A Chinese herbal granule composition based on Polygonatum sibiricum and its application

Abstract

This invention belongs to the field of traditional Chinese medicine preparation technology, and provides a traditional Chinese medicine granule composition based on Polygonatum sibiricum, its preparation method, and its application. This invention employs a three-layer intelligent response structure design, using antisolvent precipitation technology to prepare an 80-300nm Polygonatum sibiricum nanocore, ion crosslinking technology to construct a calcium alginate gel buffer layer containing probiotic nutritional factors, and fluidized bed coating technology to prepare a pH-responsive outer shell. This achieves precise intestinal targeted release performance with a gastric juice release rate of <10% and an intestinal juice cumulative release rate of >80%, a drug loading of 15-35%, and a coating efficiency of 85-95%. It solves the technical problems of poor stability, gastric acid destruction of effective components, and low bioavailability in traditional Polygonatum sibiricum preparations. Through the synergistic effect of Polygonatum sibiricum polysaccharides in invigorating qi and strengthening the spleen, and probiotic nutritional factors in intestinal regulation, it can be used to treat diseases such as spleen and stomach weakness, functional dyspepsia, and intestinal flora imbalance, and has broad application value.

Description

Technical Field

[0001] This invention relates to the field of traditional Chinese medicine preparation technology, specifically to a traditional Chinese medicine granule composition based on Polygonatum sibiricum and its application. Background Technology

[0002] With the accelerated pace of modern life and changes in dietary structure, the incidence of gastrointestinal diseases such as spleen and stomach weakness 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, a traditional Chinese medicine, has significant effects in invigorating qi and strengthening the spleen, nourishing yin and moistening dryness, demonstrating unique advantages in treating spleen and stomach weakness and intestinal dysfunction. However, its clinical application places strict requirements on the performance of drug formulations. In the complex physiological environment of the gastrointestinal tract, an ideal Polygonatum preparation needs excellent gastric acid stability to protect the active ingredients from degradation and inactivation in a strongly acidic environment. Simultaneously, the formulation must have precise intestinal-targeted release capability to ensure the full release and absorption of drug components at the target site. Furthermore, the formulation also needs good bioavailability and stability, as well as good compatibility with the intestinal microecological environment, thereby maximizing the pharmacological effects of Polygonatum. Meeting these performance requirements is of great significance 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 pathways and theoretical support for the design and development of novel drug delivery systems for traditional Chinese medicine.

[0003] Despite the broad application prospects of Polygonatum in traditional Chinese medicine preparations, current research and industrial application still face numerous technical challenges and performance defects. Existing Polygonatum preparations generally suffer from poor stability, mainly due to the complexity of the chemical structure and environmental sensitivity of its active ingredients. During storage and use, these ingredients are prone to oxidation, hydrolysis, and other chemical reactions, leading to a decrease in the content of effective components and reduced efficacy. Gastric acid damage to the active ingredients is another key technical challenge. The main active components in Polygonatum, such as polysaccharides and saponins, are highly susceptible to structural changes and loss of activity in the highly acidic environment of gastric juice. This is primarily due to the lack of effective gastric acid protection mechanisms and precise pH-responsive release control technology. Low bioavailability is a core issue restricting the clinical application of Polygonatum preparations. In traditional formulations, the effective components of Polygonatum have poor solubility, large particle size, and low membrane permeability, resulting in low in vivo absorption efficiency. This is closely related to the lack of nanotechnology and advanced drug delivery systems in current preparation processes. For example, Chinese patent CN115770252B discloses a Polygonatum polysaccharide composition, its preparation method and application, but it has problems such as poor product stability and insufficient gastrointestinal targeting. For example, Chinese patent CN113456753A discloses a Polygonatum ointment composition and its preparation method, but it has the disadvantages of low bioavailability and poor release control. Summary of the Invention

[0004] (1) Technical problem to be solved: The purpose of this invention is to provide a Chinese herbal medicine granule composition based on Polygonatum and its application, which solves the current problems of poor stability of Polygonatum in Chinese herbal medicine granules, destruction of effective components by gastric acid and low bioavailability.

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

[0006] S2. Constructing an intermediate functional buffer layer: The Polygonatum nanoparticles are coated with a sodium alginate solution containing probiotic nutrient factors and pH buffer pairs, and a calcium alginate gel functional layer with a thickness of 5-30 μm is formed in a calcium chloride solution through ion crosslinking technology.

[0007] S3. Preparation of intelligent response outer shell layer: Using fluidized bed coating technology, a coating liquid containing pH-responsive material is sprayed onto the surface of the gel functional layer to obtain intelligent response particles.

[0008] S4. Preparation of the final composition: The smart responsive particles are mixed evenly with pharmaceutical excipients to prepare a powder or compress it into tablets.

[0009] The intelligent responsive particles consist of a three-layer structure consisting of Polygonatum nanoparticles, a calcium alginate gel functional layer, and a pH-responsive outer shell layer. This three-layer structure enables the composition to have a pH-responsive function, triggering swelling at pH 5.5±0.2 and achieving a cumulative release of over 80% at pH 6.8±0.3.

[0010] This invention employs a three-layer intelligent response structure primarily designed to enhance the intestinal targeted delivery performance and bioavailability of Polygonatum odoratum (Huang Jing) traditional Chinese medicine preparations. The Huang Jing nano-core particles, prepared using antisolvent precipitation technology, utilize the solubility difference between ethanol and deionized water to achieve rapid nano-sizing of the Huang Jing ethanol extract, forming amorphous nanoparticles that significantly increase the specific surface area and dissolution rate of the active ingredients. The introduction of lecithin stabilizer effectively prevents nanoparticle aggregation, ensuring particle dispersion stability while improving cell membrane permeability. The intermediate functional buffer layer is constructed using ionic crosslinking technology of sodium alginate and calcium chloride. The resulting calcium alginate gel not only provides a physical protective barrier for the nano-core but, more importantly, achieves precise regulation of the drug release environment and synergistic regulation of the intestinal microecology by introducing probiotic nutrients and a pH buffer pair. The pH buffer pair maintains the pH stability of the local microenvironment, ensuring the controllability of the subsequent release process, while the probiotic nutrients provide nutritional support to beneficial intestinal flora, enhancing the intestine's ability to absorb the drug. The outer intelligent responsive shell layer uniformly coats pH-responsive materials using fluidized bed coating technology, forming an intelligent barrier sensitive to changes in the gastrointestinal environment. It maintains structural integrity in the acidic environment of gastric juice to protect the internal active ingredients, while swelling and dissolving in the weakly alkaline environment of the intestine, achieving precise targeted release. This multi-layered synergistic design significantly enhances the protective properties, stability, and targeted release performance of the active ingredients in Polygonatum sibiricum. The high solubility provided by the nano-core, the environmental regulation of the functional buffer layer, and the precise release control of the intelligent responsive layer work together to construct a highly efficient intestinal targeted drug delivery system. Ultimately, this achieves stable delivery and precise release of Polygonatum sibiricum preparations in the complex gastrointestinal environment, providing a new technological pathway for the modern application of traditional Chinese medicine.

[0011] Further, in step S1, the preparation method of the Polygonatum ethanol extract is as follows: take Polygonatum rhizomes, wash, slice and dry to a moisture content ≤10%, use ethanol with a volume fraction of 60-80% as the extraction solvent, with a material-to-liquid ratio of 1:(8-15) g / mL, reflux extraction at 60-80℃ for 2-4 hours, extract 2-3 times, combine the extracts, let stand and clarify for 4-12 hours, filter, concentrate under reduced pressure to a relative density of 1.10-1.25, and obtain a standardized Polygonatum ethanol extract with a polysaccharide content ≥30%, a total saponin content ≥5%, and a moisture content ≤8%.

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

[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 acetate-sodium acetate, with a buffer capacity of 10-50 mmol / L, a mass fraction of 2-8% in the intermediate functional buffer layer, a calcium chloride solution concentration 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 polymethyl methacrylate copolymer, the coating weight gain is controlled at 15-40%, the fluidized bed coating temperature is 40-80℃, 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 nutrient factor contains at least one of fructooligosaccharides, inulin, galactooligosaccharides, lactitol, and xylooligosaccharides, and also contains glutamine and arginine as intestinal cell nutritional support agents. The mass concentration of the probiotic nutrient factor in the sodium alginate solution is 1-10 mg / mL.

[0016] Furthermore, the pharmaceutical excipients include at least one of fillers, disintegrants, lubricants, and flow aids; the filler is selected from at least one of microcrystalline cellulose, lactose, mannitol, or pregelatinized starch, and is used in an amount of 20-60% of the total weight of the composition.

[0017] The disintegrant is selected from at least one of sodium carboxymethyl starch, crospovidone, or low-substituted hydroxypropyl cellulose, and is used in an amount of 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 is used in an amount of 0.5-3% of the total weight of the composition.

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

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

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

[0022] The outer smart response shell contains pH-responsive materials, forming a smart 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 fluid with a pH of 1.2. After being transferred to artificial intestinal fluid with a pH of 6.8, the release begins. The main release is achieved in the intestinal environment. The cumulative release rate is >80% after 6 hours in simulated intestinal fluid with a pH of 6.8, as measured by the USP basket method at 37±0.5℃.

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

[0025] The intelligent responsive particles constitute 30-80% of the composition, with the pharmaceutical excipients as the remainder; when prepared as a powder, the particle size distribution D90 is 100-500 μm and D50 is 50-200 μm; when prepared as a tablet, the tablet hardness is 50-150 N and the disintegration time in intestinal fluid is 15-45 minutes.

[0026] Application of a traditional Chinese medicine granule composition based on Polygonatum sibiricum in the preparation of intestinal-targeting functional drugs.

[0027] This invention employs standardized extraction and multi-layer intelligent encapsulation technology primarily to enhance the stability, targeting, and bioavailability of Polygonatum odoratum (Huang Jing) traditional Chinese medicine preparations. Standardized ethanol extraction of Polygonatum odoratum rhizomes is performed using volume-fraction ethanol under controlled temperature conditions through multiple reflux extractions. After static clarification and vacuum concentration, a standardized ethanol extract with high content of Polygonatum odoratum polysaccharides and total saponins is obtained, ensuring the quality stability of the raw material and the enrichment of effective components, laying a solid foundation for subsequent nano-processing. Precise control of the ethanol-to-deionized water volume ratio in the antisolvent precipitation technology, combined with specific injection rates, stirring speeds, and reaction temperature conditions, enables controllable nano-sizing of the Polygonatum odoratum ethanol extract. The resulting amorphous nanoparticles not only significantly improve the solubility and dispersibility of the effective components 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 citrate-sodium citrate, sodium dihydrogen phosphate-disodium hydrogen phosphate, or acetate-sodium acetate, together with the ion-crosslinked calcium alginate gel formed by calcium chloride solution, constructs a protective layer with buffering capacity. This buffer system not only maintains the pH stability of the local microenvironment, but also provides suitable conditions for the function of probiotic nutrients. The synergistic effect of probiotic nutrients such as fructooligosaccharides, inulin, galactooligosaccharides, lactitol, and xylooligosaccharides with glutamine and arginine promotes the proliferation of beneficial intestinal flora and provides nutritional support for intestinal cells, thereby enhancing the intestinal absorption capacity of drugs and immune regulation function. The outer intelligent responsive shell uses pH-responsive materials such as Eudragit L100-55, hydroxypropyl methylcellulose phthalate, or polymethyl methacrylate copolymer. It achieves uniform coating through fluidized bed coating technology, forming an intelligent barrier that is sensitive to the gastrointestinal environment. It maintains structural integrity in the acidic environment of gastric juice to protect the internal active ingredients, while swelling and dissolving in the weakly alkaline environment of the intestine to achieve precise intestinal targeted release. The combined use of fillers such as microcrystalline cellulose, lactose, mannitol, or pregelatinized starch with disintegrants such as sodium carboxymethyl starch, crospovidone, or low-substituted hydroxypropyl cellulose in pharmaceutical excipient systems, along with lubricants such as magnesium stearate, talc, or polyethylene glycol, and flow aids such as silica, tricalcium phosphate, or stearic acid, not only improves the molding properties and mechanical strength of the formulation but also optimizes the disintegration and release behavior of the drug in the intestinal environment. The organic integration of the three-layer intelligent structure with the pharmaceutical excipient system comprehensively enhances the protective, delivery, and release control performance of the active 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 improves formulation stability: This invention obtains high-quality Polygonatum ethanol extract through a standardized ethanol extraction process, and effectively solves the problem of poor stability in traditional Polygonatum preparations by combining nanotechnology and a three-layer protective structure. The synergistic effect of lecithin stabilizer and amorphous nanostructure prevents particle aggregation and degradation of active ingredients, enabling the formulation to maintain good physicochemical stability during storage and use.

[0029] 2. Achieving highly efficient gastric acid protection: In the three-layer intelligent structure design, the intermediate buffer layer formed by the pH buffer pair and calcium alginate gel, combined with the intelligent barrier function of the outer pH-responsive material, constructs a multi-layer gastric acid protection system. The release rate is less than 10% after 2 hours of retention in simulated gastric fluid, effectively protecting the active ingredients of Polygonatum from gastric acid degradation, significantly superior to traditional formulations.

[0030] 3. Significantly Improved Bioavailability: The high specific surface area and solubility of the nano-sized core particles, combined with the intestinal targeted release system, ensure that the active ingredients of Polygonatum are fully released at the optimal absorption site. The drug loading reaches 15-35%, with a coating efficiency as high as 85-95%. In a simulated intestinal fluid environment, the cumulative release rate exceeds 80% after 6 hours, resulting in significantly improved 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 major release at pH 6.8±0.3, ensuring accurate drug delivery within the intestinal environment. This intelligent on / off function enables a seamless transition from gastric juice protection to intestinal release, resulting in excellent targeting performance.

[0032] 5. Enhances intestinal microecological regulation: The synergistic combination of probiotic nutritional factors (fructooligosaccharides, inulin, galactooligosaccharides, etc.) and intestinal cell nutritional support agents (glutamine, arginine) not only exerts the traditional qi-tonifying and spleen-strengthening effects of Polygonatum, but also promotes the proliferation of beneficial intestinal flora 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 process performance: The rational configuration of the pharmaceutical excipient system ensures that the formulation has a uniform particle size distribution in powder form (D50 is 50-200μm, D90 is 100-500μm), suitable hardness (50-150N) in tablet form, and reasonable disintegration time (15-45 minutes), meeting the requirements of industrial production and clinical use.

[0034] 7. Precise and controllable process parameters: The process parameters of each preparation step have been optimized and designed. Key process conditions such as antisolvent 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. Wide range of clinical applications: The composition prepared by this invention can be used to treat a variety of diseases such as spleen and stomach weakness, functional dyspepsia, and intestinal flora imbalance, opening up new avenues 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, which represents the cutting-edge direction of the development of Chinese medicine preparation technology. Attached Figure Description

[0037] Figure 1 The image shows the microstructure of the smart responsive particles prepared in Example 1 of this invention.

[0038] Figure 2 The image shows the macroscopic morphology of the smart response particles prepared in Example 1 of this invention.

[0039] Figure 3 This is a comparison chart of drug loading and coating efficiency in embodiments and comparative examples of the present invention.

[0040] Figure 4 This is a comparison of the pH response release performance of the embodiments and comparative examples of the present invention.

[0041] Figure 5 This is a comparison of the physical properties of tablets in the embodiments and comparative examples of the present invention.

[0042] Figure 6 This is a comparison of the thermal stability and biocompatibility of the embodiments and comparative examples of the present invention. Detailed Implementation

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

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

[0045] S2. Constructing an intermediate functional buffer layer: The Polygonatum nanoparticles are coated with a sodium alginate solution containing probiotic nutrient factors and pH buffer pairs, and a calcium alginate gel functional layer with a thickness of 15 μm is formed in a calcium chloride solution by ion crosslinking technology.

[0046] S3. Preparation of intelligent response outer shell layer: Using fluidized bed coating technology, a coating liquid containing pH-responsive material is sprayed onto the surface of the gel functional layer to obtain intelligent response particles.

[0047] S4. Preparation of the final composition: The smart responsive particles are mixed evenly with pharmaceutical excipients to prepare a powder or compress it into tablets.

[0048] The intelligent responsive particles consist of a three-layer structure consisting of Polygonatum nanoparticles, a calcium alginate gel functional layer, and a pH-responsive outer shell layer. This three-layer structure enables the composition to have a pH-responsive function, triggering swelling at pH 5.5±0.2 and achieving a cumulative release of over 80% at pH 6.8±0.3.

[0049] In step S1 of this embodiment, the preparation method of the Polygonatum ethanol extract is as follows: take Polygonatum rhizomes, wash, slice and dry to a moisture content ≤10%, use 70% ethanol by volume as the extraction solvent, with a material-to-liquid ratio of 1:10 g / mL, reflux extraction at 70℃ for 3 hours, extract twice, combine the extracts, let stand and clarify for 8 hours, filter, concentrate under reduced pressure to a relative density of 1.18, and obtain a standardized Polygonatum ethanol extract with a polysaccharide content ≥30%, a total saponin content ≥5%, and a moisture content ≤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, and the reaction time is 60 minutes. The Polygonatum nanoparticles exist in an amorphous form.

[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℃, the air inlet volume is 35m³ / h, and the atomization pressure is 0.2MPa.

[0053] In step S2 of this embodiment, the probiotic nutrient factor includes fructooligosaccharides and inulin, and also contains glutamine and arginine as intestinal cell nutritional support agents. The mass concentration of the probiotic nutrient factor in the sodium alginate solution is 5 mg / mL.

[0054] The pharmaceutical excipients in 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% of the total weight of the composition.

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

[0058] The flow aid is selected from silica and is used at 1% of the total weight of the composition.

[0059] This embodiment presents a traditional Chinese medicine granule composition based on Polygonatum sibiricum. The granule composition includes smart responsive particles and pharmaceutical excipients. The smart responsive particles include a core layer, an intermediate functional buffer layer, and an outer smart responsive shell layer arranged sequentially from the inside out. The core layer consists of amorphous Polygonatum sibiricum nanoparticles with a particle size of 150 nm. The intermediate functional buffer layer is a calcium alginate gel layer containing probiotic nutrient factors and pH buffer pairs, with a thickness of 15 μm and a porosity of 20% as determined by nitrogen adsorption. The outer smart responsive shell layer contains pH-responsive materials, forming a smart 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. It begins to release after being transferred to artificial intestinal fluid with a pH of 6.8. The main release is achieved in the intestinal environment. The cumulative release rate is >80% after 6 hours in simulated intestinal fluid with a pH of 6.8, measured by the USP basket method at 37±0.5℃.

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

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

[0063] Features of Example 1: Example 1 employs a conservative and robust design with moderate parameter configurations. All process parameters are selected from the median range, demonstrating good process stability and reproducibility. In this example, the dosage of lecithin stabilizer is moderate (0.8%), the nanoparticle size is controlled at 150 nm, the thickness of the intermediate buffer layer is 15 μm, the coating weight gain is 25%, and the thickness ratio of each layer is balanced. The process conditions are mild: reaction temperature 20℃, stirring speed 1000 rpm, ionic crosslinking time 30 minutes, fluidized bed coating temperature 60℃, resulting in a high overall process safety factor. The final product has a drug loading of 25%, a coating efficiency of 90%, uniform particle distribution, tablet hardness of 100 N, and a disintegration time of 30 minutes, with all performance indicators balanced.

[0064] Application scenarios: Suitable for industrial mass production, especially for pharmaceutical companies with high requirements for process stability; suitable as a basic formula for subsequent optimization in the early stages of product development; can be used for daily conditioning of various chronic gastrointestinal diseases, such as functional dyspepsia, chronic gastritis and other patients who need to take it for a long time; 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 sibiricum, comprising the following steps: S1. Preparing Polygonatum sibiricum nanoparticles using antisolvent precipitation technology: dissolving the Polygonatum sibiricum ethanol extract obtained from Polygonatum sibiricum rhizome in ethanol, and injecting deionized water as an antisolvent in the presence of a lecithin stabilizer to obtain amorphous Polygonatum sibiricum nanoparticles with a particle size of 95 nm, wherein the amount of the lecithin stabilizer is 0.3% of the weight of the Polygonatum sibiricum ethanol extract.

[0066] S2. Constructing an intermediate functional buffer layer: The Polygonatum nanoparticles are coated with a sodium alginate solution containing probiotic nutrient factors and pH buffer pairs, and an 8μm thick calcium alginate gel functional layer is formed in a calcium chloride solution through ion crosslinking technology.

[0067] S3. Preparation of intelligent response outer shell layer: Using fluidized bed coating technology, a coating liquid containing pH-responsive material is sprayed onto the surface of the gel functional layer to obtain intelligent response particles.

[0068] S4. Preparation of the final composition: The smart responsive particles are mixed evenly with pharmaceutical excipients to prepare a powder or compress it into tablets.

[0069] The intelligent responsive particles consist of a three-layer structure consisting of Polygonatum nanoparticles, a calcium alginate gel functional layer, and a pH-responsive outer shell layer. This three-layer structure enables the composition to have a pH-responsive function, triggering swelling at pH 5.5±0.2 and achieving a cumulative release of over 80% at pH 6.8±0.3.

[0070] In step S1 of this embodiment, the preparation method of the Polygonatum ethanol extract is as follows: take Polygonatum rhizomes, wash, slice and dry to a moisture content ≤10%, use 80% ethanol as the extraction solvent, with a material-to-liquid ratio of 1:8 g / mL, reflux extraction at 75℃ for 2 hours, extract 3 times, combine the extracts, let stand and clarify for 4 hours, filter, concentrate under reduced pressure to a relative density of 1.22, and obtain a standardized Polygonatum ethanol extract with a polysaccharide content ≥30%, a total saponin content ≥5%, and a moisture content ≤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℃, and the reaction time is 45 minutes. The Polygonatum nanoparticles exist in an amorphous form.

[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 nutrient factor includes galactooligosaccharides and lactitol, and also contains glutamine and arginine as intestinal cell nutritional support agents. The mass concentration of the probiotic nutrient factor in the sodium alginate solution is 2.5 mg / mL.

[0075] The pharmaceutical excipients in this embodiment include fillers, disintegrants, lubricants, and flow aids; the fillers are selected from lactose and mannitol, and the amount used is 50% of the total weight of the composition; the disintegrants are selected from crospovidone, and the amount used is 3% of the total weight of the composition; the lubricant is selected from talc, and the amount used is 2.5% of the total weight of the composition; the flow aid is selected from tricalcium phosphate, and the amount used is 0.5% of the total weight of the composition.

[0076] This embodiment presents a traditional Chinese medicine granule composition based on Polygonatum sibiricum. The granule composition includes smart responsive particles and pharmaceutical excipients. The smart responsive particles include a core layer, an intermediate functional buffer layer, and an outer smart responsive shell layer arranged sequentially from the inside out. The core layer consists of amorphous Polygonatum sibiricum nanoparticles with a particle size of 95 nm. The intermediate functional buffer layer is a calcium alginate gel layer containing probiotic nutrient factors and pH buffer pairs, with a thickness of 8 μm and a porosity of 17% as determined by nitrogen adsorption. The outer smart responsive shell layer contains pH-responsive materials, forming a smart 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. It begins to release after being transferred to artificial intestinal fluid with a pH of 6.8. The main release is achieved in the intestinal environment. The cumulative release rate is >80% after 6 hours in simulated intestinal fluid with a pH of 6.8, measured by the USP basket method at 37±0.5℃.

[0078] The coating efficiency of the smart response particles in this embodiment was 88% as determined by gravimetric analysis, and the drug loading was 32% as determined by high performance liquid chromatography.

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

[0080] Example 2 Features: Example 2 emphasizes the design concept of high solubility and rapid release, achieving rapid drug release through small-particle-size nanocores (95nm) and a relatively thin functional layer (8μm). A high ethanol extraction concentration (80%) and relatively intense process conditions (stirring speed 1300rpm) are used, while the amount of lecithin stabilizer is low (0.3%), focusing on improving the extraction efficiency and nanoscale degree of the active ingredient. The coating weight gain is low (18%), and the fluidized bed coating temperature is relatively low (45℃), which is beneficial for protecting heat-sensitive components. The final product has a high drug loading (32%), a smart-response particle content of 72%, a small particle size distribution (D50 of 80μm), and a short disintegration time (18 minutes), demonstrating rapid onset of action.

[0081] Application scenarios: Suitable for patients with acute gastrointestinal discomfort who need rapid symptom relief; suitable for the elderly or patients with difficulty swallowing; can be used in children's gastrointestinal conditioning products, taking advantage of its rapid disintegration and small particle size; suitable for developing ready-to-eat health products or nutritional supplements; can be applied 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 sibiricum, comprising the following steps: S1. Preparing Polygonatum sibiricum nanoparticles using antisolvent precipitation technology: dissolving the Polygonatum sibiricum ethanol extract obtained from Polygonatum sibiricum rhizome in ethanol, and injecting deionized water as an antisolvent in the presence of a lecithin stabilizer to obtain amorphous Polygonatum sibiricum nanoparticles with a particle size of 260 nm, wherein the amount of the lecithin stabilizer is 1.5% of the weight of the Polygonatum sibiricum ethanol extract.

[0083] S2. Constructing an intermediate functional buffer layer: The Polygonatum nanoparticles are coated with a sodium alginate solution containing probiotic nutrient factors and pH buffer pairs, and a calcium alginate gel functional layer with a thickness of 25 μm is formed in a calcium chloride solution by ion crosslinking technology.

[0084] S3. Preparation of intelligent response outer shell layer: Using fluidized bed coating technology, a coating liquid containing pH-responsive material is sprayed onto the surface of the gel functional layer to obtain intelligent response particles.

[0085] S4. Preparation of the final composition: The smart responsive particles are mixed evenly with pharmaceutical excipients to prepare a powder or compress it into tablets.

[0086] The intelligent responsive particles consist of a three-layer structure consisting of Polygonatum nanoparticles, a calcium alginate gel functional layer, and a pH-responsive outer shell layer. This three-layer structure enables the composition to have a pH-responsive function, triggering swelling at pH 5.5±0.2 and achieving a cumulative release of over 80% at pH 6.8±0.3.

[0087] In step S1 of this embodiment, the preparation method of Polygonatum ethanol extract is as follows: take Polygonatum rhizome, wash, slice and dry to a moisture content ≤10%, use 60% ethanol by volume as extraction solvent, material-liquid ratio 1:15 g / mL, reflux extraction at 60℃ for 4 hours, extract twice, combine the extracts, let stand and clarify for 12 hours, filter, concentrate under reduced pressure to a relative density of 1.12, and obtain standardized Polygonatum ethanol extract with Polygonatum polysaccharide content ≥30%, total saponin content ≥5%, and moisture content ≤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℃, the reaction time is 100 minutes, and the Polygonatum nanoparticles exist in an amorphous form.

[0089] In step S2 of this embodiment, the pH buffer pair is selected from acetate-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 polymethyl methacrylate 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 nutrient factor includes inulin, xylooligosaccharide and lactitol, and also contains glutamine and arginine as intestinal cell nutritional support agents. The mass concentration of the probiotic nutrient factor in the sodium alginate solution is 8.5 mg / mL.

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

[0093] This embodiment provides a traditional Chinese medicine granule composition based on Polygonatum sibiricum. The granule composition includes smart responsive particles and pharmaceutical excipients. The smart responsive particles include a core layer, an intermediate functional buffer layer, and an outer smart responsive shell layer arranged sequentially from the inside out. The core layer consists of amorphous Polygonatum sibiricum nanoparticles with a particle size of 260 nm.

[0094] The intermediate functional buffer layer is a calcium alginate gel layer containing probiotic nutrients and pH buffer pairs, with a thickness of 25 μm and a porosity of 24% as determined by nitrogen adsorption. The outer smart response shell layer contains pH-responsive materials, forming a smart 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. It begins to release after being transferred to artificial intestinal fluid with a pH of 6.8. The main release is achieved in the intestinal environment. The cumulative release rate is >80% after 6 hours in simulated intestinal fluid with a pH of 6.8, measured by the USP basket method at 37±0.5℃.

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

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

[0098] Example 3 Features: Example 3 embodies the design philosophy of prioritizing sustained-release and stability, constructing multiple sustained-release barriers through a larger nanoparticle size (260nm), a thicker functional buffer layer (25μm), and high coating weight gain (35%). A lower ethanol extraction concentration (60%) and mild process conditions are used to protect the bioactivity of the active ingredients. A higher concentration of lecithin stabilizer (1.5%), a probiotic nutrient concentration of 8.5mg / mL, and a pH buffer ratio of 7% enhance the stability and intestinal regulatory function of the formulation. Although the final product has a relatively low drug loading (18%), its coating efficiency is as high as 92%, tablet hardness reaches 130N, and disintegration time is 42 minutes, demonstrating the characteristics of long-acting sustained release.

[0099] Application scenarios: Suitable for patients with chronic spleen and stomach weakness who require long-term conditioning; suitable for developing sustained-release formulations that are once or twice a day; can be used for patients with severe intestinal flora imbalance, taking advantage of its high concentration of probiotic nutrients; suitable for patients with excessive gastric acid secretion, providing better gastric acid protection through an enhanced pH buffering system; can be applied to long-term treatment regimens that require maintaining stable blood drug concentrations.

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

[0101] S2. Constructing an intermediate functional buffer layer: The Polygonatum nanoparticles are coated with a sodium alginate solution containing probiotic nutrient factors and pH buffer pairs, and a calcium alginate gel functional layer with a thickness of 22 μm is formed in a calcium chloride solution by ion crosslinking technology.

[0102] S3. Preparation of intelligent response outer shell layer: Using fluidized bed coating technology, a coating liquid containing pH-responsive material is sprayed onto the surface of the gel functional layer to obtain intelligent response particles.

[0103] S4. Preparation of the final composition: The smart responsive particles are mixed evenly with pharmaceutical excipients to prepare a powder or compress it into tablets.

[0104] The intelligent responsive particles consist of a three-layer structure consisting of Polygonatum nanoparticles, a calcium alginate gel functional layer, and a pH-responsive outer shell layer. This three-layer structure enables the composition to have a pH-responsive function, triggering swelling at pH 5.5±0.2 and achieving a cumulative release of over 80% at pH 6.8±0.3.

[0105] In step S1 of this embodiment, the preparation method of Polygonatum ethanol extract is as follows: take Polygonatum rhizome, wash, slice and dry to a moisture content ≤10%, use 75% ethanol by volume as extraction solvent, material-liquid ratio 1:12 g / mL, reflux extraction at 80℃ for 2.5 hours, extract 3 times, combine the extracts, let stand and clarify for 6 hours, filter, concentrate under reduced pressure to a relative density of 1.25, and obtain standardized Polygonatum ethanol extract with Polygonatum polysaccharide content ≥30%, total saponin content ≥5%, and moisture content ≤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, and the reaction time is 90 minutes. The Polygonatum nanoparticles exist in an amorphous form.

[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, with a buffer capacity of 48 mmol / L and a mass fraction of 6% in the intermediate functional buffer layer. 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 nutrient factor includes fructooligosaccharides, inulin, galactooligosaccharides and xylooligosaccharides, and also contains glutamine and arginine as intestinal cell nutritional support agents. The mass concentration of the probiotic nutrient factor in the sodium alginate solution is 9.2 mg / mL.

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

[0111] This embodiment presents a traditional Chinese medicine granule composition based on Polygonatum sibiricum. The granule composition includes smart responsive particles and pharmaceutical excipients. The smart responsive particles include a core layer, an intermediate functional buffer layer, and an outer smart responsive shell layer arranged sequentially from the inside out. The core layer consists of amorphous Polygonatum sibiricum nanoparticles with a particle size of 280 nm. The intermediate functional buffer layer is a calcium alginate gel layer containing probiotic nutrient factors and pH buffer pairs, with a thickness of 22 μm and a porosity of 23% as determined by nitrogen adsorption. The outer smart responsive shell layer contains pH-responsive materials, forming a smart 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. It begins to release after being transferred to artificial intestinal fluid with a pH of 6.8. The main release is achieved in the intestinal environment. The cumulative release rate is >80% after 6 hours in simulated intestinal fluid with a pH of 6.8, measured by the USP basket method at 37±0.5℃.

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

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

[0115] Features of Example 4: Example 4 employs a comprehensive performance enhancement design with composite optimization, maximizing performance through the synergistic combination of multiple materials and processes. The nanoparticles have a relatively large particle size (280nm), the lecithin stabilizer content is close to the upper limit (1.8%), the intermediate functional layer thickness is moderate (22μm), and the coating weight gain is high (38%), reflecting the design concept of multi-layer protection and precise controlled release. The process conditions are relatively harsh, with an ethanol extraction concentration of 75%, a stirring speed of 1400rpm, and a fluidized bed coating temperature of 78℃, focusing on improving preparation efficiency. A composite pH buffer pair and a composite pH-responsive material are used, resulting in the most comprehensive range of probiotic nutrients at a concentration of 9.2mg / mL. The final product achieves a coating efficiency of 94%, a smart responsive particle content of 65%, and a tablet hardness of 145N, demonstrating excellent overall performance.

[0116] Application scenarios: Suitable for the treatment of complex and difficult gastrointestinal diseases, such as intractable functional dyspepsia; suitable for patients with low immunity and intestinal flora imbalance; can be used as an adjunct therapy for postoperative gastrointestinal function recovery; suitable for the development of high-end health products or special medical purpose formula foods; can be applied to the development of compound preparations that need to take multiple effects 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: It is basically the same as Example 1, except that the amount of lecithin stabilizer used in step S1 is 0.05% of the weight of Polygonatum odoratum extract, and other conditions remain unchanged.

[0118] Comparative Example 2: It is basically the same as Example 1, except that the reaction temperature in step S1 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: It is basically the same as Example 1, except that in step S1, the volume ratio of ethanol to deionized water is 1:5, the injection rate is 1.0 mL / min, and other conditions remain unchanged.

[0120] Comparative Example 4: It 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 Polygonatum nanoparticles. Other components and process conditions remain unchanged.

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

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

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

[0124] Comparative Example 8: It is basically the same as Example 1, except that the coating weight gain is controlled at 8% in step S3, 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, a pH-responsive material is not used, but ordinary hydroxypropyl methylcellulose is used as the coating material, the coating weight gain is controlled at 25%, and other conditions remain unchanged.

[0126] Comparative Example 10: Basically the same as Example 1, except that in step S1, 95% ethanol was used as the extraction solvent for the preparation of the Polygonatum odoratum extract, the material-to-liquid ratio was 1:10 g / mL, and the extraction was carried out by reflux at 70°C for 3 hours, while other extraction conditions remained unchanged.

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

[0128] Comparative Example 12: It is basically the same as Example 1, except that the stirring speed in step S1 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: It is basically the same as Example 1, except that lecithin stabilizer is not added in step S1, and the ethanol solution of Polygonatum odoratum extract is directly injected into deionized water for antisolvent precipitation, while other conditions remain unchanged.

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

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

[0132] Performance Testing: Drug Loading Determination Experiment: The test subject was the intelligent responsive granules in a traditional Chinese medicine granule composition based on Polygonatum sibiricum. The purpose of the test was to quantitatively determine the content of the effective components of Polygonatum sibiricum in the granules and evaluate the drug loading efficiency of the formulation. The test principle was based on high performance liquid chromatography (HPLC) separation and ultraviolet detection technology. The content of the effective components in the sample was calculated by comparing the peak area of ​​the standard. Experimental Method: 100 mg of sample was accurately weighed, 10 mL of 50% methanol solution was added, ultrasonic extraction was performed for 30 minutes, and after centrifugation, the supernatant was collected and filtered through a 0.22 μm filter membrane for HPLC analysis. The chromatographic column was a C18 column (250 mm × 4.6 mm, 5 μm), and the mobile phase was a gradient elution of methanol-0.1% phosphoric acid aqueous solution. Key parameters included column temperature 30℃, flow rate 1.0 mL / min, detection wavelength 280 nm, injection volume 20 μL, and 6 parallel tests for each sample. Data Processing: The content of the effective components in the sample was calculated according to the standard curve. Drug loading (%) = content of effective components / total sample weight × 100%.

[0133] pH Response Release Behavior Test Experiment: The test subject was intelligent responsive granules based on a traditional Chinese medicine granule composition containing Polygonatum sibiricum. The purpose of the test was to evaluate the release behavior of the granules under different pH environments and verify the intelligent response function. The test principle was based on simulating the pH environment of the gastrointestinal tract, and the cumulative release rate at different time points was determined by ultraviolet spectrophotometry. The experimental method adopted the USP basket method. The granules were placed in a basket and tested for 2 hours in simulated gastric fluid (pH 1.2), and then transferred to simulated intestinal fluid (pH 6.8) for another 6 hours. The rotation speed was 100 rpm, the temperature was 37±0.5℃, and samples were taken at regular intervals to determine the concentration of the released effective components. Key parameters included a medium volume of 900 mL, a rotation speed of 100±4 rpm, a temperature of 37±0.5℃, 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 the cumulative release rate-time curve. The calculation showed that the 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 subject is tablets compressed from a traditional Chinese medicine granule composition based on Polygonatum sibiricum. The purpose of the test is to evaluate the mechanical strength of the tablets and ensure their integrity during transportation and storage. The test principle is based on compressive stress testing, evaluating mechanical strength by measuring the crushing force of the tablet under radial pressure. The experimental method uses a tablet hardness tester. The tablet is placed vertically in the middle of a fixture, and pressure is applied at a constant speed until the tablet breaks. The maximum pressure value at the time of breakage is recorded. Simultaneously, a friability test is performed. Twenty tablets are placed in a friability tester at a rotation speed of 25 rpm for 4 minutes, and then weighed to calculate the weight loss rate. Key parameters include hardness test speed of 20 mm / min, friability test rotation speed of 25 ± 1 rpm, time of 4 ± 0.1 minutes, ambient temperature of 20-25℃, and relative humidity of 45-65%. Data processing calculates the average hardness value. The acceptable standard is 50-150 N, and the friability should not exceed 1.0%.

[0135] Disintegration Time Test: The test subject was a tablet composition of traditional Chinese medicine granules based on Polygonatum sibiricum. The purpose of the test was to evaluate the disintegration performance of the tablets in a simulated intestinal environment to ensure timely drug release. The test principle was based on the physical disintegration process of the tablets in a specific medium, and the disintegration performance was evaluated by observing the time required for complete disintegration of the tablets. Experimental Method: A disintegration apparatus was used. Six tablets were placed in disintegration baskets and tested in a simulated intestinal fluid medium (pH 6.8). The temperature was 37±2℃, and the temperature rise and fall frequency was 28-32 times / minute. The time for complete disintegration of each tablet was observed and recorded. Key parameters included medium temperature 37±2℃, rise and fall amplitude 55±2mm, frequency 28-32 times / minute, medium volume 900mL, and pH value 6.8±0.1. Data Processing: The disintegration time of the six tablets was recorded, and the average value and relative standard deviation were calculated. The disintegration time of enteric-coated tablets should be within the range of 15-45 minutes.

[0136] Thermal stability analysis experiment: The test subject was a smart responsive granule composition of traditional Chinese medicine based on Polygonatum sibiricum. The purpose of the test was to evaluate the stability of the granules at different temperatures and determine the safe temperature range for storage and use. The test principle was based on thermogravimetric analysis (TGA), which analyzes thermal decomposition behavior by monitoring the weight change of the sample during programmed temperature rise. Experimental method: A thermogravimetric analyzer was used. 5-10 mg of sample was accurately weighed and placed in a crucible. Under a nitrogen protective atmosphere, the temperature was increased from room temperature to 600°C at a rate of 10°C / min, while simultaneously recording the weight change and temperature, and plotting TG and DTG curves. Differential scanning calorimetry (DSC) was used to analyze the thermal effect, with a heating rate of 10°C / min and a temperature range of 25-300°C. Key parameters included sample amount (5-10 mg), heating rate (10°C / min), nitrogen flow rate (50 mL / min), and temperature range (25-600°C). Data processing and analysis included the initial decomposition temperature, maximum decomposition rate temperature, and char residue to evaluate the thermal stability level.

[0137] In vitro release kinetics study: The test subject was a smart responsive granule composition of traditional Chinese medicine based on Polygonatum sibiricum. The purpose of the test was to study the kinetic mechanism of drug release and establish a release kinetic model. The test principle was based on fitting release data under different release conditions using a mathematical model to analyze the release mechanism. Experimental methods: Release tests were conducted in simulated gastric and intestinal fluids using the USP paddle method at a rotation speed of 100 rpm and a temperature of 37 ± 0.5℃. Sampling and analysis were performed 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℃, and at least 15 sampling time points, with sufficient sample volume for statistical analysis. Data processing: The correlation coefficient r² of each kinetic model was calculated, and the model with the largest r² value was selected as the best-fit model to analyze the release mechanism parameters.

[0138] Chemical stability evaluation experiment: The test subject was a smart responsive granule composition of traditional Chinese medicine 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 was based on accelerated stability testing, which predicts stability under normal conditions by storing under harsh conditions. The experimental method involved storing the samples under high temperature (40±2℃, relative humidity 75±5%), high humidity (25±2℃, relative humidity 90±5%), and light (4500±500 lux) conditions. Samples were periodically taken to analyze indicators such as the content of active ingredients, impurities, and changes in appearance. High-performance liquid chromatography (HPLC) was used to determine changes in the content of active ingredients, and thin-layer chromatography (TLC) was used to detect degradation products. Key parameters included the test conditions of 40±2℃ / 75±5%RH, 25±2℃ / 90±5%RH, and light 4500±500 lux, and sampling time points of 0, 1, 2, 3, and 6 months. Data processing included calculating the retention rate of active ingredients, plotting stability curves, and estimating the shelf life based on the degradation rate.

[0139] In vitro biocompatibility evaluation experiment: The test subjects were the coating materials and excipients of the traditional Chinese medicine granule composition based on Polygonatum sibiricum. The purpose of the test was to evaluate the biocompatibility of the materials and ensure their safety in use. The test principle was based on cytotoxicity assays, evaluating biocompatibility by observing the effects of the materials on cell growth and viability. The experimental method used the MTT assay, employing the L929 mouse fibroblast cell line. Sample extracts were co-cultured with cells at different concentration gradients for 24, 48, and 72 hours. After adding MTT solution and continuing culture for another 4 hours, DMSO was added to dissolve formazan crystals. The absorbance was measured at 570 nm, and cell viability was calculated. Simultaneously, a hemolysis assay was performed. Sample extracts were mixed with rabbit erythrocyte suspension, incubated at 37°C for 1 hour, centrifuged, and the absorbance of the supernatant was measured at 540 nm. Key parameters included cell density (1×10⁶).4 Cells / mL, culture temperature 37±1℃, CO2 concentration 5±1%, relative humidity 95%. Data processing was used to calculate cell viability and hemolysis rate; cell viability should be greater than 75%, and hemolysis rate should be less than 5%.

[0140] The performance of the coating compositions from Examples 1-4 and Comparative Examples 1-15 is summarized in Table 1. In Comparative Example 1, the extremely low amount of lecithin stabilizer led to severe nanoparticle agglomeration, poor dispersion stability, and a significant decrease in drug loading and coating efficiency. Premature release into gastric juice also indicated deterioration in particle protective performance. In Comparative Example 2, the low-temperature reaction conditions inhibited molecular motion and diffusion rates, resulting in poor nanoparticle formation, a wide particle size distribution, and negatively impacting subsequent coating uniformity and drug loading efficiency. In Comparative Example 3, the excessively low solvent ratio led to insufficient antisolvent effect, incomplete nanoparticle formation, reduced drug loading efficiency, and an abnormally high gastric juice release rate. In Comparative Example 4, the lack of a pH buffer resulted in an acidic gastric environment. The protective effect deteriorated sharply, premature release led to drug loss and decreased thermal stability; in Comparative Example 5, the low concentration of calcium ions resulted in insufficient cross-linking strength, a loose alginate gel layer structure, poor coating integrity, and impaired mechanical strength and disintegration performance; in Comparative Example 6, the absence of probiotic nutrients weakened intestinal regulatory function and cell compatibility, leading to decreased bioavailability; in Comparative Example 7, low-temperature coating resulted in a non-dense coating film, significantly reduced mechanical strength and barrier properties, and abnormally prolonged disintegration time; in Comparative Example 8, the coating layer was too thin to provide effective protection, pH response performance was essentially ineffective, and excessive release occurred in gastric juice. Comparative Example 9, using non-pH-responsive materials, completely lost its intelligent release function, resulting in excessive release in gastric juice and drug waste. Comparative Example 10, high-concentration ethanol extraction led to increased impurities and altered the structure of the active ingredient, affecting the overall stability and thermal stability of the formulation. Comparative Example 11, lacking an intermediate buffer layer, resulted in excessively rapid pH transitions, extremely poor release control, and a significant decrease in thermal stability. Comparative Example 12, low-speed stirring resulted in uneven mixing, decreased particle dispersibility and consistency, and a significant reduction in drug loading and coating efficiency. Comparative Example 13, lacking a stabilizer, led to the most severe aggregation phenomenon, extremely poor formulation uniformity and reproducibility, and comprehensive deterioration of all key performance aspects. Comparative Example 14, extremely low concentrations of nutrient factors failed to exert effective intestinal regulation, and cell compatibility significantly decreased. Comparative Example 15, traditional granulation processes were completely unable to achieve nanoscale dispersion and multilayer structure construction, resulting in a significant reduction in drug release and absorption efficiency and severely deteriorated disintegration performance. These factors combined to cause all comparative examples to be significantly inferior to the examples in terms of key performance aspects 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 this invention.

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

[0142]

[0143] The accompanying drawings of this invention systematically demonstrate the scientific nature and superiority of the technical solution. Figures 1-2 Scanning electron microscopy clearly revealed that the smart response particles had a regular appearance, uniform size, and smooth surface, with no obvious defects or agglomeration, proving the stability and reproducibility of the preparation process. Figure 3 Quantitative comparative data show that the drug loading of the examples reached 18-32% and the encapsulation efficiency reached 88-94%, which is significantly better than the drug loading of 12.8-26.1% and the encapsulation efficiency of 58.2-89.1% of the comparative examples, fully demonstrating the key role of optimizing the formulation and process parameters. Figure 4 The pH response performance test results showed that the release rate of the embodiment was strictly controlled within the range of 6.8-9.1% in gastric juice after 2 hours, while the cumulative release rate in intestinal juice reached 82.4-88.3% after 6 hours, achieving ideal targeted release. In contrast, the comparative embodiment generally had the problems of excessive release in gastric juice (up to 41.6%) and insufficient release in intestinal juice (down to only 52.6%), which proved the effectiveness of the three-layer intelligent response structure design. Figure 5 The physical properties data show that the tablets in the examples have a hardness in the range of 75-145N and a disintegration time controlled in the range of 18-42 minutes, which meet the requirements of the pharmacopoeia. In contrast, most of the comparative examples have defects such as insufficient hardness or slow disintegration, which verifies the rationality of the excipient formulation. Figure 6 The stability evaluation results showed that the initial decomposition temperature of the embodiment reached 238-262℃, and the cell viability remained at 87.8-93.1%, which was far superior to the decomposition temperature of 203-246℃ and the viability of 73.2-88.3% of the comparative example, demonstrating the thermal stability and biosafety of the formulation. Based on these objective data and intuitive images, the technical solution of this 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.

[0144] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and not to limit it. Although the present invention has been described in detail with reference to the above embodiments, those skilled in the art should understand that any equivalent structural transformations made under the concept of the present invention and using the contents of the specification and drawings of the present invention should be covered within the scope of protection of the claims of the present invention.

Claims

1. A method for preparing a traditional Chinese medicine granule composition based on Polygonatum sibiricum, characterized in that, Includes the following steps: S1. Preparation of Polygonatum nanoparticles using antisolvent precipitation technology: Polygonatum ethanol extract obtained from Polygonatum rhizome is dissolved in ethanol, and deionized water is injected as an antisolvent in the presence of lecithin stabilizer to obtain amorphous Polygonatum nanoparticles with a particle size of 80-300 nm, wherein the amount of lecithin stabilizer is 0.1-2.0% of the weight of Polygonatum ethanol extract; ethanol with a volume fraction of 60-80% is used as the extraction solvent, the volume ratio of ethanol to deionized water is 1:(8-15), the stirring speed is 800-1500 rpm, and the reaction temperature is controlled at 15-25℃; S2. Constructing an intermediate functional buffer layer: The Polygonatum nanoparticles are coated with a sodium alginate solution containing probiotic nutrient factors and pH buffer pairs, and a calcium alginate gel functional layer with a thickness of 5-30 μm is formed in a calcium chloride solution through ion crosslinking technology; wherein the mass fraction of the pH buffer pairs in the intermediate functional buffer layer is 2-8%, the concentration of the calcium chloride solution is 0.5-5.0%, and the mass concentration of the probiotic nutrient factors in the sodium alginate solution is 1-10 mg / mL; S3. Preparation of the smart responsive outer shell layer: Using fluidized bed coating technology, a coating solution containing pH-responsive material is sprayed onto the surface of the gel functional layer to obtain smart responsive particles; the coating weight gain is controlled at 15-40%, and the fluidized bed coating temperature is 40-80℃. S4. Preparation of the final composition: The smart responsive particles are mixed evenly with pharmaceutical excipients to prepare a powder or compress it into tablets; The intelligent responsive particles consist of a three-layer structure consisting of Polygonatum nanoparticles, a calcium alginate gel functional layer, and a pH-responsive outer shell layer. This three-layer structure enables the composition to have a pH-responsive function, triggering swelling at pH 5.5±0.2 and achieving a cumulative release of over 80% at pH 6.8±0.

3.

2. The method for preparing a traditional Chinese medicine granule composition based on Polygonatum sibiricum as described in claim 1, characterized in that, In step S1, the preparation method of Polygonatum ethanol extract is as follows: take Polygonatum rhizome, wash, slice and dry to a moisture content ≤10%, material-to-liquid ratio 1:(8-15) g / mL, reflux extract at 60-80℃ for 2-4 hours, extract 2-3 times, combine the extracts, let stand and clarify for 4-12 hours, filter, concentrate under reduced pressure to a relative density of 1.10-1.25, and obtain standardized Polygonatum ethanol extract with Polygonatum polysaccharide content ≥30%, total saponin content ≥5%, and moisture content ≤8%.

3. The method for preparing a traditional Chinese medicine granule composition based on Polygonatum sibiricum as described in claim 1, characterized in that, The injection rate is 0.5-2.0 mL / min, the reaction time is 30-120 minutes, and the Polygonatum nanoparticles exist in an amorphous form.

4. The method for preparing a traditional Chinese medicine granule composition based on Polygonatum sibiricum as described in claim 1, characterized in that, 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 acetate-sodium acetate, with a buffer capacity of 10-50 mmol / L and an ion crosslinking time of 10-60 minutes.

5. The method for preparing a traditional Chinese medicine granule composition based on Polygonatum sibiricum as described in 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 polymethyl methacrylate copolymer, with an air intake volume of 20-50 m³ / h and an atomization pressure of 0.1-0.3 MPa.

6. The method for preparing a traditional Chinese medicine granule composition based on Polygonatum sibiricum as described in claim 1, characterized in that, In step S2, the probiotic nutritional factor includes at least one of fructooligosaccharides, inulin, galactooligosaccharides, lactitol, and xylooligosaccharides, and also contains glutamine and arginine as intestinal cell nutritional support agents; the pharmaceutical excipients include at least one of fillers, disintegrants, lubricants, and flow aids. The filler is selected from at least one of microcrystalline cellulose, lactose, mannitol or pregelatinized starch, and is used in an amount of 20-60% of the total weight of the composition; The disintegrant is selected from at least one of sodium carboxymethyl starch, crospovidone, or low-substituted hydroxypropyl cellulose, and is used in an amount of 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 is used in an amount of 0.5-3% of the total weight of the composition. The flow aid is selected from at least one of silica, tricalcium phosphate or stearic acid, and is used in an amount of 0.2-2% of the total weight of the composition.

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

8. The herbal granule composition based on Polygonatum sibiricum as described in 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 fluid with a pH of 1.

2. It begins to release after being transferred to artificial intestinal fluid with a pH of 6.

8. The main release is achieved in the intestinal environment. The cumulative release rate is >80% after 6 hours in simulated intestinal fluid with a pH of 6.8, measured by the USP basket method at 37±0.5℃.

9. The herbal granule composition based on Polygonatum sibiricum as described in claim 7, characterized in that, The coating efficiency of the intelligent responsive particles was determined to be 85-95% by gravimetric analysis, and the drug loading was determined to be 15-35% by high performance liquid chromatography. The intelligent responsive particles constitute 30-80% of the composition, with the pharmaceutical excipients as the remainder; when prepared as a powder, the particle size distribution D90 is 100-500 μm and D50 is 50-200 μm; when prepared as a tablet, the tablet hardness is 50-150 N and the disintegration time in intestinal fluid is 15-45 minutes.

10. The use of a traditional Chinese medicine granule composition based on Polygonatum rhizome prepared by any one of claims 1 to 6, or a traditional Chinese medicine granule composition based on Polygonatum rhizome prepared by any one of claims 7 to 9, in the preparation of intestinal-targeting functional drugs.

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