Spleen-nourishing granules for effectively proliferating probiotics and preparation method thereof

Abstract

This invention belongs to the field of food processing technology, specifically relating to a fast-dissolving granule for Yangpi San (a traditional Chinese medicine formula) that effectively proliferates probiotics and its preparation method. The preparation method includes the following steps: (1) extracting the raw material of Yangpi San to obtain a clear liquid; (2) performing inclusion to obtain an inclusion solution; (3) continuously spraying the inclusion solution onto the surface of seed microparticles and simultaneously performing fluidized bed drying to obtain granules with high active ingredient loading; (4) uniformly spraying a hydrophilic material onto the surface of the granules with high active ingredient loading and performing a second fluidized bed drying, and then uniformly spraying a hydrophobic material while simultaneously performing a third fluidized bed drying to obtain fast-dissolving granules for Yangpi San. The beneficial effects of this invention are: through the organic integration of "extraction-inclusion-granulation-coating", it systematically solves the multiple technical contradictions of slow dissolution, easy moisture absorption, and easy loss of functional components in the traditional dosage form of Yangpi San, and achieves synergistic effect.

Description

Technical Field

[0001] This invention belongs to the field of food processing technology, specifically relating to a spleen-nourishing powder instant granule that effectively proliferates probiotics and its preparation method. Background Technology

[0002] Yongchun Yangpi Powder is a classic formula originating from the Xianfeng period of the Qing Dynasty. It is mainly composed of medicinal and edible herbs such as lotus seeds, cinnamon, atractylodes macrocephala, and amomum villosum, and has a clear effect of strengthening the spleen and replenishing qi, as well as regulating spleen and stomach weakness. With the deepening of modern research on intestinal microecology, its polysaccharides and oligosaccharides have been proven to have the potential value of promoting the proliferation of probiotics and regulating intestinal health.

[0003] Currently, most commercially available spleen-nourishing powders are traditional powders, which generally suffer from poor solubility, unpleasant taste, and easy moisture absorption and clumping. During processing and storage, active ingredients (especially volatile components) are easily lost, leading to reduced bioavailability and severely restricting the modern transformation and functional improvement of this product.

[0004] Existing technologies have attempted to improve dosage forms. For example, Chinese patent application CN115944695A discloses a "Spleen-Strengthening and Stomach-Nourishing Granules" using a conventional process of granulation after water decoction concentration and mixing with excipients. However, improvements are still needed in terms of dissolution rate and retention of volatile components. Regarding the preparation of instant granules, some research has been conducted in the prior art. For instance, Chinese patent application CN117982436A discloses a method for preparing porous spherical instant granules using fluidized bed liquid-phase lamination technology. This method prepares instant granules by spraying a β-cyclodextrin-containing extract lamination solution onto a soluble substrate, solving the problems of low drug loading and slow dissolution in traditional granulation. However, this technical solution is mainly aimed at specific products such as Qi-Stagnation and Stomach Pain Granules. Its core process lies in constructing a porous structure through grinding and lamination to achieve anhydrous swallowing. It does not involve extraction and stabilization pretreatment processes for the complex components (especially volatile components) of the spleen-nourishing powder, nor does it include a design for functional coating of the granules to simultaneously solve the problems of instant dissolution and moisture resistance.

[0005] Chinese patent application CN115813864A discloses a method for preparing curcumin fast-dissolving granules. This method improves the solubility of curcumin by preparing a curcumin-hydroxypropyl-β-cyclodextrin inclusion complex, which is then mixed with excipients and subjected to wet granulation. While this method utilizes cyclodextrin inclusion technology to address the water solubility issue of a single component, it targets only a single compound. Furthermore, the subsequent granulation process is conventional wet granulation, without employing fluidized bed deposition granulation technology. It also fails to resolve the combined challenges of rapid dissolution, high drug loading, and moisture resistance in multi-component compound granules.

[0006] In summary, the conversion of Yangpi Powder into a quick-dissolving granule dosage form faces a series of unique technical challenges: Firstly, it is necessary to achieve efficient retention and stability of the main components (especially volatile components and functional components for probiotic proliferation) through process innovation; Secondly, it is necessary to ensure the instantaneous dissolution of the granules under the premise of high loading of active ingredients; Thirdly, it is necessary to endow the product with good anti-moisture absorption performance to ensure storage stability. Conventional granulation techniques or single improvement measures (such as only inclusion, only granulation or only coating) are difficult to simultaneously meet the above mutually restrictive requirements. Summary of the Invention

[0007] The object of the present invention is to provide a quick-dissolving granule of Yangpi Powder for effectively proliferating probiotics and its preparation method, so as to overcome the defects of poor solubility, easy moisture absorption and easy loss of functional components in the existing Yangpi Powder preparations.

[0008] To achieve the above object, the present invention adopts the following technical solutions: Provide a preparation method for a quick-dissolving granule of Yangpi Powder for effectively proliferating probiotics, comprising the following steps: (1) Extract the raw materials of Yangpi Powder to obtain a clarified solution; (2) Add an inclusion material to the clarified solution obtained in step (1) for inclusion to obtain an inclusion solution; (3) Continuously spray the inclusion solution obtained in step (2) onto the surface of seed particles, and simultaneously perform fluidized bed drying to obtain granules with a high loading of active ingredients; (4) Uniformly spray a hydrophilic material onto the surface of the granules with a high loading of active ingredients obtained in step (3), and perform secondary fluidized bed drying, and then uniformly spray a hydrophobic material while performing tertiary fluidized bed drying to form a quick-dissolving granule of Yangpi Powder with a double-layer coating structure including a hydrophilic inner layer and a hydrophobic outer layer.

[0009] Another technical solution adopted by the present invention is: Provide a quick-dissolving granule of Yangpi Powder for effectively proliferating probiotics, which is prepared by the above preparation method for a quick-dissolving granule of Yangpi Powder for effectively proliferating probiotics.

[0010] The beneficial effects of this invention are as follows: By defining a three-step integrated process route of "extraction and inclusion," "granulation," and "coating," this invention constructs a technical solution for systematically improving the dosage form of Yangpi San compound. First, by pre-mixing the extract with the inclusion material, the volatile and functional components in Yangpi San are protected at the molecular level, providing a material basis for their stability in subsequent processing. Second, by applying the inclusion solution to the surface of fluidized seed particles for granulation, a porous and loose particle structure that facilitates rapid water penetration can be constructed while achieving high active ingredient loading, thus resolving the contradiction between high drug loading and rapid dissolution at the structural level. Finally, by sequentially applying hydrophilic and hydrophobic materials for double-layer coating, a functional gradient layer is formed on the particle surface. The hydrophilic inner layer ensures instantaneous wetting and disintegration upon contact with water, while the hydrophobic outer layer constructs a water-blocking barrier during storage, thereby synergistically achieving the two originally mutually restrictive properties of rapid dissolution and moisture resistance on a single particle. In summary, the method protected by this invention is not a simple summation of the effects of each step, but rather a systematic solution to the comprehensive technical problems of poor solubility, easy moisture absorption, and easy loss of functional components in traditional spleen-nourishing powder preparations through the organic integration of the process chain and synergistic effects at multiple scales such as molecules, structures, and interfaces. Ultimately, it produces spleen-nourishing powder instant-dissolving granules that have the characteristics of high active ingredient loading, instantaneous dissolution, and long-lasting moisture protection. Attached Figure Description

[0011] Figure 1 This is a bar chart showing the relative abundance distribution of species at the genus level in Experimental Example 3, a specific embodiment of the present invention. Detailed Implementation

[0012] To explain in detail the technical content, objectives, and effects of the present invention, the following description is provided in conjunction with the embodiments and accompanying drawings.

[0013] From the perspective of dosage form design, Yangpi San belongs to a multi-component traditional Chinese medicine compound system, which contains both volatile flavor components and functional substances such as polysaccharides and oligosaccharides. Its preparation process also faces the following objective technical conflicts: (1) The contradiction between high active ingredient loading and instantaneous dissolution: Increased active ingredient loading usually leads to denser particle structure, making it difficult for water to penetrate and reducing the dissolution rate; (2) The contradiction between hydrophilic quick dissolution and hydrophobic moisture protection: hydrophilic materials are conducive to rapid wetting and disintegration, but they are prone to absorbing moisture and clumping, which reduces storage stability; (3) The contradiction between the retention of active ingredients and processing stability: Volatile and heat-sensitive ingredients are prone to volatilization, oxidation or degradation during extraction, drying and granulation, resulting in loss of efficacy.

[0014] Conventional single processes are difficult to meet the above requirements simultaneously and usually can only make a trade-off among solubility, stability, or the loading amount of active ingredients.

[0015] To address the above complex technical problems, the present invention proposes an integrated process of "extraction - inclusion - fluidized bed layering granulation - double - layer functional coating", and realizes the improvement of overall performance through the functional synergy among steps. The mechanism of action is as follows: In the first step, ultrasonic - assisted extraction combined with β - cyclodextrin inclusion is adopted. Ultrasonic - enhanced mass transfer can improve the dissolution efficiency of active ingredients; β - cyclodextrin forms inclusion compounds with volatile and functional ingredients at the molecular level through host - guest inclusion, thus significantly improving their thermal stability and antioxidant properties, making them less likely to escape or degrade during subsequent fluidized bed drying and storage processes, providing a material basis for the effective retention of functional ingredients.

[0016] In the second step, fluidized bed spraying layering granulation is used. The inclusion solution is deposited layer by layer on the surface of seed particles and dried synchronously to form a porous, loose and relatively large - specific - surface - area particle skeleton structure. This structure can achieve a high loading amount of active ingredients while still maintaining good porosity, which is conducive to the rapid penetration of moisture and the disintegration of particles, solving the problem of "difficulty in兼顾 high loading amount of active ingredients and rapid dissolution" from the structural level.

[0017] In the third step, hydrophilic and hydrophobic double - layer sequential coating is implemented. The inner - layer hydrophilic material can significantly improve the wettability and dispersibility of particles, promoting instantaneous disintegration; the outer - layer hydrophobic material forms a water - blocking barrier, reducing the intrusion rate of environmental humidity into the particles, thereby inhibiting moisture absorption and caking. The two functional membranes are distributed in layers spatially and achieve the regulation effect of "wet first and then moisture - proof" temporally, enabling the simultaneous realization of two mutually contradictory properties of rapid solubility and anti - moisture absorption.

[0018] The Yangpi San used in the embodiments of the present invention is purchased from Quanzhou Li Peiyuan Food Development Co., Ltd., with the product name: Dapu Liheyuan Brand Powder - type Yangpi San, specification 250 g, and the raw materials are Codonopsis pilosula, Dioscorea opposita, Nelumbo nucifera Gaertn., Poria cocos, Hordeum vulgare L. var. nudum Hook. f., Coix lacryma - jobi L., Euryale ferox Salisb., Amomum villosum Lour., Fortunella margarita (Lour.) Swingle, Eugenia caryophyllata Thunb., Crataegus pinnatifida Bunge, Citrus reticulata Blanco, Citrus medica L. var. sarcodactylis Swingle, Cinnamomum cassia Presl, and Glycyrrhiza glabra L.

[0019] The present invention provides a method for preparing instant granules of Yangpi San that can effectively proliferate probiotics, including the following steps: (1) Extract the raw materials of Yangpi San to obtain a clarified solution; (2) Add inclusion materials to the clarified solution obtained in step (1) for inclusion to obtain an inclusion solution; (3) Continuously spray the inclusion solution obtained in step (2) on the surface of seed particles and perform fluidized bed drying synchronously to obtain granules with a high loading amount of active ingredients; (4) The hydrophilic material is evenly sprayed onto the surface of the high-activity ingredient loading particles obtained in step (3), and then a second fluidized bed drying is performed. Then the hydrophobic material is evenly sprayed and a third fluidized bed drying is performed to form the Yangpi San quick-dissolving particles with a double-layer coating structure containing a hydrophilic inner layer and a hydrophobic outer layer.

[0020] The beneficial effects of this invention are as follows: By defining a three-step integrated process route of "extraction and inclusion," "granulation," and "coating," this invention constructs a technical solution for systematically improving the dosage form of Yangpi San compound. First, by pre-mixing the extract with the inclusion material, the volatile and functional components in Yangpi San are protected at the molecular level, providing a material basis for their stability in subsequent processing. Second, by applying the inclusion solution to the surface of fluidized seed particles for granulation, a porous and loose particle structure that facilitates rapid water penetration can be constructed while achieving high active ingredient loading, thus resolving the contradiction between high drug loading and rapid dissolution at the structural level. Finally, by sequentially applying hydrophilic and hydrophobic materials for double-layer coating, a functional gradient layer is formed on the particle surface. The hydrophilic inner layer ensures instantaneous wetting and disintegration upon contact with water, while the hydrophobic outer layer constructs a water-blocking barrier during storage, thereby synergistically achieving the two originally mutually restrictive properties of rapid dissolution and moisture resistance on a single particle. In summary, the method protected by this invention is not a simple summation of the effects of each step, but rather a systematic solution to the comprehensive technical problems of poor solubility, easy moisture absorption, and easy loss of functional components in traditional spleen-nourishing powder preparations through the organic integration of the process chain and synergistic effects at multiple scales such as molecules, structures, and interfaces. Ultimately, it produces spleen-nourishing powder instant-dissolving granules that have the characteristics of high active ingredient loading, instantaneous dissolution, and long-lasting moisture protection.

[0021] Furthermore, in the above-mentioned method for preparing the spleen-nourishing powder instant granules that effectively proliferate probiotics, the extraction is ultrasonic-assisted extraction, the extraction solvent used is an ethanol solution with a volume fraction of 50%-70%, and the mass ratio of the spleen-nourishing powder raw material to the ethanol solution is 1:20 to 1:40.

[0022] As can be seen from the above, this specific range of ethanol concentration and material-liquid ratio can achieve balanced extraction of polar polysaccharides and non-polar volatile components in Yangpi Powder, maximize the dissolution efficiency of active ingredients, and avoid the dissolution of too many water-soluble impurities, thus providing a high-quality clarifying liquid for subsequent inclusion and granulation.

[0023] Furthermore, in the above-mentioned method for preparing the spleen-nourishing powder instant granules for effectively proliferating probiotics, the ultrasonic-assisted extraction conditions in step (1) are: ultrasonic time 10-40 minutes, ultrasonic power 300-500 W, ultrasonic frequency 20-80 kHz, and extraction temperature 20-40 ℃.

[0024] As can be seen from the above, this condition utilizes the cavitation effect of ultrasound to enhance mass transfer, achieving rapid and efficient low-temperature extraction. It is particularly suitable for protecting the heat-sensitive and volatile active ingredients (such as cinnamaldehyde and cardamom volatile oil) in Yangpi San, preventing their loss due to prolonged high-temperature heating, and preserving the material basis for subsequent functional effects.

[0025] Furthermore, in the above-mentioned method for preparing the spleen-nourishing powder instant granules for effectively proliferating probiotics, the inclusion material in step (2) is β-cyclodextrin, and its mass ratio with the clarified liquid is 1:400 to 1:800.

[0026] As shown above, the material ratio for the inclusion step is limited. This ratio is optimized to ensure that volatile components and functional molecules in the extract are fully included to form stable "molecular protection units," significantly improving their thermal stability during subsequent fluidized bed drying (60-70℃). It also avoids increased costs and decreased particle solubility caused by excessive use of cyclodextrin.

[0027] Furthermore, in the above-mentioned method for preparing the spleen-nourishing powder instant granules for effectively proliferating probiotics, the seed microparticles in step (3) are made of one of α-lactose, microcrystalline cellulose or starch, with a particle size range of 80-100 mesh.

[0028] As can be seen from the above, the seed microparticles that define the granulation step are defined. Seed microparticles within this particle size range have good flowability and suitable specific surface area. As a "skeleton," they enable the inclusion solution to be uniformly and firmly deposited on their surface, thereby constructing a stable, uniformly sized, and highly spherical particle core, laying the foundation for subsequent high drug loading and coating.

[0029] Furthermore, in the above-mentioned method for preparing the spleen-nourishing powder granules that effectively proliferate probiotics, the fluidized bed drying conditions in step (3) are: heating gas temperature 60-70℃, heating gas flow rate 1.2-1.6 m / s, atomization pressure 0.15-0.20MPa, and spray flow rate 7.0-9.0 mL / min.

[0030] As shown above, the key process parameters for fluidized bed granulation are defined. This combination of parameters ensures that the inclusion solution can be uniformly sprayed onto the surface of the fluidized seed particles in the form of tiny droplets and dried rapidly, thereby forming a porous, loose particle structure of "layer-by-layer self-assembly". This structure is key to achieving a balance between "high drug loading" and "rapid dissolution". Furthermore, in the above-mentioned method for preparing the spleen-nourishing powder instant granules for effectively proliferating probiotics, the hydrophilic material in step (4) is one or more of hydroxypropyl methylcellulose or polyvinylpyrrolidone K30, and its addition amount is 3%-5% of the weight of the high-activity ingredient loading granules.

[0031] The conditions for the secondary fluidized bed drying described in step (4) are as follows: the temperature of the heating gas is 50 - 60 °C, the flow rate of the heating gas is 1.5 - 3.0 m / s, the atomization pressure is 0.10 - 0.18 MPa, and the spray flow rate is 5.0 - 7.0 mL / min.

[0032] As can be seen from the above, the materials and dosages of the inner hydrophilic coating are defined. These hydrophilic polymer materials can form a dense thin film on the surface of the granules. When encountering water, they quickly hydrate and dissolve, significantly reducing the water contact angle and greatly enhancing the wettability and disintegration rate of the granules. It is the key functional layer to achieve "instantaneous rapid dissolution" (dissolution time ≤ 45 seconds). The above defines the process parameters of the hydrophilic coating. These mild conditions ensure that the hydrophilic material can form a continuous, uniform and controllable thickness thin film on the surface of the porous granules, while avoiding film cracking or incompleteness caused by too high temperature or too fast drying, ensuring the stable exertion of the hydrophilic function.

[0033] Furthermore, in the method for preparing the spleen - nourishing powder instant granules for effectively proliferating probiotics described above, the hydrophobic material in step (4) is one or several of magnesium stearate, glycerol monostearate or microcrystalline silica, and its addition amount is 0.3% - 0.5% of the mass of the high - activity ingredient - loaded granules.

[0034] The conditions for the tertiary fluidized bed drying described in step (4) are as follows: the temperature of the heating gas is 45 - 55 °C, the flow rate of the heating gas is 0.6 - 1.0 m / s, the atomization pressure is 0.08 - 0.15 MPa, and the spray flow rate is 3.0 - 5.0 mL / min.

[0035] As can be seen from the above, the materials and dosages of the outer hydrophobic coating are defined. These hydrophobic materials can form an extremely thin "hydrophobic barrier" outside the hydrophilic layer, effectively reducing the surface energy of the granules and preventing the intrusion of environmental water vapor (relative humidity 75%), thereby controlling the moisture absorption weight gain rate at an extremely low level (≤ 1.5%). Its dosage has been carefully optimized. While providing moisture - proof protection, it does not affect the instant dissolution performance of the inner hydrophilic layer, achieving the functional synergy of "outer hydrophobic and inner hydrophilic". The determination of the process parameters of the hydrophobic coating ensures that the hydrophobic material can evenly spread and adhere on the smooth surface of the hydrophilic layer, forming a complete and dense protective layer, avoiding material loss or uneven coating caused by too high flow rate or too large atomization pressure, thus ensuring the effectiveness of the hydrophobic barrier.

[0036] The present invention also provides a kind of spleen - nourishing powder instant granules for effectively proliferating probiotics, which are prepared by the method for preparing the spleen - nourishing powder instant granules for effectively proliferating probiotics described above.

[0037] Example 1 A method for preparing spleen - nourishing powder instant granules for effectively proliferating probiotics, the specific steps are as follows: (1) Mix the raw materials of Yangpi Powder with an ethanol solution of 50% volume fraction at a mass ratio of 1:20, place it under the conditions of ultrasonic power of 300 W, frequency of 20 kHz, and temperature of 20 °C for ultrasonic-assisted extraction for 40 minutes, and then filter to obtain a clear liquid.

[0038] (2) Add β-cyclodextrin to the above-mentioned clear liquid and perform stirring and inclusion at room temperature to obtain a Yangpi Powder inclusion solution, and the mass ratio of the β-cyclodextrin to the clear liquid is 1:800.

[0039] (3) Continuously spray the above-mentioned Yangpi Powder inclusion solution onto the surface of seed particles and perform synchronous drying in a fluidized bed to obtain high-loading particles. The seed particles are α-lactose with a particle size of 100 mesh, and the fluidized bed drying conditions are a heating gas temperature of 60 °C, a gas flow rate of 1.2 m / s, an atomization pressure of 0.15 MPa, and a spray flow rate of 7.0 mL / min.

[0040] (4) Spray a hydroxypropyl methylcellulose solution onto the surface of the above-mentioned high-loading particles and perform secondary fluidized bed drying to form a hydrophilic coating layer. The addition amount of the hydroxypropyl methylcellulose is 5% of the weight of the active ingredient-loaded particles, and the secondary fluidized bed drying conditions are a heating gas temperature of 50 °C, a heating gas flow rate of 1.5 m / s, an atomization pressure of 0.10 MPa, and a spray flow rate of 5.0 mL / min.

[0041] (5) Spray a magnesium stearate solution onto the surface of the above-mentioned high-loading particles with a hydrophilic coating layer and perform tertiary fluidized bed drying simultaneously to form Yangpi Powder instant-dissolving particles with a double coating. The addition amount of the magnesium stearate is 0.5% of the weight of the high-active ingredient-loaded particles, and the tertiary fluidized bed drying conditions are a heating gas temperature of 45 °C, a heating gas flow rate of 0.6 m / s, an atomization pressure of 0.08 MPa, and a spray flow rate of 3.0 mL / min.

[0042] Example 2 A preparation method of Yangpi Powder instant-dissolving particles for effectively proliferating probiotics, the specific steps are as follows: (1) Mix the raw materials of Yangpi Powder with an ethanol solution of 60% volume fraction at a mass ratio of 1:30, place it under the conditions of ultrasonic power of 400 W, frequency of 50 kHz, and temperature of 30 °C for ultrasonic-assisted extraction for 25 minutes, and then filter to obtain a clear liquid.

[0043] (2) Add β-cyclodextrin to the above-mentioned clear liquid and perform stirring and inclusion at room temperature to obtain a Yangpi Powder inclusion solution, and the mass ratio of the β-cyclodextrin to the clear liquid is 1:600.

[0044] (3) Continuously spray the above-mentioned Yangpi powder inclusion solution onto the surface of seed particles, and perform synchronous drying in a fluidized bed to obtain high-loading particles. The seed particles are microcrystalline cellulose with a particle size of 90 mesh, and the fluidized bed drying conditions are a heating gas temperature of 65 °C, a gas flow rate of 1.4 m / s, an atomization pressure of 0.18 MPa, and a spray flow rate of 8.0 mL / min.

[0045] (4) Spray a polyvinylpyrrolidone solution onto the surface of the above-mentioned high-loading particles, and perform secondary fluidized bed drying to form a hydrophilic coating layer. The addition amount of polyvinylpyrrolidone is 4% of the weight of the active ingredient-loaded particles, and the secondary fluidized bed drying conditions are a heating gas temperature of 55 °C, a heating gas flow rate of 1.8 m / s, an atomization pressure of 0.14 MPa, and a spray flow rate of 6.0 mL / min.

[0046] (5) Spray glycerol monostearate onto the surface of the above-mentioned high-loading particles with a hydrophilic coating layer, and perform tertiary fluidized bed drying simultaneously to form Yangpi powder instant particles with a double coating. The addition amount of glycerol monostearate is 0.4% of the weight of the high-active ingredient-loaded particles, and the tertiary fluidized bed drying conditions are a heating gas temperature of 50 °C, a heating gas flow rate of 0.8 m / s, an atomization pressure of 0.11 MPa, and a spray flow rate of 4.0 mL / min.

[0047] Example 3 A preparation method of Yangpi powder instant particles for effectively proliferating probiotics, the specific steps are as follows: (1) Mix the Yangpi powder raw materials with an ethanol solution with a volume fraction of 70% at a mass ratio of 1:40, place it under the conditions of an ultrasonic power of 500 W, a frequency of 80 kHz, and a temperature of 40 °C for ultrasonic-assisted extraction, and the extraction duration is 10 minutes, and then filter to obtain a clear solution.

[0048] (2) Add β-cyclodextrin to the above-mentioned clear solution, and perform stirring inclusion at room temperature to obtain a Yangpi powder inclusion solution, and the mass ratio of β-cyclodextrin to the clear solution is 1:400.

[0049] (3) Continuously spray the above-mentioned Yangpi powder inclusion solution onto the surface of seed particles, and perform synchronous drying in a fluidized bed to obtain high-loading particles. The seed particles are starch with a particle size of 80 mesh, and the fluidized bed drying conditions are a heating gas temperature of 70 °C, a gas flow rate of 1.6 m / s, an atomization pressure of 0.20 MPa, and a spray flow rate of 9.0 mL / min.

[0050] (4) A solution of hydroxypropyl methylcellulose and polyvinylpyrrolidone K30 is sprayed onto the surface of the above high-load particles, and a secondary fluidized bed drying is performed to form a hydrophilic coating layer. The amount of polyhydroxypropyl methylcellulose and polyvinylpyrrolidone K30 added is 3% of the weight of the active ingredient loaded particles, and the secondary fluidized bed drying conditions are: heating gas temperature 60 ℃, heating gas flow rate 3.0 m / s, atomization pressure 0.18 MPa, and spray flow rate 7.0 mL / min.

[0051] (5) Spray micronized silica gel onto the surface of the high-load particles with the hydrophilic coating layer, and simultaneously perform three fluidized bed drying processes to form Yangpi San fast-dissolving particles with a double-layer coating. The amount of micronized silica gel added is 0.3% of the weight of the high-activity ingredient-loaded particles, and the three fluidized bed drying conditions are: heating gas temperature 55 ℃, heating gas flow rate 1.0 m / s, atomization pressure 0.15 MPa, and spray flow rate 5.0 mL / min.

[0052] Comparative Example 1 A method for preparing spleen-nourishing powder granules that effectively promotes the proliferation of probiotics, differing from Example 3 in that it omits the β-cyclodextrin inclusion step. The specific steps are as follows: (1) Mix the raw materials of Yangpi San with 70% volume fraction ethanol solution at a mass ratio of 1:40, and perform ultrasonic-assisted extraction under the conditions of ultrasonic power of 500 W, frequency of 80 kHz and temperature of 40 ℃ for 10 minutes. Then filter to obtain clear liquid.

[0053] (2) The clarified liquid was continuously sprayed onto the surface of the seed particles and simultaneously dried in a fluidized bed to obtain active ingredient-loaded particles. The seed particles were starch with a particle size of 80 mesh, and the fluidized bed drying conditions were: heating gas temperature of 70 °C, gas flow rate of 1.6 m / s, atomization pressure of 0.20 MPa, and spray flow rate of 9.0 mL / min.

[0054] (3) A solution of hydroxypropyl methylcellulose and polyvinylpyrrolidone K30 is sprayed onto the surface of the above-mentioned active ingredient loaded particles, and a secondary fluidized bed drying is performed to form a hydrophilic coating layer. The amount of polyhydroxypropyl methylcellulose and polyvinylpyrrolidone K30 added is 3% of the weight of the active ingredient loaded particles, and the secondary fluidized bed drying conditions are: heating gas temperature 60℃, heating gas flow rate 3.0 m / s, atomization pressure 0.18 MPa, and spray flow rate 7.0 mL / min.

[0055] (4) Spray micronized silica gel onto the surface of the high-load particles with the hydrophilic coating layer, and simultaneously perform three fluidized bed drying processes to form Yangpi San fast-dissolving particles with a double-layer coating. The amount of micronized silica gel added is 0.3% of the weight of the high-activity ingredient-loaded particles, and the three fluidized bed drying conditions are: heating gas temperature 55 ℃, heating gas flow rate 1.0 m / s, atomization pressure 0.15 MPa, and spray flow rate 5.0 mL / min.

[0056] Comparative Example 2 A method for preparing spleen-nourishing powder granules, compared with Example 3, differs in that the hydrophobic coating step is omitted, and only a single hydrophilic coating treatment is performed. The specific steps are as follows: (1) Mix the raw materials of Yangpi San with 70% volume fraction ethanol solution at a mass ratio of 1:40, and perform ultrasonic-assisted extraction under the conditions of ultrasonic power of 500 W, frequency of 80 kHz and temperature of 40 ℃ for 10 minutes. Then filter to obtain clear liquid.

[0057] (2) Add β-cyclodextrin to the above clear liquid and stir and encapsulate it at room temperature for 30 minutes to obtain the Yangpi Powder encapsulated solution. The mass ratio of β-cyclodextrin to the clear liquid is 1:400.

[0058] (3) The above-mentioned spleen-nourishing powder encapsulation solution was continuously sprayed onto the surface of the seed particles and simultaneously dried in a fluidized bed to obtain high-load particles. The seed particles were starch with a particle size of 80 mesh, and the fluidized bed drying conditions were: heating gas temperature of 70 ℃, gas flow rate of 1.6 m / s, atomization pressure of 0.20 MPa, and spray flow rate of 9.0 mL / min.

[0059] (4) The above-mentioned high-load particles are placed in a fluidized bed and uniformly sprayed with a mixed solution of hydroxypropyl methylcellulose and polyvinylpyrrolidone K30 (mass ratio 1:1), and simultaneously fluidized drying is carried out to form a single hydrophilic coating layer. The amount of the mixed hydrophilic material added is 3% of the weight of the active ingredient loaded particles. The fluidized drying conditions are controlled as follows: heating gas temperature 60 ℃, flow rate 3.0 m / s, atomization pressure 0.18 MPa, spray flow rate 7.0 mL / min. After drying until the moisture content of the particles is ≤3%, the material is discharged without subsequent hydrophobic coating steps, and finally, the spleen-nourishing powder particles are obtained.

[0060] Comparative Example 3 A method for preparing spleen-nourishing powder granules, compared with Example 3, differs in that it does not use the fluidized bed spray granulation process, but instead uses the traditional wet granulation process. The specific steps are as follows: (1) Mix the raw materials of Yangpi San with 70% volume fraction ethanol solution at a mass ratio of 1:40, and perform ultrasonic-assisted extraction under the conditions of ultrasonic power of 500 W, frequency of 80 kHz and temperature of 40 ℃ for 10 minutes. Then filter to obtain clear liquid.

[0061] (2) Add β-cyclodextrin to the above clear liquid and stir and encapsulate it at room temperature for 30 minutes to obtain the Yangpi Powder encapsulated solution. The mass ratio of β-cyclodextrin to the clear liquid is 1:400.

[0062] (3) Add 80-mesh starch (the amount added is the same as the amount of seed microparticles in Example 3) to the above inclusion solution, and slowly add an appropriate amount of purified water while stirring to adjust the consistency of the soft material until the soft material can be formed into a ball by hand and easily dispersed by light touch. Pass it through a 16-mesh sieve to obtain wet granules. Place the wet granules in an oven and dry them at a constant temperature of 70 ℃ for 2 hours (turn them over every 30 minutes during the period to ensure uniform drying) to obtain active ingredient loaded granules. There is no fluidized bed spray granulation process throughout the entire process.

[0063] (4) Spray a mixed solution of hydroxypropyl methylcellulose and polyvinylpyrrolidone K30 (mass ratio 1:1) onto the surface of the above active ingredient loaded particles, and dry it in an oven at 55 °C for 1 hour to form a hydrophilic coating layer. The amount of the mixed hydrophilic material added is 3% of the weight of the active ingredient loaded particles.

[0064] (5) Spray micro-powder silica gel suspension onto the surface of the above-mentioned particles with hydrophilic coating layer, and dry in an oven at 50 ℃ for 1 hour to form a hydrophobic coating layer. The amount of micro-powder silica gel added is 0.3% of the weight of the high-activity ingredient loaded particles, and finally the spleen-nourishing powder particles are obtained.

[0065] Experimental Example 1: Evaluation of Instant Solubility Take 2.0 g of each sample (accurate to 0.001 g) and place it in 900 mL of purified water at 37 ℃ ± 0.5 ℃. Stir at a constant speed of 50 r / min. The dissolution time is recorded when the sample is completely dissolved (the solution is clear and there are no visible particles or flocculent matter). Each group is measured in parallel 3 times. After removing outliers, the average value is taken and the relative standard deviation (RSD) is calculated to be ≤5%.

[0066] Table 1. Dissolution time and appearance evaluation results of Yangpi San granules in different embodiments and comparative examples. The complete dissolution time of samples in Examples 1-3 was ≤45 s, demonstrating excellent instantaneous dissolution performance. This was primarily due to the synergistic effect of the process described in this invention: fluidized bed spray granulation constructs a porous and loose particle core, increasing the specific surface area, while the hydrophilic coating layer significantly improves particle wettability, accelerating water penetration and particle disintegration. Comparative Example 1, lacking the β-cyclodextrin inclusion step, saw some active ingredients easily aggregate to form microcrystals, resulting in a slightly longer dissolution time (75±3 s), but still superior to Comparative Examples 2 and 3. Comparative Example 2, lacking a hydrophobic coating layer, had its hydrophilic coating layer directly exposed to water, leading to particle agglomeration and adhesion, hindering water penetration and significantly reducing the dissolution rate. Comparative Example 3, using traditional wet granulation, had a dense particle structure and extremely low porosity, making it difficult for water to quickly penetrate the particle interior, resulting in a dissolution time as long as 126±8 s, only achieving a slow dissolution level. This fully demonstrates the crucial role of fluidized bed granulation and the double-layer coating process in improving instantaneous dissolution.

[0067] Experimental Example 2: Evaluation of Moisture Resistance The moisture resistance was evaluated using a constant temperature and humidity method. 5.0 g of each sample (accurate to 0.001 g) was spread evenly in a 5 cm diameter petri dish (thickness ≤ 2 mm) and placed in a constant temperature and humidity chamber. The temperature was set at 25 ± 1 ℃ and the relative humidity at 75% ± 2%. Samples were taken at 0 h, 24 h, 48 h, and 72 h, and the moisture absorption weight gain was quickly measured and calculated as follows: Moisture absorption weight gain = (mass after moisture absorption - mass before moisture absorption) / mass before moisture absorption × 100%. Each group was measured in triplicate, with an RSD ≤ 4%. The moisture absorption weight gain at 72 h was combined with the particle appearance (whether it clumps or adheres) to comprehensively evaluate the moisture resistance.

[0068] Table 2. Evaluation results of process adhesion and stability of Yangpi San instant granules in different embodiments and comparative examples. The moisture absorption weight gain rates of Examples 1-3 within 72 h were all lower than 1.5%, and the particle appearance was loose without caking or adhesion, showing excellent anti-moisture absorption stability. This is the result of the synergistic protection of the double-layer coating structure: the inner hydrophilic coating layer can form a dense film to block part of the water vapor from penetrating into the particle core; the outer hydrophobic material (such as silica micropowder) can build a hydrophobic barrier to further isolate the environmental humidity, and the double protection effectively inhibits the water vapor migration. In Comparative Example 1, due to the absence of β-cyclodextrin inclusion, some hydrophilic active ingredients were exposed on the particle surface, and the moisture absorption weight gain rate slightly increased to 1.45±0.13%, but it was still much lower than those of Comparative Examples 2 and 3, and there was no obvious caking; in Comparative Example 2, the hydrophobic coating layer was missing, and only the hydrophilic coating layer could not effectively block the water vapor, and the moisture absorption weight gain rate within 72 h reached 5.87±0.32%. The particles seriously caked due to moisture absorption and completely lost the anti-moisture absorption ability; in Comparative Example 3, the traditional granulation process was adopted, the porosity of the particle surface was uneven, the coating layer was not attached densely and there were tiny cracks, and the water vapor was easy to penetrate through the cracks. The moisture absorption weight gain rate was 2.76±0.21%, and there was slight moisture absorption adhesion on the particle surface, which fully verified the key value of the combination of the double-layer coating and fluidized bed granulation of the present invention in improving the storage stability of the product.

[0069] Test Example 3: Verification of the regulation of intestinal flora and the proliferation of probiotics by Yangpi Powder instant granules In order to verify the regulation of intestinal flora and the proliferation effect of probiotics by the Yangpi Powder instant granules of the present invention, an experiment was carried out using an SPF-grade mouse model. The experiment was divided into a blank control group (CK) and a Yangpi Powder group (YPS). The blank control group was given an equal volume of sterile water, and the Yangpi Powder group was given a Yangpi Powder solution prepared by dissolving the Yangpi Powder instant granules of the present invention in sterile water according to the dose converted by body weight. The administration was carried out by gavage for 28 consecutive days. After the experiment, mouse fecal samples were collected, and the intestinal flora was analyzed by high-throughput 16S rRNA gene sequencing. The results showed that the abundances of probiotics such as Lactobacillus and Bifidobacterium in the intestines of the mice in the Yangpi Powder group increased significantly, while the numbers of potential pathogenic bacteria such as Escherichia coli and Clostridium decreased. The Yangpi Powder instant granules prepared by the present invention can increase the number of beneficial bacteria, and thus may improve the digestion, absorption and spleen-stomach functions of the host.

[0070] Please refer to Figure 1 , which is a columnar chart of the relative abundances of species at the genus level. It can be seen from the results in Figure 1 that compared with the blank control group, the intestinal flora of the mice in the Yangpi Powder group had obvious structural changes at the genus level. Generally speaking, after the intervention of Yangpi Powder, the relative abundances of various genera related to intestinal health and energy metabolism showed an upward trend, while the relative abundances of some potentially unfavorable genera decreased. In terms of beneficial genera, Oscillibacter, Eubacterium, Acetatifactor and RuminococcusThe relative abundance of the spleen-nourishing powder group was significantly higher than that in the control group (P < 0.01). Among them, Oscillibacter and Eubacterium The abundance of [a substance] increased significantly, indicating that the intervention of Yangpi San (a traditional Chinese medicine formula) helps maintain gut microbiota related to metabolic homeostasis. Meanwhile, Lactobacillus and Bifidobacterium Traditional probiotic strains also showed a certain increase in the Yangpi San group, indicating that Yangpi San has a tendency to promote the growth of beneficial bacteria. Furthermore, Figure 1 The data also shows that in the spleen-nourishing powder group... Ruminococcus The relative abundance of this bacterium was significantly increased compared to the control group. This bacterium is associated with enhanced intestinal barrier and improved metabolism, indicating that Yangpi San helps improve intestinal microecological function.

[0071] Regarding potentially harmful or opportunistic pathogens Escherichia, Salmonella and Clostridioides The relative abundance of harmful bacteria in the Yangpi San group was lower than that in the control group, and the overall level was low, indicating that the intervention of Yangpi San did not cause the proliferation of harmful bacteria, but rather helped to inhibit their relative abundance to a certain extent.

[0072] In summary, Yangpi San can positively regulate the intestinal flora structure at the genus level, promoting the proliferation of various beneficial bacteria while reducing the relative abundance of some potentially harmful bacteria, thus helping to maintain the balance of the intestinal microecology. This result is consistent with the direction of Yangpi San in improving the intestinal environment and promoting intestinal health.

[0073] The above description is merely an embodiment of the present invention and does not limit the patent scope of the present invention. Any equivalent modifications made based on the content of the present invention specification and drawings, or direct or indirect applications in related technical fields, are similarly included within the patent protection scope of the present invention.

Claims

1. A preparation method of instant Yangpi powder granules for effectively proliferating probiotics, characterized in that, Includes the following steps: (1) Extract the raw materials of Yangpi San to obtain a clear liquid; (2) Add inclusion material to the clarified liquid obtained in step (1) to form an inclusion solution; (3) The inclusion solution obtained in step (2) is continuously sprayed onto the surface of the seed particles and simultaneously subjected to fluidized bed drying to obtain particles with high active ingredient loading. (4) The hydrophilic material is evenly sprayed onto the surface of the high-activity ingredient loading particles obtained in step (3), and then a second fluidized bed drying is performed. Then the hydrophobic material is evenly sprayed and a third fluidized bed drying is performed to form the Yangpi San quick-dissolving particles with a double-layer coating structure containing a hydrophilic inner layer and a hydrophobic outer layer.

2. The method for preparing the spleen-nourishing powder instant granules for effectively proliferating probiotics according to claim 1, characterized in that, The extraction is ultrasound-assisted extraction, and the extraction solvent used is an ethanol solution with a volume fraction of 50%-70%. The mass ratio of the spleen-nourishing powder raw material to the ethanol solution is 1:20 to 1:

40.

3. The method for preparing the spleen-nourishing powder instant granules for effectively proliferating probiotics according to claim 2, characterized in that, The ultrasonic-assisted extraction conditions in step (1) are: ultrasonic time 10-40 minutes, ultrasonic power 300-500 W, ultrasonic frequency 20-80 kHz, and extraction temperature 20-40 ℃.

4. The method for preparing the spleen-nourishing powder instant granules for effectively proliferating probiotics according to claim 1, characterized in that, The inclusion material in step (2) is β-cyclodextrin, and its mass ratio with the clarified liquid is 1:400 to 1:

800.

5. The method for preparing the spleen-nourishing powder instant granules for effectively proliferating probiotics according to claim 1, characterized in that, The seed microparticles in step (3) are made of one of α-lactose, microcrystalline cellulose or starch, with a particle size range of 80-100 mesh.

6. The method for preparing the spleen-nourishing powder instant granules for effectively proliferating probiotics according to claim 1, characterized in that, The fluidized bed drying conditions in step (3) are: heating gas temperature 60-70℃, heating gas flow rate 1.2-1.6 m / s, atomization pressure 0.15-0.20 MPa, and spray flow rate 7.0-9.0 mL / min.

7. The method for preparing the spleen-nourishing powder instant granules for effectively proliferating probiotics according to claim 1, characterized in that, The hydrophilic material mentioned in step (4) is one or more of hydroxypropyl methylcellulose or polyvinylpyrrolidone K30, and its addition amount is 3%-5% of the weight of the highly active ingredient loaded particles; The conditions for the secondary fluidized bed drying in step (4) are: heating gas temperature 50-60℃, heating gas flow rate 1.5-3.0m / s, atomization pressure 0.10-0.18 MPa, and spray flow rate 5.0-7.0 mL / min.

8. The method for preparing the spleen-nourishing powder instant granules for effectively proliferating probiotics according to claim 1, characterized in that, The hydrophobic material mentioned in step (4) is one or more of magnesium stearate, glyceryl monostearate, or micronized silica gel, and its addition amount is 0.3%-0.5% of the mass of the highly active ingredient-loaded particles; The three-stage fluidized bed drying conditions in step (4) are: heating gas temperature 45-55℃, heating gas flow rate 0.6-1.0m / s, atomization pressure 0.08-0.15 MPa, and spray flow rate 3.0-5.0 mL / min.

9. A spleen-nourishing powder instant granule for effectively proliferating probiotics, characterized in that, It is prepared by the method for preparing Yangpi San instant granules that effectively proliferates probiotics as described in any one of claims 1 to 8.

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