weigh, and extract by ultrasonication at 30 ℃ and 500 W for 60 min. Cool to room temperature, weigh, and replenish the lost weight with methanol. Shake well, let stand for 30 min, take 10 mL of supernatant, centrifuge at 10000 r / min for 10 min, take the supernatant, filter through a 0.45 μm organic phase filter membrane, and collect the filtrate, which is the sample to be tested. Weigh 5 g of the test sample, 5 g of reference standard 2, and 5 g of reference standard 4 respectively. Dissolve them using the paddle method at 50 rpm, 37 ℃, and 900 mL of pH 6.8 phosphate buffer solution. Take 5 mL samples at 5, 15, 30, 60, 120, and 240 min each time. Filter the samples immediately through a 0.45 μm aqueous filter membrane and collect the filtrate to obtain the dissolution solution at each time point. The instrument conditions were as follows: a C18 column; mobile phase A was acetonitrile, and mobile phase B was 0.1% phosphoric acid solution; the flow rate was 1 mL / min; gradient elution was used: 0–10 min, 90%–80% of phase B; 10–20 min, 80%–70% of phase B; 20–30 min, 70%–60% of phase B; column temperature was 30 ℃; detection wavelength was 327 nm; and the injection volume was 20 μL. A standard curve was plotted with the concentration of the standard working solution on the x-axis and the corresponding peak area on the y-axis to obtain the chlorogenic acid concentration in the dissolution medium and the chlorogenic acid concentration in the test sample at each time point. The total mass of chlorogenic acid in the test sample was calculated by multiplying the chlorogenic acid concentration in the test sample by the fixed volume. The cumulative dissolution rate was calculated by multiplying the chlorogenic acid concentration at a certain time point by the volume of the dissolution medium and dividing by the total mass of chlorogenic acid in the test sample. The results are shown in Table 4.

[0043] Table 4 Results of in vitro dissolution test

[0044] As shown in Table 4, the in vitro dissolution of the sample in the examples exhibited a synergistic characteristic of rapid dissolution and efficient release, with its cumulative dissolution rate higher than that of other control groups at all time points. In the initial 5 minutes of dissolution, the cumulative dissolution rate of the active ingredient reached 25.0%, demonstrating excellent dissolution initiation efficiency. At 15 minutes, the dissolution rate rapidly climbed to 52.0%, reaching 68.0%, 79.0%, and 87.0% at 30, 60, and 120 minutes, respectively, showing a steady increasing trend. By 240 minutes, the cumulative dissolution rate reached 92.5%, with near-complete release of the active ingredient, without any burst release or dissolution lag, exhibiting an ideal dissolution kinetic curve. This excellent performance is attributed to the synergistic optimization of the process system: ultrafine pulverization technology improved the specific surface area of ​​the medicinal materials and the dispersion of the active ingredient; the porous excipient system constructed efficient dissolution channels; double coating technology enabled the regulation of the dissolution rhythm; and the combined efficient extraction process of hot reflux-decoction ensured the full dissolution and stable release of the active ingredient.

[0045] The in vitro dissolution performance of Comparative Example 2, using the traditional process, was inferior to that of the Example, exhibiting typical characteristics of slow dissolution rate and incomplete release. The cumulative dissolution rate was only 7.5% at 5 min, and 15.0%, 26.3%, 37.5%, and 52.5% at 15, 30, 60, and 120 min, respectively, remaining low throughout the process. At 240 min, the cumulative dissolution rate was only 67.5%, with the effective component release rate less than 70%, indicating significant defects in the traditional process: conventional pulverization methods resulted in larger particle sizes and smaller specific surface areas, leading to greater dissolution resistance; the traditional soaking-decoction extraction mode failed to fully release the effective components within the medicinal materials, and the lack of porous excipients and coating optimization limited the diffusion and release of the effective components, ultimately resulting in low dissolution efficiency and completeness.

[0046] The in vitro dissolution of Comparative Example 4, lacking the porous excipient system, exhibited a delayed initial dissolution but complete release in the later stages. At 5 min, the cumulative dissolution rate was 12.0%, lower than the 25.0% of the Example; at 15 min, 30 min, 60 min, and 120 min, the rates were 35.0%, 50.0%, 68.0%, and 80.0%, respectively. The initial dissolution rate was consistently lower than that of the Example, demonstrating a significant dissolution initiation lag effect. However, with prolonged dissolution time, the cumulative dissolution rate reached 92.0% at 240 min, essentially consistent with the 92.5% of the Example. This indicates that the core function of the porous excipient is to construct channels for the rapid dissolution of the active ingredient. Its absence directly leads to a decrease in initial dissolution efficiency, but has no impact on the final release amount of the active ingredient. Sufficient release can be achieved later through the gradual diffusion of the active ingredient in the dissolution medium.

[0047] In summary, the embodiments achieved the ideal effect of "rapid start-up, stable release, and full dissolution" of the active ingredient through the optimization of the entire process chain of "ultra-micron pulverization - efficient extraction - submicron dispersion - porous excipient loading - dual coating regulation," which is superior to the traditional process and the control group lacking key process modules. This optimized process provides reliable technical support for improving the in vitro dissolution performance of heat-clearing and detoxifying granules, thereby improving the bioavailability of the formulation. The scientific nature and rationality of its process design have been fully verified by in vitro dissolution data.

[0048] The above description is only used to illustrate the technical solution of the present invention and is not intended to limit it. Equal modifications and variations made by those skilled in the art to the technical solution of the present invention, as long as they do not depart from the overall concept of the present invention, shall still fall within the scope of the present invention.

Claims

1. A method for preparing nano-dispersed porous coated heat-clearing and detoxifying granules, characterized in that, The preparation method of the nano-dispersed porous coated heat-clearing and detoxifying granules specifically includes the following steps: S001, buffalo horn is processed using a high-speed slicer to obtain buffalo horn slices, which are divided into two parts. One part is subjected to airflow pulverization and drying to obtain buffalo horn micron powder, and the other part is reserved. S002, take Coptis chinensis, Scrophularia ningpoensis, Lonicera japonica, Rehmannia glutinosa, Isatis indigotica, Forsythia suspensa, and Anemarrhena asphodeloides, pulverize them separately and mix them evenly to obtain ultrafine powder of plant medicinal materials, take gypsum and ball mill it, and after sieving, obtain gypsum powder. S003, take the prepared buffalo horn slices, add ultrapure water for hot reflux extraction, filter and collect the reflux liquid, collect the dregs, add ultrapure water for decoction, filter, collect the decoction, combine the reflux liquid and decoction for concentration treatment, and obtain buffalo horn extract. S004, mix plant-based medicinal materials ultrafine powder and gypsum powder, add ultrapure water for hot reflux extraction, filter and collect the extract for concentration to obtain plant-based medicinal material extract, take the plant-based medicinal material extract, add buffalo horn extract and mix, add ultrapure water for homogenization, add polyethylene glycol 6000 and Tween 80, stir and then grind and vacuum concentrate to obtain submicron dispersed extract; S005, micronized sucrose, micronized dextrin, porous microcrystalline cellulose, and mannitol are subjected to three-dimensional mixing to obtain a porous excipient mixture. Submicron dispersion is diluted with ultrapure water, and povidone K30 is added and stirred to dissolve to obtain a spray. The porous excipient mixture is then granulated with buffalo horn micronized powder. During the granulation process, the spray is continuously sprayed in, and the wet particles are collected and dried to obtain a porous particle intermediate. S006, take calcium sulfate whiskers, add titanate coupling agent for pretreatment to obtain modified calcium sulfate whiskers, take hydroxypropyl methylcellulose and polyvinyl alcohol, add ultrapure water and stir to obtain a double network matrix solution, add modified calcium sulfate whiskers, povidone K30, polyethylene glycol 6000 and calcium chloride solution, stir and keep warm, then sieve to remove bubbles to obtain the main coating solution, take ethyl cellulose aqueous dispersion, add ultrapure water to dilute, stir evenly and let stand to remove bubbles to obtain an aqueous hydrophobic coating solution; S007, the porous particle intermediate is coated with a main coating layer. During the coating process, the main coating liquid is continuously sprayed in. After hot air drying, an aqueous hydrophobic coating liquid is sprayed in for coating. After hot air drying and cooling, the nano-dispersed porous coated heat-clearing and detoxifying particles are obtained.

2. The preparation method according to claim 1, characterized in that, In step S001, the buffalo horn slices are divided into two parts, 0.2 parts and 0.8 parts respectively; 0.2 parts of buffalo horn slices were processed by airflow pulverization.

3. The preparation method according to claim 1, characterized in that, In step S002, the mass ratio of Coptis chinensis, Scrophularia ningpoensis, Lonicera japonica, Rehmannia glutinosa, Isatis indigotica, Forsythia suspensa, and Anemarrhena asphodeloides is 1:5:5:10:10:5:

5.

4. The preparation method according to claim 1, characterized in that, In step S003, the mass-to-volume ratio of the buffalo horn slices to ultrapure water is 1:10; the mass-to-volume ratio of the dregs to ultrapure water is 1:

6.

5. The preparation method according to claim 1, characterized in that, In step S004, the mass ratio of ultrafine plant medicinal material powder to gypsum powder is 41:20; the mass-volume ratio of the mixture to ultrapure water is 1:10; the mass ratio of plant medicinal material extract to buffalo horn extract is 4:1; the mass-volume ratio of the mixed extract to ultrapure water is 1:1; the amount of polyethylene glycol 6000 added is 0.2% of the weight of the homogenized liquid, and the amount of Tween 80 added is 0.1% of the weight of the homogenized liquid.

6. The preparation method according to claim 1, characterized in that, In step S005, the mass ratio of micronized sucrose, micronized dextrin, porous microcrystalline cellulose, and mannitol is 206:103:32:8; the mass ratio of submicron dispersed extract to ultrapure water is 1:1; the amount of povidone K30 added is 0.5% of the weight of the diluent; and the mass ratio of porous excipient mixture, buffalo horn micronized powder, and spray liquid is 109:1:

52.

7. The preparation method according to claim 1, characterized in that, In step S006, the amount of titanate coupling agent added is 1.2% of the weight of calcium sulfate whiskers; the mass ratio of hydroxypropyl methylcellulose to polyvinyl alcohol is 1:1; the mass-volume ratio of hydroxypropyl methylcellulose to ultrapure water is 1:16; the volume-mass ratio of the dual-network matrix solution, modified calcium sulfate whiskers, povidone K30, polyethylene glycol 6000, and calcium chloride solution is 80:3:2:1:2, and the concentration of calcium chloride solution is 0.3%; the mass-volume ratio of ethyl cellulose aqueous dispersion to ultrapure water is 1:

1.

8. The preparation method according to claim 1, characterized in that, In step S007, the mass-to-volume ratio of the porous particle intermediate to the main coating liquid is 7:2, and the mass-to-volume ratio of the porous particle intermediate to the aqueous hydrophobic coating liquid is 10:1.

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