Traditional Chinese medicine granule composition based on rhizoma polygonati and application of traditional Chinese medicine granule composition

Abstract

The invention belongs to the technical field of traditional Chinese medicine preparations, and provides a traditional Chinese medicine granule composition based on rhizoma polygonati and a preparation method and application thereof. A three-layer intelligent response structure design is adopted, a 80-300 nm rhizoma polygonati nano core is prepared through an anti-solvent precipitation technology, a calcium alginate gel buffer layer containing probiotic nutritional factors is constructed through an ionic crosslinking technology, a pH response shell layer is prepared through a fluidized bed coating technology, and the release rate lt in gastric juice is achieved; the cumulative release rate gt in intestinal juice is 10%; according to the invention, the rhizoma polygonati polysaccharide and probiotic nutritional factors are added into the preparation, the precise intestinal targeted release performance is 80%, the drug loading capacity is 15-35%, the coating efficiency is 85-95%, and the technical problems that a traditional rhizoma polygonati preparation is poor in stability, effective components are damaged by gastric acid, and the bioavailability is low are solved; the traditional Chinese medicine composition can be used for treating diseases such as weakness of the spleen and the stomach, functional dyspepsia and dysbacteriosis of intestinal flora, and has wide application value.

Description

Technical Field

[0001] The present invention relates to the technical field of Chinese medicine preparations, and in particular to a Chinese medicine granule composition based on polygonatum and application thereof. Background Art

[0002] With the accelerated pace of modern life and changing dietary patterns, the incidence of gastrointestinal disorders such as spleen and stomach deficiency and functional dyspepsia continues to rise. Intestinal-targeted drug delivery systems are playing an increasingly important role in the treatment of digestive system diseases. Polygonatum sibiricum, a traditional Chinese medicinal herb, boasts remarkable benefits in invigorating Qi and strengthening the spleen, nourishing Yin and moistening dryness. It exhibits unique advantages in treating conditions such as spleen and stomach deficiency and intestinal dysfunction. However, its clinical application places stringent demands on the performance of drug formulations. In the complex physiological environment of the gastrointestinal tract, an ideal Polygonatum sibiricum preparation must possess excellent gastric acid stability to protect the active ingredients from degradation and inactivation in the highly acidic environment. Furthermore, the formulation must exhibit precise intestinal-targeted release capabilities to ensure sufficient release and absorption of the drug ingredients at the target site. Furthermore, the formulation must exhibit excellent bioavailability and stability, as well as good compatibility with the intestinal microecological environment, to maximize the pharmacological effects of Polygonatum sibiricum. Meeting these performance requirements is crucial for improving the clinical efficacy of traditional Chinese medicine preparations, promoting the modernization of traditional Chinese medicine, and providing patients with safer and more effective treatment options. It also provides new technical approaches and theoretical support for the design and development of novel drug delivery systems for traditional Chinese medicine.

[0003] Although Polygonatum sibiricum has broad application prospects in the field of traditional Chinese medicine preparations, current research and industrial applications still face many technical challenges and performance defects. Existing Polygonatum sibiricum preparations generally have the problem of poor stability, which is mainly due to the complexity of the chemical structure and environmental sensitivity of the active ingredients of Polygonatum sibiricum. Chemical reactions such as oxidation and hydrolysis are prone to occur during storage and use, resulting in a decrease in the content of active ingredients and a decrease in efficacy. The destruction of active ingredients by gastric acid is another key technical difficulty. The main active ingredients in Polygonatum sibiricum, such as polysaccharides and saponins, are very prone to structural changes and loss of activity in the strong acid environment of gastric juice. This is mainly due to the lack of effective gastric acid protection mechanism and precise pH-responsive release control technology. Low bioavailability is the core problem that restricts the clinical application of Polygonatum sibiricum preparations. In the form of traditional preparations, the active ingredients of Polygonatum sibiricum have poor solubility, large particle size, and low membrane permeability, resulting in low absorption efficiency in the body. This is closely related to the lack of nanotechnology and advanced drug delivery systems in the existing preparation process. For example, Chinese patent publication number CN115770252B discloses a polygonatum polysaccharide composition and its preparation method and application, but there are problems with poor product stability and insufficient gastrointestinal targeting. For example, Chinese patent publication number CN113456753A discloses a polygonatum paste composition and its preparation method, but there are shortcomings with low bioavailability and poor release control. Summary of the Invention

[0004] (1) Technical problems to be solved: The purpose of the present invention is to provide a Chinese medicine granule composition based on Polygonatum sibiricum and its application, so as to solve the problems of poor stability of Chinese medicine granules of Polygonatum sibiricum, destruction of effective ingredients by gastric acid and low bioavailability.

[0005] (2) Technical solution: In order to achieve the above-mentioned purpose, the present invention provides the following technical solution: A method for preparing a Chinese medicine granule composition based on polygonatum, comprising the following steps: S1. Preparing polygonatum nano-core particles by adopting anti-solvent precipitation technology: the polygonatum ethanol extract obtained by extracting polygonatum rhizomes is dissolved in ethanol, and deionized water is injected as an anti-solvent in the presence of lecithin stabilizer to obtain amorphous polygonatum nano-particles with a particle size of 80-300 nm, wherein the amount of the lecithin stabilizer is 0.1-2.0% by weight of the polygonatum ethanol extract.

[0006] S2. Constructing an intermediate functional buffer layer: coating the polygonatum nanoparticles with a sodium alginate solution containing probiotic nutritional factors and a pH buffer pair, and forming a calcium alginate gel functional layer with a thickness of 5-30 μm in a calcium chloride solution by ion crosslinking technology.

[0007] S3. Preparation of smart responsive shell layer: Using fluidized bed coating technology, spray coating liquid containing pH responsive material onto the surface of the gel functional layer to obtain smart responsive particles.

[0008] S4. Prepare the final composition: mix the smart response particles with pharmaceutical excipients evenly and prepare into powder or press into tablets.

[0009] The smart response particles are formed into a three-layer structure by sequentially coating a polygonatum nano core particle, a calcium alginate gel functional layer, and a pH-responsive outer shell layer. The three-layer structure enables the composition to have a pH-responsive function, triggering swelling at a pH of 5.5±0.2 and achieving a cumulative release of more than 80% at a pH of 6.8±0.3.

[0010] The present invention adopts the design of three-layer intelligent response structure to be mainly used for enhancing the intestinal targeted delivery performance and bioavailability of polygonatum Chinese medicine preparation.Polygonatum nano core particles prepared by anti-solvent precipitation technology, the solubility difference of ethanol and deionized water is utilized to realize the rapid nanoization of polygonatum alcohol extract, the nano particles formed in amorphous state significantly increase the specific surface area and the dissolution rate of effective ingredient, and the introduction of lecithin stabilizer effectively prevents the agglomeration phenomenon of nano particles, ensures that the permeability of cell membrane is improved while particle dispersion stability.The construction of intermediate function buffer layer adopts the ion crosslinking technology of sodium alginate and calcium chloride, and the calcium alginate gel formed not only provides physical protection barrier for nano core, more importantly, by introducing probiotics nutritional factor and pH buffer, realize the accurate regulation of drug release environment and the coordinated regulation of intestinal microecology, pH buffer is to the pH stability that can maintain local microenvironment, ensure the controllability of subsequent release process, and probiotics nutritional factor then provides nutritional support for intestinal beneficial flora, enhances intestinal absorption capacity to drugs. The outer intelligent response shell layer uses fluidized bed coating technology to evenly coat the pH-responsive material, forming an intelligent barrier that is sensitive to changes in the gastrointestinal environment. It maintains structural integrity in the acidic environment of gastric fluid to protect the internal active ingredients, while swelling and dissolving in the weakly alkaline environment of the intestine, achieving precise targeted release. This multi-level collaborative design significantly improves the protection, stability, and targeted release performance of the active ingredients of Polygonatum sibiricum. The high solubility provided by the nanostructured core, the environmental regulation of the functional buffer layer, and the precise release control of the intelligent response layer work together to construct an efficient intestinal targeted drug delivery system, ultimately achieving stable delivery and precise release of Polygonatum sibiricum preparations in the complex gastrointestinal environment, providing a new technical path for the modern application of traditional Chinese medicine.

[0011] Furthermore, in step S1, the preparation method of the polygonatum ethanol extract is: taking the polygonatum rhizome, washing, slicing and drying to a moisture content of ≤10%, using ethanol with a volume fraction of 60-80% as the extraction solvent, a solid-liquid ratio of 1:(8-15) g / mL, reflux extraction at a temperature of 60-80°C for 2-4 hours, extracting 2-3 times, and the combined extracts were allowed to stand and clarify for 4-12 hours, then filtered, and concentrated under reduced pressure to a relative density of 1.10-1.25 to obtain a standardized polygonatum ethanol extract with a polygonatum polysaccharide content of ≥30%, a total saponin content of ≥5%, and a moisture content of ≤8%.

[0012] Furthermore, in step S1, the volume ratio of ethanol to deionized water is 1:(8-15), the injection speed is 0.5-2.0 mL / min, the stirring speed is 800-1500 rpm, the reaction temperature is controlled at 15-25° C., the reaction time is 30-120 minutes, and the polygonatum nanoparticles exist in an amorphous state.

[0013] Furthermore, in step S2, the pH buffer pair is selected from at least one of citric acid-sodium citrate, sodium dihydrogen phosphate-disodium hydrogen phosphate, or acetic acid-sodium acetate, with a buffer capacity of 10-50 mmol / L, a mass fraction in the intermediate functional buffer layer of 2-8%, a concentration of the calcium chloride solution of 0.5-5.0%, and an ion crosslinking time of 10-60 minutes.

[0014] Furthermore, in step S3, the pH-responsive material is selected from at least one of Eudragit L100-55, hydroxypropyl methylcellulose phthalate, or polymethacrylic acid copolymer, the coating weight gain is controlled at 15-40%, the fluidized bed coating temperature is 40-80°C, the air inlet volume is 20-50 m³ / h, and the atomization pressure is 0.1-0.3 MPa.

[0015] Furthermore, in step S2, the probiotic nutritional factor comprises at least one of fructooligosaccharides, inulin, galacto-oligosaccharides, lactitol and xylo-oligosaccharides, and further comprises glutamine and arginine as intestinal cell nutritional support agents, and the mass concentration of the probiotic nutritional factor in the sodium alginate solution is 1-10 mg / mL.

[0016] Furthermore, the pharmaceutical excipients include at least one of a filler, a disintegrant, a lubricant and a flow aid; the filler is selected from at least one of microcrystalline cellulose, lactose, mannitol or pregelatinized starch, and the amount is 20-60% of the total weight of the composition.

[0017] The disintegrant is selected from at least one of sodium carboxymethyl starch, cross-linked polyvinylpyrrolidone or low-substituted hydroxypropyl cellulose, and its usage is 2-10% of the total weight of the composition.

[0018] The lubricant is selected from at least one of magnesium stearate, talc or polyethylene glycol, and its usage is 0.5-3% of the total weight of the composition.

[0019] The flow aid is selected from at least one of silicon dioxide, tricalcium phosphate or stearic acid, and the amount used is 0.2-2% of the total weight of the composition.

[0020] The present invention also discloses a Chinese medicine granule composition based on polygonatum, which is prepared by the above-mentioned preparation method; the medicine granule composition includes smart response particles and pharmaceutical excipients, and the smart response particles include an inner core layer, an intermediate functional buffer layer and an outer smart response shell layer arranged in sequence from the inside to the outside, and the inner core layer is amorphous polygonatum nanoparticles with a particle size of 80-300nm.

[0021] The intermediate functional buffer layer is a calcium alginate gel layer containing probiotic nutritional factors and pH buffer pairs, with a thickness of 5-30 μm and a porosity of 15-25% as measured by nitrogen adsorption method.

[0022] The outer intelligent response shell contains pH response material, forming an intelligent response mechanism based on pH changes.

[0023] Furthermore, the intelligent response mechanism is triggered by pH changes. The release rate is <10% after 2 hours of retention in artificial gastric juice with a pH of 1.2. Release begins after entering artificial intestinal juice with a pH of 6.8, and the main release is achieved in the intestinal environment. The USP basket method is used for measurement at 37±0.5°C, and the cumulative release rate is >80% after 6 hours in simulated intestinal juice with a pH of 6.8.

[0024] Furthermore, the coating efficiency of the smart response particles was determined to be 85-95% by weight method, and the drug loading was determined to be 15-35% by high performance liquid chromatography.

[0025] The content of the smart response particles in the composition is 30-80%, and the pharmaceutical excipients are the balance; when prepared in powder form, the particle size distribution D90 is 100-500 μm, and D50 is 50-200 μm; when prepared in tablet form, the tablet hardness is 50-150N, and the disintegration time in intestinal fluid is 15-45 minutes.

[0026] Application of a Chinese medicinal granule composition based on polygonatum in the preparation of an intestinal targeted functional drug.

[0027] The present invention adopts the design of standardized extraction and multi-layer intelligent encapsulation technology, which is mainly used to enhance the stability, targeting and bioavailability of polygonatum traditional Chinese medicine preparations. By subjecting the rhizome of polygonatum to standardized alcohol extraction, multiple reflux extractions are carried out under controlled temperature conditions using volume fraction ethanol, and standardized alcohol extracts with high content of polygonatum polysaccharides and total saponins are obtained by standing for clarification and concentrating under reduced pressure, thereby ensuring the quality stability of the raw materials and the enrichment degree of the effective ingredients, and laying a solid foundation for subsequent nano-processing. The precise control of the volume ratio of ethanol to deionized water in the anti-solvent precipitation technology, combined with specific injection speed, stirring speed and reaction temperature conditions, realizes the controllable nano-processing of polygonatum alcohol extract, and the amorphous nanoparticles formed not only significantly improve the solubility and dispersibility of the effective ingredients, but also provide an ideal core carrier for the subsequent encapsulation process. In the design of the intermediate functional buffer layer, the introduction of pH buffer pairs such as citric acid-sodium citrate, sodium dihydrogen phosphate-disodium hydrogen phosphate or acetic acid-sodium acetate, and the ion-cross-linked calcium alginate gel formed with calcium chloride solution together construct a protective layer with buffering capacity. This buffer system can not only maintain the pH stability of the local microenvironment, but also provide suitable conditions for the function of probiotic nutritional factors. The synergistic effect of probiotic nutritional factors such as oligofructose, inulin, oligogalactose, lactitol and xylo-oligosaccharides with glutamine and arginine not only promotes the proliferation of beneficial intestinal flora, but also provides nutritional support for intestinal cells, thereby enhancing the intestinal absorption capacity of drugs and immune regulation function. The outer intelligent response shell layer uses pH-responsive materials such as Eudragit L100-55, hydroxypropyl methylcellulose phthalate or polymethacrylic acid copolymer, and is evenly coated through fluidized bed coating technology to form an intelligent barrier that is sensitive to the gastrointestinal environment. It maintains structural integrity in the acidic environment of gastric fluid to protect the internal active ingredients, and swells and dissolves in the weakly alkaline environment of the intestine to achieve precise intestinal targeted release. The combination of fillers such as microcrystalline cellulose, lactose, mannitol or pregelatinized starch with disintegrants such as sodium carboxymethyl starch, cross-linked polyvinylpyrrolidone or low-substituted hydroxypropyl cellulose in the pharmaceutical excipient system, combined with lubricants such as magnesium stearate, talc or polyethylene glycol and the synergistic effect of flow aids such as silicon dioxide, tricalcium phosphate or stearic acid, not only improves the molding properties and mechanical strength of the preparation, but also optimizes the disintegration and release behavior of the drug in the intestinal environment. The organic combination of the three-layer intelligent structure and the pharmaceutical excipient system has comprehensively improved the protection, delivery and release control properties of the effective ingredients of Polygonatum sibiricum in the complex gastrointestinal environment, ultimately realizing the transformation of traditional Chinese medicine preparations into modern intelligent drug delivery systems.

[0028] (3) Beneficial Technical Effects: 1. Significantly Improved Preparation Stability: This invention obtains high-quality Polygonatum odoratum alcohol extracts through a standardized alcohol extraction process. Combined with nanotechnology and a three-layer protective structure, it effectively solves the problem of poor stability of traditional Polygonatum odoratum preparations. The synergistic effect of the lecithin stabilizer and the amorphous nanostructure prevents particle agglomeration and degradation of the active ingredients, ensuring that the preparation maintains good physical and chemical stability during storage and use.

[0029] 2. Achieve efficient gastric acid protection: The three-layer intelligent structural design combines a pH buffering pair with a calcium alginate gel to form an intermediate buffer layer, combined with the intelligent barrier function of the outer pH-responsive material, to create a multi-layer gastric acid protection system. After a two-hour retention period in artificial gastric fluid, the release rate is less than 10%, effectively protecting the active ingredients of Polygonatum from gastric acid damage, significantly outperforming traditional formulations.

[0030] 3. Significantly Improved Bioavailability: The high surface area and solubility of the nanosized core particles, combined with an intestinal-targeted release system, fully release the active ingredients of Polygonatum sibiricum to the optimal absorption site. Drug loading reaches 15-35%, with an encapsulation efficiency of 85-95%. In a simulated intestinal fluid environment, the cumulative release rate exceeds 80% over 6 hours, significantly improving bioavailability compared to traditional formulations.

[0031] 4. Precise intestinal targeted release: The intelligent response mechanism is precisely triggered by pH changes, initiating swelling at pH 5.5 ± 0.2 and achieving primary release at pH 6.8 ± 0.3, ensuring precise drug delivery in the intestinal environment. This intelligent switching function enables a seamless transition from gastric fluid protection to intestinal release, with excellent targeted performance.

[0032] 5. Enhance the intestinal microecological regulatory function: The synergistic configuration of probiotic nutritional factors (fructooligosaccharides, inulin, galactoligosaccharides, etc.) and intestinal cell nutritional support agents (glutamine, arginine) not only exerts the traditional Qi-invigorating and spleen-strengthening effects of Polygonatum odoratum, but also promotes the proliferation of beneficial intestinal bacteria and improves the intestinal microecological environment, thus achieving an organic combination of the efficacy of traditional Chinese medicine and modern prebiotic technology.

[0033] 6. Excellent formulation performance: The rational configuration of the pharmaceutical excipient system ensures uniform particle size distribution in powder form (D50 is 50-200μm, D90 is 100-500μm), appropriate hardness in tablet form (50-150N), and reasonable disintegration time (15-45 minutes), meeting all requirements for industrial production and clinical use.

[0034] 7. Precise and controllable process parameters: The process parameters of each preparation step have been optimized. Key process conditions such as anti-solvent precipitation, ionic crosslinking, and fluidized bed coating are precisely controllable, ensuring the reproducibility and stability of product quality and providing technical support for large-scale production.

[0035] 8. Extensive clinical application value: The composition prepared by the present invention can be used to treat various diseases such as spleen and stomach deficiency, functional dyspepsia, and intestinal flora imbalance, opening up a new path for the modern application of traditional Chinese medicine and having important clinical promotion value and market prospects.

[0036] 9. Outstanding technological innovation: For the first time, nanotechnology, intelligent response technology, prebiotic technology and traditional Chinese medicine preparation technology are organically combined to form a new type of intelligent Chinese medicine delivery system with independent intellectual property rights, representing the cutting-edge direction of the development of Chinese medicine preparation technology. BRIEF DESCRIPTION OF THE DRAWINGS

[0037] Figure 1 This is the microscopic morphology of the smart response particles prepared in Example 1 of the present invention.

[0038] Figure 2 This is the macroscopic morphology of the smart response particles prepared in Example 1 of the present invention.

[0039] Figure 3 The figure is a comparison of drug loading and coating efficiency between the examples of the present invention and the comparative example.

[0040] Figure 4 The pH response release performance comparison of the embodiment of the present invention and the comparative example is shown.

[0041] Figure 5 The following is a comparison of the physical properties of the tablets of the present invention and the comparative example.

[0042] Figure 6 The thermal stability and biocompatibility of the examples of the present invention and the comparative examples are compared. DETAILED DESCRIPTION

[0043] To make the objectives, technical solutions and advantages of the embodiments of the present invention more clear, the technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings in the embodiments of the present invention.

[0044] Example 1: A method for preparing a traditional Chinese medicine granule composition based on polygonatum, comprising the following steps: S1. Preparing polygonatum nano core particles using anti-solvent precipitation technology: dissolving the polygonatum ethanol extract obtained by extracting the polygonatum rhizome in ethanol, and injecting deionized water as an anti-solvent in the presence of a lecithin stabilizer to obtain amorphous polygonatum nanoparticles with a particle size of 150 nm, wherein the amount of the lecithin stabilizer is 0.8% by weight of the polygonatum ethanol extract.

[0045] S2. Constructing an intermediate functional buffer layer: coating the polygonatum nanoparticles with a sodium alginate solution containing probiotic nutritional factors and a pH buffer pair, and forming a calcium alginate gel functional layer with a thickness of 15 μm in a calcium chloride solution by ion crosslinking technology.

[0046] S3. Preparation of smart responsive shell layer: Using fluidized bed coating technology, spray coating liquid containing pH responsive material onto the surface of the gel functional layer to obtain smart responsive particles.

[0047] S4. Prepare the final composition: mix the smart response particles with pharmaceutical excipients evenly and prepare into powder or press into tablets.

[0048] The smart response particles are formed into a three-layer structure by sequentially coating a polygonatum nano core particle, a calcium alginate gel functional layer, and a pH-responsive outer shell layer. The three-layer structure enables the composition to have a pH-responsive function, triggering swelling at a pH of 5.5±0.2 and achieving a cumulative release of more than 80% at a pH of 6.8±0.3.

[0049] In step S1 of this embodiment, the preparation method of the polygonatum ethanol extract is as follows: taking the polygonatum rhizome, washing, slicing and drying to a moisture content of ≤10%, using 70% volume fraction ethanol as the extraction solvent, a solid-liquid ratio of 1:10 g / mL, reflux extraction at 70°C for 3 hours, extracting twice, and the combined extracts were allowed to stand for 8 hours to clarify and then filtered, and concentrated under reduced pressure to a relative density of 1.18 to obtain a standardized polygonatum ethanol extract with a polygonatum polysaccharide content of ≥30%, a total saponin content of ≥5%, and a moisture content of ≤8%.

[0050] In step S1 of this embodiment, the volume ratio of ethanol to deionized water is 1:10, the injection rate is 1.0 mL / min, the stirring speed is 1000 rpm, the reaction temperature is controlled at 20° C., the reaction time is 60 minutes, and the polygonatum nanoparticles exist in an amorphous state.

[0051] In step S2 of this embodiment, the pH buffer pair is selected from sodium dihydrogen phosphate-disodium hydrogen phosphate, the buffer capacity is 25 mmol / L, the mass fraction in the intermediate functional buffer layer is 4%, the concentration of the calcium chloride solution is 2.0%, and the ion crosslinking time is 30 minutes.

[0052] In step S3 of this embodiment, the pH-responsive material is selected from Eudragit L100-55, the coating weight gain is controlled at 25%, the fluidized bed coating temperature is 60° C., the air inlet volume is 35 m³ / h, and the atomization pressure is 0.2 MPa.

[0053] In step S2 of this embodiment, the probiotic nutritional factor comprises oligofructose and inulin, and further comprises glutamine and arginine as intestinal cell nutritional support agents, and the mass concentration of the probiotic nutritional factor in the sodium alginate solution is 5 mg / mL.

[0054] The pharmaceutical excipients of this embodiment include fillers, disintegrants, lubricants and flow aids.

[0055] The filler is selected from microcrystalline cellulose and is used in an amount of 40% by weight of the total composition.

[0056] The disintegrant is selected from sodium carboxymethyl starch, and the amount used is 5% of the total weight of the composition.

[0057] The lubricant is selected from magnesium stearate and is used in an amount of 1.5% by weight of the total composition.

[0058] The flow aid is selected from silicon dioxide and is used in an amount of 1% by weight of the total composition.

[0059] A Chinese medicinal granule composition based on Polygonatum sibiricum of this embodiment includes smart response particles and pharmaceutical excipients. The smart response particles include an inner core layer, an intermediate functional buffer layer and an outer smart response shell layer, which are arranged in sequence from the inside to the outside. The inner core layer is amorphous Polygonatum sibiricum nanoparticles with a particle size of 150 nm; the intermediate functional buffer layer is a calcium alginate gel layer containing probiotic nutritional factors and pH buffer pairs, with a thickness of 15 μm and a porosity of 20% determined by nitrogen adsorption method; the outer smart response shell layer contains pH response materials, forming an intelligent response mechanism based on pH changes.

[0060] The intelligent response mechanism is triggered by pH changes. The release rate is <10% after 2 hours of retention in artificial gastric fluid with a pH of 1.2. Release begins after entering artificial intestinal fluid with a pH of 6.8, and the main release is achieved in the intestinal environment. The USP basket method is used for measurement at 37±0.5℃, and the cumulative release rate is >80% after 6 hours in simulated intestinal fluid with a pH of 6.8.

[0061] The coating efficiency of the smart response particles of this embodiment was determined to be 90% by weight method, and the drug loading was determined to be 25% by high performance liquid chromatography.

[0062] The content of the smart response particles in this embodiment in the composition is 55%, and the pharmaceutical excipients are the remainder; when prepared in powder form, the particle size distribution D90 is 300 μm and D50 is 125 μm; when prepared in tablet form, the tablet hardness is 100 N and the disintegration time in intestinal fluid is 30 minutes.

[0063] Features of Example 1: Example 1 utilizes a conservative and robust design with medium-range parameters. All process parameters were selected within the median range, demonstrating excellent process stability and reproducibility. In this example, the lecithin stabilizer dosage was moderate (0.8%), the nanoparticle size was controlled at 150 nm, the intermediate buffer layer thickness was 15 μm, the coating weight gain was 25%, and the thickness ratio of each layer structure was balanced. Mild process conditions included a reaction temperature of 20°C, a stirring speed of 1000 rpm, an ionic crosslinking time of 30 minutes, and a fluidized bed coating temperature of 60°C, resulting in a high overall process safety factor. The final product exhibited a drug loading of 25%, a coating efficiency of 90%, uniform particle distribution, a tablet hardness of 100 N, and a disintegration time of 30 minutes, demonstrating balanced performance indicators.

[0064] Application scenarios: Suitable for industrial batch production, especially for pharmaceutical companies with high requirements for process stability; suitable as a basic formula for subsequent optimization in the early stage of product development; can be used for daily conditioning of various chronic spleen and stomach diseases, such as functional dyspepsia, chronic gastritis, etc., for patients who need long-term use; suitable for clinical application scenarios with moderate requirements for drug release rate.

[0065] Example 2: A method for preparing a traditional Chinese medicine granule composition based on Polygonatum, comprising the following steps: S1. Preparing Polygonatum nano core particles using anti-solvent precipitation technology: dissolving the Polygonatum odoratum ethanol extract obtained by extracting the Polygonatum odoratum rhizome in ethanol, and injecting deionized water as an anti-solvent in the presence of a lecithin stabilizer to obtain amorphous Polygonatum nanoparticles with a particle size of 95 nm, wherein the amount of the lecithin stabilizer is 0.3% by weight of the Polygonatum odoratum ethanol extract.

[0066] S2. Constructing an intermediate functional buffer layer: coating the polygonatum nanoparticles with a sodium alginate solution containing probiotic nutritional factors and a pH buffer pair, and forming a calcium alginate gel functional layer with a thickness of 8 μm in a calcium chloride solution by ion crosslinking technology.

[0067] S3. Preparation of smart responsive shell layer: Using fluidized bed coating technology, spray coating liquid containing pH responsive material onto the surface of the gel functional layer to obtain smart responsive particles.

[0068] S4. Prepare the final composition: mix the smart response particles with pharmaceutical excipients evenly and prepare into powder or press into tablets.

[0069] The smart response particles are formed into a three-layer structure by sequentially coating a polygonatum nano core particle, a calcium alginate gel functional layer, and a pH-responsive outer shell layer. The three-layer structure enables the composition to have a pH-responsive function, triggering swelling at a pH of 5.5±0.2 and achieving a cumulative release of more than 80% at a pH of 6.8±0.3.

[0070] In step S1 of this embodiment, the preparation method of the polygonatum ethanol extract is as follows: taking the polygonatum rhizome, washing, slicing and drying to a moisture content of ≤10%, using 80% volume fraction ethanol as the extraction solvent, a solid-liquid ratio of 1:8 g / mL, reflux extraction at 75°C for 2 hours, extracting 3 times, and the combined extracts were allowed to stand for 4 hours to clarify and then filtered, and concentrated under reduced pressure to a relative density of 1.22 to obtain a standardized polygonatum ethanol extract with a polygonatum polysaccharide content of ≥30%, a total saponin content of ≥5%, and a moisture content of ≤8%.

[0071] In step S1 of this embodiment, the volume ratio of ethanol to deionized water is 1:12, the injection rate is 0.8 mL / min, the stirring speed is 1300 rpm, the reaction temperature is controlled at 18° C., the reaction time is 45 minutes, and the polygonatum nanoparticles exist in an amorphous state.

[0072] In step S2 of this embodiment, the pH buffer pair is selected from citric acid-sodium citrate, the buffer capacity is 35 mmol / L, the mass fraction in the intermediate functional buffer layer is 3%, the concentration of the calcium chloride solution is 1.2%, and the ion crosslinking time is 20 minutes.

[0073] In step S3 of this embodiment, the pH-responsive material is selected from hydroxypropyl methylcellulose phthalate, the coating weight gain is controlled at 18%, the fluidized bed coating temperature is 45°C, the air inlet volume is 28 m³ / h, and the atomization pressure is 0.15 MPa.

[0074] In step S2 of this embodiment, the probiotic nutritional factor comprises galacto-oligosaccharides and lactitol, and further comprises glutamine and arginine as intestinal cell nutritional support agents. The mass concentration of the probiotic nutritional factor in the sodium alginate solution is 2.5 mg / mL.

[0075] The pharmaceutical excipients of this embodiment include a filler, a disintegrant, a lubricant and a flow aid; the filler is selected from lactose and mannitol, and the amount is 50% of the total weight of the composition; the disintegrant is selected from cross-linked polyvinylpyrrolidone, and the amount is 3% of the total weight of the composition; the lubricant is selected from talc, and the amount is 2.5% of the total weight of the composition; the flow aid is selected from tricalcium phosphate, and the amount is 0.5% of the total weight of the composition.

[0076] A Chinese medicinal granule composition based on Polygonatum sibiricum of this embodiment includes smart response particles and pharmaceutical excipients. The smart response particles include an inner core layer, an intermediate functional buffer layer and an outer smart response shell layer, which are arranged in sequence from the inside to the outside. The inner core layer is amorphous Polygonatum sibiricum nanoparticles with a particle size of 95 nm; the intermediate functional buffer layer is a calcium alginate gel layer containing probiotic nutritional factors and pH buffer pairs, with a thickness of 8 μm and a porosity of 17% determined by nitrogen adsorption method; the outer smart response shell layer contains pH response material, forming an intelligent response mechanism based on pH changes.

[0077] The intelligent response mechanism is triggered by pH changes. The release rate is <10% after 2 hours of retention in artificial gastric fluid with a pH of 1.2. Release begins after entering artificial intestinal fluid with a pH of 6.8, and the main release is achieved in the intestinal environment. The USP basket method is used for measurement at 37±0.5℃, and the cumulative release rate is >80% after 6 hours in simulated intestinal fluid with a pH of 6.8.

[0078] The coating efficiency of the smart response particles of this embodiment was determined to be 88% by weight method, and the drug loading was determined to be 32% by high performance liquid chromatography.

[0079] The content of the smart response particles in the composition of this embodiment is 72%, and the pharmaceutical excipients are the remainder; when prepared in powder form, the particle size distribution D90 is 180 μm and D50 is 80 μm; when prepared in tablet form, the tablet hardness is 75N and the disintegration time in intestinal fluid is 18 minutes.

[0080] Features of Example 2: Example 2 highlights the design concept of high solubility and rapid drug release, achieving rapid drug release through a small nanoparticle core (95 nm) and a relatively thin functional layer (8 μm). A high ethanol extraction concentration (80%) and relatively aggressive process conditions (stirring speed 1300 rpm) were employed, along with a low lecithin stabilizer dosage (0.3%), focusing on improving the extraction efficiency and nano-sizing of the active ingredient. The coating weight gain was low (18%), and the fluidized bed coating temperature was relatively low (45°C), which helped protect heat-sensitive ingredients. The final product exhibited a high drug loading (32%), a 72% content of intelligent responsive particles, a small particle size distribution (D50 of 80 μm), and a short disintegration time (18 minutes), demonstrating rapid onset of action.

[0081] Application scenarios: Suitable for patients with acute spleen and stomach discomfort who need rapid relief of symptoms; suitable for rapid-release preparations used by the elderly or patients with dysphagia; can be used in children's spleen and stomach conditioning products, taking advantage of its rapid disintegration and smaller particle size; suitable for the development of ready-to-eat health products or nutritional supplements; can be used in the field of functional foods that require rapid absorption.

[0082] Example 3: A method for preparing a traditional Chinese medicine granule composition based on Polygonatum, comprising the following steps: S1. Preparing Polygonatum nano core particles using anti-solvent precipitation technology: dissolving the Polygonatum odoratum ethanol extract obtained by extracting the Polygonatum odoratum rhizome in ethanol, and injecting deionized water as an anti-solvent in the presence of a lecithin stabilizer to obtain amorphous Polygonatum nanoparticles with a particle size of 260 nm, wherein the amount of the lecithin stabilizer is 1.5% by weight of the Polygonatum odoratum ethanol extract.

[0083] S2. Constructing an intermediate functional buffer layer: coating the polygonatum nanoparticles with a sodium alginate solution containing probiotic nutritional factors and a pH buffer pair, and forming a calcium alginate gel functional layer with a thickness of 25 μm in a calcium chloride solution by ion crosslinking technology.

[0084] S3. Preparation of smart responsive shell layer: Using fluidized bed coating technology, spray coating liquid containing pH responsive material onto the surface of the gel functional layer to obtain smart responsive particles.

[0085] S4. Prepare the final composition: mix the smart response particles with pharmaceutical excipients evenly and prepare into powder or press into tablets.

[0086] The smart response particles are formed into a three-layer structure by sequentially coating a polygonatum nano core particle, a calcium alginate gel functional layer, and a pH-responsive outer shell layer. The three-layer structure enables the composition to have a pH-responsive function, triggering swelling at a pH of 5.5±0.2 and achieving a cumulative release of more than 80% at a pH of 6.8±0.3.

[0087] In step S1 of this embodiment, the preparation method of the polygonatum ethanol extract is as follows: taking the polygonatum rhizome, washing, slicing and drying to a moisture content of ≤10%, using 60% volume fraction ethanol as the extraction solvent, a solid-liquid ratio of 1:15 g / mL, reflux extraction at 60°C for 4 hours, extracting twice, and the combined extracts were allowed to stand and clarify for 12 hours, then filtered and concentrated under reduced pressure to a relative density of 1.12 to obtain a standardized polygonatum ethanol extract with a polygonatum polysaccharide content of ≥30%, a total saponin content of ≥5%, and a moisture content of ≤8%.

[0088] In step S1 of this embodiment, the volume ratio of ethanol to deionized water is 1:15, the injection rate is 1.8 mL / min, the stirring speed is 900 rpm, the reaction temperature is controlled at 24° C., the reaction time is 100 minutes, and the polygonatum nanoparticles exist in an amorphous state.

[0089] In step S2 of this embodiment, the pH buffer pair is selected from acetic acid-sodium acetate, the buffer capacity is 42 mmol / L, the mass fraction in the intermediate functional buffer layer is 7%, the concentration of the calcium chloride solution is 4.2%, and the ion crosslinking time is 50 minutes.

[0090] In step S3 of this embodiment, the pH-responsive material is selected from polymethacrylic acid copolymer, the coating weight gain is controlled at 35%, the fluidized bed coating temperature is 75°C, the air inlet volume is 45 m³ / h, and the atomization pressure is 0.28 MPa.

[0091] In step S2 of this embodiment, the probiotic nutritional factors include inulin, xylo-oligosaccharide and lactitol, and further contain glutamine and arginine as intestinal cell nutritional support agents. The mass concentration of the probiotic nutritional factors in the sodium alginate solution is 8.5 mg / mL.

[0092] The pharmaceutical excipients of this embodiment include a filler, a disintegrant, a lubricant and a flow aid; the filler is selected from pregelatinized starch, and the amount is 35% of the total weight of the composition; the disintegrant is selected from low-substituted hydroxypropyl cellulose, and the amount is 8% of the total weight of the composition; the lubricant is selected from polyethylene glycol, and the amount is 2.8% of the total weight of the composition; the flow aid is selected from stearic acid, and the amount is 1.8% of the total weight of the composition.

[0093] A Chinese medicinal granule composition based on Polygonatum sibiricum of this embodiment includes intelligent response particles and pharmaceutical excipients. The intelligent response particles include an inner core layer, an intermediate functional buffer layer and an outer intelligent response shell layer arranged in sequence from the inside to the outside. The inner core layer is amorphous Polygonatum sibiricum nanoparticles with a particle size of 260 nm.

[0094] The middle functional buffer layer is a calcium alginate gel layer containing probiotic nutritional factors and pH buffer pairs, with a thickness of 25μm and a porosity of 24% measured by nitrogen adsorption method; the outer intelligent response shell contains pH response materials, forming an intelligent response mechanism based on pH changes.

[0095] The intelligent response mechanism is triggered by pH changes. The release rate is <10% after 2 hours of retention in artificial gastric fluid with a pH of 1.2. Release begins after entering artificial intestinal fluid with a pH of 6.8, and the main release is achieved in the intestinal environment. The USP basket method is used for measurement at 37±0.5℃, and the cumulative release rate is >80% after 6 hours in simulated intestinal fluid with a pH of 6.8.

[0096] The coating efficiency of the smart response particles of this embodiment was determined to be 92% by weight method, and the drug loading was determined to be 18% by high performance liquid chromatography.

[0097] The content of the smart response particles in the composition of this embodiment is 42%, and the pharmaceutical excipients are the remainder; when prepared in powder form, the particle size distribution D90 is 450 μm and D50 is 180 μm; when prepared in tablet form, the tablet hardness is 130N and the disintegration time in intestinal fluid is 42 minutes.

[0098] Features of Example 3: Example 3 embodies a design approach that prioritizes sustained and controlled release with stability. Multiple sustained-release barriers are constructed through a large nanoparticle size (260 nm), a thick functional buffer layer (25 μm), and a high coating weight gain (35%). A low ethanol extraction concentration (60%) and mild processing conditions are employed, prioritizing the preservation of the bioactivity of the active ingredient. A high lecithin stabilizer dosage (1.5%), a probiotic nutrient concentration of 8.5 mg / mL, and a pH buffer mass fraction of 7% enhance the formulation's stability and intestinal regulation. Although the final product exhibits a relatively low drug loading (18%), the coating efficiency is as high as 92%, the tablet hardness reaches 130 N, and the disintegration time is 42 minutes, demonstrating long-lasting sustained-release properties.

[0099] Application scenarios: Suitable for patients with chronic spleen and stomach deficiency who require long-term conditioning; suitable for the development of once-a-day or twice-a-day sustained-release preparations; can be used for patients with severe intestinal flora imbalance, taking advantage of its high concentration of probiotic nutritional factors; suitable for patients with excessive gastric acid secretion, providing better gastric acid protection through the enhanced pH buffer system; can be used in long-term treatment plans that require maintaining stable blood drug concentrations.

[0100] Example 4: A method for preparing a traditional Chinese medicine granule composition based on Polygonatum, comprising the following steps: S1. Preparing Polygonatum nano-core particles using anti-solvent precipitation technology: dissolving the Polygonatum odoratum ethanol extract obtained by extracting the Polygonatum odoratum rhizome in ethanol, and injecting deionized water as an anti-solvent in the presence of a lecithin stabilizer to obtain amorphous Polygonatum nano-particles with a particle size of 280 nm, wherein the amount of the lecithin stabilizer is 1.8% by weight of the Polygonatum odoratum ethanol extract.

[0101] S2. Constructing an intermediate functional buffer layer: coating the polygonatum nanoparticles with a sodium alginate solution containing probiotic nutritional factors and a pH buffer pair, and forming a calcium alginate gel functional layer with a thickness of 22 μm in a calcium chloride solution by ion crosslinking technology.

[0102] S3. Preparation of smart responsive shell layer: Using fluidized bed coating technology, spray coating liquid containing pH responsive material onto the surface of the gel functional layer to obtain smart responsive particles.

[0103] S4. Prepare the final composition: mix the smart response particles with pharmaceutical excipients evenly and prepare into powder or press into tablets.

[0104] The smart response particles are formed into a three-layer structure by sequentially coating a polygonatum nano core particle, a calcium alginate gel functional layer, and a pH-responsive outer shell layer. The three-layer structure enables the composition to have a pH-responsive function, triggering swelling at a pH of 5.5±0.2 and achieving a cumulative release of more than 80% at a pH of 6.8±0.3.

[0105] In step S1 of this embodiment, the preparation method of the polygonatum ethanol extract is as follows: taking the polygonatum rhizome, washing, slicing and drying to a moisture content of ≤10%, using 75% volume fraction ethanol as the extraction solvent, a solid-liquid ratio of 1:12 g / mL, reflux extraction at 80°C for 2.5 hours, extracting 3 times, and the combined extracts were allowed to stand for 6 hours to clarify and then filtered, and concentrated under reduced pressure to a relative density of 1.25 to obtain a standardized polygonatum ethanol extract with a polygonatum polysaccharide content of ≥30%, a total saponin content of ≥5%, and a moisture content of ≤8%.

[0106] In step S1 of this embodiment, the volume ratio of ethanol to deionized water is 1:8, the injection rate is 2.0 mL / min, the stirring speed is 1400 rpm, the reaction temperature is controlled at 25° C., the reaction time is 90 minutes, and the polygonatum nanoparticles exist in an amorphous state.

[0107] In step S2 of this embodiment, the pH buffer pair is selected from sodium dihydrogen phosphate-disodium hydrogen phosphate and citric acid-sodium citrate, the buffer capacity is 48 mmol / L, the mass fraction in the intermediate functional buffer layer is 6%, the concentration of the calcium chloride solution is 3.8%, and the ion crosslinking time is 45 minutes.

[0108] In step S3 of this embodiment, the pH-responsive material is selected from Eudragit L100-55 and hydroxypropyl methylcellulose phthalate, the coating weight gain is controlled at 38%, the fluidized bed coating temperature is 78°C, the air inlet volume is 48 m³ / h, and the atomization pressure is 0.25 MPa.

[0109] In step S2 of this embodiment, the probiotic nutritional factors include oligofructose, inulin, galacto-oligosaccharide and xylo-oligosaccharide, and further contain glutamine and arginine as intestinal cell nutritional support agents. The mass concentration of the probiotic nutritional factors in the sodium alginate solution is 9.2 mg / mL.

[0110] The pharmaceutical excipients of this embodiment include fillers, disintegrants, lubricants and flow aids; the fillers are selected from microcrystalline cellulose and mannitol, and the amount is 28% of the total weight of the composition; the disintegrants are selected from sodium carboxymethyl starch and cross-linked polyvinylpyrrolidone, and the amount is 9% of the total weight of the composition; the lubricants are selected from magnesium stearate and talc, and the amount is 2.2% of the total weight of the composition; the flow aids are selected from silicon dioxide and tricalcium phosphate, and the amount is 1.5% of the total weight of the composition.

[0111] A Chinese medicinal granule composition based on Polygonatum sibiricum of this embodiment includes smart response particles and pharmaceutical excipients. The smart response particles include an inner core layer, an intermediate functional buffer layer and an outer smart response shell layer, which are arranged in sequence from the inside to the outside. The inner core layer is amorphous Polygonatum sibiricum nanoparticles with a particle size of 280 nm; the intermediate functional buffer layer is a calcium alginate gel layer containing probiotic nutritional factors and pH buffer pairs, with a thickness of 22 μm and a porosity of 23% determined by nitrogen adsorption method; the outer smart response shell layer contains pH response material, forming an intelligent response mechanism based on pH changes.

[0112] The intelligent response mechanism is triggered by pH changes. The release rate is <10% after 2 hours of retention in artificial gastric fluid with a pH of 1.2. Release begins after entering artificial intestinal fluid with a pH of 6.8, and the main release is achieved in the intestinal environment. The USP basket method is used for measurement at 37±0.5℃, and the cumulative release rate is >80% after 6 hours in simulated intestinal fluid with a pH of 6.8.

[0113] The coating efficiency of the smart response particles of this embodiment was determined to be 94% by weight method, and the drug loading was determined to be 20% by high performance liquid chromatography.

[0114] The content of the smart response particles in the composition of this embodiment is 65%, and the pharmaceutical excipients are the remainder; when prepared in powder form, the particle size distribution D90 is 420 μm and D50 is 165 μm; when prepared in tablet form, the tablet hardness is 145N and the disintegration time in intestinal fluid is 38 minutes.

[0115] Features of Example 4: Example 4 utilizes a composite optimized design for comprehensive performance enhancement, maximizing performance through the synergistic integration of multiple materials and processes. The nanoparticles feature a large particle size (280 nm), a lecithin stabilizer dosage close to the upper limit (1.8%), a moderate intermediate functional layer thickness (22 μm), and a high coating weight gain (38%), embodying the design concept of multi-layer protection and precise controlled release. The process conditions are relatively rigorous, with an ethanol extraction concentration of 75%, a stirring speed of 1400 rpm, and a fluidized bed coating temperature of 78°C, focusing on improving production efficiency. The use of a composite pH buffer pair and a composite pH-responsive material ensures a comprehensive range of probiotic nutritional factors, reaching a concentration of 9.2 mg / mL. The final product achieves a coating efficiency of 94%, a 65% content of intelligent responsive particles, and a tablet hardness of 145 N, demonstrating excellent overall performance.

[0116] Application scenarios: Suitable for the treatment of difficult and complicated spleen and stomach diseases, such as refractory functional dyspepsia; suitable for patients with low immunity and intestinal flora disorders; can be used for auxiliary treatment of gastrointestinal function recovery after surgery; suitable for the development of high-end health products or special medical purpose formula foods; can be used in the development of compound preparations that need to take into account multiple functions at the same time; suitable for export products or high-end markets with extremely high requirements for product quality and stability.

[0117] Comparative Example 1: basically the same as Example 1, except that the amount of lecithin stabilizer used in step S1 is 0.05% by weight of the polygonatum ethanol extract, and other conditions remain unchanged.

[0118] Comparative Example 2: basically the same as Example 1, except that in step S1, the reaction temperature is controlled at 5°C, the stirring speed is 1000 rpm, the reaction time is 60 minutes, and other process parameters remain unchanged.

[0119] Comparative Example 3: basically the same as Example 1, except that in step S1, the volume ratio of ethanol to deionized water is 1:5, the injection speed is 1.0 mL / min, and other conditions remain unchanged.

[0120] Comparative Example 4: is basically the same as Example 1, except that no pH buffer is added in step S2, and only sodium alginate solution is used to coat the polygonatum nanoparticles, and other components and process conditions remain unchanged.

[0121] Comparative Example 5: basically the same as Example 1, except that the concentration of the calcium chloride solution in step S2 is 0.2%, the ionic crosslinking time is 30 minutes, and other conditions remain unchanged.

[0122] Comparative Example 6: basically the same as Example 1, except that no probiotic nutritional factor is added in step S2, and only sodium alginate solution containing pH buffer is used for coating, and other conditions remain unchanged.

[0123] Comparative Example 7: Basically the same as Example 1, except that in step S3, the fluidized bed coating temperature is 25°C, the air inlet volume is 35m³ / h, the atomization pressure is 0.2MPa, and other process parameters remain unchanged.

[0124] Comparative Example 8: basically the same as Example 1, except that the coating weight gain in step S3 is controlled at 8%, the fluidized bed coating temperature is 60°C, and other conditions remain unchanged.

[0125] Comparative Example 9: Basically the same as Example 1, except that in step S3, no pH-responsive material is used. Instead, ordinary hypromellose is used as the coating material, the coating weight gain is controlled at 25%, and other conditions remain unchanged.

[0126] Comparative Example 10: is basically the same as Example 1, except that in step S1, the preparation of the polygonatum ethanol extract uses 95% by volume ethanol as the extraction solvent, the solid-liquid ratio is 1:10 g / mL, and reflux extraction is carried out at 70°C for 3 hours, and other extraction conditions remain unchanged.

[0127] Comparative Example 11: Basically the same as Example 1, except that the construction of the intermediate functional buffer layer in step S2 is omitted, and the pH response material is directly coated on the surface of the Polygonatum nanoparticles. The coating weight gain is controlled at 25%, and other conditions remain unchanged.

[0128] Comparative Example 12: basically the same as Example 1, except that in step S1, the stirring speed is 300 rpm, the injection speed is 1.0 mL / min, the reaction time is 60 minutes, and other process parameters remain unchanged.

[0129] Comparative Example 13 is basically the same as Example 1, except that no lecithin stabilizer is added in step S1, and the ethanol solution of the ethanol extract of Polygonatum sibiricum is directly injected into deionized water for anti-solvent precipitation, and other conditions remain unchanged.

[0130] Comparative Example 14 is basically the same as Example 1, except that the mass concentration of the probiotic nutrient factor in the sodium alginate solution in step S2 is 0.2 mg / mL, the concentration of the calcium chloride solution is 2.0%, and other conditions remain unchanged.

[0131] Comparative Example 15: is basically the same as Example 1, except that the traditional wet granulation process is used instead of the anti-solvent precipitation technology, the polygonatum ethanol extract and microcrystalline cellulose are mixed in a mass ratio of 1:2, and an appropriate amount of distilled water is added to form a soft material, which is granulated through a 16-mesh sieve, dried at 60°C to a moisture content of less than 5%, and then subjected to subsequent coating treatment.

[0132] Performance Testing: Drug Loading Determination Experiment: The test subjects were the Smart Response Granules in a Polygonatum-based Traditional Chinese Medicine Granule Composition. The test objective was to quantitatively determine the content of the active ingredient of Polygonatum in the granules and evaluate the drug loading efficiency of the formulation. The test principle is based on HPLC separation and UV detection. The active ingredient content in the sample is calculated by comparing the peak area with that of a standard. Experimental Method: 100 mg of sample was accurately weighed, 10 mL of 50% methanol solution was added, and ultrasonic extraction was performed for 30 minutes. After centrifugation, the supernatant was filtered through a 0.22 μm filter membrane and analyzed by HPLC. The chromatographic column was a C18 column (250 mm × 4.6 mm, 5 μm), and the mobile phase was a gradient elution of methanol and 0.1% aqueous phosphoric acid. Key parameters included column temperature of 30°C, flow rate of 1.0 mL / min, detection wavelength of 280 nm, injection volume of 20 μL, and six replicates for each sample. Data processing: The active ingredient content in the sample was calculated based on the standard curve. Drug loading (%) = active ingredient content / total sample weight × 100%.

[0133] pH-responsive release behavior test: The test subjects were intelligent responsive granules, a traditional Chinese medicine granule composition based on Polygonatum sibiricum. The purpose of the test was to evaluate the release behavior of the granules under different pH environments and verify the intelligent responsiveness function. The test principle was based on a simulated gastrointestinal pH environment, and the cumulative release rate at different time points was determined by UV spectrophotometry. The experimental method used the USP basket method. The granules were loaded into a basket and tested in artificial gastric fluid (pH 1.2) for 2 hours, followed by a further 6 hours in artificial intestinal fluid (pH 6.8). The rotation speed was 100 rpm and the temperature was 37±0.5°C. Samples were taken at regular intervals to determine the concentration of the released active ingredient. Key parameters included a medium volume of 900 mL, a rotation speed of 100±4 rpm, a temperature of 37±0.5°C, and sampling time points of 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, and 8 hours. Data processing was used to plot a cumulative release rate-time curve. The calculated release rate in gastric fluid after 2 hours should be less than 10%, and the cumulative release rate in intestinal fluid after 6 hours should be greater than 80%.

[0134] Mechanical strength test experiment: The test object is a tablet compressed from a Chinese herbal medicine granule composition based on Polygonatum sibiricum. The purpose of the test is to evaluate the mechanical strength of the tablets and ensure the integrity of the tablets during transportation and storage. The test principle is based on the compression stress test, and the mechanical strength is evaluated by measuring the crushing force of the tablet under radial pressure. The experimental method uses a tablet hardness tester, places the tablet vertically in the middle of the clamp, applies pressure at a constant speed until the tablet breaks, and records the maximum pressure value when broken. At the same time, a friability test is performed, 20 tablets are placed in the friability tester, the speed is 25 rpm, and after rotating for 4 minutes, they are weighed to calculate the weight loss rate. Key parameters include hardness test speed of 20 mm / min, friability test speed of 25±1 rpm, time of 4±0.1 minutes, test environment temperature of 20-25°C, and relative humidity of 45-65%. Data processing calculates the average hardness value, the qualified standard is 50-150N, and the friability should not exceed 1.0%.

[0135] Disintegration time test experiment: The test object is a tablet of a Chinese herbal medicine granule composition based on Polygonatum sibiricum. The purpose of the test is to evaluate the disintegration performance of the tablet in a simulated intestinal environment to ensure that the drug can be released in a timely manner. The test principle is based on the physical disintegration process of the tablet in a specific medium, and the disintegration performance is evaluated by observing the time required for the tablet to completely disintegrate. The experimental method uses a disintegrator, 6 tablets are placed in a disintegration basket, and tested in a simulated intestinal fluid (pH 6.8) medium with a temperature of 37±2°C and a lifting and lowering frequency of 28-32 times / minute. The time it takes for each tablet to completely disintegrate is observed and recorded. Key parameters include medium temperature of 37±2°C, lifting amplitude of 55±2mm, frequency of 28-32 times / minute, medium volume of 900mL, and pH value of 6.8±0.1. Data processing records the disintegration time of 6 tablets, calculates the average value and relative standard deviation, and the disintegration time of enteric-coated tablets should be within the range of 15-45 minutes.

[0136] Thermal stability analysis experiment: The test object is the intelligent response granules of the traditional Chinese medicine granule composition based on Polygonatum sibiricum. The purpose of the test is to evaluate the stability of the granules at different temperatures and determine the safe temperature range for storage and use. The test principle is based on thermogravimetric analysis technology, and the thermal decomposition behavior is analyzed by monitoring the weight change of the sample during the programmed temperature increase process. The experimental method uses a thermogravimetric analyzer, accurately weighs 5-10 mg of sample and puts it into a crucible. Under a nitrogen protective atmosphere, the temperature is increased from room temperature to 600°C at a rate of 10°C / min, and the weight change and temperature are recorded simultaneously. TG and DTG curves are plotted. The thermal effect is analyzed in combination with differential scanning calorimetry (DSC), with a heating rate of 10°C / min and a temperature range of 25-300°C. Key parameters include sample amount 5-10 mg, heating rate 10°C / min, protective gas nitrogen flow rate 50 mL / min, and temperature range 25-600°C. Data processing and analysis of the starting decomposition temperature, maximum decomposition rate temperature and residual carbon rate are used to evaluate the thermal stability level.

[0137] In vitro release kinetics: The test subjects were intelligent responsive granules, a traditional Chinese medicine granule composition based on Polygonatum sibiricum. The purpose of the test was to investigate the kinetic mechanism of drug release and establish a release kinetic model. The testing principle was based on mathematical modeling to fit release data under different release conditions and analyze the release mechanism. Release tests were conducted in simulated gastric and intestinal fluids using the USP paddle method at a speed of 100 rpm and a temperature of 37±0.5°C. Samples were taken and analyzed at regular intervals, and cumulative release rate-time curves were plotted. Zero-order kinetics, first-order kinetics, the Higuchi equation, and the Korsmeyer-Peppas equation were used to fit the release data. Key parameters included a medium volume of 900 mL, a rotation speed of 100±4 rpm, a temperature of 37±0.5°C, at least 15 sampling time points, and sufficient sample volume for statistical analysis. Data processing involved calculating the correlation coefficient (r²) for each kinetic model. The model with the largest r² value was selected as the best-fitting model, and release mechanism parameters were analyzed.

[0138] Chemical Stability Evaluation Experiment: The test subjects were intelligent responsive granules, a traditional Chinese medicine granule composition based on Polygonatum sibiricum. The purpose of the test was to evaluate the chemical stability of the granules under different storage conditions and determine the shelf life and storage conditions. The test principle is based on accelerated stability testing, which uses storage under harsh conditions to predict stability under normal conditions. The experimental method is to store samples under high temperature (40±2°C, 75±5% relative humidity), high humidity (25±2°C, 90±5% relative humidity), and light (4500±500 lux). Sampling was regularly analyzed for indicators such as active ingredient content, impurity content, and appearance changes. High-performance liquid chromatography was used to determine changes in active ingredient content, and thin-layer chromatography was used to detect degradation products. Key parameters include test conditions of 40±2°C / 75±5% RH, 25±2°C / 90±5% RH, light of 4500±500 lux, and sampling time points of 0, 1, 2, 3, and 6 months. Data processing was used to calculate the active ingredient retention rate, plot stability curves, and estimate the shelf life based on the degradation rate.

[0139] In vitro biocompatibility evaluation experiment: The test objects are the coating materials and excipients of the traditional Chinese medicine granule composition based on Polygonatum. The purpose of the test is to evaluate the biocompatibility of the material and ensure its safety. The test principle is based on the cytotoxicity test, and the biocompatibility is evaluated by observing the effect of the material on cell growth and activity. The experimental method adopts the MTT method, and the L929 mouse fibroblast cell line is used. The sample extract is co-cultured with the cells at different concentration gradients for 24, 48, and 72 hours. After adding MTT solution and continuing to culture for 4 hours, DMSO is added to dissolve the formazan crystals, and the absorbance value is measured at a wavelength of 570nm to calculate the cell survival rate. At the same time, a hemolysis test is carried out. The sample extract is mixed with the rabbit red blood cell suspension, cultured at 37°C for 1 hour, and then centrifuged to measure the absorbance of the supernatant at 540nm. The key parameters include cell density 1×104 Cells were cultured at 37 ± 1°C, a CO2 concentration of 5 ± 1%, and a relative humidity of 95%. Data was processed to calculate cell viability and hemolysis rate. The cell viability should be greater than 75%, and the hemolysis rate should be less than 5%.

[0140] The properties of the coating compositions of Examples 1 to 4 and Comparative Examples 1 to 15 are summarized in Table 1. In Comparative Example 1, the extremely low amount of lecithin stabilizer resulted in severe agglomeration of nanoparticles, poor dispersion stability, and a significant decrease in drug loading and coating efficiency. At the same time, premature release in gastric juice indicated that the protective performance of the particles deteriorated. The low temperature reaction conditions of Comparative Example 2 inhibited molecular motion and diffusion rate, resulting in poor nano-sizing effect and a wide particle size distribution, which affected the subsequent coating uniformity and drug loading efficiency. In Comparative Example 3, the excessively low solvent ratio resulted in insufficient anti-solvent effect, incomplete nanoparticle formation, reduced drug loading efficiency, and an abnormally increased gastric juice release rate. The lack of pH buffer in Comparative Example 4 resulted in a poor gastric acid environment. The protective effect deteriorated sharply under low temperature, and premature release led to drug loss and decreased thermal stability; the low concentration calcium ion cross-linking strength of Comparative Example 5 was insufficient, the calcium alginate gel layer structure was loose, the coating integrity was poor, and the mechanical strength and disintegration performance were affected; the lack of probiotic nutritional factors in Comparative Example 6 weakened the intestinal regulatory function and cell compatibility, and the bioavailability decreased; the low temperature coating of Comparative Example 7 resulted in a non-dense coating film, a significant decrease in mechanical strength and barrier properties, and an abnormally prolonged disintegration time; the coating layer of Comparative Example 8 was too thin to provide effective protection, the pH response performance was basically invalid, and excessive release in gastric juice was not possible. In Comparative Example 9, the use of non-pH-responsive materials completely lost the intelligent release function, resulting in large-scale release in gastric juice and drug waste; in Comparative Example 10, high-concentration ethanol extraction led to increased impurities and changes in the structure of the active ingredient, affecting the overall stability and thermal stability of the preparation; in Comparative Example 11, the lack of an intermediate buffer layer resulted in too rapid a pH conversion, extremely poor release control, and a significant decrease in thermal stability; in Comparative Example 12, low-speed stirring resulted in uneven mixing, decreased particle dispersibility and consistency, and significantly reduced drug loading and coating efficiency; in Comparative Example 13, the absence of a stabilizer led to the most serious agglomeration phenomenon, extremely poor preparation uniformity and reproducibility, and comprehensive deterioration of various key properties; in Comparative Example 14, extremely low concentrations of nutritional factors failed to exert effective intestinal regulation, and cell compatibility was significantly reduced; in Comparative Example 15, the traditional granulation process was completely unable to achieve nanoscale dispersion and multilayer structure construction, significantly reduced drug release and absorption efficiency, and seriously deteriorated disintegration performance. These factors combined resulted in all comparative examples being significantly inferior to the examples in terms of key properties such as drug loading, release behavior, mechanical strength, thermal stability, and biocompatibility, fully verifying the synergistic importance and overall superiority of the various elements of the technical solution of the present invention.

[0141] Table 1 Summary of the properties of the compositions of Examples 1 to 4 and Comparative Examples 1 to 15:

[0142] The accompanying drawings of the present invention systematically demonstrate the scientific nature and superiority of the technical solution. Figures 1 and 2 Scanning electron microscopy clearly revealed that the smart response particles have a regular appearance, uniform size, smooth surface, and no obvious defects or agglomeration, proving the stability and reproducibility of the preparation process. Figure 3 Quantitative comparison data show that the drug loading of the embodiments reaches 18-32%, and the coating efficiency reaches 88-94%, which are significantly better than the 12.8-26.1% drug loading and 58.2-89.1% coating efficiency of the comparative examples, fully demonstrating the key role of optimizing the formulation and process parameters. Figure 4 The pH response performance test results show that the 2-hour release rate of the embodiment in gastric juice is strictly controlled in the range of 6.8-9.1%, while the 6-hour cumulative release rate in intestinal juice reaches 82.4-88.3%, achieving ideal targeted release. In contrast, the control example generally has problems of excessive release in gastric juice (up to 41.6%) and insufficient release in intestinal juice (the lowest is only 52.6%), which proves the effectiveness of the three-layer intelligent response structure design. Figure 5 The physical property data show that the hardness of the example tablets is in the range of 75-145N, and the disintegration time is controlled at 18-42 minutes, both of which meet the requirements of the pharmacopoeia. However, most of the comparative examples have the defects of insufficient hardness or too slow disintegration, which verifies the rationality of the excipient formula. Figure 6 The stability evaluation results show that the initial decomposition temperature of the embodiment reaches 238-262°C, and the cell viability remains at 87.8-93.1%, which is much better than the 203-246°C decomposition temperature and 73.2-88.3% viability of the comparative example, demonstrating the thermal stability and biosafety of the preparation. Combining these objective data and intuitive images, the technical solution of the present invention exhibits significant advantages in multiple aspects such as microstructure, macroscopic performance, and functional effects, providing a solid scientific basis for the industrial application of intelligent drug delivery systems.

[0143] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and are not intended to limit the present invention. Although the present invention has been described in detail with reference to the above embodiments, ordinary technicians in the relevant field should understand that any equivalent structural transformations made within the scope of the present invention using the contents of the present invention's description and drawings should be included within the scope of protection of the claims of the present invention.

Claims

1. A method for preparing a Chinese medicine granule composition based on Polygonatum sibiricum, characterized in that: The following steps are involved: S1. Preparing Polygonatum sibiricum nanoparticles using an antisolvent precipitation technique: dissolving a Polygonatum sibiricum ethanol extract obtained from Polygonatum sibiricum rhizomes in ethanol, injecting deionized water as an antisolvent in the presence of a lecithin stabilizer to obtain amorphous Polygonatum sibiricum nanoparticles with a particle size of 80-300 nm, wherein the lecithin stabilizer is used in an amount of 0.1-2.0% by weight of the Polygonatum sibiricum ethanol extract; S2. Constructing an intermediate functional buffer layer: coating the Polygonatum sibiricum nanoparticles with a sodium alginate solution containing probiotic nutrient factors and a pH buffer, and forming a calcium alginate gel functional layer with a thickness of 5-30 μm in a calcium chloride solution by ion crosslinking; S3. Preparation of smart response shell layer: using fluidized bed coating technology, spray coating liquid containing pH response material on the surface of the gel functional layer to obtain smart response particles; S4. Preparation of final composition: mixing the smart response particles with pharmaceutical excipients evenly, preparing them into powder or pressing them into tablets; the smart response particles are coated with Polygonatum nano-core particles, calcium alginate gel functional layer and pH response shell layer in sequence to form a three-layer structure. The three-layer structure enables the composition to have pH response function, triggering swelling at pH 5.5±0.2, and achieving more than 80% cumulative release at pH 6.8±0.

3.

2. The method for preparing a Chinese medicine granule composition based on Polygonatum sibiricum according to claim 1, wherein: In step S1, the preparation method of the polygonatum odoratum alcohol extract is as follows: taking the polygonatum odoratum rhizome, washing, slicing and drying to a moisture content of ≤10%, using ethanol with a volume fraction of 60-80% as the extraction solvent, a solid-liquid ratio of 1:(8-15) g / mL, reflux extraction at a temperature of 60-80°C for 2-4 hours, extracting 2-3 times, and merging the extracts and standing for 4-12 hours to clarify, then filtering, and concentrating under reduced pressure to a relative density of 1.10-1.25 to obtain a standardized polygonatum odoratum alcohol extract with a polygonatum polysaccharide content of ≥30%, a total saponin content of ≥5%, and a moisture content of ≤8%.

3. The method for preparing a Chinese medicine granule composition based on Polygonatum sibiricum according to claim 1, wherein: In step S1, the volume ratio of ethanol to deionized water is 1:(8-15), the injection speed is 0.5-2.0 mL / min, the stirring speed is 800-1500 rpm, the reaction temperature is controlled at 15-25° C., the reaction time is 30-120 minutes, and the polygonatum nanoparticles exist in an amorphous state.

4. The method for preparing a Chinese medicine granule composition based on Polygonatum sibiricum according to claim 1, wherein: In step S2, the pH buffer pair is selected from at least one of citric acid-sodium citrate, sodium dihydrogen phosphate-disodium hydrogen phosphate, or acetic acid-sodium acetate, has a buffer capacity of 10-50 mmol / L, and a mass fraction of 2-8% in the intermediate functional buffer layer. The concentration of the calcium chloride solution is 0.5-5.0%, and the ion crosslinking time is 10-60 minutes.

5. The method for preparing a Chinese medicine granule composition based on Polygonatum sibiricum according to claim 1, characterized in that: In step S3, the pH-responsive material is selected from at least one of Eudragit L100-55, hydroxypropyl methylcellulose phthalate, or polymethacrylic acid copolymer, the coating weight gain is controlled at 15-40%, the fluidized bed coating temperature is 40-80°C, the air inlet volume is 20-50 m³ / h, and the atomization pressure is 0.1-0.3 MPa.

6. The method for preparing a Chinese medicine granule composition based on Polygonatum sibiricum according to claim 1, characterized in that: In step S2, the probiotic nutritional factor comprises at least one of oligofructose, inulin, oligogalactose, lactitol and xylo-oligosaccharide, and further comprises glutamine and arginine as intestinal cell nutritional support agents, and the mass concentration of the probiotic nutritional factor in the sodium alginate solution is 1-10 mg / mL; the pharmaceutical excipients include at least one of a filler, a disintegrant, a lubricant and a flow aid; the filler is selected from at least one of microcrystalline cellulose, lactose, mannitol or pregelatinized starch, and the amount is 20-60% of the total weight of the composition; the disintegrant is selected from at least one of sodium carboxymethyl starch, cross-linked polyvinylpyrrolidone or low-substituted hydroxypropyl cellulose, and the amount is 2-10% of the total weight of the composition; the lubricant is selected from at least one of magnesium stearate, talc or polyethylene glycol, and the amount is 0.5-3% of the total weight of the composition; the flow aid is selected from at least one of silicon dioxide, tricalcium phosphate or stearic acid, and the amount is 0.2-2% of the total weight of the composition.

7. A Chinese medicine granule composition based on Polygonatum sibiricum, characterized in that: The Chinese medicine granule composition is prepared by the preparation method described in any one of claims 1 to 6; the medicine granule composition includes smart response particles and pharmaceutical excipients, and the smart response particles include an inner core layer, an intermediate functional buffer layer and an outer smart response shell layer arranged in sequence from the inside to the outside, and the inner core layer is amorphous Polygonatum nanoparticles with a particle size of 80-300nm; the intermediate functional buffer layer is a calcium alginate gel layer containing probiotic nutritional factors and pH buffer pairs, with a thickness of 5-30μm and a porosity of 15-25% determined by nitrogen adsorption method; the outer smart response shell layer contains pH response materials, forming an intelligent response mechanism based on pH changes.

8. The Chinese medicine granule composition based on Polygonatum sibiricum according to claim 7, characterized in that: The intelligent response mechanism is triggered by pH changes. The release rate is <10% after 2 hours of retention in artificial gastric juice with a pH of 1.

2. Release begins after entering artificial intestinal juice with a pH of 6.8, and the main release is achieved in the intestinal environment. The USP basket method is used for measurement at 37±0.5℃, and the cumulative release rate is >80% after 6 hours in simulated intestinal juice with a pH of 6.

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9. The Chinese medicine granule composition based on Polygonatum sibiricum according to claim 7, characterized in that: The coating efficiency of the smart response particles is determined to be 85-95% by a weight method, and the drug loading is determined to be 15-35% by a high-performance liquid chromatography method; the content of the smart response particles in the composition is 30-80%, and the pharmaceutical excipients are the remainder; when prepared in powder form, the particle size distribution D90 is 100-500 μm, and D50 is 50-200 μm; when prepared in tablet form, the tablet hardness is 50-150N, and the disintegration time in intestinal fluid is 15-45 minutes.

10. Use of a Chinese medicinal granule composition based on polygonatum prepared by the preparation method according to any one of claims 1 to 6 or a Chinese medicinal granule composition based on polygonatum according to any one of claims 7 to 9 in the preparation of an intestinal targeted functional drug.

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