A traditional Chinese medicine composition for preventing and treating cardiovascular and cerebrovascular diseases and a preparation method thereof

Abstract

This invention belongs to the field of traditional Chinese medicine nano-oral preparations, and provides a traditional Chinese medicine composition for the prevention and treatment of cardiovascular and cerebrovascular diseases and its preparation method. This invention uses a core-shell type nanocomposite dry powder design of Panax notoginseng total saponins core and Astragalus polysaccharide shell, combined with ethanol water dispersion, pH control, high pressure homogenization and spray drying, to form an oral solid system with controlled particle size and dispersibility after reconstitution. It achieves a balance between reconstitution stability, gastrointestinal release regulation, storage stability and oral utilization, and solves the problem of mutual restraint between nanoparticle reconstitution dispersion and release regulation. It is applicable to oral traditional Chinese medicine preparations related to the prevention and treatment of cardiovascular and cerebrovascular diseases.

Description

Technical Field

[0001] This invention relates to the field of traditional Chinese medicine nano-oral preparations, specifically to a traditional Chinese medicine composition for the prevention and treatment of cardiovascular and cerebrovascular diseases and its preparation method. Background Technology

[0002] Traditional Chinese medicine (TCM) preparations for the prevention and treatment of cardiovascular and cerebrovascular diseases are typically designed for long-term oral administration, stable storage, and continuous gastrointestinal exposure. This places high demands on the release rhythm of active ingredients, reconstitution dispersion, water content, powder flowability, and adaptability to oral solid dosage forms. Panax notoginseng total saponins, as an important active component of Panax notoginseng, have clear application value in related TCM preparations. However, their oral formulations not only need to form a relatively uniform particle size dispersion system after reconstitution, but also need to avoid excessively rapid release in the gastric environment and maintain effective release in intestinal phosphate buffer. On the other hand, oral solid dosage forms must undergo drying, storage, transportation, and reconstitution before administration. Simply pursuing nano-sizing may lead to moisture absorption, agglomeration, or particle size drift after reconstitution, while simply pursuing dry powder stability may weaken the dispersion advantage during oral absorption. Therefore, constructing a nanocomposite dry powder system that combines reconstitution stability, gastrointestinal release regulation, and solid dosage form compatibility around the active components of natural drugs is of great significance for improving the quality consistency and industrialization feasibility of oral TCM preparations.

[0003] Existing oral or related delivery systems for Panax notoginseng saponins have attempted to improve stability and absorption through liposomes, nanoparticles, adhesive materials, or composite carriers. However, shortcomings remain, such as complex interface materials, difficulty in maintaining dispersion after reconstitution, and challenges in simultaneously optimizing the drying and release processes. For example, Chinese patent CN1491658A discloses Panax notoginseng saponin liposomes and their formulations. Its specification focuses on liposome stability and multi-dosage form applications, but liposome colloidal systems still face challenges such as membrane material hydrolysis and oxidation, structural changes caused by environmental pH and temperature, and drug leakage. Other literature discloses Panax notoginseng saponin lecithin / zein hybrid nanoparticles, which utilize a core-shell structure to enhance protection under acidic and digestive enzyme conditions and improve oral absorption. However, these systems primarily rely on protein and lipid carriers and have not established a unified process system for polysaccharide encapsulation between Panax notoginseng saponins and Astragalus polysaccharides, reconstitution particle size maintenance, dry powder moisture content, and compatibility with oral solid excipients. Summary of the Invention

[0004] The purpose of this invention is to provide a traditional Chinese medicine composition for the prevention and treatment of cardiovascular and cerebrovascular diseases and its preparation method, which solves the problems of difficulty in simultaneously achieving reconstitution and dispersion stability and gastrointestinal release regulation of oral nano-preparations of Panax notoginseng total saponins, and the mutual restraint between storage stability and oral utilization.

[0005] This invention achieves a balance between the promoting effect of hydrophilic coating on reconstitution and dispersion and the regulating effect of interfacial confinement on gastrointestinal release through a core-shell composite of Panax notoginseng total saponins core and Astragalus polysaccharide layer, as well as continuous regulation of composite dispersion, high-pressure homogenization and spray drying. At the same time, it reduces the adverse effects of drying and solidification on the advantages of nano-dispersion.

[0006] To achieve the above objectives, the present invention provides the following technical solution: A traditional Chinese medicine composition for preventing and treating cardiovascular and cerebrovascular diseases includes a nano-composite dry powder component consisting of total saponins of Panax notoginseng, polysaccharides of Astragalus membranaceus, and a core-shell type. The Panax notoginseng total saponins-Astragalus polysaccharide core-shell type nanocomposite dry powder component includes a Panax notoginseng total saponins core and an Astragalus polysaccharide layer coated on the surface of the Panax notoginseng total saponins core; The mass ratio of the total saponins of Panax notoginseng to the polysaccharides of Astragalus membranaceus is 1:0.2–1:1.8; The Panax notoginseng total saponins-Astragalus polysaccharide core-shell type nanocomposite dry powder component was added to deionized water at a concentration of 1 mg / mL, and after being gently shaken at 25°C for 5 min, the D50 of the formed nanocomposite particles was measured within 30 min after reconstitution using dynamic light scattering method, and the PDI was 0.05–0.30.

[0007] Furthermore, the total saponins of Panax notoginseng are derived from Panax notoginseng medicinal material, and the polysaccharides of Astragalus membranaceus are derived from Astragalus membranaceus medicinal material; based on the dry weight of the core-shell type nanocomposite dry powder components of the total saponins of Panax notoginseng and the polysaccharides of Astragalus membranaceus, the content of the total saponins of Panax notoginseng is 35.7–83.3 wt%, and the content of the polysaccharides of Astragalus membranaceus is 16.7–64.3 wt%.

[0008] Furthermore, the dry powder D50 of the Panax notoginseng total saponins-Astragalus polysaccharide core-shell type nanocomposite dry powder component is 5–60 μm, and the water content is 0.5–8.0 wt%.

[0009] Furthermore, the Panax notoginseng total saponins-Astragalus polysaccharide core-shell type nanocomposite dry powder component is prepared through the following steps: A1. Disperse total saponins of Panax notoginseng in a 30–70 vol% ethanol aqueous solution to obtain a dispersion of total saponins of Panax notoginseng; dissolve Astragalus polysaccharide in deionized water to obtain an Astragalus polysaccharide solution; A2. The Panax notoginseng total saponin dispersion and the Astragalus polysaccharide solution are mixed at a mass ratio of Panax notoginseng total saponins to Astragalus polysaccharide of 1:0.2–1:1.8, the pH is adjusted to 4.2–6.2, and the mixture is stirred at 25–55℃ for 30–120 min to obtain a composite dispersion. In the composite dispersion process, the carboxyl content of Astragalus polysaccharide, the pH of the composite dispersion, and the mass ratio of Panax notoginseng total saponins to Astragalus polysaccharide are used as control parameters for the interface composite process. The composite dispersion is used as the feed system for the high-pressure homogenization step after stirring. A3. The composite dispersion is subjected to high-pressure homogenization at a pressure of 20–80 MPa and a cycle of 1–5 times to obtain a core-shell nanocomposite dispersion. A4. Spray dry the core-shell nanocomposite dispersion with an inlet air temperature of 130–180℃ and an outlet air temperature of 65–95℃ to obtain the Panax notoginseng total saponins-Astragalus polysaccharide core-shell nanocomposite dry powder component.

[0010] Furthermore, the total saponins of Panax notoginseng in step A1 are prepared through the following steps: B1. Grind the Panax notoginseng into 20–80 mesh and add 50–80 vol% ethanol aqueous solution, wherein the mass-volume ratio of Panax notoginseng to ethanol aqueous solution is 1 g: 6–15 mL. B2. Extract at 40–80℃ for 1–3 h, repeat extraction 1–3 times, filter, combine filtrates, and concentrate under reduced pressure at 40–70℃ to a concentrate equivalent to 0.2–1.0 g / mL of crude drug. B3. Extract the concentrate with 1-butanol 2–5 times, combine the 1-butanol phases, wash with deionized water 1–3 times, concentrate under reduced pressure at 40–70℃, and dry at 45–80℃ for 4–24 h to obtain total Panax notoginseng saponins. B4. The total content of the obtained Panax notoginseng saponins, calculated as ginsenoside Rg1, ginsenoside Rb1 and notoginsenoside R1, is 50–95 wt%.

[0011] Furthermore, the astragalus polysaccharide in step A1 is prepared through the following steps: C1. Grind the Astragalus membranaceus into 20–80 mesh and add deionized water, wherein the mass-to-volume ratio of Astragalus membranaceus to deionized water is 1g:8–20mL. C2. Extract at 70–95℃ for 1–4 h, repeat the extraction 1–3 times, filter, combine the aqueous extracts, and concentrate at 45–75℃ to a concentrate equivalent to 0.2–1.0 g / mL of crude drug. C3. Add ethanol to the concentrate until the final ethanol concentration is 60–80 vol%, let stand at 2–10 °C for 6–24 h, and collect the precipitate; dissolve the precipitate in deionized water, treat it first with an ultrafiltration membrane with a molecular weight cutoff of 150 kDa and collect the permeate, then treat the permeate with an ultrafiltration membrane with a molecular weight cutoff of 10 kDa and collect the 10 kDa ultrafiltration membrane retentate, and dry it at 45–80 °C for 4–24 h to obtain Astragalus polysaccharide; C4. The weight-average molecular weight (Mw) of the obtained Astragalus polysaccharides was 10–150 kDa, and the carboxyl content was 0.2–1.5 mmol / g.

[0012] Furthermore, the traditional Chinese medicine composition is an oral solid composition; Based on the dry weight of the traditional Chinese medicine composition, the oral solid composition comprises 10–90 wt% of the Panax notoginseng total saponins-Astragalus polysaccharide core-shell nanocomposite dry powder component and 10–90 wt% of excipients, wherein the sum of the contents of the Panax notoginseng total saponins-Astragalus polysaccharide core-shell nanocomposite dry powder component and the excipients is 100 wt%. The excipients are selected from one or more of D-mannitol, microcrystalline cellulose, starch, and magnesium stearate.

[0013] Furthermore, the nanocomposite particles after reconstitution of the Panax notoginseng total saponins-Astragalus polysaccharide core-shell nanocomposite dry powder components have the following interface parameters: the surface coverage of Astragalus polysaccharide is 60–95 wt%, the apparent coverage is calculated as the percentage of the total mass of Astragalus polysaccharide input after deducting the mass of free Astragalus polysaccharide, relative to the total mass of Astragalus polysaccharide input; the binding rate of Panax notoginseng total saponins is 70–98 wt%; and the zeta potential is -35 mV to -10 mV.

[0014] Furthermore, according to the Chinese Pharmacopoeia General Chapter 0931, under constant speed stirring at 37°C, the cumulative release rate of total saponins of Panax notoginseng in 0.1 mol / L hydrochloric acid aqueous solution for 2 hours is 15–45 wt%, and the cumulative release rate of total saponins of Panax notoginseng in pH 6.8 phosphate buffer solution for 8 hours is 60–95 wt%. The cumulative release rate of total saponins of Panax notoginseng is calculated based on the total amount of ginsenoside Rg1, ginsenoside Rb1 and Panax notoginseng saponin R1.

[0015] Furthermore, according to the Chinese Pharmacopoeia General Rules 0931, when the release test of the Panax notoginseng total saponins-Astragalus polysaccharide core-shell type nanocomposite dry powder component was carried out under constant speed stirring conditions at 37℃, the cumulative release rate of Panax notoginseng total saponins in 0.1mol / L hydrochloric acid aqueous solution for 2h was 15-45wt%, and the cumulative release rate of Panax notoginseng total saponins after being transferred to pH 6.8 phosphate buffer for a cumulative period of 8h was 60-95wt%. The cumulative release rate of Panax notoginseng total saponins was calculated based on the total amount of ginsenoside Rg1, ginsenoside Rb1 and Panax notoginseng saponin R1.

[0016] This invention also discloses a method for preparing a traditional Chinese medicine composition for preventing and treating cardiovascular and cerebrovascular diseases, comprising the following steps: S1. Provides a nano-composite dry powder component consisting of Panax notoginseng total saponins, Astragalus polysaccharide core-shell type; S2. The Panax notoginseng total saponins-Astragalus polysaccharide core-shell type nanocomposite dry powder component is mixed with one or more excipients selected from D-mannitol, microcrystalline cellulose, starch and magnesium stearate to prepare an oral solid traditional Chinese medicine composition.

[0017] Furthermore, step S2 uses one of the following methods to produce granules, tablets, or capsules: dry mixing, wet granulation, dry granulation, direct tableting, or capsule filling.

[0018] Furthermore, the Panax notoginseng total saponins-Astragalus polysaccharide core-shell type nanocomposite dry powder component provided in step S1 is prepared from a composite dispersion with a solid content of 3–8 wt%; the water content of the Panax notoginseng total saponins-Astragalus polysaccharide core-shell type nanocomposite dry powder component is 0.5–8.0 wt%.

[0019] Furthermore, in the Panax notoginseng total saponins-Astragalus polysaccharide core-shell type nanocomposite dry powder component provided in step S1, the coating layer uses Astragalus polysaccharide as the shell material, and no polyvinylpyrrolidone, hydroxypropyl methylcellulose or chitosan is added as the shell material.

[0020] In some embodiments, the Panax notoginseng total saponin dispersion and the Astragalus polysaccharide solution are prepared from metered Panax notoginseng total saponins and Astragalus polysaccharides, respectively. The combined dispersion has a solid content of 3–8 wt% based on the total mass of Panax notoginseng total saponins and Astragalus polysaccharides, and the feed mass ratio of Panax notoginseng total saponins to Astragalus polysaccharides is 1:0.2–1:1.8. The composite dispersion serves as the feed system for the high-pressure homogenization step. The pH, solid content, and feed mass ratio of the composite dispersion are used together to define the composite state before entering the high-pressure homogenization step.

[0021] Furthermore, the core-shell nanocomposite dispersion obtained after high-pressure homogenization was spray-dried to form a core-shell nanocomposite dry powder component of Panax notoginseng total saponins and Astragalus polysaccharides. The inlet air temperature of the spray drying was 130–180℃ and the outlet air temperature was 65–95℃. The obtained composite dry powder component was added to deionized water at a concentration of 1 mg / mL and gently shaken at 25℃ for 5 min. When measured by dynamic light scattering method within 30 min after reconstitution, the D50 of the formed reconstituted nanocomposite particles was 150–450 nm, the PDI was 0.05–0.30, the binding rate of Panax notoginseng total saponins was 70–98 wt%, the surface coverage of Astragalus polysaccharides was 60–95 wt%, and the residual ethanol content was 100–5000 ppm.

[0022] In a specific embodiment, 100 mg of the Panax notoginseng total saponins-Astragalus polysaccharide core-shell type nanocomposite dry powder component was added to 100 mL of deionized water and gently shaken at 25°C for 5 min. After redissolving in deionized water, it was used as a sample for particle size and potential detection. The same redissolved sample was used to record D50, PDI and ζ potential. The recorded fields included the mass of the composite dry powder component, the volume of deionized water, the test time after redissolution, D50, PDI and ζ potential. The recorded fields were used to determine the dispersion state of the nanocomposite particles after redissolution.

[0023] Furthermore, the binding rate of total saponins of Panax notoginseng was calculated based on the total mass of total saponins of Panax notoginseng and the mass of free total saponins of Panax notoginseng obtained from the reconstitution and dispersion system. The surface coverage rate of Astragalus polysaccharides was calculated based on the total mass of Astragalus polysaccharides and the mass of free Astragalus polysaccharides obtained from the reconstitution and dispersion system. The separated composite particles were then used for D50 and PDI retesting.

[0024] In some embodiments, during the 1-butanol extraction step, the volume of the concentrate, the volume of 1-butanol, the number of extractions, and the volume of the combined 1-butanol phase are recorded for each extraction. The combined 1-butanol phase is washed with deionized water and then enters the vacuum concentration step. The total saponins obtained are controlled by the total content of ginsenoside Rg1, ginsenoside Rb1 and notoginsenoside R1, the residual 1-butanol content, and the residual ethanol content, wherein the residual 1-butanol content is 10–500 ppm and the residual ethanol content is 100–5000 ppm.

[0025] Furthermore, in the process of grading Astragalus polysaccharides, the aqueous solution of the precipitate obtained by alcohol precipitation is first treated with an ultrafiltration membrane with a molecular weight cutoff of 150 kDa and the permeate is collected. Then, the permeate is treated with an ultrafiltration membrane with a molecular weight cutoff of 10 kDa and the retentate is collected and dried. The retentate is then used as Astragalus polysaccharide in the Panax notoginseng total saponins-Astragalus polysaccharide complex step.

[0026] In a specific implementation, the identification of the source of Astragalus membranaceus is carried out after the Astragalus membranaceus is pulverized and water is added in advance. The test object is the Astragalus membranaceus sample. The test result of Astragaloside IV is used to confirm the source of Astragalus membranaceus. The quality control indicators of the obtained Astragalus polysaccharide are weight average molecular weight Mw, carboxyl content and ethanol residue, wherein the ethanol residue is 100-5000 ppm.

[0027] Furthermore, the residual solvent of the Panax notoginseng total saponins-Astragalus polysaccharide core-shell type nanocomposite dry powder component can be used as a quality control indicator, wherein the residual ethanol content is 100–5000 ppm and the residual 1-butanol content is 10–500 ppm. The residual solvent detection results are used to evaluate the preparation quality of the Panax notoginseng total saponins-Astragalus polysaccharide core-shell type nanocomposite dry powder component.

[0028] In some embodiments, when the oral solid composition contains the corresponding excipients, the excipients are selected from one or more of D-mannitol, microcrystalline cellulose, starch and magnesium stearate, wherein the content of D-mannitol is 5–50 wt%, the content of microcrystalline cellulose is 0.5–40 wt%, the content of starch is 0.5–30 wt%, and the content of magnesium stearate is 0.1–2.0 wt%, all based on the dry weight of the traditional Chinese medicine composition, and the sum of the content of the Panax notoginseng total saponins-Astragalus polysaccharide core-shell type nanocomposite dry powder component and the excipients is 100 wt%.

[0029] Furthermore, the total saponin release test of Panax notoginseng included an acidic release stage and a pH 6.8 phosphate buffer release stage. The acidic release stage used 0.1 mol / L hydrochloric acid aqueous solution as the release medium and lasted for 2 hours. The pH 6.8 phosphate buffer release stage lasted for a cumulative total of 8 hours. The cumulative release rate of total saponins of Panax notoginseng was calculated based on the combined amount of ginsenoside Rg1, ginsenoside Rb1 and notoginsenoside R1. The release test was conducted in accordance with the General Chapter 0931 of the Chinese Pharmacopoeia under constant speed stirring conditions at 37°C using a paddle method.

[0030] In a specific implementation, the moisture absorption weight gain rate is calculated as the percentage of the difference between the sample mass after exposure and the sample mass before exposure relative to the sample mass before exposure. The D50 retention rate is calculated as the percentage of the reconstituted D50 after treatment relative to the reconstituted D50 before treatment. The same reconstituted medium, the same reconstituted concentration, and the same particle size data processing caliber are used before and after treatment. The moisture absorption weight gain rate test conditions are 24h exposure at 25℃ and 75%RH.

[0031] Beneficial technical effects 1. This invention uses a core-shell nanocomposite dry powder component composed of a Panax notoginseng total saponin core and an Astragalus polysaccharide layer, so that Astragalus polysaccharide forms a hydrophilic coating interface on the surface of Panax notoginseng total saponins, reducing the tendency of particle agglomeration during the reconstitution process after drying, thereby improving the reconstitution and dispersion state of nanocomposite particles, and is more conducive to the storage of solid oral dosage forms and dispersion before administration compared with conventional simple nano-systems.

[0032] 2. This invention controls the mass ratio of Panax notoginseng total saponins to Astragalus polysaccharides, the pH of the composite dispersion, the high-pressure homogenization pressure, and the number of cycles, so that the binding rate of Panax notoginseng total saponins, the surface coverage of Astragalus polysaccharides, and the zeta potential are in an adjustable state. It synergistically regulates the reconstituted particle size and PDI from two aspects: the thickness of the interfacial layer and the repulsion between particles, thereby reducing the risk of release rhythm imbalance caused by simply increasing the hydrophilic coating.

[0033] 3. This invention uses a continuous preparation path of ethanol-water dispersion, astragalus polysaccharide aqueous solution compounding, high-pressure homogenization and spray drying to fix the liquid-phase nanocomposite state into dry powder form. This allows the preparation process to simultaneously take into account particle size adjustment, water content control and residual solvent quality control. Compared with the scheme that only relies on the liquid colloidal system, it is more suitable for the batch preparation and storage of oral solid Chinese medicine compositions.

[0034] 4. This invention combines the Panax notoginseng total saponins-Astragalus polysaccharide core-shell type nanocomposite dry powder components with one or more excipients selected from D-mannitol, microcrystalline cellulose, starch and magnesium stearate to form oral solid compositions such as granules, tablets or capsules. This allows the reconstitution and dispersion characteristics of the active composite dry powder to be connected with the formulation molding and processing, thereby improving the adaptability of oral formulation development. Attached Figure Description

[0035] Figure 1 The particle size distribution diagrams of DLS after resolution in Examples 1, 9, and 10 are shown.

[0036] Figure 2 The cumulative particle size distribution of DLS after resolution in Examples 1, 9, and 10 is shown.

[0037] Figure 3 The diagram shows the relationship between the D50-PDI parameters of Example 1, Comparative Example 9, and Comparative Example 10.

[0038] Figure 4 The scatter plot shows the mean zeta potential of Example 1, Comparative Example 9, and Comparative Example 10.

[0039] Figure 5 The graph shows the binding rate of total saponins from Panax notoginseng in Example 1, Comparative Example 9, and Comparative Example 11.

[0040] Figure 6 The image shows the surface coverage of Astragalus polysaccharides in Examples 1, 9, and 11.

[0041] Figure 7 The graphs show the two-stage cumulative release curves for Example 1, Comparative Example 1, and Comparative Example 10.

[0042] Figure 8 The graph shows the dQ / dt release rate of total saponins from Panax notoginseng in Example 1, Comparative Example 1, and Comparative Example 10.

[0043] Figure 9 The graph shows the piecewise fitting rate constant k values ​​for Example 1, Comparative Example 1, and Comparative Example 10.

[0044] Figure 10 The graph shows the correlation between the 2-hour and 8-hour release rates of Example 1, Comparative Example 1, and Comparative Example 10.

[0045] Figure 11 The graph shows the relationship between moisture absorption weight gain and D50 retention rate for Example 1, Comparative Example 7, and Comparative Example 8.

[0046] Figure 12 The graph shows the changes in D50 before and after reconstitution in Examples 1, 7, and 8.

[0047] Figure 13 The dry powder particle size difference distribution diagrams are for Example 1 and Comparative Example 7.

[0048] Figure 14 The cumulative particle size distribution of the dry powder in Example 1 and Comparative Example 7 is shown in the diagram.

[0049] Figure 15 The graph shows the relationship between the dry powder D50 and the reconstituted D50 of Example 1 and Comparative Example 7.

[0050] Figure 16 The graph shows the relationship between moisture content and D50 retention rate for Example 1 and Comparative Example 7.

[0051] Figure 17 Macroscopic optical photographs of the Panax notoginseng total saponins-Astragalus polysaccharide core-shell type nanocomposite dry powder components and their granular oral solid traditional Chinese medicine composition obtained in Example 1.

[0052] Figure 18 The image shows a scanning electron microscope (SEM) image of the Panax notoginseng total saponins-Astragalus polysaccharide core-shell type nanocomposite dry powder obtained in Example 1. Figure 18 a is a low-magnification scanning electron microscope image of the overall distribution of micron-sized secondary particles of the Panax notoginseng total saponins-Astragalus polysaccharide core-shell type nanocomposite dry powder components obtained in Example 1; Figure 18 b and Figure 18 c is a medium- to high-magnification scanning electron microscope image of the surface morphology of the spherical secondary particles classified into the Panax notoginseng total saponins-Astragalus polysaccharide core-shell type nanocomposite dry powder obtained in Example 1; Figure 18 d is a scanning electron microscope image of the multi-level structure of the broken particle cross-section of the Panax notoginseng total saponins-Astragalus polysaccharide core-shell type nanocomposite dry powder component obtained in Example 1.

[0053] Figure 19 This is a transmission electron microscopy (TEM) characterization image of the Panax notoginseng total saponins-Astragalus polysaccharide core-shell nanocomposite dry powder obtained in Example 1 after reconstitution. Figure 19 a is a bright-field transmission electron microscope image of the near-spherical morphology of the core-shell type nanocomposite particles of Panax notoginseng total saponins-Astragalus polysaccharide after reconstitution; Figure 19 b is a magnified transmission electron microscope image of the core-shell interface structure of the Panax notoginseng total saponins-Astragalus polysaccharide core-shell nanocomposite particles after reconstitution; Figure 19 c is a high-resolution transmission electron microscope image of the crystallinity characterization of the Panax notoginseng total saponins-Astragalus polysaccharide core-shell nanocomposite particles after reconstitution; Figure 19 d is a selected area electron diffraction image of the amorphous characteristics of the Panax notoginseng total saponins-Astragalus polysaccharide core-shell nanocomposite particles after reconstitution. Detailed Implementation

[0054] 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.

[0055] Example 1 Overall production scale and product form This embodiment prepares 1.00 kg of Panax notoginseng total saponins-Astragalus polysaccharide core-shell type nanocomposite dry powder component, and formulates it into 10.00 kg of granule-type oral solid traditional Chinese medicine composition. Both Panax notoginseng and Astragalus are commercially available medicinal materials, dry in appearance and free from mold; ethanol, 1-butanol, and deionized water are all conventional pharmaceutical or analytical grade; D-mannitol, microcrystalline cellulose, starch, and magnesium stearate are all commercially available pharmaceutical excipients.

[0056] Raw materials, components or material specifications In this embodiment, the content of total Panax notoginseng saponins-Astragalus polysaccharide core-shell type nanocomposite dry powder is 83.0 wt%, the content of Astragalus polysaccharide is 17.0 wt%, and the mass ratio of total Panax notoginseng saponins to Astragalus polysaccharide is 1:0.205. In the oral solid traditional Chinese medicine composition, the content of total Panax notoginseng saponins-Astragalus polysaccharide core-shell type nanocomposite dry powder is 10.0 wt%, and the excipients are 90.0 wt%. The excipients consist of 50.0 wt% D-mannitol, 37.5 wt% microcrystalline cellulose, 2.4 wt% starch, and 0.1 wt% magnesium stearate. All contents are based on the dry weight of the oral solid traditional Chinese medicine composition.

[0057] Step 1: Preparation of total saponins from Panax notoginseng B1. Take 12.00 kg of Panax notoginseng, grind it to 20 mesh, and add 72.0 L of 50 vol% ethanol aqueous solution. The mass-volume ratio of Panax notoginseng to ethanol aqueous solution is 1 g: 6 mL.

[0058] B2. Extract for 1 hour in a 40℃ water bath, repeat once, filter with a 200-mesh filter cloth, collect the filtrate, and concentrate under reduced pressure at 40℃ and 0.08MPa to a concentrate equivalent to 0.2g / mL of raw drug.

[0059] B3. The concentrate was extracted twice with 1-butanol. The volume of the concentrate, the volume of 1-butanol, and the separation time were recorded each time. The 1-butanol phases were combined and washed once with deionized water. The concentrate was then concentrated under reduced pressure at 40℃ and 0.08MPa absolute pressure, and then dried at 45℃ for 4h to obtain total saponins of Panax notoginseng.

[0060] B4. The total content of ginsenoside Rg1, ginsenoside Rb1 and notoginsenoside R1 was determined to be 50.0 wt% by high performance liquid chromatography; the residual amount of 1-butanol was 10 ppm and the residual amount of ethanol was 100 ppm by gas chromatography.

[0061] Step 2: Preparation of Astragalus Polysaccharides C1. Take 8.00 kg of Astragalus membranaceus, grind it to 20 mesh, take a water sample in advance to test for astragaloside IV as a source confirmation item for Astragalus membranaceus, then add 64.0 L of deionized water. The mass-volume ratio of Astragalus membranaceus to deionized water is 1 g: 8 mL.

[0062] C2. Extract at 70℃ for 1 hour, repeat once, filter and combine the aqueous extracts, then concentrate at 45℃ to a concentration equivalent to 0.2 g / mL of crude drug.

[0063] C3. Add ethanol to the concentrate until the final ethanol concentration is 60 vol%, let it stand at 2℃ for 6 h, and collect the precipitate; dissolve the precipitate in deionized water, and perform ultrafiltration successively using ultrafiltration membranes with molecular weight cutoff of 150 kDa and 10 kDa. Collect the permeate in the first stage and the retentate in the second stage, and dry it at 45℃ for 4 h to obtain Astragalus polysaccharide.

[0064] C4. The weight-average molecular weight (Mw) of Astragalus polysaccharide was determined to be 10 kDa by size exclusion chromatography, the carboxyl content was determined to be 0.20 mmol / g by titration, and the residual ethanol content was determined to be 100 ppm by gas chromatography.

[0065] Step 3: Preparation of Panax notoginseng total saponins-Astragalus polysaccharide core-shell type nanocomposite dry powder components A1. Take 830.0g of total saponins of Panax notoginseng, disperse them in 30 vol% ethanol aqueous solution, and stir mechanically at 300 rpm for 10 min to obtain a dispersion of total saponins of Panax notoginseng; take 170.0g of Astragalus polysaccharide, dissolve it in deionized water, and stir mechanically at 300 rpm for 20 min to obtain an Astragalus polysaccharide solution.

[0066] A2. Add the total saponins of Panax notoginseng to the polysaccharide solution of Astragalus membranaceus, add deionized water to make the solid content of the composite dispersion corresponding to the total mass of total saponins of Panax notoginseng and polysaccharide of Astragalus membranaceus 3.0 wt%, adjust the pH to 4.2 with dilute hydrochloric acid or dilute sodium hydroxide aqueous solution, and stir at 300 rpm for 30 min at 25℃ to obtain the composite dispersion.

[0067] A3. Input the composite dispersion into a high-pressure homogenizer and circulate it once at 20MPa. The feed temperature is controlled at 25℃. After discharge, use an ice-water jacket to keep the material temperature below 30℃ to obtain a core-shell nanocomposite dispersion.

[0068] A4. The core-shell nanocomposite dispersion was spray-dried at an inlet air temperature of 130°C, an outlet air temperature of 65°C, an atomization pressure of 0.20 MPa, and a feed rate of 10 mL / min. A light yellow dry powder was collected to obtain the Panax notoginseng total saponins-Astragalus polysaccharide core-shell nanocomposite dry powder component. In this embodiment, Astragalus polysaccharide was used as the shell material for the coating layer; polyvinylpyrrolidone, hydroxypropyl methylcellulose, or chitosan were not added as shell materials.

[0069] Step 4: Preparation of oral solid traditional Chinese medicine composition Take 1.00 kg of Panax notoginseng total saponins-Astragalus polysaccharide core-shell type nanocomposite dry powder, 5.00 kg of D-mannitol, 3.75 kg of microcrystalline cellulose, 0.24 kg of starch, and 0.01 kg of magnesium stearate. First, place the Panax notoginseng total saponins-Astragalus polysaccharide core-shell type nanocomposite dry powder, D-mannitol, microcrystalline cellulose, and starch in a mixer and mix at 20 rpm for 20 min at 25℃ and 45% relative humidity. Then, add magnesium stearate and mix at 15 rpm for 3 min. Use a dry mixing method to prepare a granular oral solid traditional Chinese medicine composition. The mixing endpoint is judged as a relative deviation of no more than 5% in the content of Panax notoginseng total saponins at three consecutive sampling points.

[0070] Quality testing methods and results 100 mg of the Panax notoginseng total saponins-Astragalus polysaccharide core-shell nanocomposite dry powder component was added to 100 mL of deionized water and gently shaken at 25 °C for 5 min. After reconstitution, the D50, PDI, and ζ-potential were recorded using dynamic light scattering method after 30 min. The D50 was 150 ± 3 nm, the PDI was 0.05 ± 0.01, and the ζ-potential was -35.0 ± 0.8 mV (n=3). The D50 of the dry powder was measured to be 5.0 ± 0.2 μm using laser particle size distribution method, and the water content was measured to be 0.50 ± 0.04 wt% using drying loss method (n=3). After centrifugation to separate free Panax notoginseng total saponins and free Astragalus polysaccharides, the binding rate of Panax notoginseng total saponins was calculated to be 70.0 ± 1.2 wt%, and the surface coverage rate of Astragalus polysaccharides was 60.0 ± 1.5 wt% (n=3). In the release test, the cumulative release rate of total saponins from Panax notoginseng in 0.1 mol / L hydrochloric acid aqueous solution for 2 h was 15.0 ± 0.8 wt%, and the cumulative release rate of total saponins from Panax notoginseng in pH 6.8 phosphate buffer for 8 h was 60.0 ± 1.0 wt%, n=3. The hygroscopic weight gain was 0.50 ± 0.05 wt%, the D50 retention rate after reconstitution was 80.0 ± 1.8%, the residual ethanol was 100 ppm, and the residual 1-butanol was 10 ppm.

[0071] Features and application scenarios of this embodiment This embodiment adopts a relatively conservative astragalus polysaccharide ratio, milder compounding and homogenization conditions, and sets the proportion of active compound dry powder in the oral solid composition in a low range, which is suitable for oral Chinese medicine preparations with high requirements for dry powder moisture content, reconstituted particle size and granule processing stability.

[0072] Example 2 Overall production scale and product form In this embodiment, 1.00 kg of Panax notoginseng total saponins-Astragalus polysaccharide core-shell type nanocomposite dry powder component was prepared according to step 3 for quality testing. After obtaining sufficient composite dry powder component by scaling up or combining multiple batches according to the same process, 10.00 kg of tablet-type oral solid traditional Chinese medicine composition was prepared by dry weight. Panax notoginseng and Astragalus are both commercially available medicinal materials. Ethanol, 1-butanol and deionized water are all conventional pharmaceutical or analytical grade. D-mannitol, microcrystalline cellulose, starch and magnesium stearate are all commercially available pharmaceutical excipients.

[0073] Raw materials, components or material specifications In this embodiment, the content of total Panax notoginseng saponins-Astragalus polysaccharide core-shell type nanocomposite dry powder is 36.0 wt%, the content of Astragalus polysaccharide is 64.0 wt%, and the mass ratio of total Panax notoginseng saponins to Astragalus polysaccharide is 1:1.778. In the oral solid traditional Chinese medicine composition, the content of total Panax notoginseng saponins-Astragalus polysaccharide core-shell type nanocomposite dry powder is 90.0 wt%, and the excipients are 10.0 wt%. The excipients consist of 5.0 wt% D-mannitol, 0.5 wt% microcrystalline cellulose, 2.5 wt% starch, and 2.0 wt% magnesium stearate. All contents are based on the dry weight of the oral solid traditional Chinese medicine composition.

[0074] Step 1: Preparation of total saponins from Panax notoginseng B1. Take 12.00 kg of Panax notoginseng, grind it to 80 mesh, and add 180.0 L of 80 vol% ethanol aqueous solution. The mass-volume ratio of Panax notoginseng to ethanol aqueous solution is 1 g: 15 mL.

[0075] B2. Extract at 80℃ for 3 hours, repeat the extraction 3 times, filter with 200 mesh filter cloth, combine the filtrates, and concentrate under reduced pressure at 70℃ and 0.08MPa to a concentrate equivalent to 1.0g / mL of crude drug.

[0076] B3. The concentrate was extracted five times with 1-butanol. The volume of the concentrate, the volume of 1-butanol, and the separation time were recorded each time. The 1-butanol phases were combined and washed three times with deionized water. The concentrate was then concentrated under reduced pressure at 70℃ and 0.08MPa absolute pressure, and then dried at 80℃ for 24h to obtain total saponins of Panax notoginseng.

[0077] B4. The total content of ginsenoside Rg1, ginsenoside Rb1 and notoginsenoside R1 was determined to be 95.0 wt% by high performance liquid chromatography; the residual amount of 1-butanol was 500 ppm and the residual amount of ethanol was 5000 ppm by gas chromatography.

[0078] Step 2: Preparation of Astragalus Polysaccharides C1. Take 8.00 kg of Astragalus membranaceus, grind it to 80 mesh, take a water sample in advance to test for astragaloside IV as a source confirmation item for Astragalus membranaceus, then add 160.0 L of deionized water. The mass-volume ratio of Astragalus membranaceus to deionized water is 1 g: 20 mL.

[0079] C2. Extract at 95℃ for 4 hours, repeat the extraction 3 times, filter and combine the aqueous extracts, and concentrate at 75℃ to a concentrate equivalent to 1.0 g / mL of crude drug.

[0080] C3. Add ethanol to the concentrate until the final ethanol concentration is 80 vol%, let it stand at 10℃ for 24 h, and collect the precipitate; dissolve the precipitate in deionized water, and perform ultrafiltration successively using ultrafiltration membranes with a molecular weight cutoff of 150 kDa and 10 kDa. Collect the permeate in the first stage and the retentate in the second stage, and dry it at 80℃ for 24 h to obtain Astragalus polysaccharide.

[0081] C4. The weight-average molecular weight (Mw) of Astragalus polysaccharide was determined to be 150 kDa by size exclusion chromatography, the carboxyl content was determined to be 1.50 mmol / g by titration, and the residual ethanol content was determined to be 5000 ppm by gas chromatography.

[0082] Step 3: Preparation of Panax notoginseng total saponins-Astragalus polysaccharide core-shell type nanocomposite dry powder components A1. Take 360.0g of total saponins of Panax notoginseng, disperse them in 70 vol% ethanol aqueous solution, and stir mechanically at 600 rpm for 20 min to obtain a dispersion of total saponins of Panax notoginseng; take 640.0g of Astragalus polysaccharide, dissolve it in deionized water, and stir mechanically at 600 rpm for 40 min to obtain an Astragalus polysaccharide solution.

[0083] A2. Add the total saponins of Panax notoginseng to the polysaccharide solution of Astragalus membranaceus, add deionized water to make the solid content of the composite dispersion corresponding to the total mass of total saponins of Panax notoginseng and polysaccharide of Astragalus membranaceus 8.0 wt%, adjust the pH to 6.2 with dilute hydrochloric acid or dilute sodium hydroxide aqueous solution, and stir at 600 rpm for 120 min at 55℃ to obtain the composite dispersion.

[0084] A3. The composite dispersion is fed into a high-pressure homogenizer and circulated 5 times at 80MPa. The feed temperature is controlled at 30℃. After each cycle, jacket cooling is used to keep the material temperature below 40℃ to obtain a core-shell nanocomposite dispersion.

[0085] A4. The core-shell nanocomposite dispersion was spray-dried at an inlet air temperature of 180°C, an outlet air temperature of 95°C, an atomization pressure of 0.50 MPa, and a feed rate of 30 mL / min. A light yellow dry powder was collected to obtain the Panax notoginseng total saponins-Astragalus polysaccharide core-shell nanocomposite dry powder component. In this embodiment, Astragalus polysaccharide was used as the shell material for the coating layer; no polyvinylpyrrolidone, hydroxypropyl methylcellulose, or chitosan was added as the shell material.

[0086] Step 4: Preparation of oral solid traditional Chinese medicine composition Take 9.00 kg of Panax notoginseng total saponins-Astragalus polysaccharide core-shell type nanocomposite dry powder, 0.50 kg of D-mannitol, 0.05 kg of microcrystalline cellulose, 0.25 kg of starch, and 0.20 kg of magnesium stearate. First, place the Panax notoginseng total saponins-Astragalus polysaccharide core-shell type nanocomposite dry powder, D-mannitol, microcrystalline cellulose, and starch in a wet granulator. Premix at 120 rpm for 10 min at 25℃ and 40% relative humidity. Spray in 0.35 kg of deionized water to form wet granules. Dry at 40℃ until the granule moisture content is below 5.0 wt%. Add magnesium stearate and mix at 15 rpm for 3 min. Compress into tablets. The final molding endpoint is judged by the difference in tablet weight, intact appearance, and a relative deviation of Panax notoginseng total saponin content not exceeding 5%.

[0087] Quality testing methods and results 100 mg of the Panax notoginseng total saponins-Astragalus polysaccharide core-shell nanocomposite dry powder component was added to 100 mL of deionized water and gently shaken at 25 °C for 5 min. After reconstitution, the D50, PDI, and ζ-potential were recorded using dynamic light scattering method after 30 min. The D50 was 450 ± 8 nm, the PDI was 0.30 ± 0.02, and the ζ-potential was -10.0 ± 0.7 mV (n=3). The D50 of the dry powder was measured to be 60.0 ± 1.5 μm using laser particle size distribution method, and the water content was measured to be 8.00 ± 0.20 wt% using drying loss method (n=3). After centrifugation to separate the free Panax notoginseng total saponins and free Astragalus polysaccharides, the binding rate of Panax notoginseng total saponins was calculated to be 98.0 ± 1.0 wt%, and the surface coverage rate of Astragalus polysaccharides was 95.0 ± 1.4 wt% (n=3). In the release test, the cumulative release rate of total saponins from Panax notoginseng was 45.0 ± 1.2 wt% after 2 h in 0.1 mol / L hydrochloric acid aqueous solution and 95.0 ± 1.5 wt% after 8 h in pH 6.8 phosphate buffer (n=3). The hygroscopic weight gain was 12.0 ± 0.4 wt%, the D50 retention rate after reconstitution was 120.0 ± 2.5%, the residual ethanol was 5000 ppm, and the residual 1-butanol was 500 ppm.

[0088] Features and application scenarios of this embodiment This embodiment uses a relatively high astragalus polysaccharide ratio, a relatively high solid content, and strong homogenization conditions, and sets the proportion of active compound dry powder in a relatively high range. It is suitable for oral Chinese medicine preparations with high single-dose active compound dry powder content and high requirements for tablet forming and interface coating.

[0089] Example 3 Overall production scale and product form In this embodiment, 1.00 kg of Panax notoginseng total saponins-Astragalus polysaccharide core-shell type nanocomposite dry powder component was prepared according to step 3 for quality testing. After obtaining sufficient composite dry powder component by scaling up or combining multiple batches according to the same process, 10.00 kg of tablet-type oral solid traditional Chinese medicine composition was prepared by dry weight. Panax notoginseng and Astragalus are both commercially available medicinal materials. Ethanol, 1-butanol and deionized water are all conventional pharmaceutical or analytical grade. D-mannitol, microcrystalline cellulose, starch and magnesium stearate are all commercially available pharmaceutical excipients.

[0090] Raw materials, components or material specifications In this embodiment, the content of total Panax notoginseng saponins-Astragalus polysaccharide core-shell type nanocomposite dry powder is 52.5 wt%, the content of Astragalus polysaccharide is 47.5 wt%, and the mass ratio of total Panax notoginseng saponins to Astragalus polysaccharide is 1:0.905. In the oral solid traditional Chinese medicine composition, the content of total Panax notoginseng saponins-Astragalus polysaccharide core-shell type nanocomposite dry powder is 28.0 wt%, and the excipients are 72.0 wt%. The excipients consist of 29.5 wt% D-mannitol, 40.0 wt% microcrystalline cellulose, 0.5 wt% starch, and 2.0 wt% magnesium stearate. All contents are based on the dry weight of the oral solid traditional Chinese medicine composition.

[0091] Step 1: Preparation of total saponins from Panax notoginseng B1. Take 12.00 kg of Panax notoginseng, grind it to 60 mesh, and add 120.0 L of 65 vol% ethanol aqueous solution. The mass-volume ratio of Panax notoginseng to ethanol aqueous solution is 1 g: 10 mL.

[0092] B2. Extract at 60℃ for 2 hours, repeat the extraction twice, filter with a 200-mesh filter cloth, combine the filtrates, and concentrate under reduced pressure at 55℃ and 0.08MPa to a concentrate equivalent to 0.6g / mL of raw drug.

[0093] B3. The concentrate was extracted three times with 1-butanol. The volume of the concentrate, the volume of 1-butanol, and the separation time were recorded each time. The 1-butanol phases were combined and washed twice with deionized water. The concentrate was then concentrated under reduced pressure at 55℃ and 0.08MPa absolute pressure, and then dried at 60℃ for 12h to obtain total saponins of Panax notoginseng.

[0094] B4. The total content of ginsenoside Rg1, ginsenoside Rb1 and notoginsenoside R1 was determined to be 72.0 wt% by high performance liquid chromatography; the residual amount of 1-butanol was 250 ppm and the residual amount of ethanol was 2500 ppm by gas chromatography.

[0095] Step 2: Preparation of Astragalus Polysaccharides C1. Take 8.00 kg of Astragalus membranaceus, grind it to 60 mesh, take a water sample in advance to test for astragaloside IV as a source confirmation item for Astragalus membranaceus, then add 112.0 L of deionized water. The mass-volume ratio of Astragalus membranaceus to deionized water is 1 g: 14 mL.

[0096] C2. Extract at 85℃ for 2.5 h, repeat the extraction twice, filter and combine the aqueous extracts, and concentrate at 60℃ to a concentrate equivalent to 0.6 g / mL of crude drug.

[0097] C3. Add ethanol to the concentrate until the final ethanol concentration is 70 vol%, let it stand at 6℃ for 12 h, and collect the precipitate; dissolve the precipitate in deionized water, and perform ultrafiltration successively using ultrafiltration membranes with a molecular weight cutoff of 150 kDa and 10 kDa. Collect the permeate in the first stage and the retentate in the second stage, and dry it at 60℃ for 12 h to obtain Astragalus polysaccharide.

[0098] C4. The weight-average molecular weight (Mw) of Astragalus polysaccharide was determined to be 80 kDa by size exclusion chromatography, the carboxyl content was determined to be 0.80 mmol / g by titration, and the residual ethanol content was determined to be 2500 ppm by gas chromatography.

[0099] Step 3: Preparation of Panax notoginseng total saponins-Astragalus polysaccharide core-shell type nanocomposite dry powder components A1. Take 525.0g of total saponins of Panax notoginseng, disperse them in 50 vol% ethanol aqueous solution, and stir mechanically at 450 rpm for 15 min to obtain a dispersion of total saponins of Panax notoginseng; take 475.0g of Astragalus polysaccharide, dissolve it in deionized water, and stir mechanically at 450 rpm for 30 min to obtain an Astragalus polysaccharide solution.

[0100] A2. Add the total saponins of Panax notoginseng to the polysaccharide solution of Astragalus membranaceus, add deionized water to make the solid content of the composite dispersion corresponding to the total mass of total saponins of Panax notoginseng and polysaccharide of Astragalus membranaceus 5.5wt%, adjust the pH to 5.2 with dilute hydrochloric acid or dilute sodium hydroxide aqueous solution, and stir at 450 rpm for 75 min at 40℃ to obtain the composite dispersion.

[0101] A3. Input the composite dispersion into a high-pressure homogenizer and circulate it 3 times at 50MPa. The feed temperature is controlled at 28℃. After each cycle, jacket cooling is used to keep the material temperature below 35℃ to obtain a core-shell nanocomposite dispersion.

[0102] A4. The core-shell nanocomposite dispersion was spray-dried at an inlet air temperature of 155°C, an outlet air temperature of 80°C, an atomization pressure of 0.35 MPa, and a feed rate of 20 mL / min. A light yellow dry powder was collected to obtain the Panax notoginseng total saponins-Astragalus polysaccharide core-shell nanocomposite dry powder component. In this embodiment, Astragalus polysaccharide was used as the shell material for the coating layer; polyvinylpyrrolidone, hydroxypropyl methylcellulose, or chitosan were not added as shell materials.

[0103] Step 4: Preparation of oral solid traditional Chinese medicine composition Take 2.80 kg of Panax notoginseng total saponins-Astragalus polysaccharide core-shell type nanocomposite dry powder, 2.95 kg of D-mannitol, 4.00 kg of microcrystalline cellulose, 0.05 kg of starch, and 0.20 kg of magnesium stearate. First, place the Panax notoginseng total saponins-Astragalus polysaccharide core-shell type nanocomposite dry powder, D-mannitol, microcrystalline cellulose, and starch in a mixer and mix at 25 rpm for 25 min at 25℃ and 45% relative humidity. Then, add magnesium stearate and mix at 15 rpm for 3 min. Tablets are then made using a direct compression method. The final tableting endpoint is judged by the following criteria: intact tablets, tablet weight variation meeting the set internal control requirements, and a relative deviation of Panax notoginseng total saponin content not exceeding 5%.

[0104] Quality testing methods and results 100 mg of the Panax notoginseng total saponins-Astragalus polysaccharide core-shell nanocomposite dry powder component was added to 100 mL of deionized water and gently shaken at 25 °C for 5 min. After reconstitution, the D50, PDI, and ζ-potential were recorded using dynamic light scattering method after 30 min. The D50 was 300 ± 6 nm, the PDI was 0.18 ± 0.01, and the ζ-potential was -22.0 ± 0.6 mV (n=3). The D50 of the dry powder was measured to be 30.0 ± 0.8 μm using laser particle size distribution method, and the water content was measured to be 5.00 ± 0.10 wt% using drying loss method (n=3). After centrifugation to separate free Panax notoginseng total saponins and free Astragalus polysaccharides, the binding rate of Panax notoginseng total saponins was calculated to be 85.0 ± 1.1 wt%, and the surface coverage rate of Astragalus polysaccharides was 80.0 ± 1.3 wt% (n=3). In the release test, the cumulative release rate of total saponins from Panax notoginseng was 30.0 ± 0.9 wt% after 2 h in 0.1 mol / L hydrochloric acid aqueous solution and 80.0 ± 1.2 wt% after 8 h in pH 6.8 phosphate buffer (n=3). The hygroscopic weight gain was 6.0 ± 0.3 wt%, the D50 retention rate after reconstitution was 100.0 ± 2.0%, the residual ethanol was 2500 ppm, and the residual 1-butanol was 250 ppm.

[0105] Features and application scenarios of this embodiment This embodiment uses a moderate ratio of total Panax notoginseng saponins to Astragalus polysaccharides, moderate compound dispersion and homogenization conditions, and a higher proportion of microcrystalline cellulose to improve direct compression compatibility. It is suitable for oral Chinese medicine preparations that have comprehensive requirements for tablet forming strength, reconstitution dispersion state and moderate loading.

[0106] Example 4 Overall production scale and product form In this embodiment, 1.00 kg of Panax notoginseng total saponins-Astragalus polysaccharide core-shell type nanocomposite dry powder component was prepared according to step 3 for quality testing. After obtaining sufficient composite dry powder component by scaling up or combining multiple batches according to the same process, 10.00 kg of tablet-type oral solid traditional Chinese medicine composition was prepared by dry weight. Panax notoginseng and Astragalus are both commercially available medicinal materials. Ethanol, 1-butanol and deionized water are all conventional pharmaceutical or analytical grade. D-mannitol, microcrystalline cellulose, starch and magnesium stearate are all commercially available pharmaceutical excipients.

[0107] Raw materials, components or material specifications In this embodiment, the content of total Panax notoginseng saponins-Astragalus polysaccharide core-shell type nanocomposite dry powder is 50.0 wt%, the content of Astragalus polysaccharide is 50.0 wt%, and the mass ratio of total Panax notoginseng saponins to Astragalus polysaccharide is 1:1.0. In the oral solid traditional Chinese medicine composition, the content of total Panax notoginseng saponins-Astragalus polysaccharide core-shell type nanocomposite dry powder is 50.0 wt%, and the excipients are 50.0 wt%; the excipients consist of 17.5 wt% D-mannitol, 2.0 wt% microcrystalline cellulose, 30.0 wt% starch, and 0.5 wt% magnesium stearate, and the contents of each are based on the dry weight of the oral solid traditional Chinese medicine composition.

[0108] Step 1: Preparation of total saponins from Panax notoginseng B1. Take 12.00 kg of Panax notoginseng, grind it to 40 mesh, and add 144.0 L of 70 vol% ethanol aqueous solution. The mass-volume ratio of Panax notoginseng to ethanol aqueous solution is 1 g: 12 mL.

[0109] B2. Extract at 70℃ for 2.5h, repeat extraction twice, filter with 200 mesh filter cloth, combine the filtrates, and concentrate under reduced pressure at 60℃ and 0.08MPa to a concentrate equivalent to 0.8g / mL of crude drug.

[0110] B3. The concentrate was extracted four times with 1-butanol. The volume of the concentrate, the volume of 1-butanol, and the separation time were recorded each time. The 1-butanol phases were combined and washed twice with deionized water. The concentrate was then concentrated under reduced pressure at 60℃ and 0.08MPa, and dried at 70℃ for 18h to obtain total saponins of Panax notoginseng.

[0111] B4. The total content of ginsenoside Rg1, ginsenoside Rb1 and notoginsenoside R1 was determined to be 90.0 wt% by high performance liquid chromatography; the residual amount of 1-butanol was 120 ppm and the residual amount of ethanol was 800 ppm by gas chromatography.

[0112] Step 2: Preparation of Astragalus Polysaccharides C1. Take 8.00 kg of Astragalus membranaceus, grind it to 40 mesh, take a water sample in advance to test for astragaloside IV as a source confirmation item for Astragalus membranaceus, then add 96.0 L of deionized water. The mass-volume ratio of Astragalus membranaceus to deionized water is 1 g: 12 mL.

[0113] C2. Extract at 80℃ for 3 hours, repeat the extraction twice, filter and combine the aqueous extracts, and concentrate at 55℃ to a concentrate equivalent to 0.8 g / mL of crude drug.

[0114] C3. Add ethanol to the concentrate until the final ethanol concentration is 75 vol%, let it stand at 4℃ for 18 h, and collect the precipitate; dissolve the precipitate in deionized water, and perform ultrafiltration successively using ultrafiltration membranes with molecular weight cutoff of 150 kDa and 10 kDa. Collect the permeate in the first stage and the retentate in the second stage, and dry it at 70℃ for 18 h to obtain Astragalus polysaccharide.

[0115] C4. The weight-average molecular weight (Mw) of Astragalus polysaccharide was determined to be 120 kDa by size exclusion chromatography, the carboxyl content was determined to be 1.20 mmol / g by titration, and the residual ethanol content was determined to be 800 ppm by gas chromatography.

[0116] Step 3: Preparation of Panax notoginseng total saponins-Astragalus polysaccharide core-shell type nanocomposite dry powder components A1. Take 500.0g of total saponins of Panax notoginseng and disperse them in 60 vol% ethanol aqueous solution. Stir at 500 rpm for 15 min to obtain a dispersion of total saponins of Panax notoginseng. Take 500.0g of Astragalus polysaccharide and dissolve it in deionized water. Stir at 500 rpm for 30 min to obtain an Astragalus polysaccharide solution.

[0117] A2. Add the total saponins of Panax notoginseng to the polysaccharide solution of Astragalus membranaceus, add deionized water to make the solid content of the composite dispersion corresponding to the total mass of total saponins of Panax notoginseng and polysaccharide of Astragalus membranaceus 7.0 wt%. Adjust the pH to 5.8 with dilute hydrochloric acid or dilute sodium hydroxide aqueous solution, and stir at 500 rpm for 90 min at 45℃ to obtain the composite dispersion.

[0118] A3. The composite dispersion is fed into a high-pressure homogenizer and circulated 4 times at 65MPa. The feed temperature is controlled at 28℃. After each cycle, jacket cooling is used to keep the material temperature below 35℃ to obtain a core-shell nanocomposite dispersion.

[0119] A4. The core-shell nanocomposite dispersion was spray-dried at an inlet air temperature of 165°C, an outlet air temperature of 88°C, an atomization pressure of 0.40 MPa, and a feed rate of 24 mL / min. A light yellow dry powder was collected to obtain the Panax notoginseng total saponins-Astragalus polysaccharide core-shell nanocomposite dry powder component. In this embodiment, Astragalus polysaccharide was used as the shell material for the coating layer; no polyvinylpyrrolidone, hydroxypropyl methylcellulose, or chitosan was added as the shell material.

[0120] Step 4: Preparation of oral solid traditional Chinese medicine composition Take 5.00 kg of Panax notoginseng total saponins-Astragalus polysaccharide core-shell type nanocomposite dry powder, 1.75 kg of D-mannitol, 0.20 kg of microcrystalline cellulose, 3.00 kg of starch, and 0.05 kg of magnesium stearate. First, place the Panax notoginseng total saponins-Astragalus polysaccharide core-shell type nanocomposite dry powder, D-mannitol, microcrystalline cellulose, and starch in a dry granulator. Premix at 25 rpm for 20 min at 25℃ and 45% relative humidity. After dry granulation and granulation, add magnesium stearate and mix at 15 rpm for 3 min. Capsules are then prepared using a capsule filling method. The filling endpoint is judged by a relative deviation of no more than 5% in terms of fill weight variation, particle flowability, and Panax notoginseng total saponin content.

[0121] Quality testing methods and results 100 mg of the Panax notoginseng total saponins-Astragalus polysaccharide core-shell nanocomposite dry powder component was added to 100 mL of deionized water and gently shaken at 25 °C for 5 min. After reconstitution, the D50, PDI, and ζ-potential were recorded using dynamic light scattering method after 30 min. The D50 was 155 ± 4 nm, the PDI was 0.06 ± 0.01, and the ζ-potential was -32.0 ± 0.9 mV (n=3). The D50 of the dry powder was measured to be 55.0 ± 1.2 μm using laser particle size distribution method, and the water content was measured to be 5.00 ± 0.12 wt% using drying loss method (n=3). After centrifugation to separate free Panax notoginseng total saponins and free Astragalus polysaccharides, the binding rate of Panax notoginseng total saponins was calculated to be 90.0 ± 1.0 wt%, and the surface coverage rate of Astragalus polysaccharides was 88.0 ± 1.2 wt% (n=3). In the release test, the cumulative release rate of total saponins from Panax notoginseng in 0.1 mol / L hydrochloric acid aqueous solution for 2 h was 28.0 ± 0.9 wt%, and the cumulative release rate of total saponins from Panax notoginseng in pH 6.8 phosphate buffer solution for 8 h was 88.0 ± 1.3 wt%, n=3. The hygroscopic weight gain was 3.0 ± 0.2 wt%, the D50 retention rate after reconstitution was 110.0 ± 2.0%, the residual ethanol was 800 ppm, and the residual 1-butanol was 120 ppm.

[0122] Features and application scenarios of this embodiment This embodiment uses a relatively balanced ratio of Panax notoginseng total saponins and Astragalus polysaccharides, and combines dry granulation and capsule filling methods to achieve good formulation compatibility between the compound dry powder, starch and D-mannitol. It is suitable for oral Chinese medicine formulations that have comprehensive requirements for fill volume stability, capsule filling and particle size retention after reconstitution.

[0123] Comparative Example 1: It is basically the same as Example 1, except that in step A1, 909.1g of total saponins of Panax notoginseng and 90.9g of polysaccharide of Astragalus membranaceus were used, so that the mass ratio of total saponins of Panax notoginseng to polysaccharide of Astragalus membranaceus was 1:0.10, and other conditions remained unchanged.

[0124] Comparative Example 2: It is basically the same as Example 1, except that the pH of the composite dispersion is adjusted to 3.8 in step A2, while other conditions remain unchanged.

[0125] Comparative Example 3: It is basically the same as Example 1, except that the composite stirring temperature in step A2 is 60°C, and other conditions remain unchanged.

[0126] Comparative Example 4: It is basically the same as Example 1, except that in step A2, it is stirred at 300 rpm for 15 min at 25°C, while other conditions remain unchanged.

[0127] Comparative Example 5: It is basically the same as Example 1, except that the high-pressure homogenization pressure in step A3 is 10 MPa, the number of cycles is still 1, and other conditions remain unchanged.

[0128] Comparative Example 6: It is basically the same as Example 1, except that in step A1, the total saponins of Panax notoginseng are dispersed in a 20 vol% ethanol aqueous solution, the mechanical stirring speed is 300 rpm, and the stirring time is 10 min, while other conditions remain unchanged.

[0129] Comparative Example 7: It is basically the same as Example 1, except that in step A4, the inlet air temperature of spray drying is 120°C, the outlet air temperature is still controlled at 65°C, the atomization pressure is 0.20MPa, the feed rate is 10mL / min, and other conditions remain unchanged.

[0130] Comparative Example 8: It is basically the same as Example 1, except that in step C3, after the precipitate obtained by alcohol precipitation is dissolved in deionized water, the permeate is first collected by an ultrafiltration membrane with a molecular weight cutoff of 150 kDa, and then treated by an ultrafiltration membrane with a molecular weight cutoff of 10 kDa and the permeate is collected. The permeate is concentrated and dried at 45°C for 4 h to obtain Astragalus polysaccharide with a weight average molecular weight Mw of 8 kDa. In step A1, 170.0 g of the Astragalus polysaccharide is still taken, and other conditions remain unchanged.

[0131] Comparative Example 9: This example is essentially the same as Example 1, except that in step A1, Astragalus polysaccharides are not taken and an Astragalus polysaccharide solution is not prepared. Instead, 1000.0 g of total Panax notoginseng saponins are dispersed in a 30 vol% ethanol aqueous solution. In step A2, deionized water is added to bring the solid content of the dispersion corresponding to the total Panax notoginseng saponins to 3.0 wt%. The pH is adjusted to 4.2, and the mixture is stirred at 300 rpm for 30 min at 25°C. Other conditions remain unchanged. This comparative example is used to verify the synergistic effect between the core of the total Panax notoginseng saponins and the coating layer of Astragalus polysaccharides.

[0132] Comparative Example 10: Essentially the same as Example 1, except that the high-pressure homogenization in step A3 was omitted. The composite dispersion obtained in step A2 was stirred at 300 rpm for 30 minutes at 25°C and then directly entered step A4 for spray drying, with other conditions remaining unchanged. This comparative example was used to verify the synergistic effect of Panax notoginseng total saponins, Astragalus polysaccharides, and the high-pressure homogenization interface construction method.

[0133] Comparative Example 11: This example is essentially the same as Example 1, except that in step A1, 170.0 g of Astragalus polysaccharide was replaced with 170.0 g of D-mannitol. The D-mannitol was dissolved in deionized water and mixed with the Panax notoginseng total saponin dispersion. The amount of Panax notoginseng total saponins remained at 830.0 g, and other conditions were unchanged. This comparative example was used to verify the synergistic effect of the Panax notoginseng total saponin core and the Astragalus polysaccharide coating layer.

[0134] Characterization and performance testing: Reconstituted particle size, PDI, and zeta potential tests: 100 mg of the Panax notoginseng total saponins-Astragalus polysaccharide core-shell nanocomposite dry powder component was added to 100 mL of deionized water and gently shaken at 25℃ for 5 min. After reconstitution, D50, PDI, and zeta potential were measured 30 min later. The principle is that dynamic light scattering records the fluctuations in scattering intensity caused by Brownian motion and converts them into particle size distribution. Simultaneously, the zeta potential is calculated using electrophoretic mobility. Refer to ISO 22412:2025 or equivalent DLS method; for each batch, n=3, report the mean ± standard deviation, and record the reconstitution time, concentration, and temperature. ISO 22412:2025 is applicable to the determination of average hydrodynamic particle size and particle size distribution of liquid dispersion systems using dynamic light scattering.

[0135] Particle size and moisture content testing: Using the Panax notoginseng total saponins-Astragalus polysaccharide core-shell type nanocomposite dry powder component as the object, the particle size and residual moisture of the powder after spray drying were evaluated. The dry powder D50 was determined using laser particle size distribution method. After dry dispersion, D10, D50, and D90 were recorded. Moisture content was determined using the loss on drying method, treated at 105℃ to constant weight or according to the pharmacopoeia equivalent moisture determination method. For each batch, n=3, the mean ± standard deviation was calculated, and the dispersion pressure, shading rate, drying time, and constant weight criterion were recorded.

[0136] Test of total saponin content and binding rate of Panax notoginseng: Using the reconstituted dispersion and the supernatant obtained by centrifugation as the subjects, the total amount and free amount of Panax notoginseng saponins were evaluated. The combined amounts of ginsenoside Rg1, ginsenoside Rb1, and notoginsenoside R1 were determined by HPLC or UPLC. The binding rate was calculated by subtracting the free amount from the total input and then dividing by the total input. The equivalent method for liquid chromatography of Panax notoginseng saponins was referenced; for each batch (n=3), the chromatographic column, mobile phase, detection wavelength or detector, linear range, and recovery rate were recorded. Notoginsenoside R1, ginsenoside Rg1, and Rb1 could be detected simultaneously using a liquid chromatography system.

[0137] Astragalus polysaccharide molecular weight, carboxyl content, and surface coverage testing: Using Astragalus polysaccharide raw materials, reconstituted supernatant, and separated composite particles as samples, the shell material specifications and coating degree were evaluated. Weight-average molecular weight (Mw) was determined using size exclusion chromatography, carboxyl content was determined by titration, and free Astragalus polysaccharide was determined using the phenol-sulfuric acid method or the equivalent sugar content method. Surface coverage was calculated by subtracting the free amount from the total amount of Astragalus polysaccharide added. For each batch, n=3, the mean ± standard deviation was reported, along with the standard curve and dilution factor.

[0138] Two-stage release test of total saponins from Panax notoginseng: Using compound dry powder or oral solid composition as the subjects, the release inhibition behavior in the acidic stage and the release behavior in the pH 6.8 stage were evaluated. The mixture was first placed in 0.1 mol / L hydrochloric acid aqueous solution for 2 h, then transferred to pH 6.8 phosphate buffer for a cumulative 8 h. The mixture was stirred at a constant speed using a paddle at 37℃, and samples were taken periodically. The total stoichiometry of Rg1, Rb1, and R1 was determined by HPLC. The cumulative release rate and RSD were calculated according to the Chinese Pharmacopoeia General Chapter 0931 for dissolution and release or equivalent methods; n=3. Publicly available drug documents also use the Chinese Pharmacopoeia General Chapter 0931 for dissolution or release testing, using 0.1 mol / L hydrochloric acid and pH 6.8 as the release medium.

[0139] Moisture absorption weight gain rate and reconstitution D50 retention rate test: Using dry powder samples as the object, the changes in powder mass and particle size retention after reconstitution were evaluated after the effect of storage humidity. The samples were spread evenly on a weighing bottle and placed at 25℃ and 75%RH for 24 hours. The mass before and after exposure was weighed, and the moisture absorption weight gain rate was calculated by dividing the mass difference by the mass before exposure. Samples from the same batch were reconstituted under the conditions of Experiment 1, and the D50 retention rate was calculated by dividing the D50 after treatment by the D50 before treatment. Each batch had n=3 samples, and the exposure area, sample thickness, and weighing interval were recorded.

[0140] Residual solvent and mixing homogeneity tests: Using compound dry powder and oral solid compositions as examples, the homogeneity of ethanol, 1-butanol residues, and total saponins from Panax notoginseng were evaluated. Residual solvents were assessed using headspace gas chromatography, with ethanol and 1-butanol reference standard curves set up. Mixing homogeneity was determined by measuring Rg1, Rb1, and R1 summation at three consecutive sampling points, and the relative deviations were calculated. (Refer to USP) <467> ICH Q3C or equivalent residual solvent method; report ppm, RSD and whether internal control limits are met. USP <467> Residual solvents are defined as volatile organic chemicals used or generated in the preparation of drugs, excipients or formulations and that may remain thereafter. ICH Q3C provides a safety limit framework for the control of residual solvents in pharmaceuticals.

[0141] Figure 1 The following are particle size distribution diagrams of DLS after reconstitution in Examples 1, 9, and 10. Figure 2 The following are cumulative particle size distribution diagrams of DLS after resolution in Examples 1, 9, and 10. Figure 3 The graph shows the D50-PDI parameter relationship for Example 1, Comparative Example 9, and Comparative Example 10. Figure 4 This is a scatter plot of the mean zeta potential for Example 1, Comparative Example 9, and Comparative Example 10. Figure 1 As can be seen, after resolution in Example 1, the particle size is mainly concentrated around 150 nm, and the differential distribution peak is narrow and single, indicating that the particles can form a relatively uniform nano-dispersion system after resolution. In Comparative Examples 9 and 10, the particle size peaks generally shift towards larger particle sizes, and the distribution range becomes significantly wider, indicating that particles are more prone to aggregation when the Astragalus polysaccharide coating layer is lacking or a stable interface structure is not formed. Further combining... Figure 2 It can be seen that the D10, D50 and D90 distribution ranges of Example 1 are more concentrated and the cumulative distribution curve has a higher slope, indicating that its particle size distribution range is smaller and the resolution and dispersion process is more controllable. Figure 3 The results show that the D50 of Example 1 is about 150 nm and the PDI is about 0.05, both lower than those of Comparative Example 9 and Comparative Example 10. This indicates that the synergistic formation of the Panax notoginseng total saponin core and the Astragalus polysaccharide coating layer can simultaneously reduce particle size and polydispersity. Figure 4 Further analysis shows that the zeta potential of Example 1 is approximately -35 mV, significantly higher than that of the comparative example, indicating that the particle surface has a strong electrostatic stabilizing effect, which is beneficial for inhibiting secondary agglomeration after resolution. These results, from the perspectives of particle size distribution, dispersion uniformity, and surface charge, collectively demonstrate that the Astragalus polysaccharide coating layer and the high-pressure homogeneous interface construction can effectively improve the resolution stability of the nanocomposite system.

[0142] Figure 5 The graph shows the binding rate of total saponins from Panax notoginseng in Example 1, Comparative Example 9, and Comparative Example 11. Figure 6 This image shows the surface coverage of Astragalus polysaccharides in Examples 1, 9, and 11. (Source: [Insert source here]) Figure 5 As can be seen, the binding rate of total Panax notoginseng saponins in Example 1 is about 70%, which is significantly higher than that of Comparative Example 9, which lacks the Astragalus polysaccharide coating layer, and Comparative Example 11, which uses D-mannitol to replace Astragalus polysaccharide. This indicates that Astragalus polysaccharide does not simply play a diluting or filling role, but can participate in interfacial compounding and promote the effective fixation of total Panax notoginseng saponins in the particles. Figure 6 Further, it was shown that the surface coverage of Astragalus polysaccharides in Example 1 was approximately 60%, while Comparative Examples 9 and 11 could not form an effective Astragalus polysaccharide coating layer, indicating that the Astragalus polysaccharides in Example 1 could be stably distributed on the outer layer of the particles and form a clear coating structure. Combined with... Figure 5 and Figure 6 It can be seen that the increase in the binding rate of total saponins of Panax notoginseng corresponds to the formation of the surface coverage of Astragalus polysaccharides, indicating that the system can form core-shell nanocomposite particles with the enriched phase of total saponins of Panax notoginseng as the core and the enriched phase of Astragalus polysaccharides as the outer layer, which proves the effectiveness of the interface composite design of this scheme from the perspective of structural composition.

[0143] Figure 7 This is a two-stage cumulative release curve for Example 1, Comparative Example 1, and Comparative Example 10. Figure 8 The graph shows the dQ / dt ratio of the total saponin release rate from Panax notoginseng in Example 1, Comparative Example 1, and Comparative Example 10. Figure 9 The graph shows the piecewise fitting rate constant k values ​​for Example 1, Comparative Example 1, and Comparative Example 10. Figure 10 This is a graph showing the correlation between the 2-hour and 8-hour release rates of Example 1, Comparative Example 1, and Comparative Example 10. Figure 7 As can be seen, Example 1 showed a release rate of approximately 15% in the acidic phase over 2 hours and a cumulative release rate of approximately 60% over 8 hours, demonstrating controlled release in the early stages and continuous release thereafter. Comparative Examples 1 and 10 showed significantly faster release in the acidic phase, indicating that improper formulation or insufficient interface construction can lead to enhanced early burst release. Figure 8 Further, it was shown that the peak release rate of Example 1 was low in the acidic stage, and the release rate remained relatively slow after entering the pH 6.8 stage, while the release rates of Comparative Example 1 and Comparative Example 10 showed a significant increase in the early stage, indicating that Example 1 has a more stable regulatory ability on the release process of Panax notoginseng total saponins. Figure 9 The results show that the fitting rate constant k for the acidic phase in Example 1 is approximately 0.72 h. -1 At pH 6.8, k is approximately 0.34 h. -1 The release rate is significantly suppressed in the acidic phase, but can still maintain continuous release in subsequent phases. Figure 10 Further evidence from the correlation between the 2-hour and 8-hour release rates demonstrates that Example 1 can maintain a moderate total release level while reducing the early release ratio, indicating that a reasonable ratio of Panax notoginseng total saponins to Astragalus polysaccharides and the interface structure formed by high-pressure homogenization help to achieve two-stage release regulation.

[0144] Figure 11 This is a graph showing the relationship between moisture absorption weight gain and D50 retention rate for Example 1, Comparative Example 7, and Comparative Example 8. Figure 12 This is a graph showing the change in D50 before and after reconstitution of Examples 1, 7, and 8 before and after storage. (Source: [Insert source here]) Figure 11 As can be seen, the moisture absorption weight gain rate of Example 1 is about 0.5%, and the D50 retention rate is about 80%, showing low moisture absorption and high particle size retention ability. Due to the change in spray drying conditions, Comparative Example 7 and Comparative Example 8 showed a trend of increased moisture absorption weight gain rate or decreased D50 retention rate due to the change in the molecular weight of Astragalus polysaccharide. This indicates that the drying and curing state and the shell size of Astragalus polysaccharide can affect the storage stability of dry powder. Figure 12 Further, it was shown that the D50 of Example 1 changed little after reconstitution, while the particle size of Comparative Examples 7 and 8 increased significantly after reconstitution, indicating that the dry powder obtained in Example 1 could still be well restored to a nano-dispersed state after storage. The above results show that suitable spray drying parameters combined with the Astragalus polysaccharide coating structure can reduce the risk of particle fusion or agglomeration after the dry powder absorbs moisture, thereby improving storage stability and reconstitution consistency.

[0145] Figure 13 The following are the particle size distribution diagrams of the dry powder from Example 1 and Comparative Example 7. Figure 14 The cumulative particle size distribution of the dry powder in Example 1 and Comparative Example 7 is shown in the diagram. Figure 15 This is a graph showing the relationship between the dry powder D50 and the reconstituted D50 of Example 1 and Comparative Example 7. Figure 16 This is a graph showing the moisture content-D50 retention rate relationship for Example 1 and Comparative Example 7. Figure 13 As can be seen, the dry powder particle size in Example 1 is mainly concentrated around 5 μm, with a narrow differential distribution, indicating that spray drying can form micron-sized secondary particles with relatively uniform particle size. In Comparative Example 7, the particle size peak shifts to the right and the distribution widens, indicating that when the spray drying conditions deviate from the appropriate range, the secondary particles are more likely to coarsen and produce particle size dispersion. Figure 14 Further, it is shown that the distribution range of D10, D50 and D90 of the dry powder in Example 1 is narrower and the cumulative distribution curve is more concentrated, indicating that the particle size of the dry powder particles is more controllable. Figure 15 The results show that the dry powder D50 of Example 1 is about 5 μm and the reconstituted D50 is about 150 nm, while the dry powder D50 and reconstituted D50 of Comparative Example 7 are significantly increased, indicating that the secondary particle size control of the dry powder is directly related to the maintenance of the nanoparticle size after reconstitution. Figure 16Further, it was shown that Example 1 had a moisture content of approximately 0.5% and a D50 retention rate of approximately 80%, while Comparative Example 7 showed an increased moisture content accompanied by a decrease in D50 retention rate. This indicates that lower residual moisture helps reduce interparticle bridging, collapse, or irreversible agglomeration during storage. Therefore, Example 1, by controlling the micron-sized dry powder particle size and moisture content after spray drying, achieved a balance between dry powder processing adaptability and reconstituted nano-dispersion.

[0146] Figure 17 Macroscopic optical photographs of the Panax notoginseng total saponins-Astragalus polysaccharide core-shell type nanocomposite dry powder components and their granular oral solid traditional Chinese medicine composition obtained in Example 1. Figure 17 As can be seen, the Panax notoginseng total saponins-Astragalus polysaccharide core-shell type nanocomposite dry powder component is a light yellow opaque dry powder, while the granular oral solid traditional Chinese medicine composition is a light yellow to off-white granular solid with a uniform appearance and no obvious lumps. The composition contains 10.0 wt% Panax notoginseng total saponins-Astragalus polysaccharide core-shell type nanocomposite dry powder component, 90.0 wt% excipients, and 0.50 ± 0.04 wt% moisture. These macroscopic results indicate that the spray-dried nanocomposite dry powder has low moisture content and good powdering properties, meeting the process requirements for subsequent dry mixing and preparation of the granular oral solid traditional Chinese medicine composition, thus providing a feasible basis for its transformation from a nano-dispersion system to a solid dosage form.

[0147] Figure 18 The image shows a scanning electron microscope (SEM) image of the Panax notoginseng total saponins-Astragalus polysaccharide core-shell nanocomposite dry powder component obtained in Example 1, wherein... Figure 18 Image a is a low-magnification scanning electron microscope image. Figure 18 b and Figure 18 c is a medium-to-high magnification scanning electron microscope image. Figure 18 d represents a scanning electron microscope image of the fragmented particles or cross-section. (From...) Figure 18 As can be seen, after spray drying, the sample forms micron-sized secondary particles, which are relatively uniformly distributed overall. Figure 18 b and Figure 18 c shows that the particles are mainly spherical secondary particles with slight wrinkling and nanoscale undulation texture on the surface, indicating that the droplet shrinkage and solidification process during the drying process is relatively complete. Figure 18 Further analysis reveals that the secondary particles contain a multi-level structure formed by the accumulation of 100-nanometer-sized Panax notoginseng total saponins-Astragalus polysaccharide core-shell nanocomposite particles. This morphological result indicates that spray drying does not simply form dense lumps, but rather organizes the nanocomposite particles into micron-sized dry powder that is easy to process into solid dosage forms, while retaining the morphological basis for restoring the nano-dispersion structure after reconstitution.

[0148] Figure 19 Transmission electron microscopy characterization of the reconstituted Panax notoginseng total saponins-Astragalus polysaccharide core-shell nanocomposite dry powder component obtained in Example 1, wherein... Figure 19 Image a is a bright-field transmission electron microscope image. Figure 19 b is a magnified transmission electron microscope image of a portion of the image. Figure 19 c is a high-resolution transmission electron microscope image. Figure 19 d is the selected area electron diffraction pattern. (From...) Figure 19 As can be seen, after resolution, the sample forms near-spherical nanocomposite particles at the hundred-nanometer scale; Figure 19 b further shows that a low-contrast organic interface between the Panax notoginseng total saponin enrichment core and the Astragalus polysaccharide enrichment shell can be observed inside the particles. The shell thickness is several nanometers to about 10 nm, indicating that the core-shell nanostructure can still be maintained after resolution. Figure 19 c. No clearly indexable long-range lattice fringes were observed. Figure 19 The diffuse halo characteristic of d indicates that the total saponins of Panax notoginseng and polysaccharides of Astragalus membranaceus mainly exist as amorphous or low-crystallinity organic composite phases, rather than forming large-sized crystals. Combined with the parameters of D50 (150±3 nm), PDI (0.05±0.01), and ζ-potential (-35.0±0.8 mV) after resolution, it can be seen that this core-shell nanocomposite dry powder still exhibits small particle size, narrow particle size distribution, and good aqueous dispersion stability after resolution. This further verifies the comprehensive effectiveness of this scheme in terms of structure construction, dry powder processing, and retention of resolution performance at the microstructural level.

[0149] Table 1 Performance of Examples and Comparative Examples

[0150] As can be seen from the performance of the examples and comparative examples in Table 1, Examples 1-4 formed a relatively complete parameter gradient in terms of reconstitution particle size, PDI, interface coverage, binding rate, two-stage release, and D50 retention after storage. Among them, Example 1 highlights low particle size and low hygroscopicity, Example 2 reflects high binding rate, high coverage, and a high release area, and Examples 3 and 4 reflect the equilibrium state under intermediate ratios. After changing the ratio, pH, compounding temperature, stirring time, homogenization pressure, ethanol volume fraction, spray drying temperature, and molecular weight of Astragalus polysaccharide in Comparative Examples 1-8, the interface coverage, reconstitution dispersion, or release curves all deviated in different directions. Comparative Examples 9-11 were dissected around the Astragalus polysaccharide coating layer and the high-pressure homogenization interface construction. The trends of increasing particle size, increasing PDI, decreasing coverage, and decreasing D50 retention were more obvious, indicating that these variables are the key differences that should be prioritized for verification in subsequent experiments.

[0151] 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 traditional Chinese medicine composition for preventing and treating cardiovascular and cerebrovascular diseases, characterized in that, Includes Panax notoginseng total saponins-Astragalus polysaccharide core-shell type nanocomposite dry powder components; The Panax notoginseng total saponins-Astragalus polysaccharide core-shell type nanocomposite dry powder component includes a Panax notoginseng total saponins core and an Astragalus polysaccharide layer coated on the surface of the Panax notoginseng total saponins core; The mass ratio of the total saponins of Panax notoginseng to the polysaccharides of Astragalus membranaceus is 1:0.2–1:1.8; The nanocomposite particles formed by redissolving the Panax notoginseng total saponins-Astragalus polysaccharide core-shell type nanocomposite dry powder components in deionized water have a D50 of 150–450 nm and a PDI of 0.05–0.

30.

2. The traditional Chinese medicine composition according to claim 1, characterized in that, The total saponins of Panax notoginseng are derived from Panax notoginseng, and the polysaccharides of Astragalus membranaceus are derived from Astragalus membranaceus. Based on the dry weight of the Panax notoginseng total saponins-Astragalus polysaccharide core-shell type nanocomposite dry powder components, the content of Panax notoginseng total saponins is 35.7–83.3 wt%, and the content of Astragalus polysaccharide is 16.7–64.3 wt%.

3. The traditional Chinese medicine composition according to claim 1, characterized in that, The Panax notoginseng total saponins-Astragalus polysaccharide core-shell type nanocomposite dry powder component is prepared through the following steps: A1. Disperse total saponins of Panax notoginseng in a 30–70 vol% ethanol aqueous solution to obtain a dispersion of total saponins of Panax notoginseng; dissolve Astragalus polysaccharide in deionized water to obtain an Astragalus polysaccharide solution; A2. The Panax notoginseng total saponin dispersion and the Astragalus polysaccharide solution are mixed at a mass ratio of Panax notoginseng total saponins to Astragalus polysaccharide of 1:0.2–1:1.8, the pH is adjusted to 4.2–6.2, and the mixture is stirred at 25–55℃ for 30–120 min to obtain a composite dispersion. A3. The composite dispersion is subjected to high-pressure homogenization at a pressure of 20–80 MPa and a cycle of 1–5 times to obtain a core-shell nanocomposite dispersion. A4. Spray dry the core-shell nanocomposite dispersion with an inlet air temperature of 130–180℃ and an outlet air temperature of 65–95℃ to obtain the Panax notoginseng total saponins-Astragalus polysaccharide core-shell nanocomposite dry powder component.

4. The traditional Chinese medicine composition according to claim 3, characterized in that, The total saponins of Panax notoginseng in step A1 are prepared through the following steps: B1. Grind the Panax notoginseng into 20–80 mesh and add 50–80 vol% ethanol aqueous solution, wherein the mass-volume ratio of Panax notoginseng to ethanol aqueous solution is 1 g: 6–15 mL. B2. Extract at 40–80℃ for 1–3 h, repeat extraction 1–3 times, filter, combine filtrates, and concentrate under reduced pressure at 40–70℃ to a concentrate equivalent to 0.2–1.0 g / mL of crude drug. B3. Extract the concentrate with 1-butanol 2–5 times, combine the 1-butanol phases, wash with deionized water 1–3 times, concentrate under reduced pressure at 40–70℃, and dry at 45–80℃ for 4–24 h to obtain total Panax notoginseng saponins. B4. The total content of the obtained Panax notoginseng saponins, calculated as ginsenoside Rg1, ginsenoside Rb1 and notoginsenoside R1, is 50–95 wt%.

5. The traditional Chinese medicine composition according to claim 1, characterized in that, The traditional Chinese medicine composition is an oral solid composition; Based on the dry weight of the traditional Chinese medicine composition, the oral solid composition comprises 10–90 wt% of the Panax notoginseng total saponins-Astragalus polysaccharide core-shell nanocomposite dry powder component and 10–90 wt% of excipients, wherein the sum of the contents of the Panax notoginseng total saponins-Astragalus polysaccharide core-shell nanocomposite dry powder component and the excipients is 100 wt%. The excipients are selected from one or more of D-mannitol, microcrystalline cellulose, starch, and magnesium stearate.

6. The traditional Chinese medicine composition according to claim 1, characterized in that, The cumulative release rate of total saponins from Panax notoginseng-Astragalus polysaccharide core-shell nanocomposite dry powder in 0.1 mol / L hydrochloric acid aqueous solution for 2 h was 15–45 wt%, and the cumulative release rate of total saponins from Panax notoginseng in pH 6.8 phosphate buffer solution for 8 h was 60–95 wt%.

7. The traditional Chinese medicine composition according to claim 1, characterized in that, The moisture absorption and weight gain of the Panax notoginseng total saponins-Astragalus polysaccharide core-shell type nanocomposite dry powder component is 0.5–12 wt%, and the D50 retention rate after reconstitution is 80–120%.

8. A method for preparing a traditional Chinese medicine composition according to any one of claims 1-7, characterized in that, Includes the following steps: S1. Provides a nano-composite dry powder component consisting of Panax notoginseng total saponins, Astragalus polysaccharide core-shell type; S2. The Panax notoginseng total saponins-Astragalus polysaccharide core-shell type nanocomposite dry powder component is mixed with one or more excipients selected from D-mannitol, microcrystalline cellulose, starch and magnesium stearate to prepare an oral solid traditional Chinese medicine composition.

9. The preparation method according to claim 8, characterized in that, Step S2 uses one of the following methods to produce granules, tablets, or capsules: dry mixing, wet granulation, dry granulation, direct tableting, or capsule filling.

10. The preparation method according to claim 8, characterized in that, The Panax notoginseng total saponins-Astragalus polysaccharide core-shell type nanocomposite dry powder component provided in step S1 is prepared from a composite dispersion with a solid content of 3-8 wt%; the water content of the Panax notoginseng total saponins-Astragalus polysaccharide core-shell type nanocomposite dry powder component is 0.5-8.0 wt%.

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