A moisture-proof taste-masking synergistic coating method for traditional Chinese medicine granules

Abstract

This invention discloses a method for synergistic moisture-proof and flavor-masking coating of traditional Chinese medicine granules, belonging to the field of pharmaceutical formulation technology. The method includes: S1, obtaining porous starch by enzymatic hydrolysis, ferric chloride complexation, and integrated twin-screw extrusion-enzymatic hydrolysis of corn starch, followed by surface ammoniation modification with 3-aminopropyltriethoxysilane and then mixing and adsorbing with traditional Chinese medicine granules to obtain granules covered with a sacrificial inner layer; S2, alternately coating the granule surface with sodium carboxymethyl cellulose and poly-L-arginine through layer-by-layer self-assembly to form a composite intermediate layer; S3, in-situ coordination polymerization of tannic acid and ferric chloride on the granule surface to form a polymer coating layer; S4, freezing the granules and then using a mixture of behenicol glyceryl ester and cocoa butter as the hot-melt coating material, followed by fluidized bed hot-melt coating. This invention solves the problems of the prior art, such as the separation of moisture-proof and flavor-masking functions, easy escape of volatile oils, and insufficient coating density. The resulting granules have low moisture absorption, high volatile oil retention, long-lasting flavor masking, and precise pH-responsive drug release.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical preparation technology and relates to a method for moisture-proof and odor-masking synergistic coating of traditional Chinese medicine granules. Background Technology

[0002] Traditional Chinese medicine (TCM) granules hold an important place in clinical applications due to their advantages such as convenient administration, accurate dosage, and easy storage. However, TCM granules contain a large amount of hygroscopic components such as sugars, starches, resins, and tannins, resulting in strong hygroscopicity. This makes them prone to softening, discoloration, clumping, and even mold growth, seriously affecting product quality and shelf life. Furthermore, many active ingredients in TCM have a strong bitter taste or distinctive odor, impacting patient compliance. Therefore, developing granule coating technologies that combine good moisture resistance with taste masking is a research hotspot in the field of TCM preparations.

[0003] Regarding moisture protection, current measures to prevent solid dosage forms from absorbing moisture mainly include reducing impurities in the raw materials, adding suitable excipients, and using moisture-proof coatings and packaging. Among these, coating technology is a relatively effective isolation and protection measure. Chinese patent CN103127220A discloses a moisture-proof coating method for Danshen extract powder or granules, using glyceryl behenate or glyceryl palmitate stearate for hot-melt coating in a fluidized bed, achieving good moisture-proof effects. However, this process uses only glyceryl behenate or glyceryl palmitate stearate as the coating material, and the coating layer naturally cools and solidifies on the granule surface, leaving room for improvement in its density. Furthermore, this technology only addresses the moisture-proof problem and does not address the adsorption of volatile oils from the traditional Chinese medicine or the masking of odors.

[0004] In terms of taste masking, β-cyclodextrin inclusion technology is a commonly used method. This involves encapsulating volatile oils within the cavity of β-cyclodextrin to reduce evaporation loss and mask unpleasant odors. Chinese patent CN111643567A discloses an oral tablet containing a volatile oil inclusion compound from Sichuan pepper, utilizing β-cyclodextrin to enhance stability and mask unpleasant odors. Chinese patent CN109985021A discloses a mixed powder hot-melt coating technology, utilizing the adsorption principle of micropowders on the surface of large particles to coat the surface of drug particles with taste-masking excipient powder, followed by heat treatment to form a film and achieve the taste-masking effect. However, the above-mentioned taste-masking technologies only solve the problem of masking bitterness or off-flavors, without considering the moisture-proof requirements of traditional Chinese medicine granules. Furthermore, the encapsulation or coating layer is prone to leakage during subsequent processing and storage, resulting in insufficient taste-masking durability.

[0005] It is evident that in existing technologies, moisture-proof coatings and odor-masking coatings are typically developed as independent functional layers. These functions are disconnected and lack synergistic design, making it difficult to simultaneously meet the dual requirements of moisture protection and odor masking for traditional Chinese medicine granules. This is particularly true for granules rich in volatile oils, which possess strong penetrating and plasticizing effects, easily penetrating and damaging the structural integrity of the coating film, leading to odor masking failure. Current technologies have not yet provided an effective solution to this systemic need for granules containing volatile oils.

[0006] Therefore, developing a synergistic coating method that combines good moisture-proof performance and odor-masking effect, especially a technical solution that can achieve multi-layer synergistic protection for Chinese medicine particles containing volatile oils, has become an urgent technical problem to be solved in this field. Summary of the Invention

[0007] The purpose of this invention is to provide a method for synergistic moisture-proof and flavor-masking coating of traditional Chinese medicine granules, in order to solve the technical problems in the prior art where the moisture-proof and flavor-masking functions are mutually exclusive, volatile oils easily penetrate and damage the coating film, the hot-melt coating has insufficient density, and the application form of flavor-masking materials is limited. This method aims to achieve synergistic effects of moisture-proofing, flavor-masking, and intestinal-targeted release of traditional Chinese medicine granules.

[0008] The technical solution adopted in this invention is a method for synergistic moisture-proof and odor-masking coating of traditional Chinese medicine granules, which mainly includes the following steps: S1. Corn starch is subjected to enzymatic hydrolysis, ferric chloride complexation, and twin-screw extrusion-enzymatic hydrolysis integrated treatment to obtain porous starch; the above porous starch is modified by surface amination with 3-aminopropyltriethoxysilane to obtain surface-aminated porous starch; the above surface-aminated porous starch is mixed with the Chinese medicine granules to be coated for adsorption, so that the volatile oil in the Chinese medicine granules enters the pores of the porous starch, and after drying, Chinese medicine granules covered with a sacrificial inner layer are obtained. S2. Carboxymethyl cellulose sodium solution and poly-L-arginine solution are alternately coated on the surface of the above-mentioned Chinese medicine granules covered with sacrificial inner layer through layer-by-layer self-assembly to form a composite intermediate layer. After drying, the drug-loaded granules coated with the composite intermediate layer are obtained. S3. Tannic acid solution and ferric chloride solution are subjected to in-situ coordination polymerization on the surface of the drug-loaded particles coated by the above composite intermediate layer to form a tannic acid-ferric chloride polymer coating layer, and drug-loaded particles coated by the polymer coating layer are obtained. S4. After freezing the drug-loaded particles coated with the above polymer coating layer, a mixture of behenicol glyceryl ester and cocoa butter is used as the hot melt coating material. A freeze-heat melt outer layer is formed on the surface of the particles through fluidized bed hot melt coating. After drying and sieving, moisture-proof and flavor-masking synergistic coated Chinese medicine particles are obtained.

[0009] Furthermore, the preparation method of the porous starch in step S1 is as follows: Disperse corn starch in deionized water, adjust the slurry to a solid-liquid mass ratio of 30%–40%, adjust the pH to 4.5–6.0, add a compound enzyme solution, the amount of compound enzyme solution used is 1%–3% of the mass of corn starch, and pre-enzymatically hydrolyze in a water bath at 45℃–55℃ for 30 min–60 min; Add a 5%–10% ferric chloride solution, the amount of which is 0.5%–2% of the corn starch mass, and perform a complexation reaction at 45℃–55℃ for 20–40 minutes to obtain a complex slurry. The complex slurry is transferred to a twin-screw extruder, with the barrel temperature set to 60℃~80℃, the die head temperature to 70℃~90℃, the screw speed to 100r / min~200r / min, and the residence time to 2min~5min. The extrudate is cooled, dried, pulverized, and sieved to obtain porous starch.

[0010] Specifically, the above-mentioned complex enzyme solution is prepared by mixing α-amylase and saccharifying enzyme at a mass ratio of 1:(4-6) to obtain mixed enzyme powder, and then adding the mixed enzyme powder to citrate buffer at a solid-liquid ratio of 1:9.

[0011] Furthermore, the preparation method of the surface-aminated porous starch in step S1 is as follows: Take the above porous starch and disperse it in anhydrous ethanol at a solid-liquid ratio of 1:(8-10). Add 3-aminopropyltriethoxysilane and reflux reaction. After the reaction was completed, the solid was collected by centrifugation, washed with anhydrous ethanol and deionized water, and dried to obtain porous starch with surface aminated coating.

[0012] Specifically, in step S1, the amount of 3-aminopropyltriethoxysilane used is 5% to 10% of the mass of porous starch, the reflux reaction temperature is 78℃ to 82℃, and the reaction time is 8h to 10h.

[0013] Furthermore, the preparation method of the above-mentioned traditional Chinese medicine granules covered with a sacrificial inner layer in step S1 is as follows: Take the above-mentioned surface-aminated porous starch and mix it with the Chinese medicine granules to be coated at a mass ratio of 1:(1.2~1.4), and stir and mix at 20℃~30℃ for 30min~60min; Seal and let stand for 12 to 24 hours, stirring for 1 to 3 minutes every 2 to 4 hours during this period; After adsorption is complete, the herbs are dried to obtain granules covered with a sacrificial inner layer.

[0014] Furthermore, the method for constructing the aforementioned composite intermediate layer in step S2 is as follows: A sodium carboxymethyl cellulose solution with a mass concentration of 2 g / L to 5 g / L was prepared, and the pH was adjusted to 4.0 to 5.0 to obtain the sodium carboxymethyl cellulose solution. A poly-L-arginine solution with a mass concentration of 1 g / L to 4 g / L was prepared, and the pH was adjusted to 4.0 to 5.0 to obtain a poly-L-arginine solution. Take the above-mentioned Chinese medicine granules covered with the sacrificial inner layer, disperse them in citrate buffer at a solid-liquid ratio of 1:(5-10) and soak for 5-10 minutes. After filtration and washing, pretreated drug-loaded granules are obtained. The pretreated drug-loaded particles were immersed in sodium carboxymethyl cellulose solution at a solid-liquid ratio of 1:(5-10), stirred and adsorbed for 15-30 minutes, filtered and washed, and then immersed in poly-L-arginine solution at a solid-liquid ratio of 1:(5-10), stirred and adsorbed for 15-30 minutes, filtered and washed to complete the construction of the first composite layer. Repeat the above operation 1 to 3 times to build a composite layer on the surface of the particles one by one, and dry at 35℃ to 40℃ for 2 to 4 hours to obtain drug-loaded particles coated with a composite intermediate layer.

[0015] Furthermore, the method for forming the tannic acid-ferric chloride polymer coating layer in step S3 is as follows: A tannic acid solution with a mass concentration of 0.5 g / L to 2 g / L was prepared, and the pH was adjusted to 7.5 to 8.5. A ferric chloride solution with a mass concentration of 0.1 g / L to 0.5 g / L was prepared, and the pH was adjusted to 2.0 to 3.0. Take the drug-loaded particles coated with the above composite intermediate layer, immerse them in tannic acid solution at a solid-liquid ratio of 1:(5-10), and stir for 5 min to 15 min; Under stirring conditions, ferric chloride solution was added dropwise at a rate of 1 mL / min to 3 mL / min, with the mass ratio of tannic acid to ferric chloride controlled at (10 to 15):1, and the pH was maintained at 7.5 to 8.5 during the addition process. After the addition is complete, continue stirring and react for 15 to 60 minutes; After the reaction was completed, the particles were collected by filtration and washed with deionized water to obtain drug-loaded particles coated with a polymer coating layer.

[0016] Furthermore, the method for freezing and melting the outer coating in step S4 is as follows: Take the drug-loaded particles coated with the polymer coating layer and freeze them at -30℃ to -20℃ for 30 min to 60 min to obtain frozen particles; Glyceryl behenate and cocoa butter were mixed at a mass ratio of (1.5-2.5):1, heated to 55℃-65℃, and stirred to obtain a hot melt coating mixture; Frozen granules are fed into a fluidized bed coating machine for coating. After coating, the granules are cooled, dried, and sieved to obtain moisture-proof and flavor-masking coated Chinese medicine granules.

[0017] Preferably, in step S4, the specific operations of coating include: The inlet air temperature is 45℃~55℃, the inlet air velocity is 1.0m / s~2.5m / s, the material temperature is 35℃~45℃, the atomization pressure is 0.2MPa~0.4MPa, the spraying rate of the hot melt coating mixture is 5g / min~15g / min, and the coating weight gain is controlled to be 5%~15% of the total particle mass.

[0018] Compared with the prior art, the present invention has the following advantages: First, this invention addresses the core technical problems of the disconnect between the moisture-proof and flavor-masking functions of traditional Chinese medicine granules, the easy penetration and damage of the coating film by volatile oils, the insufficient density of hot-melt coatings, and the limited application forms of flavor-masking materials. It innovatively constructs a four-layer synergistic coating system consisting of a sacrificial inner adsorption system, a poly-L-arginine and sodium carboxymethyl cellulose composite intermediate layer, a tannic acid-ferric chloride polymer coating layer, and a freeze-melt outer layer. Unlike existing technologies that use a single moisture-proof layer or a simple physical mixture of flavor-masking layers, this invention integrates sacrificial adsorption, layer-by-layer self-assembly interface bridging, metal-polyphenol network dense sealing, and freeze-melt hydrophobic blocking into the same granule coating process for the first time. Each layer functionally supports and progressively enhances the others. Specifically, the sacrificial inner layer physically adsorbs and fixes volatile oils through surface-aminated porous starch, while simultaneously providing positive charge anchors; the composite intermediate layer forms a dense multilayer film rich in polar groups through layer-by-layer self-assembly, providing an ideal bonding interface for subsequent polymer layers; the tannic acid-ferric chloride polymer coating layer utilizes Fe... 3+ The high coordination constant of the ortho-phenolic hydroxyl group forms a stable metal-polyphenol network, possessing both pH-responsive drug release characteristics and a dense moisture barrier. The freeze-thaw outer layer utilizes the temperature difference between the pre-frozen particles and the molten coating material to instantly solidify the behenic acid glyceride and cocoa butter mixture, forming a highly dense, non-porous hydrophobic film. The four-layer synergy of this invention increases the critical relative humidity of the particles to over 76% and reduces the moisture absorption rate to below 3% after 84 hours, demonstrating the accuracy and reliability of this synergistic system.

[0019] Secondly, this invention addresses the shortcomings of existing taste-masking technologies in their insufficient adaptability to volatile oil-containing Chinese herbal medicine particles by proposing a step-by-step sealing strategy. The surface-aminated porous starch in the sacrificial inner layer efficiently adsorbs free volatile oils from the Chinese herbal medicine particles into the pores through hydrophobic interactions and capillary effects, achieving the first layer of fixation. The multi-layered composite membrane of the composite intermediate layer acts as the second physical barrier, further preventing the outward diffusion of volatile oils. The dense network of the tannic acid-ferric chloride polymer coating layer provides the third layer of sealing. The freeze-thawed outer layer serves as the final sealing layer, completely isolating any escape pathway for volatile oils. Compared with existing taste-masking schemes that rely on cyclodextrin inclusion or single polymer coating, this invention's four-fold sealing mechanism exhibits excellent retention effects for volatile oil components of different polarities. After 6 months of accelerated stability testing, the total volatile oil retention rate reached over 90%, with the retention rate of key components remaining at a high level simultaneously, achieving a long-lasting and broad-spectrum taste-masking effect.

[0020] Third, this invention, through the synergistic design of the composite intermediate layer and the tannic acid-ferric chloride polymer coating layer, endows the coated particles with dual pH-responsive characteristics: stability in the stomach and accelerated release in the intestine. Under acidic gastric conditions, the Fe in the tannic acid-ferric chloride metal-polyphenol network... 3+ Released from the coordination network and disintegrated within it, the poly-L-arginine and sodium carboxymethyl cellulose composite layer in the intermediate layer remains stable under acidic conditions, causing the network to shrink and become dense, thus controlling the release of volatile oils to a low level. Upon entering the intestinal environment, the tannic acid-ferric chloride polymer coating layer disintegrates, while the poly-L-arginine in the intermediate layer undergoes deprotonation and weakened electrostatic binding, leading to relaxation of the composite layer and accelerated release of volatile oils. Compared to existing technologies that rely solely on a single pH-responsive layer or enteric coating, this invention's dual pH-responsive synergistic mechanism achieves more precise targeted release. In in vitro release experiments, the cumulative release rate of the sample in simulated gastric fluid was less than 40% over 24 hours, while it exceeded 80% in simulated intestinal fluid, significantly superior to the control products, effectively avoiding the irritation or loss caused by premature drug release in the stomach.

[0021] Fourth, this invention uses a mixture of behenicol and cocoa butter as the coating material in the freeze-thaw outer layer, and innovatively introduces a particle pre-freezing process. Compared with the existing single behenicol hot-melt coating, the melting point of the behenicol and cocoa butter mixture is lower, and the corresponding coating temperature is also lower, avoiding adverse effects on heat-sensitive Chinese medicine components. At the same time, the particle pre-freezing process causes the molten coating material to solidify instantly upon contact with the particle surface, forming a highly dense film layer with a significantly lower water permeability than conventional cooling coating. Control experiments show that although control product 7, coated with a single behenicol, has a certain moisture-proof effect, its coating temperature is higher, the film layer density is limited, and it cannot achieve the in vivo release performance improvement brought by cocoa butter. The freeze-thaw outer layer of this invention maintains excellent moisture-proof performance while taking into account good process adaptability and in vivo drug release characteristics.

[0022] In summary, this invention, through a four-layer synergistic design—a sacrificial inner adsorption system, a poly-L-arginine / sodium carboxymethyl cellulose composite intermediate layer, a tannic acid-ferric chloride polymer coating layer, and a freeze-thaw outer layer—systematically solves a series of technical problems in existing Chinese medicine granule coating technologies, such as the separation of moisture-proof and flavor-masking functions, easy loss of volatile oils, insufficient density of hot-melt coatings, and limited application forms of flavor-masking materials. The prepared moisture-proof and flavor-masking synergistically coated Chinese medicine granules possess comprehensive advantages, including low moisture absorption, high volatile oil retention, long-lasting flavor-masking effect, precise pH-responsive drug release, strong interlayer bonding, and excellent long-term stability. They have broad application prospects in the fields of moisture-proof and flavor-masking and intestinal-targeted release of volatile oil-containing Chinese medicine granules. Detailed Implementation

[0023] Various exemplary embodiments of the present invention will now be described in detail. This detailed description should not be considered as a limitation of the present invention, but rather as a more detailed description of certain aspects, features, and embodiments of the present invention.

[0024] It should be understood that the terminology used in this invention is merely for describing particular embodiments and is not intended to limit the invention. Furthermore, with respect to numerical ranges in this invention, it should be understood that each intermediate value between the upper and lower limits of the range is also specifically disclosed. Any stated value or intermediate value within a stated range, as well as each smaller range between any other stated value or intermediate value within said range, is also included in this invention. The upper and lower limits of these smaller ranges may be independently included or excluded from the range.

[0025] Unless otherwise stated, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. While only preferred methods and materials have been described herein, any methods and materials similar or equivalent to those described herein may be used in the implementation or testing of this invention. All references to this specification are incorporated by way of citation to disclose and describe methods and / or materials associated with those references. In the event of any conflict with any incorporated reference, the content of this specification shall prevail.

[0026] Various modifications and variations can be made to the specific embodiments described in this specification without departing from the scope or spirit of the invention, as will be apparent to those skilled in the art. Other embodiments derived from this specification will also be apparent to those skilled in the art. This specification and embodiments are merely exemplary.

[0027] The terms “include,” “including,” “have,” “contain,” etc., used in this article are all open-ended terms, meaning that they include but are not limited to.

[0028] Unless otherwise specified in the examples, the standard conditions shall apply. Unless otherwise specified, the reagents or instruments used are all commercially available products.

[0029] This invention uses Jinlida granules as a model for research. The prescription for Jinlida granules is as follows: Ginseng 184.5g, Polygonatum sibiricum 244.5g, Atractylodes lancea (stir-fried with wheat bran) 122.2g, Sophora flavescens 100g, Ophiopogon japonicus 244.5g, Rehmannia glutinosa 184.5g, Polygonum multiflorum (processed) 149g, Cornus officinalis 244.5g, Poria cocos 149g, Eupatorium fortunei 100g, Coptis chinensis 100g, Anemarrhena asphodeloides 122.2g, Epimedium brevicornu (processed) 100g, Salvia miltiorrhiza 160g, Pueraria lobata 244.5g, Litchi chinensis seed 244.5g, Lycium chinense root bark 149g.

[0030] The method for preparing Jinlida finished granules used in this invention is as follows: The volatile oils of the above seventeen herbs, including Peilan and stir-fried Atractylodes lancea, are extracted, distilled, and filtered into an aqueous solution for later use. Cornus officinalis is soaked in 7 times its volume of 75% ethanol as a solvent for 24 hours, then percolated. The percolate is collected, the ethanol is recovered, and the extract is concentrated to a thick paste with a relative density of 1.30–1.35 (60°C). The paste is then dried for later use. Ginseng, Ophiopogon japonicus, processed Epimedium, Anemarrhena asphodeloides, and Pueraria lobata are extracted three times by reflux with ethanol, each time for 2 hours. The extracts are combined, filtered, and the ethanol is recovered from the filtrate and concentrated to a thick paste with a relative density of 1.30–1.35 (60°C). The paste is dried and set aside. The remaining nine ingredients, including Polygonatum sibiricum, are decocted twice with water, each time for 2 hours. The decoctions are filtered, and the filtrates are combined and combined with the above-mentioned distilled aqueous solution. The mixture is concentrated to a clear paste with a relative density of 1.10-1.15 (60℃). Ethanol is added to make the alcohol content reach 60%, and the mixture is refrigerated for 24 hours. The paste is filtered, and the ethanol is recovered from the filtrate and concentrated to a thick paste with a relative density of 1.30-1.35 (60℃). The paste is dried, and the above-mentioned dried pastes are combined, pulverized into fine powder, and an appropriate amount of microcrystalline cellulose is added. The mixture is then mixed, granulated, dried, and sprayed with the prepared volatile oil. The mixture is then mixed to make 1000g of the final product.

[0031] Note: In this invention, microcrystalline cellulose is used instead of lactose and dextrin in the original standard as the granulation excipient. Microcrystalline cellulose is a pharmaceutical excipient listed in the 2020 edition of the Chinese Pharmacopoeia, Volume IV. It is odorless and tasteless, which can eliminate the interference of the sweetness of the excipient on the evaluation of the taste masking effect. This allows the volatile oil evaporation in the blank control group to be entirely attributed to the uncoated state, thus more objectively verifying the moisture-proof and taste-masking effect of this invention.

[0032] Example 1 S1. Construction of the sacrificial inner layer adsorption system: S11. Preparation of porous starch: S111, Raw material pretreatment: Disperse corn starch in deionized water to make a slurry with a solid-liquid mass ratio of 35%, and stir at 100 r / min for 8 min; Adjust the pH to 5.0, add the compound enzyme solution (2% of the corn starch mass), and pre-enzymatically hydrolyze in a 50℃ water bath for 45 minutes. The complex enzyme solution is prepared by mixing α-amylase and saccharifying enzyme at a mass ratio of 1:5 to obtain mixed enzyme powder. The mixed enzyme powder is added to citrate buffer at a solid-liquid ratio of 1:9 (i.e., mixed enzyme powder: citrate buffer = 1:9, mass ratio), and stirred at 25℃ and 100r / min for 10min until completely dissolved to obtain a complex enzyme solution with a total enzyme powder mass concentration of 10%. The activity of α-amylase is 6000 U / g, and the activity of saccharifying enzyme is 75,000 U / g; In this embodiment, the citrate buffer solution used contains 35 g / L of disodium hydrogen phosphate dodecahydrate and 11.5 g / L of citric acid monohydrate, with a pH of 5.0.

[0033] S112, transition metal ion complexation: Add a 7.5% (w / w) ferric chloride hexahydrate solution to the pre-enzymatic hydrolysis system. The amount of ferric chloride hexahydrate solution used is 1.25% of the mass of corn starch. The complexation reaction was carried out at 50℃ and 100 r / min for 30 min to obtain a complex slurry, which made Fe 3+ It coordinates with the hydroxyl groups on the starch molecule.

[0034] S113, Integrated reactive extrusion-enzymatic hydrolysis treatment: The complex slurry was transferred to a twin-screw extruder. The extruder heating section temperature was set to 70°C, the barrel temperature to 80°C, the screw speed to 150 r / min, and the material residence time in the extruder to 3.5 min. After cooling, the extrudate was dried in a 50°C oven for 18 h. After crushing and passing through a 200-mesh sieve, porous starch was obtained.

[0035] S12, Surface amination modification of porous starch: Take 100 parts of the prepared porous starch and disperse it in 900 parts of anhydrous ethanol. Stir at 100 r / min for 10 min to obtain an anhydrous ethanol dispersion of starch. 3-Aminopropyltriethoxysilane was added to the dispersion at 7.5% of the mass of porous starch, and refluxed at 80℃ and 100r / min for 9h to allow the silanoxy group of 3-aminopropyltriethoxysilane to undergo a dehydration condensation reaction with the hydroxyl group on the support surface, thereby introducing a primary amino group onto the support surface. After the reaction was completed, the solid was centrifuged and collected. The solid was washed four times with anhydrous ethanol and then four times with deionized water. It was then dried in an air-drying environment at 70°C for 18 hours to obtain porous starch with surface aminated coating.

[0036] S13. Preparation of sacrificial inner layer adsorption particles: Take 100 parts of the surface-aminated porous starch prepared by S12 and mix it with Jinlida finished granules at a mass ratio of 1:1.3. Stir and mix at 25℃ and 100r / min for 45min. After mixing, seal and let stand for 18 hours. During this period, stir for 2 minutes at 100 r / min every 3 hours to allow some of the free or volatile oils in the Chinese medicine granules to fully enter the pore structure of the surface-aminated porous starch. After adsorption, the mixture was dried at 37.5℃ and a vacuum of -0.085MPa for 18 hours to obtain traditional Chinese medicine granules covered with a sacrificial inner layer.

[0037] S2. Construction of the composite intermediate layer: S21. Solution preparation: Sodium carboxymethyl cellulose (pharmaceutical grade sodium carboxymethyl cellulose conforming to the standards of the 2020 edition of the Chinese Pharmacopoeia, Part IV, with a degree of substitution of 0.7 and a viscosity of 103 mPa·s in a 2% aqueous solution at 25℃) was dissolved in deionized water and stirred at 100 r / min for 10 min at 25℃. The pH was adjusted to 4.5 with 0.1 mol / L hydrochloric acid to obtain a solution with a sodium carboxymethyl cellulose mass concentration of 3.5 g / L.

[0038] Poly-L-arginine hydrochloride (weight average molecular weight 22 kDa) was dissolved in deionized water to prepare a solution with a poly-L-arginine mass concentration of 2.5 g / L. The pH was adjusted to 4.5 with 0.1 mol / L hydrochloric acid to obtain an arginine solution.

[0039] S22. Surface pretreatment of drug-loaded particles: Take 100 portions of the traditional Chinese medicine granules with a sacrificial inner layer prepared by S13, disperse them in citrate buffer at a solid-liquid ratio of 1:7.5, and soak for 7.5 min; The particles were collected by filtration and gently washed twice with deionized water to obtain pretreated drug-loaded particles.

[0040] S23, Construction of the first composite layer: The pretreated drug-loaded particles were immersed in sodium carboxymethyl cellulose solution at a solid-liquid ratio of 1:7.5 and adsorbed by stirring at 25°C and 100 r / min for 22.5 min. After adsorption, the particles were collected by filtration, washed twice with deionized water to remove unadsorbed free sodium carboxymethyl cellulose from the surface, and then immersed in arginine solution at a solid-liquid ratio of 1:7.5. The adsorption was carried out at 25℃ and 100r / min for 22.5min with stirring. The particles are collected by filtration and washed three times with deionized water to remove unadsorbed free poly-L-arginine on the surface. No drying is required after washing before the next adsorption.

[0041] S24. Layer-by-layer construction of composite layers: Repeat step S23 twice to construct three composite layers on the particle surface layer by layer. By controlling the number of cycles, the total thickness and density of the intermediate layer can be adjusted. The drug-loaded particles were dried in a ventilated drying oven at 37.5℃ for 3 hours to obtain the composite intermediate layer-coated drug-loaded particles.

[0042] S3, Formation of the tannic acid-ferric chloride polymer coating layer Preparation of S31, Tannic Acid-Ferric Chloride Coordination Polymerization Reaction Solution Tannic acid (purity 99.2%, derived from gallnut, with a weight-average molecular weight of 1735 Da based on gallic acid equivalent) was dissolved in deionized water to prepare a tannic acid aqueous solution with a mass concentration of 1.25 g / L. The pH of the tannic acid aqueous solution was adjusted to 8.0 using a 10% sodium hydroxide solution.

[0043] Dissolve ferric chloride hexahydrate in deionized water to prepare a ferric chloride aqueous solution with a mass concentration of 0.3 g / L. Adjust the pH to 2.5 with dilute hydrochloric acid to prevent premature hydrolysis and precipitation of iron ions.

[0044] S32, in-situ coordination polymerization of tannic acid and ferric chloride on the surface of the intermediate layer One hundred parts of the drug-loaded particles coated with the composite intermediate layer prepared by S24 were immersed in the tannic acid solution prepared by S31 at a solid-liquid ratio of 1:7.5. The mixture was stirred at 25℃ and 100r / min for 10min to allow the tannic acid molecules to be pre-adsorbed onto the particle surface through hydrogen bonding and electrostatic interaction with the polar groups of the composite intermediate layer on the particle surface via phenolic hydroxyl groups. Under stirring conditions, ferric chloride aqueous solution was slowly added to the reaction system at a dropping rate of 2 mL / min, and the mass ratio of tannic acid to ferric chloride was controlled at 12.5:1. During the dropping process, the pH of the reaction system was monitored in real time using an online pH meter, and the pH was automatically maintained within the range of 8.0 by titration with a 10% sodium hydroxide solution. After the addition was complete, the reaction was continued at 25°C for 37.5 min with stirring. The ortho-phenolic hydroxyl groups on the tannic acid molecules were deprotonated and reacted with Fe. 3+ A coordination complexation reaction occurs, forming a polymer coating layer in situ on the particle surface; After the reaction was completed, the particles were collected by filtration and washed four times with deionized water to remove unreacted tannic acid, ferric chloride and reaction byproducts, to obtain drug-loaded particles coated with a polymer coating layer.

[0045] S4, freeze-thawed / hot-melt outer coating: S41. Pre-freezing treatment of intermediate layer particles: Take the drug-loaded particles coated with the polymer coating layer prepared by S32, place them in a freeze dryer, and freeze them at -25℃ for 45 minutes to make the overall temperature of the particles uniformly drop to below -20℃.

[0046] S42. Melting of hot melt coating material: Mix behenicol glycerides and cocoa butter in a mass ratio of 2:1, place in a heating container, heat to 60°C, and stir at 100 r / min for 7.5 min to ensure uniform mixing of the two phases, thus obtaining a hot melt coating mixture.

[0047] S43. Fluidized bed hot melt coating of frozen particles: The S41 cryogenically treated granules are fed into the material container of the fluidized bed coating machine. The inlet air temperature is set to 47.5℃, and the inlet air velocity is adjusted to 1.75m / s to make the granules form a stable fluidized state. The material temperature is controlled at 40℃. Turn on the spray gun system, set the atomization pressure to 0.3MPa, and spray the molten hot melt coating material onto the surface of the fluidized frozen particles at a rate of 10g / min through the bottom spray method. After the molten coating material droplets come into contact with the surface of the low temperature particles, they quickly solidify and form a dense, non-porous coating layer on the surface of the particles. Control the coating weight gain to 10% of the total particle mass. After coating is completed, stop spraying liquid and continue to circulate cold air at 27.5℃ to cool the particles for 7.5 minutes to allow the coating layer to fully solidify.

[0048] S44. Finished product drying and sieving: The hot-melt coated granules were dried in a ventilated drying oven at 37.5℃ for 3 hours to remove residual moisture; The dried granules were sieved, and granules with a particle size in the range of 1 mm to 2 mm were collected as finished products to obtain moisture-proof and odor-masking synergistic coated Chinese medicine granules, which were recorded as sample 1.

[0049] Example 2 S1. Construction of the sacrificial inner layer adsorption system: S11. Preparation of porous starch: S111, Raw material pretreatment: Disperse corn starch in deionized water to make a slurry with a solid-liquid mass ratio of 40%, and stir at 120 r / min for 5 min; Adjust the pH to 6.0, add a compound enzyme solution (1% of the corn starch mass), and pre-enzymatically hydrolyze in a 55℃ water bath for 60 min. The complex enzyme solution is prepared by mixing α-amylase and saccharifying enzyme at a mass ratio of 1:4 to obtain mixed enzyme powder. The mixed enzyme powder is added to citrate buffer at a solid-liquid ratio of 1:9 (i.e., mixed enzyme powder: citrate buffer = 1:9, mass ratio), and stirred at 30℃ and 120r / min for 5min until completely dissolved to obtain a complex enzyme solution with a total enzyme powder mass concentration of 10%. The activity of α-amylase is 8000 U / g, and the activity of saccharifying enzyme is 100,000 U / g; In this embodiment, the citrate buffer solution used contains 40 g / L of disodium hydrogen phosphate dodecahydrate and 15 g / L of citric acid monohydrate, with a pH of 6.0.

[0050] S112, transition metal ion complexation: Add a 10% (w / w) ferric chloride hexahydrate solution to the pre-enzymatic hydrolysis system. The amount of ferric chloride hexahydrate solution used is 0.5% of the mass of corn starch. The complex slurry was obtained by complexing reaction at 55℃ and 120r / min for 20min.

[0051] S113, Integrated reactive extrusion-enzymatic hydrolysis treatment: The complex slurry was transferred to a twin-screw extruder. The extruder heating section temperature was set to 80°C, the barrel temperature to 90°C, the screw speed to 200 r / min, and the material residence time in the extruder to 2 min. After cooling, the extrudate was dried in an oven at 55°C for 12 h. After crushing and passing through a 200-mesh sieve, porous starch was obtained.

[0052] S12, Surface amination modification of porous starch: Take 100 parts of the prepared porous starch and disperse it in 1000 parts of anhydrous ethanol. Stir at 120 r / min for 5 min to obtain an anhydrous ethanol dispersion of starch. 3-Aminopropyltriethoxysilane was added to the dispersion at 10% of the mass of porous starch, and the mixture was refluxed at 82℃ and 120r / min for 8h. After the reaction was completed, the solid was centrifuged and collected. It was washed three times with anhydrous ethanol and then three times with deionized water. It was then dried in an air-drying environment at 80°C for 12 hours to obtain porous starch with surface aminated coating.

[0053] S13. Preparation of sacrificial inner layer adsorption particles: Take 100 parts of the surface-aminated porous starch prepared by S12 and mix it with Jinlida finished granules at a mass ratio of 1:1.4. Stir and mix at 30℃ and 120r / min for 30min. After mixing, seal and let stand for 12 hours, stirring at 120 r / min for 1 minute every 2 hours during this period; After adsorption, the mixture was dried at 40℃ and a vacuum of -0.09MPa for 12 hours to obtain traditional Chinese medicine granules covered with a sacrificial inner layer.

[0054] S2. Construction of the composite intermediate layer: S21. Solution preparation: Sodium carboxymethyl cellulose (pharmaceutical grade sodium carboxymethyl cellulose conforming to the standards of the 2020 edition of the Chinese Pharmacopoeia, Part IV, with a degree of substitution of 0.9 and a viscosity of 198 mPa·s at 25℃ for a 2% aqueous solution) was dissolved in deionized water, stirred at 30℃ and 120 r / min for 5 min, and the pH was adjusted to 5.0 with 0.1 mol / L hydrochloric acid to obtain a solution with a sodium carboxymethyl cellulose mass concentration of 5 g / L.

[0055] Poly-L-arginine hydrochloride (weight average molecular weight 30 kDa) was dissolved in deionized water to prepare a solution with a poly-L-arginine mass concentration of 4 g / L. The pH was adjusted to 5.0 with 0.1 mol / L hydrochloric acid to obtain an arginine solution.

[0056] S22. Surface pretreatment of drug-loaded particles: Take 100 portions of the Chinese herbal medicine granules with a sacrificial inner layer prepared by S13, disperse them in citrate buffer at a solid-liquid ratio of 1:10, and soak for 5 minutes; The particles were collected by filtration and gently washed once with deionized water to obtain pretreated drug-loaded particles.

[0057] S23, Construction of the first composite layer: The pretreated drug-loaded particles were immersed in sodium carboxymethyl cellulose solution at a solid-liquid ratio of 1:10 and adsorbed by stirring at 30℃ and 120r / min for 15min. After adsorption, the particles were collected by filtration, washed once with deionized water, and immersed in arginine solution at a solid-liquid ratio of 1:10. The adsorption was carried out by stirring at 30℃ and 120r / min for 15min. The particles are collected by filtration and washed twice with deionized water. No drying is required after washing before the next adsorption.

[0058] S24. Layer-by-layer construction of composite layers: Repeat step S23 once to construct two composite layers layer by layer on the particle surface; The drug-loaded particles were dried in a ventilated drying oven at 40°C for 2 hours to obtain a composite intermediate layer-coated drug-loaded particles.

[0059] S3, Formation of the tannic acid-ferric chloride polymer coating layer Preparation of S31, Tannic Acid-Ferric Chloride Coordination Polymerization Reaction Solution Dissolve tannic acid (quality requirements are the same as in Example 1) in deionized water to prepare a tannic acid aqueous solution with a mass concentration of 2 g / L. Adjust the pH of the tannic acid aqueous solution to 8.5 with a mass concentration of 10% sodium hydroxide solution.

[0060] Dissolve ferric chloride hexahydrate in deionized water to prepare a ferric chloride aqueous solution with a mass concentration of 0.5 g / L. Adjust the pH to 3.0 with dilute hydrochloric acid.

[0061] S32, in-situ coordination polymerization of tannic acid and ferric chloride on the surface of the intermediate layer One hundred parts of the drug-loaded particles coated with the composite intermediate layer prepared by S24 were immersed in the tannic acid solution prepared by S31 at a solid-liquid ratio of 1:10 and stirred at 30℃ and 120r / min for 5min. Under stirring conditions, ferric chloride aqueous solution was slowly added to the reaction system at a dropping rate of 3 mL / min, and the mass ratio of tannic acid to ferric chloride was controlled at 15:1. During the dropping process, the pH of the reaction system was monitored in real time using an online pH meter, and the pH was automatically maintained at 8.5 by titration with a 10% sodium hydroxide solution. After the addition is complete, continue stirring the reaction at 30°C for 15 minutes. After the reaction was completed, the particles were collected by filtration and washed three times with deionized water to obtain drug-loaded particles coated with a polymer coating layer.

[0062] S4, freeze-thawed / hot-melt outer coating: S41. Pre-freezing treatment of intermediate layer particles: Take the drug-loaded particles coated with the polymer coating layer prepared by S32, place them in a freeze dryer, and freeze them at -20℃ for 60 minutes to make the overall temperature of the particles uniformly drop to below -15℃.

[0063] S42. Melting of hot melt coating material: Mix glyceryl behenate and cocoa butter at a mass ratio of 2.5:1, place in a heating container, heat to 65°C, and stir at 120 r / min for 5 min to ensure uniform mixing of the two phases, thus obtaining a hot melt coating mixture.

[0064] S43. Fluidized bed hot melt coating of frozen particles: The S41 cryogenically treated granules are fed into the material container of the fluidized bed coating machine. The inlet air temperature is set to 50℃, and the inlet air velocity is adjusted to 2.5m / s to make the granules form a stable fluidized state. The material temperature is controlled at 45℃. Turn on the spray gun system, set the atomization pressure to 0.4MPa, and spray the molten hot melt coating material onto the surface of the fluidized frozen particles at a rate of 15g / min through the bottom spray method. After the molten coating material droplets come into contact with the surface of the low-temperature particles, they quickly solidify and form a dense, non-porous coating layer on the surface of the particles. Control the coating weight gain to 15% of the total particle mass. After coating is completed, stop spraying liquid and continue to circulate 30°C cold air to cool the particles for 5 minutes to allow the coating layer to fully solidify.

[0065] S44. Finished product drying and sieving: The hot melt coated granules were dried in a 40℃ ventilated drying oven for 2 hours to remove residual moisture. The dried granules were sieved, and granules with a particle size in the range of 1 mm to 2 mm were collected as finished products to obtain moisture-proof and odor-masking synergistic coated Chinese medicine granules, which were recorded as sample 2.

[0066] Example 3 S1. Construction of the sacrificial inner layer adsorption system: S11. Preparation of porous starch: S111, Raw material pretreatment: Disperse corn starch in deionized water to make a slurry with a solid-liquid mass ratio of 30%, and stir at 80 r / min for 10 min; Adjust the pH to 4.5, add the compound enzyme solution (3% of the corn starch mass), and pre-enzymatically hydrolyze in a 45℃ water bath for 30 minutes. The complex enzyme solution is prepared by mixing α-amylase and saccharifying enzyme at a mass ratio of 1:6 to obtain mixed enzyme powder. The mixed enzyme powder is added to citrate buffer at a solid-liquid ratio of 1:9 (i.e., mixed enzyme powder: citrate buffer = 1:9, mass ratio), and stirred at 20℃ and 80r / min for 15min until completely dissolved to obtain a complex enzyme solution with a total enzyme powder mass concentration of 10%. The activity of α-amylase is 4000 U / g, and the activity of saccharifying enzyme is 50,000 U / g; In this embodiment, the citrate buffer solution used contains 30 g / L of disodium hydrogen phosphate dodecahydrate and 8 g / L of citric acid monohydrate, with a pH of 4.5.

[0067] S112, transition metal ion complexation: Add a 5% (w / w) ferric chloride hexahydrate solution to the pre-enzymatic hydrolysis system. The amount of ferric chloride hexahydrate solution used is 2% of the mass of corn starch. The complexation reaction was carried out at 45℃ and 80r / min for 40min to obtain a complex slurry, which made Fe 3+ It coordinates with the hydroxyl groups on the starch molecule.

[0068] S113, Integrated reactive extrusion-enzymatic hydrolysis treatment: The complex slurry was transferred to a twin-screw extruder. The extruder heating section temperature was set to 60°C, the barrel temperature to 70°C, the screw speed to 100 r / min, and the material residence time in the extruder to 5 min. After cooling, the extrudate was dried in an oven at 45°C for 24 h. After crushing and passing through a 200-mesh sieve, porous starch was obtained.

[0069] S12, Surface amination modification of porous starch: Take 100 parts of the prepared porous starch and disperse it in 800 parts of anhydrous ethanol. Stir at 80 r / min for 15 min to obtain an anhydrous ethanol dispersion of starch. 3-Aminopropyltriethoxysilane was added to the dispersion at 5% of the mass of porous starch, and the mixture was refluxed at 78℃ and 80r / min for 10h. After the reaction was completed, the solid was centrifuged and collected. It was washed five times with anhydrous ethanol and then five times with deionized water. It was then dried in a ventilated environment at 60°C for 24 hours to obtain porous starch with surface amination.

[0070] S13. Preparation of sacrificial inner layer adsorption particles: Take 100 parts of the surface-aminated porous starch prepared by S12 and mix it with Jinlida finished granules at a mass ratio of 1:1.2. Stir and mix at 20℃ and 80r / min for 60min. After mixing, seal and let stand for 24 hours, stirring at 80 r / min for 3 minutes every 4 hours during this period; After adsorption, the mixture was dried at 35℃ and a vacuum of -0.08MPa for 24 hours to obtain traditional Chinese medicine granules covered with a sacrificial inner layer.

[0071] S2. Construction of the composite intermediate layer: S21. Solution preparation: Sodium carboxymethyl cellulose (pharmaceutical grade sodium carboxymethyl cellulose conforming to the standards of the 2020 edition of the Chinese Pharmacopoeia, Part IV, with a degree of substitution of 0.6 and a viscosity of 52 mPa·s in a 2% aqueous solution at 25℃) was dissolved in deionized water, stirred at 20℃ and 80 r / min for 15 min, and the pH was adjusted to 4.0 with 0.1 mol / L hydrochloric acid to obtain a solution with a sodium carboxymethyl cellulose mass concentration of 2 g / L.

[0072] Poly-L-arginine hydrochloride (weight average molecular weight 15 kDa) was dissolved in deionized water to prepare a solution with a poly-L-arginine mass concentration of 1 g / L. The pH was adjusted to 4.0 with 0.1 mol / L hydrochloric acid to obtain an arginine solution.

[0073] S22. Surface pretreatment of drug-loaded particles: Take 100 portions of the Chinese herbal medicine granules with a sacrificial inner layer prepared by S13, disperse them in citrate buffer at a solid-liquid ratio of 1:5, and soak for 10 minutes. The particles were collected by filtration and gently washed twice with deionized water to obtain pretreated drug-loaded particles.

[0074] S23, Construction of the first composite layer: The pretreated drug-loaded particles were immersed in sodium carboxymethyl cellulose solution at a solid-liquid ratio of 1:5 and adsorbed by stirring at 20℃ and 80r / min for 30min. After adsorption, the particles were collected by filtration, washed twice with deionized water, and immersed in arginine solution at a solid-liquid ratio of 1:5. The adsorption was carried out at 20℃ and 80r / min for 30min with stirring. The particles are filtered and collected, washed three times with deionized water, and can be adsorbed again without drying after washing.

[0075] S24. Layer-by-layer construction of composite layers: Repeat step S23 three times to build four composite layers on the particle surface layer by layer. By controlling the number of cycles, the total thickness and density of the intermediate layer can be adjusted. The drug-loaded particles were dried in a ventilated drying oven at 35°C for 4 hours to obtain a composite intermediate layer-coated drug-loaded particles.

[0076] S3, Formation of the tannic acid-ferric chloride polymer coating layer Preparation of S31, Tannic Acid-Ferric Chloride Coordination Polymerization Reaction Solution Dissolve tannic acid (quality requirements are the same as in Example 1) in deionized water to prepare a tannic acid aqueous solution with a mass concentration of 0.5 g / L. Adjust the pH of the tannic acid aqueous solution to 7.5 with a mass concentration of 10% sodium hydroxide solution.

[0077] Dissolve ferric chloride hexahydrate in deionized water to prepare a ferric chloride aqueous solution with a mass concentration of 0.1 g / L. Adjust the pH to 2.0 with dilute hydrochloric acid.

[0078] S32, in-situ coordination polymerization of tannic acid and ferric chloride on the surface of the intermediate layer One hundred parts of the drug-loaded particles coated with the composite intermediate layer prepared by S24 were immersed in the tannic acid solution prepared by S31 at a solid-liquid ratio of 1:5 and stirred at 20℃ and 80r / min for 15min. Under stirring conditions, ferric chloride aqueous solution was slowly added to the reaction system at a dropping rate of 1 mL / min, and the mass ratio of tannic acid to ferric chloride was controlled at 10:1. During the dropping process, the pH of the reaction system was monitored in real time using an online pH meter, and the pH was automatically maintained within the range of 7.5 by titration with a 10% sodium hydroxide solution. After the addition was complete, the reaction was continued with stirring at 20°C for 60 minutes. The ortho-phenolic hydroxyl groups on the tannic acid molecules were deprotonated and reacted with Fe. 3+ A coordination complexation reaction occurs, forming a polymer coating layer in situ on the particle surface; After the reaction was completed, the particles were collected by filtration and washed five times with deionized water to obtain drug-loaded particles coated with a polymer coating layer.

[0079] S4, freeze-thawed / hot-melt outer coating: S41. Pre-freezing treatment of intermediate layer particles: Take the drug-loaded particles coated with the polymer coating layer prepared by S32, place them in a freeze dryer, and freeze them at -30℃ for 30 minutes to make the overall temperature of the particles uniformly drop to below -25℃.

[0080] S42. Melting of hot melt coating material: Mix behenicol glyceryl ester and cocoa butter in a mass ratio of 1.5:1, place in a heating container, heat to 55°C, and stir at 80 r / min for 10 min to ensure uniform mixing of the two phases, thus obtaining a hot melt coating mixture.

[0081] S43. Fluidized bed hot melt coating of frozen particles: The S41 cryogenically treated granules are fed into the material container of the fluidized bed coating machine. The inlet air temperature is set to 45℃, and the inlet air velocity is adjusted to 1.0m / s to make the granules form a stable fluidized state. The material temperature is controlled at 35℃. Turn on the spray gun system, set the atomization pressure to 0.2MPa, and spray the molten hot melt coating material onto the surface of the fluidized frozen particles at a rate of 5g / min through a bottom spray method. After the molten coating material droplets come into contact with the surface of the low-temperature particles, they quickly solidify, forming a dense, non-porous coating layer on the surface of the particles. Control the coating weight gain to 5% of the total particle mass. After coating is completed, stop spraying liquid and continue to circulate 25°C cold air to cool the particles for 10 minutes to allow the coating layer to fully solidify.

[0082] S44. Finished product drying and sieving: The hot melt coated granules were dried in a 35°C ventilated drying oven for 4 hours to remove residual moisture. The dried granules were sieved, and granules with a particle size in the range of 1 mm to 2 mm were collected as finished products to obtain moisture-proof and odor-masking synergistic coated Chinese medicine granules, which were recorded as sample 3.

[0083] Comparative Example 1 The comparative preparation of moisture-proof and odor-masking coated Chinese herbal granules is carried out in the same manner as in Example 1, except that the surface amination modification is omitted in step S1, that is, step S12 is not performed, and unmodified porous starch is directly used for subsequent adsorption and coating.

[0084] The specific steps are as follows: S1. Construction of the sacrificial inner layer adsorption system: S11, Preparation of porous starch: S11 is the same as in Example 1. After obtaining porous starch, the surface amination modification of S12 is not performed. The porous starch is directly used in subsequent steps. S12. Preparation of sacrificial inner layer adsorption particles: Take 100 parts of unmodified porous starch and mix it with the Chinese medicine granules to be coated at a mass ratio of 1:1.3. Stir and mix at 25℃ and 100r / min for 45min. After mixing, seal and let stand for 18h, stirring at 100r / min for 2min every 3h. After adsorption, dry at 37.5℃ and vacuum degree -0.085MPa for 18h to obtain Chinese medicine granules covered with a sacrificial inner layer (unaminated). Steps S2, S3 and S4 are the same as in Example 1. The finally obtained coated Chinese medicine granules are recorded as control 1.

[0085] Comparative Example 2 The comparative preparation of moisture-proof and odor-masking coated Chinese herbal granules is carried out in the same manner as in Example 1, except that in step S12, 3-aminopropyltriethoxysilane is replaced with ethylenediamine as the amination reagent.

[0086] The specific steps are as follows: S1. Construction of the sacrificial inner layer adsorption system: S11. Preparation of porous starch: Same as in Example 1, porous starch is obtained; S12, Surface amination modification of porous starch: Take 100 parts of the prepared porous starch and disperse it in 900 parts of anhydrous ethanol. Stir at 100 r / min for 10 min to obtain an anhydrous ethanol dispersion of starch. Ethylenediamine was added to the dispersion at 7.5% of the mass of porous starch, and the mixture was refluxed at 80℃ and 100r / min for 9h to allow the amino group of ethylenediamine to react with the hydroxyl group on the surface of the support, thereby introducing primary amino groups onto the surface of the support. After the reaction was completed, the solid was centrifuged and collected. The solid was washed four times with anhydrous ethanol and then four times with deionized water. It was then dried in a ventilated environment at 70°C for 18 hours to obtain ethylenediamine-modified surface-aminated porous starch. Steps S13, S2, S3, and S4 are the same as in Example 1, and the final coated Chinese medicine granules are designated as control 2.

[0087] Comparative Example 3 The comparative preparation of moisture-proof and odor-masking coated Chinese herbal granules is carried out in the same manner as in Example 1, except that the layer-by-layer self-assembly process is omitted in step S2, and sodium carboxymethyl cellulose and poly-L-arginine are pre-mixed and coated in one step.

[0088] The specific steps are as follows: S1. Construction of the sacrificial inner layer adsorption system: Same as in Example 1, to obtain Chinese medicine granules covered with a sacrificial inner layer.

[0089] S2. Construction of the composite intermediate layer: S21. Solution preparation: Same as in Example 1, prepare sodium carboxymethyl cellulose solution and poly-L-arginine solution respectively; A sodium carboxymethyl cellulose solution and a poly-L-arginine solution were mixed at a volume ratio of 1:1 and stirred at 25°C and 100 r / min for 10 min to obtain a mixed solution. S22. Surface pretreatment of drug-loaded particles: Same as in Example 1; S23, One-time mixed coating: Take 100 parts of the Chinese herbal medicine granules with a sacrificial inner layer prepared by S13, disperse them in the above mixed solution at a solid-liquid ratio of 1:7.5, and stir and adsorb at 25℃ and 100r / min for 45min. The particles were collected by filtration, washed three times with deionized water, and dried at 37.5℃ for 3 hours to obtain drug-loaded particles coated with a composite intermediate layer. Steps S3 and S4 are the same as in Example 1, and the final coated Chinese medicine granules are designated as reference standard 3.

[0090] Comparative Example 4 The comparative preparation of moisture-proof and odor-masking coated Chinese herbal granules is carried out in the same manner as in Example 1, except that in step S2, poly-L-arginine is replaced with chitosan as a cationic polyelectrolyte, while the other process parameters remain unchanged.

[0091] The specific steps are as follows: S1. Construction of the sacrificial inner layer adsorption system: Same as in Example 1.

[0092] S2. Construction of the composite intermediate layer: S21. Solution preparation: The sodium carboxymethyl cellulose solution was prepared in the same manner as in Example 1; Chitosan (90% degree of deacetylation, 200kDa) was dissolved in a 2% (v / v) aqueous acetic acid solution and stirred at 25°C and 100r / min until completely dissolved to prepare a chitosan solution with a mass concentration of 2.5g / L. The pH was adjusted to 4.5 with 0.1mol / L sodium hydroxide solution to obtain the chitosan solution. S22. Surface pretreatment of drug-loaded particles: Same as in Example 1; S23, Construction of the first composite layer: The pretreated drug-loaded particles were immersed in sodium carboxymethyl cellulose solution at a solid-liquid ratio of 1:7.5 and adsorbed by stirring at 25°C and 100 r / min for 22.5 min. After adsorption, the particles were collected by filtration, washed twice with deionized water, and immersed in chitosan solution at a solid-liquid ratio of 1:7.5. The adsorption was carried out at 25℃ and 100r / min for 22.5min with stirring. The filtered particles are washed three times with deionized water. No drying is required after washing before the next adsorption. S24. Layer-by-layer construction of composite layers: Repeat step S23 twice to construct three composite layers layer by layer on the particle surface; The drug-loaded particles coated with a composite intermediate layer were dried in a ventilated drying oven at 37.5℃ for 3 hours. Steps S3 and S4 are the same as in Example 1, and the final coated Chinese medicine granules are designated as control 4.

[0093] Comparative Example 5 The comparative preparation of moisture-proof and odor-masking coated Chinese herbal granules is carried out in the same manner as in Example 1, except that in step S3, tannic acid is replaced with gallic acid and coordinated with ferric chloride for polymerization.

[0094] The specific steps are as follows: Steps S1 and S2 are the same as in Example 1, resulting in drug-loaded particles coated with a composite intermediate layer.

[0095] S3. Formation of the gallic acid-ferric chloride polymer coating layer: S31. Preparation of gallic acid-ferric chloride coordination polymerization reaction solution: Gallic acid (purity 99.3%) was dissolved in deionized water to prepare an aqueous solution of gallic acid with a mass concentration of 1.25 g / L. The pH of the aqueous solution of gallic acid was adjusted to 8.0 with a mass concentration of 10% sodium hydroxide solution.

[0096] Dissolve ferric chloride hexahydrate in deionized water to prepare a ferric chloride aqueous solution with a mass concentration of 0.3 g / L. Adjust the pH to 2.5 with dilute hydrochloric acid.

[0097] S32, In-situ coordination polymerization of gallic acid-ferric chloride on the surface of the intermediate layer: One hundred parts of the drug-loaded particles coated with the composite intermediate layer prepared by S24 were immersed in the gallic acid solution prepared by S31 at a solid-liquid ratio of 1:7.5 and stirred at 25℃ and 100r / min for 10min. Under stirring conditions, ferric chloride aqueous solution was slowly added to the reaction system at a dropping rate of 2 mL / min, and the mass ratio of gallic acid to ferric chloride was controlled at 3:1. During the dropping process, the pH of the reaction system was monitored in real time using an online pH meter, and the pH was automatically maintained within the range of 8.0 by titration with a 10% sodium hydroxide solution. After the addition is complete, continue stirring the reaction at 25°C for 37.5 min. After the reaction was completed, the particles were collected by filtration and washed four times with deionized water to obtain drug-loaded particles coated with a polymer coating layer. Step S4 is the same as in Example 1, and the final coated Chinese medicine granules are designated as control 5.

[0098] Comparative Example 6 The comparative preparation of moisture-proof and odor-masking coated Chinese herbal granules is carried out in the same manner as in Example 1, except that in step S3, ferric chloride is replaced with calcium chloride to carry out a coordination reaction with tannic acid.

[0099] The specific steps are as follows: Steps S1 and S2 are the same as in Example 1, resulting in drug-loaded particles coated with a composite intermediate layer.

[0100] S3. Formation of the tannic acid-calcium chloride polymer coating layer: S31. Preparation of tannic acid solution: Same as in Example 1; Preparation of calcium chloride solution: Dissolve calcium chloride dihydrate in deionized water to prepare a calcium chloride aqueous solution with a mass concentration of 0.3 g / L, and adjust the pH to 2.5 with dilute hydrochloric acid; S32, Tannic acid-calcium chloride in-situ coordination polymerization: One hundred parts of the drug-loaded particles coated with the composite intermediate layer prepared by S24 were immersed in the tannic acid solution prepared by S31 at a solid-liquid ratio of 1:7.5 and stirred at 25℃ and 100r / min for 10min. Under stirring conditions, calcium chloride aqueous solution was slowly added dropwise to the reaction system at a dropping rate of 2 mL / min. During the dropwise addition, the pH of the reaction system was monitored in real time using an online pH meter, and the pH was automatically maintained at 8.0 by titration with a 10% sodium hydroxide solution. After the addition is complete, continue stirring the reaction at 25°C for 37.5 min. After the reaction was completed, the particles were collected by filtration and washed four times with deionized water to obtain drug-loaded particles coated with a polymer coating layer. Step S4 is the same as in Example 1, and the final coated Chinese medicine granules are designated as reference standard 6.

[0101] Comparative Example 7 The comparative preparation of moisture-proof and odor-masking coated Chinese herbal granules is carried out in the same manner as in Example 1, except that in step S4, only glyceryl behenate is used as the hot-melt coating material, and cocoa butter is not used, and the coating process parameters are adjusted accordingly.

[0102] The specific steps are as follows: Steps S1, S2, and S3 are the same as in Example 1, resulting in drug-loaded particles coated with a polymer coating layer.

[0103] S4, freeze-thawed / hot-melt outer coating: S41. Pre-freezing treatment of intermediate layer particles: Same as in Example 1; S42. Melting of hot melt coating material: Take glyceryl behenate and place it in a heating container, heat it to 70°C, and stir it at 100 r / min for 7.5 min until it is completely melted to obtain a molten hot melt coating material; S43. Fluidized bed hot melt coating of frozen particles: The S41 cryogenically treated granules are fed into the material container of the fluidized bed coating machine. The inlet air temperature is set to 55℃, and the inlet air velocity is adjusted to 1.75m / s to make the granules form a stable fluidized state. The material temperature is controlled at 47℃. Turn on the spray gun system, set the atomization pressure to 0.3MPa, and spray the molten hot melt coating material onto the surface of the fluidized frozen particles at a rate of 10g / min using a bottom spray method. Control the coating weight gain to 10% of the total particle mass. After coating is completed, stop spraying liquid and continue to circulate cold air at 27.5℃ to cool the particles for 7.5 minutes to allow the coating layer to fully solidify. S44. Finished product drying and sieving: Same as in Example 1, the final coated Chinese medicine granules are designated as reference standard 7.

[0104] Analysis and Testing To verify the technical effects of this invention and compare it with comparative schemes, systematic analysis and testing were conducted on the obtained moisture-proof and odor-masking synergistic coated Chinese herbal medicine granule samples 1-3 and reference standards 1-7. Furthermore, uncoated Jinlida granules were used as a blank control to evaluate the difference in moisture-proof and odor-masking performance before and after coating.

[0105] I. Tests on the hygroscopicity and moisture-proof properties of coated particles To evaluate the moisture-proof effect of each coated granule, a hygroscopicity test was designed with reference to General Chapter 9103 of Part IV of the 2020 edition of the Chinese Pharmacopoeia.

[0106] Take approximately 2g of each sample to be tested and the reference standard, weigh them accurately, and place them in a weighing bottle (approximately 2mm thick) that has been pre-weighed. Place the weighing bottle open in a constant temperature and humidity chamber and weigh it after 84 hours at 25℃ and 75% relative humidity. Calculate the moisture absorption rate after 84 hours according to Equation 1.

[0107] Critical relative humidity (CRH) was determined using the saturated salt solution method: the test sample and the reference standard were placed in a desiccator containing saturated salt solutions at different relative humidities (RH 30%–90%), and weighed after equilibration for 72 hours. The relative humidity corresponding to the inflection point of the curve was plotted on the ordinate with the moisture absorption rate and the abscissa. The relative humidity corresponding to the inflection point of the curve was the CRH. The results are shown in Table 1.

[0108] Formula 1 In Equation 1, W0 represents the initial mass (g). W 84h The mass (g) after 84 hours.

[0109] Table 1: 84-hour moisture absorption rate and critical relative humidity (CRH) of each coated particle As shown in Table 1, the moisture absorption rates of samples 1-3 of this invention were all below 3.0% within 84 hours, with sample 2 having the lowest moisture absorption rate of only 2.1% after 84 hours. The moisture absorption rate of the blank control was 10.5% after 84 hours, and the CRH was 51%.

[0110] The 84-hour moisture absorption rates of each reference standard were between those of the blank control and the samples of this invention. The 84-hour moisture absorption rate of reference standard 1 was 8.9%, and its CRH was 58%, significantly higher than that of sample 1, indicating that the surface amination modification of the S1 layer is a prerequisite for the effective electrostatic adsorption of the subsequent S2 layer. The primary amino groups on the surface of the surface-aminated porous starch are protonated to -NH3 under weakly acidic conditions. + The positively charged layer provides a uniform positive charge anchor point for the negatively charged sodium carboxymethyl cellulose. Without this anchor point, the S2 layer cannot adhere effectively, resulting in a significant decrease in its moisture-proof effect.

[0111] Reference standard 2 had an 84-hour moisture absorption rate of 7.5% and a CRH of 63%, which was better than reference standard 1 but worse than sample 1. Ethylenediamine is a small molecule amination agent that grafts onto starch hydroxyl groups through a nucleophilic substitution reaction. However, it lacks the Si-O-Si covalent bond formed between the silane end of 3-aminopropyltriethoxysilane and the starch hydroxyl group, resulting in poor grafting stability and uneven amino density distribution, making it difficult to form a uniform positive charge interface. Therefore, its moisture-proof effect is not as good as that of sample 1 modified with 3-aminopropyltriethoxysilane.

[0112] The 84-hour moisture absorption rate of reference standard 3 was 6.4%, and its CRH was 66%, significantly higher than that of sample 1. In this invention, the layer-by-layer self-assembly technology, through alternating immersion in polyelectrolyte solutions with opposite charges, can progressively construct a multilayer film with controllable thickness and a dense structure on the particle surface. In contrast, the one-time mixing and coating in this comparative example cannot form an ordered multilayer structure, and sodium carboxymethyl cellulose and poly-L-arginine may prematurely recombine and precipitate in the solution, resulting in uneven coating and a significant decrease in moisture-proof effect.

[0113] Reference standard 4 had an 84-hour moisture absorption rate of 5.7% and a CRH of 69%, which were higher than those of sample 1. Chitosan is a cationic polysaccharide that can form a composite film with sodium carboxymethyl cellulose through electrostatic interaction. However, the amino group density of chitosan is much lower than that of poly-L-arginine, resulting in a weaker electrostatic interaction with sodium carboxymethyl cellulose. Consequently, the composite film formed has poor density and lower moisture-proof performance than that of poly-L-arginine.

[0114] Reference standard 5 had an 84-hour moisture absorption rate of 5.2% and a CRH of 70%, higher than sample 1. Gallic acid is a hydrolyzed monomer of tannic acid, and although it contains three adjacent phenolic hydroxyl groups that can react with Fe... 3+ Coordination occurs, but the molecules are small and lack the multi-arm macromolecular structure of tannic acid. The resulting coordination network is relatively loose and cannot form tannic acid-Fe. 3+ Such a dense, continuous metal-polyphenol network coating layer has significantly lower moisture-proof performance than the tannic acid system.

[0115] The 84-hour moisture absorption rate of reference standard 6 was 4.5%, and its CRH was 72%, which were higher than those of sample 1. 2+ Although it can coordinate with the phenolic hydroxyl groups of tannic acid, its coordination constant is much lower than that of Fe. 3+ The resulting coordination network has poor stability and its moisture-proof effect is lower than that of Fe. 3+ system.

[0116] The 84-hour moisture absorption rate of reference standard 7 was 3.3%, and the CRH was 74%, which was higher than that of sample 1. While the hot-melt coating technology using glyceryl behenate alone can improve the hygroscopicity of particles, the addition of cocoa butter to glyceryl behenate in this invention lowers the melting point of the mixture, reducing the coating temperature. Simultaneously, the introduction of cocoa butter allows the coating film to maintain good moisture resistance while also exhibiting better in vivo release performance, further increasing the CRH from 74% to 76%–80%. This demonstrates the synergistic advantages of the glyceryl behenate and cocoa butter mixture combined with the freeze-melt process.

[0117] II. Evaluation of Volatile Oil Retention Rate and Odor Masking Effect To evaluate the retention effect of each coated granule on the volatile oils of traditional Chinese medicine, the total volatile oil content in each sample and reference standard was determined by steam distillation, referring to Chapter 2204 of the 2020 edition of the Chinese Pharmacopoeia, Part IV, and the retention rate relative to the initial volatile oil content was calculated. Simultaneously, to track the retention of volatile oils at the molecular level, the retention rates of p-cymene in the volatile oil of *Eupatorium fortunei* and atractylodes lancea in the volatile oil of *Atractylodes lancea* were quantitatively determined using the external standard method, referring to GC-MS.

[0118] Accelerated stability tests were conducted on all samples under 40℃ and 75% relative humidity. After 6 months, samples were taken to determine the retention rates of total volatile oil and key components. The results are shown in Table 2.

[0119] Table 2: Results of volatile oil detection and analysis in accelerated stability test As shown in Table 2, after 6 months of accelerated stability testing, the total volatile oil retention rates of samples 1-3 of this invention all reached over 90%, with para-cymene retention rates of 88.5%-94.0% and atractylone retention rates of 86.2%-92.8%. Among them, sample 2 had the highest retention rates in all categories. In contrast, the blank control showed a total volatile oil retention rate of only 48.6% after 6 months, with para-cymene at 42.5% and atractylone at 39.8%, indicating that more than half of the volatile oil and approximately 60% of the key components had evaporated and been lost.

[0120] The retention rates of each reference standard were between those of the blank control and the sample of this invention. The total volatile oil retention rates of reference standards 1 to 7 were 58.3%, 68.2%, 72.5%, 75.8%, 78.6%, 82.3%, and 85.0%, respectively, with the retention rates of key components also increasing progressively.

[0121] This progressive pattern confirms the contribution of each layer to the retention of volatile oils. The sacrificial inner layer of this invention provides basic retention by physically adsorbing and fixing volatile oils through porous starch. However, if amination is lacking (reference 1) or if ethylenediamine (reference 2), which has poor stability, is used, the retention rate is significantly lower. The composite intermediate layer of this invention uses a multi-layer composite film constructed with layer-by-layer self-assembly technology to form a physical barrier, further reducing the escape of volatile oils (references 3 and 4). The dense structure of the tannic acid-ferric chloride polymer coating layer of this invention enhances the sealing effect (references 5 and 6). The final layer, the freeze-thawed outer coating, uses a freeze-thawed dense hydrophobic film to provide the final seal (reference 7). It can be seen that the four-layer synergy fundamentally inhibits the escape of volatile oils during long-term storage, increasing the total volatile oil retention rate to over 90%, and the retention rate of key components also increases simultaneously. This proves that the four-layer synergistic coating system of this invention has a good retention effect on different types of volatile oil components. Each layer supports each other in terms of masking function, and the layer-by-layer progression enhances the overall masking effect.

[0122] III. pH-responsive in vitro release experiment To investigate the release behavior of the coated particles of this invention under different pH conditions, the cumulative release rate of each sample and reference standard in simulated gastric fluid (pH 1.2) and simulated intestinal fluid (pH 6.8) was determined using the rotating basket method, referring to Chapter 0931 "Determination of Dissolution and Release Rate" in Part IV of the 2020 edition of the Chinese Pharmacopoeia. Approximately 2 g of each sample was taken and released for 24 h at 37℃ and 100 r / min. The cumulative release rate of total volatile oil in the release medium was then measured. The results are shown in Table 3.

[0123] Table 3: Cumulative release rate (%) of each coated particle in different pH media over 24 hours As shown in Table 3, samples 1-3 of this invention exhibited slow release in simulated gastric fluid at pH 1.2, with a cumulative release rate of only 32.8%-38.3% over 24 hours; however, release was significantly accelerated in simulated intestinal fluid at pH 6.8, with a cumulative release rate of 80.4%-84.7% over 24 hours, demonstrating a significant pH dependence. The blank control showed release rates exceeding 95% in both media, exhibiting no pH selectivity. The release rates of all control samples at pH 1.2 were significantly higher than those of the samples of this invention, while their release rates at pH 6.8 were lower than those of the samples of this invention, indicating that the control samples lacked a dense pH-responsive network.

[0124] The ideal pH-dependent release achieved by samples 1-3 of this invention is attributed to the synergistic effect of the dual pH response of the composite intermediate layer and the tannic acid-ferric chloride polymer coating layer. Specifically, under acidic gastric conditions, the Fe in the metal-polyphenol network of the tannic acid-ferric chloride polymer coating layer... 3+ Release from the coordination network and network disintegration are observed, but the composite intermediate layer remains stable under acidic conditions (due to poly-L-arginine guanidine protonation and enhanced electrostatic binding with sodium carboxymethyl cellulose), resulting in network contraction and densification, and volatile oil release is controlled at a low level. Upon entering the intestinal environment, the tannic acid-ferric chloride polymer coating layer disintegrates, while the poly-L-arginine in the composite intermediate layer undergoes deprotonation and weakened electrostatic binding, leading to relaxation of the composite layer and accelerated release of volatile oil. These results demonstrate that the four-layer synergistic coating system of this invention can achieve an ideal release curve that is stable in the stomach and accelerates release in the intestine, significantly superior to the control products.

[0125] The embodiments described above are merely preferred embodiments of the present invention and are not intended to limit the scope of the present invention. Various modifications and improvements made by those skilled in the art to the technical solutions of the present invention without departing from the spirit of the present invention should fall within the protection scope defined by the claims of the present invention.

Claims

1. A method for synergistic moisture-proof and odor-masking coating of traditional Chinese medicine granules, characterized in that, Includes the following steps: S1. Corn starch is subjected to enzymatic hydrolysis, ferric chloride complexation, and twin-screw extrusion-enzymatic hydrolysis integrated treatment to obtain porous starch; the porous starch is modified by surface amination with 3-aminopropyltriethoxysilane to obtain surface-aminated porous starch; the surface-aminated porous starch is mixed with the Chinese medicine granules to be coated for adsorption, so that the volatile oil in the Chinese medicine granules enters the pores of the porous starch, and after drying, Chinese medicine granules covered with a sacrificial inner layer are obtained; S2. Sodium carboxymethyl cellulose solution and poly-L-arginine solution are alternately coated on the surface of the traditional Chinese medicine granules covered with the sacrificial inner layer through layer-by-layer self-assembly to form a composite intermediate layer. After drying, the drug-loaded granules coated with the composite intermediate layer are obtained. S3. Tannic acid solution and ferric chloride solution are subjected to in-situ coordination polymerization on the surface of the drug-loaded particles coated by the composite intermediate layer to form a tannic acid-ferric chloride polymer coating layer, and drug-loaded particles coated by the polymer coating layer are obtained. S4. After freezing the drug-loaded particles coated with the polymer coating layer, a mixture of behenicol glyceryl ester and cocoa butter is used as the hot-melt coating material. A freeze-melt outer layer is formed on the surface of the particles through fluidized bed hot-melt coating. After drying and sieving, moisture-proof and flavor-masking synergistic coated Chinese medicine particles are obtained.

2. The coating method according to claim 1, characterized in that, The method for preparing porous starch in step S1 is as follows: Disperse corn starch in deionized water, adjust the slurry to a solid-liquid mass ratio of 30%–40%, adjust the pH to 4.5–6.0, add a compound enzyme solution, the amount of compound enzyme solution used is 1%–3% of the mass of corn starch, and pre-enzymatically hydrolyze in a water bath at 45℃–55℃ for 30 min–60 min; Add a 5%–10% ferric chloride solution, the amount of which is 0.5%–2% of the corn starch mass, and perform a complexation reaction at 45℃–55℃ for 20–40 minutes to obtain a complex slurry. The complex slurry is transferred to a twin-screw extruder, with the barrel temperature set to 60℃~80℃, the die head temperature to 70℃~90℃, the screw speed to 100r / min~200r / min, and the residence time to 2min~5min. The extrudate is cooled, dried, pulverized, and sieved to obtain porous starch.

3. The method according to claim 2, characterized in that, The complex enzyme solution is prepared by mixing α-amylase and saccharifying enzyme at a mass ratio of 1:(4-6) to obtain a mixed enzyme powder, and then adding the mixed enzyme powder to a citrate buffer solution at a solid-liquid ratio of 1:

9.

4. The method according to claim 1, characterized in that, The preparation method of the surface-aminated porous starch in step S1 is as follows: The porous starch was dispersed in anhydrous ethanol at a solid-liquid ratio of 1:(8-10), and 3-aminopropyltriethoxysilane was added for reflux reaction. After the reaction was completed, the solid was collected by centrifugation, washed with anhydrous ethanol and deionized water, and dried to obtain porous starch with surface aminated coating.

5. The method according to claim 4, characterized in that, In step S1, the amount of 3-aminopropyltriethoxysilane used is 5% to 10% of the mass of porous starch, the reflux reaction temperature is 78℃ to 82℃, and the reaction time is 8h to 10h.

6. The method according to claim 1, characterized in that, The method for preparing the traditional Chinese medicine granules covered with a sacrificial inner layer in step S1 is as follows: Take the surface-aminated porous starch and mix it with the Chinese medicine granules to be coated at a mass ratio of 1:(1.2-1.4), and stir and mix at 20℃-30℃ for 30min-60min; Seal and let stand for 12 to 24 hours, stirring for 1 to 3 minutes every 2 to 4 hours during this period; After adsorption is complete, the herbs are dried to obtain granules covered with a sacrificial inner layer.

7. The method according to claim 1, characterized in that, The method for constructing the composite intermediate layer in step S2 is as follows: A sodium carboxymethyl cellulose solution with a mass concentration of 2 g / L to 5 g / L was prepared, and the pH was adjusted to 4.0 to 5.0 to obtain the sodium carboxymethyl cellulose solution. A poly-L-arginine solution with a mass concentration of 1 g / L to 4 g / L was prepared, and the pH was adjusted to 4.0 to 5.0 to obtain a poly-L-arginine solution. Take the Chinese medicine granules covered with the sacrificial inner layer, disperse them in citrate buffer at a solid-liquid ratio of 1:(5-10) and soak for 5-10 minutes. After filtration and washing, pretreated drug-loaded granules are obtained. The pretreated drug-loaded particles were immersed in sodium carboxymethyl cellulose solution at a solid-liquid ratio of 1:(5-10), stirred and adsorbed for 15-30 minutes, filtered and washed, and then immersed in poly-L-arginine solution at a solid-liquid ratio of 1:(5-10), stirred and adsorbed for 15-30 minutes, filtered and washed to complete the construction of the first composite layer. Repeat the above operation 1 to 3 times to build a composite layer on the surface of the particles one by one, and dry at 35℃ to 40℃ for 2 to 4 hours to obtain drug-loaded particles coated with a composite intermediate layer.

8. The method according to claim 1, characterized in that, The method for forming the tannic acid-ferric chloride polymer coating layer in step S3 is as follows: A tannic acid solution with a mass concentration of 0.5 g / L to 2 g / L was prepared, and the pH was adjusted to 7.5 to 8.

5. A ferric chloride solution with a mass concentration of 0.1 g / L to 0.5 g / L was prepared, and the pH was adjusted to 2.0 to 3.

0. Take the drug-loaded particles coated with the composite intermediate layer and immerse them in a tannic acid solution at a solid-liquid ratio of 1:(5-10) and stir for 5-15 minutes. Under stirring conditions, ferric chloride solution was added dropwise at a rate of 1 mL / min to 3 mL / min, with the mass ratio of tannic acid to ferric chloride controlled at (10 to 15):1, and the pH was maintained at 7.5 to 8.5 during the addition process. After the addition is complete, continue stirring and react for 15 to 60 minutes; After the reaction was completed, the particles were collected by filtration and washed with deionized water to obtain drug-loaded particles coated with a polymer coating layer.

9. The method according to claim 1, characterized in that, The method for freezing and melting the outer coating in step S4 is as follows: Take the drug-loaded particles coated with the polymer coating layer and freeze them at -30℃ to -20℃ for 30 min to 60 min to obtain frozen particles; Glyceryl behenate and cocoa butter were mixed at a mass ratio of (1.5-2.5):1, heated to 55℃-65℃, and stirred to obtain a hot melt coating mixture; Frozen granules are fed into a fluidized bed coating machine for coating. After coating, the granules are cooled, dried, and sieved to obtain moisture-proof and flavor-masking coated Chinese medicine granules.

10. The method according to claim 9, characterized in that, In step S4, the specific operations of coating include: The inlet air temperature is 45℃~55℃, the inlet air velocity is 1.0m / s~2.5m / s, the material temperature is 35℃~45℃, the atomization pressure is 0.2MPa~0.4MPa, the spraying rate of the hot melt coating mixture is 5g / min~15g / min, and the coating weight gain is controlled to be 5%~15% of the total particle mass.

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