Ultrafine powder tabletting preparation and preparation method thereof

Abstract

The invention provides a superfine powder tableting preparation and a preparation method thereof, and the preparation method comprises the following steps: embedding a traditional Chinese medicine extract with hydrophobized mesoporous silica, carrying out spray coating on an active core embedded with the hydrophobized mesoporous silica by using a coating solution formed by ferric ammonium citrate and a film-forming polymer to form FAC layer microspheres, and carrying out freeze drying on the FAC layer microspheres to obtain the superfine powder tableting preparation. The preparation method comprises the following steps: carrying out secondary coating on FAC layer microspheres by using a gallic acid-resistant starch composite coating solution, carrying out ultraviolet irradiation before coating to prepare MOG microspheres, uniformly mixing the MOG microspheres with a filling agent, a disintegrating agent and a flow aid, and directly tabletting to prepare the submicron powder tabletting preparation. The superfine powder tabletting preparation prepared by the invention has good mechanical property, moisture resistance and colon targeting property, and the technical problems of the superfine powder preparation in multiple aspects of tabletting forming, targeted delivery, physical stability and the like are fundamentally solved.

Description

Technical Field

[0001] This invention belongs to the field of drug tableting technology, specifically relating to an ultrafine powder tableting formulation and its preparation method. Background Technology

[0002] Oral tablets, as the most commonly used dosage form, face systemic technical bottlenecks in their conventional preparation processes (such as wet granulation, dry granulation followed by tableting, or direct powder compression) when addressing the delivery needs of modern functional foods and novel drugs, especially when handling highly active, unstable ingredients requiring colon-targeted release:

[0003] 1. The inherent contradiction between the stability of active ingredients and the formulation process: Many functional plant extracts, probiotics, peptides, and unsaturated fatty acids are heat-sensitive. Traditional pulverization, granulation, drying, and certain coating processes can generate localized high temperatures, leading to the inactivation, degradation, or oxidation of active ingredients. To improve bioavailability, active ingredients are often micronized or even nano-sized. However, the resulting high specific surface area and surface energy exacerbate hygroscopicity, agglomeration, crystal transformation, and chemical degradation. Uniform mixing of low doses of highly active ingredients with a large amount of excipients is crucial to ensuring consistent content in each tablet. Ultrafine powders are prone to static electricity and agglomeration, leading to uneven mixing and content differences, which traditional mixing processes have limited control over.

[0004] 2. Insufficient reliability of colon-targeted release systems: Coating materials that rely on the pH difference between the stomach and colon (such as acrylic resins) are susceptible to individual gastrointestinal pH fluctuations and food intake, leading to premature release in the stomach or incomplete release in the colon, resulting in poor targeting accuracy. Systems that achieve delayed release by controlling the coating layer's dissolution time are greatly affected by physiological factors such as gastric emptying time and intestinal peristalsis, exhibiting significant individual differences and making precise control of the release timing difficult. Although utilizing colon-specific enzymes is an ideal targeting strategy, existing carriers (such as pectin, chitosan, and other polysaccharides) have slow enzymatic hydrolysis rates, limited specificity, and often insufficient mechanical strength and moisture resistance after film formation, making it difficult to meet the requirements of tableting processes and long-term stable protection of the contents.

[0005] 3. Comprehensive Defects in Formulation Performance: To ensure tablet stability during storage, thick coatings or hydrophobic materials are often used. However, this often delays or even hinders tablet disintegration and dissolution at the target site, affecting efficacy. Many advanced drug delivery systems in existing technologies, such as microcapsules and liposomes, are inherently fragile and prone to structural collapse and capsule wall rupture under the high pressure of direct compression, leading to exposure of the active ingredient and loss of controlled-release function. Coated pellets or granules prepared for colon-targeting may have surface properties unfavorable to flow, resulting in uneven filling and large differences in tablet weight during compression, requiring the addition of large amounts of flow aids, thereby diluting the active ingredient or introducing unnecessary excipients.

[0006] In summary, developing a technology that can simultaneously address activity protection, precise targeting, good tablet compressibility, and process controllability is a crucial breakthrough urgently needed in the fields of functional foods and novel oral drug formulations. Existing technologies often only address one or two of these issues, failing to achieve synergistic optimization at multiple levels, including molecular structure, microstructure, and macroscopic properties. Therefore, a novel formulation design approach and manufacturing process are urgently required to overcome the combined pain points of the aforementioned technologies. Summary of the Invention

[0007] Technical problem to be solved: Addressing the core technical issues of insufficient mechanical strength and poor physicochemical stability (easily absorbs moisture, agglomerates, and degrades) of ultrafine powder / nano-sized active ingredients in direct tableting in existing technologies, the present invention aims to provide an ultrafine powder tablet formulation and its preparation method. This is achieved by constructing microspheres with an active core embedded in hydrophobic mesoporous silica, an ferric ammonium citrate (FAC) intermediate layer, and a phototriggered metal-organic gel (MOG) shell, thus preparing an ultrafine powder tablet formulation that can be directly tableted, releases into the colon, and exhibits high moisture resistance.

[0008] Technical solution: A method for preparing an ultrafine powder tablet formulation, comprising the following steps:

[0009] S1. Polyvinylpyrrolidone-vinyl acetate copolymer (PVP-VA) and ferric ammonium citrate (FAC) are dissolved in an aqueous ethanol solution and filtered through a filter membrane to obtain an FAC-PVP-VA coating solution.

[0010] S2. TCME-MSNs nanoparticles are loaded into a fluidized bed hopper, coated with FAC-PVP-VA coating solution by spray coating, and after coating, fluidized drying is continued to obtain FAC layer microspheres;

[0011] S3. Gallic acid is dissolved in an ethanol aqueous solution, resistant starch is added to water, and the mixture is gelatinized by stirring in a high-temperature water bath. After cooling, the mixture is added to the gallic acid solution under strong stirring and mixed evenly to obtain a gallic acid-resistant starch composite coating solution.

[0012] S4. The FAC layer microspheres prepared in S2 are reloaded into the fluidized bed and coated with gallic acid-resistant starch composite coating solution by spray coating. Before the spraying ends, the ultraviolet light irradiation system at the top of the fluidized bed is turned on and the light intensity is adjusted to ensure that the entire fluidized bed material area is covered. After the spraying ends, fluidization and light irradiation are maintained. Finally, the light is turned off and fluidized drying is continued to obtain MOG microspheres.

[0013] S5. After uniformly mixing MOG microspheres, fillers, disintegrants and glidants, the mixture is directly compressed into tablets to obtain an ultrafine powder tablet formulation.

[0014] Preferably, in step S1, the mass ratio of polyvinylpyrrolidone-vinyl acetate copolymer (PVP-VA) to ferric ammonium citrate (FAC) is 2-4:1-8.

[0015] Preferably, the preparation method of TCME-MSNs nanoparticles in step S2 includes the following steps:

[0016] S21. Take Chinese medicinal materials and add water at a mass ratio of 1:4~10, decoct for 1~3 hours, filter and collect the filtrate, repeat the extraction once, combine the filtrates, concentrate to a relative density of 1.19~1.21, dry at 45~50℃ and then pulverize into ultrafine powder to obtain Chinese medicinal extract TCME.

[0017] S22. Mesoporous silica nanoparticles (MSNs) were dispersed in DMSO, arachidic acid was added, followed by EDC and NHS. The mixture was reacted at 70-75°C for 30-50 h. After centrifugation, the precipitate was washed with anhydrous ethanol to obtain hydrophobic MSNs.

[0018] S23. Add the Chinese herbal extract TCME to anhydrous ethanol and disperse it by ultrasonication. Add hydrophobic MSNs in portions and slowly at 50-60℃ with stirring. After the addition is complete, continue stirring for 2-5 h. Then, remove the ethanol by rotary evaporation and vacuum dry overnight to obtain TCME-MSNs nanoparticles.

[0019] Preferably, in step S2, the mass-to-volume ratio of TCME-MSNs nanoparticles to FAC-PVP-VA coating solution is 1~2:15~40.

[0020] Preferably, in step S3, the mass ratio of gallic acid to resistant starch is 1~2:1.2~2.5.

[0021] Preferably, in step S4, the mass-to-volume ratio of FAC layer microspheres to gallic acid-resistant starch composite coating solution is 1:15~25.

[0022] Preferably, the remaining amount of gallic acid-resistant starch composite coating solution before the end of spraying in step S4 is 10-15%.

[0023] Preferably, the light intensity in step S4 is 10~30 mW / cm². 2 .

[0024] Preferably, the weight percentage of the components of the ultrafine powder tablet formulation in step S5 is: MOG microspheres 10-25%, filler 20-55%, disintegrant 3-15%, and glidant 1-5%.

[0025] Preferably, the filler in step S5 is any one or more of lactose, microcrystalline cellulose, mannitol, and starch.

[0026] Preferably, the disintegrant in step S5 is any one or more of povidone, croscarmellose sodium, carboxymethyl starch sodium, and hydroxypropyl methylcellulose.

[0027] Preferably, the gliding agent in step S5 is any one or more of magnesium stearate, calcium stearate, and talc.

[0028] The ultrafine powder tablets prepared by the above method.

[0029] Beneficial effects:

[0030] 1. This invention first physically loads traditional Chinese medicine extracts onto hydrophobic mesoporous silica (MSNs) to inhibit spontaneous aggregation and impart moisture resistance. Secondly, an FAC layer is formed on the surface of the silica nanoparticles through coating with ferric ammonium citrate (FAC). A secondary coating is then performed using a gallic acid-resistant starch composite coating solution. Finally, a photo-triggered coordination reaction forms a MOG shell in situ on the microsphere surface. Gallic acid contains multiple hydroxyl and carbonyl oxygen atoms that can strongly chelate with metal ions. After gallic acid-resistant starch coating, light effectively penetrates the gallic acid layer, triggering a photoreduction reaction in the underlying FAC layer, releasing Fe. 2+ Fe 2+ The Fe molecules coordinate with gallic acid molecules, and in the oxygen-rich environment of a fluidized bed, the coordinated Fe... 2+ It is easily oxidized in situ to Fe. 3+ This leads to the formation of a stronger and more stable Fe group with gallic acid. 3+ - Gallic acid coordination bonds form a metal-organic gel (MOG) shell. Due to the excellent UV shielding properties of silica, the active ingredients in the core are not deactivated by UV radiation. This shell allows the microspheres to have a suitable particle size distribution, excellent powder flowability, and high mechanical strength, providing mechanical support for the core and enabling it to withstand the shear and pressure of direct tableting, thus preventing microcapsule breakage.

[0031] 2. The tablet formulation prepared by this invention achieves colon-targeted release of the active ingredient. The MOG shell remains intact in the stomach and small intestine due to its dense coordination network, while in the colon, the resistant starch in the shell is specifically degraded by amylases released by the gut microbiota. The weakly alkaline pH weakens the coordination bonds, causing the MOG shell to disintegrate and the active ingredient to be released in the colon, thus avoiding premature leakage of the active ingredient in the gastrointestinal tract.

[0032] 3. The tablet formulation prepared in this invention has Fe... 3+- Gallic acid coordination bonds form a dense, hydrophobic nanomesh that effectively blocks water molecule penetration. At the same time, the internal hydrophobic silica also has good moisture resistance, ensuring the physical integrity of the tablet formulation during long-term storage and fundamentally reducing the risk of chemical degradation such as hydrolysis and oxidation of active ingredients caused by moisture.

[0033] 4. The excellent flowability, compressibility and moisture resistance of the tablet formulation prepared by this invention are due to the structure of the microspheres themselves, rather than relying on a large amount of added flow aids and anti-sticking agents. This makes the excipient composition of the final tablet simpler and greener. At the same time, the direct tableting process avoids the high energy consumption and high destructive dry / wet granulation steps, reducing the complexity of production.

[0034] 5. FAC is not only a source of iron ions, but also a food-grade iron fortifier. After being released in the colon, it can be directly absorbed and is itself a nutrient, thus achieving "nutritional enhancement of excipients." Gallic acid is a powerful antioxidant. The MOG shell it forms protects the contents, and the gallic acid on its surface can first eliminate free radicals encountered during the gastrointestinal tract, providing an antioxidant defense for the active ingredients inside. Attached Figure Description

[0035] Figure 1 Product image of Codonopsis pilosula ultrafine powder;

[0036] Figure 2 Product image of Codonopsis pilosula slices;

[0037] Figure 3 This is a product image of Astragalus membranaceus tablets;

[0038] Figure 4 This is a product image of licorice tablets;

[0039] Figure 5 The cumulative release rate of the ultrafine powder tablet formulation in simulated colonic fluid. Detailed Implementation

[0040] The present invention will be further described below with reference to embodiments. These embodiments are illustrative of the present invention, but the present invention is not limited to these embodiments:

[0041] Example 1

[0042] This embodiment describes the preparation of Codonopsis pilosula extract, and the specific method includes the following steps:

[0043] Codonopsis pilosula was added to water at a mass ratio of 1:6, decocted for 1.5 h, filtered and the filtrate was collected. The extraction was repeated once, the filtrates were combined and concentrated to a relative density of 1.20, and dried at 50℃ to obtain Codonopsis pilosula extract.

[0044] Example 2

[0045] This embodiment describes the preparation of Codonopsis pilosula TCME-MSNs nanoparticles, and the specific method includes the following steps:

[0046] S1. Weigh 2 g of mesoporous silica nanoparticles (MSNs) and disperse them in 700 mL of DMSO. Add 2.5 g of arachidic acid, 1 g of EDC and 1.2 g of NHS. React at 70 °C for 36 h. Centrifuge at 12000 rpm for 10 min. Wash the precipitate with anhydrous ethanol to obtain hydrophobic MSNs.

[0047] S2. The Codonopsis pilosula extract prepared in Example 1 was ultra-finely pulverized and added to anhydrous ethanol. It was ultrasonically dispersed at 200 W for 15 min to form a dispersion. Hydrophobic MSNs were added to the dispersion in portions at 55℃ and 800 rpm. The mass ratio of Codonopsis pilosula extract to hydrophobic MSNs was 1:3. After the addition was complete, the mixture was stirred at 55℃ for 2 h. The mixture was then transferred to a rotary evaporator and the ethanol was removed by rotary evaporation at 55℃. The mixture was then vacuum dried overnight at 40℃ to obtain Codonopsis pilosula TCME-MSNs nanoparticles.

[0048] Example 3

[0049] This embodiment describes the preparation of Codonopsis pilosula MOG microspheres, and the specific method includes the following steps:

[0050] S1. Polyvinylpyrrolidone-vinyl acetate copolymer (PVP-VA) and ferric ammonium citrate were dissolved in an ethanol-water solution (7:3, v / v) at a mass ratio of 2:1. The solution was stirred at 300 rpm for 50 min at 50 °C, cooled to room temperature, and filtered through a 0.45 μm filter membrane to obtain a FAC-PVP-VA coating solution with a solid content of 4%.

[0051] S2. The Codonopsis pilosula TCME-MSNs nanoparticles prepared in Example 2 were loaded into a fluidized bed hopper and coated with FAC-PVP-VA coating solution by spraying. The mass-volume ratio of TCME-MSNs nanoparticles to FAC-PVP-VA coating solution was 1:22. The parameters were set as follows: air inlet temperature 35℃, material temperature 28℃, fan frequency 35 Hz, atomization pressure 0.8 bar, spray rate 1.3 mL / min, spray for 10 s, stop for 20 s, fluidization was started, and after the material temperature and fluidization state stabilized, spray coating was started until all the FAC-PVP-VA coating solution was sprayed. After coating, fluidized drying was continued for 15 min at an air inlet temperature of 35℃ to obtain FAC layer microspheres with a uniform thin film on the surface.

[0052] S3. The mass ratio of gallic acid to resistant starch RS3 is 1:1.5. Gallic acid is dissolved in an aqueous ethanol solution (8:2, v / v). Resistant starch RS3 is added to water and gelatinized by stirring in an 85°C water bath for 30 min. After cooling to 40°C, the cooled gelatinized starch is slowly poured into the gallic acid solution under strong stirring and mixed evenly to obtain a gallic acid-resistant starch composite coating solution with a total solid content of about 5%. It should be prepared and used immediately.

[0053] S4. Reload the FAC layer microspheres prepared in S3 into the fluidized bed and set the parameters as follows: inlet air temperature 30℃, material temperature 26℃, fan frequency 30 Hz, atomization pressure 1.0 bar, spray rate 1.0 mL / min, spray for 5 s, stop for 25 s, start fluidization, and after the material temperature and fluidization state stabilize, start spray coating. The mass-volume ratio of FAC layer microspheres to gallic acid-resistant starch composite coating solution is 1:15.

[0054] S5. Before the gallic acid-resistant starch composite coating solution spraying ends (when 10% remains), turn on the 365 nm LED ultraviolet irradiation system at the top of the fluidized bed and adjust the light intensity to 30 mW / cm². 2 To ensure that the light covers the entire fluidized bed material area, after spraying, continue fluidization and light exposure for 15 minutes, then turn off the light and continue fluidization drying at 30°C for 10 minutes to obtain Codonopsis pilosula MOG microspheres.

[0055] Example 4

[0056] This embodiment describes the preparation of Codonopsis pilosula MOG microspheres, and the specific method includes the following steps:

[0057] S1. Polyvinylpyrrolidone-vinyl acetate copolymer (PVP-VA) and ferric ammonium citrate were dissolved in an ethanol-water solution (7:3, v / v) at a mass ratio of 3:1. The solution was stirred at 50°C and 300 rpm for 50 min, cooled to room temperature, and filtered through a 0.45 μm filter membrane to obtain a FAC-PVP-VA coating solution with a solid content of 4%.

[0058] S2. The TCME-MSNs nanoparticles prepared in Example 2 were loaded into a fluidized bed hopper and coated with FAC-PVP-VA coating solution by spraying. The mass-volume ratio of TCME-MSNs nanoparticles to FAC-PVP-VA coating solution was 1:25. The parameters were set as follows: air inlet temperature 35℃, material temperature 28℃, fan frequency 35 Hz, atomization pressure 0.8 bar, spray rate 1.3 mL / min, spray for 10 s, stop for 20 s, start fluidization, and after the material temperature and fluidization state stabilized, spray coating was started until all the FAC-PVP-VA coating solution was sprayed. After coating, fluidized drying was continued for 15 min at an air inlet temperature of 35℃ to obtain FAC layer microspheres with a uniform thin film on the surface.

[0059] S3. The mass ratio of gallic acid to resistant starch RS3 is 1:2. Gallic acid is dissolved in an aqueous ethanol solution (8:2, v / v). Resistant starch RS3 is added to water and gelatinized by stirring in an 85°C water bath for 30 min. After cooling to 40°C, the cooled gelatinized starch is slowly poured into the gallic acid solution under strong stirring and mixed evenly to obtain a gallic acid-resistant starch composite coating solution with a total solid content of about 5%. It should be prepared and used immediately.

[0060] S4. Reload the FAC layer microspheres prepared in S3 into the fluidized bed and set the parameters as follows: inlet air temperature 30℃, material temperature 26℃, fan frequency 30 Hz, atomization pressure 1.0 bar, spray rate 1.0 mL / min, spray for 5 s, stop for 25 s, start fluidization, and after the material temperature and fluidization state stabilize, start spray coating. The mass-volume ratio of FAC layer microspheres to gallic acid-resistant starch composite coating solution is 1:15.

[0061] S5. Before the gallic acid-resistant starch composite coating solution spraying ends (when 12% remains), turn on the 365 nm LED ultraviolet irradiation system at the top of the fluidized bed and adjust the light intensity to 25 mW / cm². 2 To ensure that the light covers the entire fluidized bed material area, after spraying, continue fluidization and light exposure for 20 minutes, then turn off the light and continue fluidization drying at 30°C for 10 minutes to obtain Codonopsis pilosula MOG microspheres.

[0062] Example 5

[0063] This embodiment describes the preparation of Codonopsis pilosula MOG microspheres, and the specific method includes the following steps:

[0064] S1. Polyvinylpyrrolidone-vinyl acetate copolymer (PVP-VA) and ferric ammonium citrate were dissolved in an ethanol-water solution (7:3, v / v) at a mass ratio of 4:1. The solution was stirred at 300 rpm for 50 min at 50 °C, cooled to room temperature, and filtered through a 0.45 μm filter membrane to obtain a FAC-PVP-VA coating solution with a solid content of 4%.

[0065] S2. The TCME-MSNs nanoparticles prepared in Example 2 were loaded into a fluidized bed hopper and coated with FAC-PVP-VA coating solution by spraying. The mass-volume ratio of TCME-MSNs nanoparticles to FAC-PVP-VA coating solution was 1:30. The parameters were set as follows: air inlet temperature 35℃, material temperature 28℃, fan frequency 35 Hz, atomization pressure 0.8 bar, spray rate 1.3 mL / min, spray for 10 s, stop for 20 s, start fluidization, and after the material temperature and fluidization state stabilized, spray coating was started until all the FAC-PVP-VA coating solution was sprayed. After coating, fluidized drying was continued for 15 min at an air inlet temperature of 35℃ to obtain FAC layer microspheres with a uniform thin film on the surface.

[0066] S3. The mass ratio of gallic acid to resistant starch RS3 is 2:1.5. Gallic acid is dissolved in an aqueous ethanol solution (8:2, v / v). Resistant starch RS3 is added to water and gelatinized by stirring in an 85°C water bath for 30 min. After cooling to 40°C, the cooled gelatinized starch is slowly poured into the gallic acid solution under strong stirring and mixed evenly to obtain a gallic acid-resistant starch composite coating solution with a total solid content of about 5%. It should be prepared and used immediately.

[0067] S4. Reload the FAC layer microspheres prepared in S3 into the fluidized bed and set the parameters as follows: inlet air temperature 30℃, material temperature 26℃, fan frequency 30 Hz, atomization pressure 1.0 bar, spray rate 1.0 mL / min, spray for 5 s, stop for 25 s, start fluidization, and after the material temperature and fluidization state stabilize, start spray coating. The mass-volume ratio of FAC layer microspheres to gallic acid-resistant starch composite coating solution is 1:20.

[0068] S5. Before the gallic acid-resistant starch composite coating solution spraying ends (when 15% remains), turn on the 365 nm LED ultraviolet irradiation system at the top of the fluidized bed and adjust the light intensity to 30 mW / cm². 2 To ensure that the light covers the entire fluidized bed material area, after spraying, continue fluidization and light exposure for 15 minutes, then turn off the light and continue fluidization drying at 30°C for 10 minutes to obtain Codonopsis pilosula MOG microspheres.

[0069] Example 6

[0070] The difference between this embodiment and Embodiment 1 is that in this embodiment, Codonopsis pilosula is replaced with Astragalus membranaceus, and the remaining steps are the same as in Embodiment 1 to obtain Astragalus membranaceus extract.

[0071] Example 7

[0072] The difference between this embodiment and Example 2 is that in this embodiment, the Codonopsis pilosula extract is replaced with the Astragalus membranaceus extract prepared in Example 6, and the remaining steps are the same as in Example 2, so astragalus TCME-MSNs nanoparticles are obtained.

[0073] Example 8

[0074] The difference between this embodiment and Example 3 is that in this embodiment, the Codonopsis pilosula TCME-MSNs nanoparticles are replaced with the Astragalus membranaceus TCME-MSNs nanoparticles prepared in Example 7, and the remaining steps are the same as in Example 3 to obtain Astragalus membranaceus MOG microspheres.

[0075] Example 9

[0076] The difference between this embodiment and Embodiment 1 is that in this embodiment, Codonopsis pilosula is replaced with Glycyrrhiza uralensis, and the remaining steps are the same as in Embodiment 1 to obtain Glycyrrhiza uralensis extract.

[0077] Example 10

[0078] The difference between this embodiment and Example 2 is that in this embodiment, the Codonopsis pilosula extract is replaced with the licorice extract prepared in Example 9, and the remaining steps are the same as in Example 2, to obtain licorice TCME-MSNs nanoparticles.

[0079] Example 11

[0080] The difference between this embodiment and Example 3 is that in this embodiment, the Codonopsis pilosula TCME-MSNs nanoparticles are replaced with the Glycyrrhiza TCME-MSNs nanoparticles prepared in Example 10, and the remaining steps are the same as in Example 3 to obtain Glycyrrhiza MOG microspheres.

[0081] Table 1. Physical properties of the extract, TCME-MSNs nanoparticles, and MOG microspheres

[0082]

[0083] As shown in Table 1, the particle sizes of Examples 3-5 (Codonopsis pilosula MOG microspheres), Example 8 (Astragalus membranaceus MOG microspheres), and Example 10 (Glycyrrhiza uralensis MOG microspheres) of this invention are between 42 and 63 μm, and the angle of repose is between 22 and 28°. This range is the generally accepted ideal range for direct compression tableting, ensuring both good flowability and sufficient compressibility and content uniformity of the formulation. Examples 1 (Codonopsis pilosula extract), 6 (Astragalus membranaceus extract), and 9 (Glycyrrhiza uralensis extract) were untreated, with a D50 of 136-177 nm. The excessively large particle size and uneven distribution led to uneven filling, affecting tablet weight variation and content uniformity. The angle of repose was 55-65°, resulting in extremely poor flowability, causing poor material feeding from the tableting hopper and excessive tablet weight variation, making them unsuitable for direct compression. Examples 2 (Codonopsis pilosula TCME-MSNs nanoparticles), 7 (Astragalus membranaceus TCME-MSNs nanoparticles), and 10 (Glycyrrhiza uralensis TCME-MSNs nanoparticles) have a D50 of 192-253 nm, placing them at the nanoscale where they are highly prone to aggregation and have extremely poor flowability. Due to their large specific surface area and strong aggregation tendency, their angle of repose is 45-57°, resulting in poor flowability. This demonstrates that the present invention achieves the standard of free-flowing powder through a secondary coating technology, laying a physical foundation for dosage accuracy and production continuity in high-speed tableting processes.

[0084] Example 12

[0085] This embodiment describes the preparation of an ultrafine powder tablet formulation, and the specific method includes the following steps:

[0086] S1. Mix the following ingredients in a mixing hopper according to the following weight ratio: 15% of Codonopsis pilosula MOG microspheres prepared in Example 3, 22% of microcrystalline cellulose PH101, 8% sodium carboxymethyl starch, and 2% magnesium stearate.

[0087] S2. Compress directly into tablets using a tablet press, with a tablet weight of 300 mg / tablet.

[0088] Example 13

[0089] This embodiment describes the preparation of an ultrafine powder tablet formulation, and the specific method includes the following steps:

[0090] S1. Mix the following ingredients in a mixing hopper according to the following weight ratio: 20% MOG microspheres prepared in Example 3, 35% lactose Granulac 200, 12% povidone K29 / 32, and 1% calcium stearate.

[0091] S2. Compress directly into tablets using a tablet press, with a tablet weight of 300 mg / tablet.

[0092] Example 14

[0093] The difference between this embodiment and Example 12 is that the Codonopsis pilosula MOG microspheres in this embodiment were prepared in Example 4, and the remaining steps are the same as in Example 12.

[0094] Example 15

[0095] The difference between this embodiment and Embodiment 12 is that the Codonopsis pilosula MOG microspheres in this embodiment were prepared in Embodiment 5, while the remaining steps are the same as in Embodiment 12.

[0096] Example 16

[0097] The difference between this embodiment and Embodiment 12 is that in this embodiment, the Codonopsis pilosula MOG microspheres are replaced with Astragalus membranaceus MOG microspheres prepared in Embodiment 8, and the remaining steps are the same as in Embodiment 12.

[0098] Example 17

[0099] The difference between this embodiment and embodiment 13 is that in this embodiment, the Codonopsis pilosula MOG microspheres are replaced with Astragalus membranaceus MOG microspheres prepared in embodiment 8, and the remaining steps are the same as in embodiment 13.

[0100] Example 18

[0101] The difference between this embodiment and embodiment 12 is that in this embodiment, the Codonopsis pilosula MOG microspheres are replaced with the Glycyrrhiza uralensis MOG microspheres prepared in embodiment 10, and the remaining steps are the same as in embodiment 12.

[0102] Example 19

[0103] The difference between this embodiment and Example 13 is that in this embodiment, the Codonopsis pilosula MOG microspheres are replaced with the Glycyrrhiza uralensis MOG microspheres prepared in Example 10, and the remaining steps are the same as in Example 13.

[0104] To further illustrate the technical effects of the present invention, a comparative example is also provided, as follows:

[0105] Comparative Example 1

[0106] The difference between this comparative example and Example 12 is that the Codonopsis MOG microspheres in this comparative example are replaced with the Codonopsis extract prepared in Example 1, and the other steps are the same as in Example 12.

[0107] Comparative Example 2

[0108] The difference between this comparative example and Example 12 is that the Codonopsis pilosula MOG microspheres are replaced with Codonopsis pilosula TCME-MSNs nanoparticles prepared in Example 2, while the other steps are the same as in Example 12.

[0109] Comparative Example 3

[0110] The difference between this comparative example and Example 12 is that the components and mass of the tablet formulation in this comparative example are as follows: 1.4% Codonopsis pilosula extract prepared in Example 1, 68% spray-dried lactose, 20% microcrystalline cellulose PH120, 7% crosporovinylpyrrolidone, 3% low-substituted hydroxypropyl cellulose, and 1% magnesium stearate. The remaining steps are the same as in Example 12.

[0111] Comparative Example 4

[0112] The difference between this comparative example and comparative example 3 is that the Codonopsis pilosula extract in this comparative example is replaced with the Codonopsis pilosula TCME-MSNs nanoparticles prepared in Example 2, and the other steps are the same as those in comparative example 3.

[0113] Comparative Example 5

[0114] The difference between this comparative example and Comparative Example 3 is that this comparative example involves dry granulation followed by tableting, and the specific method includes the following steps:

[0115] S1. The Codonopsis pilosula extract (47.4%), microcrystalline cellulose PH120 (20.6%), mannitol (13%), sodium carboxymethyl cellulose (1%), colloidal SiO2 (1%), and magnesium stearate (1%) prepared in Example 1 were mixed evenly in a mixing hopper according to the above weight ratio at a speed of 20 rpm for 10 min. Then, 50% of the total amount of magnesium stearate was added to the mixing hopper and mixed at a speed of 20 rpm for 3 min to obtain a premix.

[0116] S2. Pelletize the premixed material using a dry granulation machine with a roller pressure of 8 MPa and a rotation speed of 4 rpm. Add SiO2 and sodium carboxymethyl cellulose to the mixing hopper and mix for 10 min at a rotation speed of 20 rpm. Add the remaining magnesium stearate to the mixing hopper and mix for 3 min at a rotation speed of 20 rpm.

[0117] S3. Compress directly into tablets using a tablet press, with a tablet weight of 300 mg / tablet.

[0118] Comparative Example 6

[0119] The difference between this comparative example and Comparative Example 5 is that the Codonopsis pilosula extract in this comparative example is replaced with the Codonopsis pilosula TCME-MSNs nanoparticles prepared in Example 2, while the other steps are the same as in Comparative Example 5.

[0120] Comparative Example 7

[0121] The difference between this comparative example and Example 12 is that this comparative example involves wet granulation followed by tableting, and the specific method includes the following steps:

[0122] S1. The Codonopsis pilosula extract (20%), lactose Granulac 200 (44%), microcrystalline cellulose 101 (26%), povidone K29 / 32 (6%), sodium carboxymethyl cellulose (2%), and magnesium stearate (1%) prepared in Example 1 were premixed in a wet granulator at 150 rpm for 10 min to obtain the premix.

[0123] S2. Adjust the pressure of the atomizing spray gun to 1.2 bar, the speed of the peristaltic pump to 50 rpm, and the spraying speed to between 0.34 and 0.54 kg / min. Mix the premix with water and perform wet granulation. Use a 4×4 mm square hole screen to granulate the particles to obtain wet granules.

[0124] S3. After drying the wet granules in a fluidized bed, the moisture content of the granules is not higher than 2%, and the granules are sieved through a 0.8 mm mesh screen to obtain dry granules.

[0125] S4. Mix the dry granules with magnesium stearate and sodium carboxymethyl starch at 15 rpm for 7 min to obtain the total mixed granules;

[0126] S5. Compress directly into tablets using a tablet press, with a tablet weight of 300 mg / tablet.

[0127] Comparative Example 8

[0128] The difference between this comparative example and comparative example 7 is that the Codonopsis pilosula extract in this comparative example is replaced with the Codonopsis pilosula TCME-MSNs nanoparticles prepared in Example 2, and the other steps are the same as those in comparative example 7.

[0129] Table 2 Compressibility (15 kN) and moisture resistance of tablet formulations

[0130]

[0131] As shown in Table 2, Examples 12-15 (Codonopsis pilosula tablets), Examples 16-17 (Astragalus membranaceus tablets), and Examples 18-19 (Glycyrrhiza uralensis tablets) exhibited a hardness of 143-157 N and a friability of 0.12-0.24% under a main pressure of 15 kN. This result indicates that the MOG shell of the MOG microspheres provides excellent mechanical strength and compressibility. The structure formed by the MOG microspheres themselves is sufficient to withstand the pressure of direct tableting and maintains complete mechanical properties in subsequent tests without relying on the particle strengthening effect of traditional granulation processes. Comparative Examples 1-4 involved directly mixing the extract and TCME-MSNs nanoparticles with excipients and then compressing them into tablets. Under a main pressure of 15 kN, the hardness was consistently below 90 N, and the friability was generally >0.6%. Regardless of whether optimized excipients were used, the direct tableting process could not achieve sufficient mechanical strength in the 14 kN test. This indicates that simply relying on excipient adjustment and tableting parameter optimization cannot solve the physical property defects of the active ingredient itself. Comparative Examples 5-6 (dry granulation) had hardnesses of 94 N and 106 N, respectively, while Comparative Example 7 (wet granulation) had a hardness of 112 N and a friability of 0.39%. Both dry and wet granulation significantly improved the interparticle bonding through physical compaction and binders, resulting in improved mechanical properties of the tablets in the tests, but still lower than the examples. Furthermore, the high shear force of the dry granulation process may damage the nanostructure (Comparative Example 6). The wet granulation process in Comparative Example 8 is incompatible with the hydrophobic mesoporous SiO2 nanocarrier structure, leading to nanocarrier failure and premature drug leakage. The tablets prepared in Examples 12-19 and Comparative Examples 1-8 were placed in a constant temperature and humidity chamber (25°C, 75% RH) and their weight was measured after 24 hours to calculate the moisture absorption weight gain rate. Examples 12-19 had a dense MOG shell that physically blocked water molecule penetration, and the internal hydrophobic mesoporous SiO2 core further repelled moisture; the 24-hour moisture absorption weight gain rate was 0.27-0.41%. Although Comparative Examples 1, 3, 5, and 7 used different excipients and tableting processes, the Codonopsis pilosula extract contained a large amount of hygroscopic components, and the powder was directly exposed without any protective structure. The moisture absorption weight gain rate was 7.21-32.27% after 24 hours. In Comparative Examples 2, 4, and 6, the hydrophobic SiO2 carrier of TCME-MSNs nanoparticles provided good moisture resistance, but the effect was not as good as that of the examples.

[0132] Table 3. Cumulative release rate of the tableted formulation in simulated gastric and intestinal fluids.

[0133]

[0134] The tablet formulations prepared in Examples 12-19 and Comparative Examples 1-8 were placed in a dissolution apparatus basket at 100 rpm. The amount of active ingredient dissolved in the solution was measured and the cumulative release rate was calculated after 2 h in hydrochloric acid solution at pH 1.2. The solution was then transferred to acetate buffer at pH 4.5 and sampled at 4 h. The solution was then transferred to phosphate buffer at pH 5.5 and sampled at 6 h. The solution was then transferred to phosphate buffer at pH 6.5 and sampled at 8 h. Finally, the solution was transferred to simulated colonic fluid (containing rat cecal contents) and sampled at 2 h, 4 h, 6 h, 8 h, and 10 h.

[0135] The cumulative release rates in simulated gastric and intestinal fluids are shown in Table 3. The tablet formulations prepared in Examples 12-19 all showed a small release in both simulated gastric and intestinal fluids. The cumulative release rate increased over time. In simulated gastric fluid, the cumulative release rate was less than 1% after 2 hours, and after 8 hours, it ranged from 10.66% to 12.44%, lower than all comparative examples. The MOG shell of the tablet formulations prepared in Examples 12-19 effectively blocked the penetration and erosion of water molecules, gastric acid, and digestive enzymes through its high-strength coordination bond network. The internal hydrophobic mesoporous SiO2 further inhibited the molecular migration, aggregation, and oxidative degradation of the active ingredient. During this stage, the active ingredient was tightly protected, and the formulation remained inert in the upper digestive tract, avoiding early release of the active ingredient in the gastrointestinal fluid. This significantly reduced drug release loss before reaching the colon, laying the foundation for colon-targeted delivery.

[0136] The cumulative release rate results in simulated colonic fluid are as follows: Figure 5 As shown, the tablet formulations prepared in Examples 12-19 exhibited a cumulative release rate of 33.82-38.66% in simulated colonic fluid over 2 hours, followed by a significant increase in release rate, reaching 97.32-99.66% over 10 hours. The MOG shell of the tablet formulation remained intact in gastric and intestinal fluids, effectively blocking the release of the active ingredient. Upon entering the colonic environment, exogenous stimulation (amylase secreted by colonic flora) and endogenous conditions (weakly alkaline pH) began to work synergistically. The colonic flora secreted abundant amylases and amylopectin, which specifically degraded the resistant starch component in the MOG shell, disrupting the integrity of the gel network. Under the weakly alkaline pH environment, this further weakened the Fe... 3+- Gallic acid coordination bonds break at cross-linking points, and after the outer shell is initially opened by the enzyme, the pH environment accelerates the dissociation and disintegration of the entire network. Even with differences in enzyme activity between individuals, the synergistic effect of pH ensures that release is completed within a reasonable time. This enzyme-driven, pH-synergistic mechanism precisely and controllably disrupts the integrity of the MOG network, causing programmed disintegration of the outer shell and targeted release of the active ingredient into the colon. In contrast, comparative examples 1-8, which were almost completely released in gastrointestinal fluid, achieved a cumulative release rate of 92.67-100% in the colonic simulated fluid after 2 hours.

[0137] The above description is merely a preferred embodiment of the present invention and is not intended to limit the present invention in any way. Any person skilled in the art can make many possible variations and modifications to the technical solutions of the present invention, or modify them into equivalent embodiments, without departing from the spirit and technical essence of the present invention. Therefore, any simple modifications, equivalent substitutions, equivalent changes, and modifications made to the above embodiments based on the technical essence of the present invention, without departing from the content of the technical solutions of the present invention, shall still fall within the scope of protection of the present invention.

Claims

1. A method for preparing an ultrafine powder tablet formulation, characterized in that, Includes the following steps: S1. Polyvinylpyrrolidone-vinyl acetate copolymer (PVP-VA) and ferric ammonium citrate (FAC) are dissolved in an aqueous ethanol solution and filtered through a filter membrane to obtain an FAC-PVP-VA coating solution. S2. TCME-MSNs nanoparticles are loaded into a fluidized bed hopper, coated with FAC-PVP-VA coating solution by spray coating, and after coating, fluidized drying is continued to obtain FAC layer microspheres; S3. Gallic acid is dissolved in an ethanol aqueous solution, resistant starch is added to water, and the mixture is gelatinized by stirring in a high-temperature water bath. After cooling, the mixture is added to the gallic acid solution under strong stirring and mixed evenly to obtain a gallic acid-resistant starch composite coating solution. S4. The FAC layer microspheres prepared in S2 are reloaded into the fluidized bed and coated with gallic acid-resistant starch composite coating solution by spray coating. Before the spraying ends, the ultraviolet light irradiation system at the top of the fluidized bed is turned on and the light intensity is adjusted to ensure that the entire fluidized bed material area is covered. After the spraying ends, fluidization and light irradiation are maintained. Finally, the light is turned off and fluidized drying is continued to obtain MOG microspheres. S5. After uniformly mixing MOG microspheres, fillers, disintegrants and glidants, the mixture is directly compressed into tablets to obtain an ultrafine powder tablet formulation.

2. The preparation method according to claim 1, characterized in that: In step S1, the mass ratio of polyvinylpyrrolidone-vinyl acetate copolymer (PVP-VA) to ferric ammonium citrate (FAC) is 2-4:1-8.

3. The preparation method according to claim 1, characterized in that, The preparation method of TCME-MSNs nanoparticles in step S2 includes the following steps: S21. Take Chinese medicinal materials and add water at a mass ratio of 1:4~10, decoct for 1~3 hours, filter and collect the filtrate, repeat the extraction once, combine the filtrates, concentrate to a relative density of 1.19~1.21, dry at 45~50℃ and then pulverize into ultrafine powder to obtain Chinese medicinal extract TCME. S22. Mesoporous silica nanoparticles (MSNs) were dispersed in DMSO, arachidic acid was added, followed by EDC and NHS. The mixture was reacted at 70-75°C for 30-50 h. After centrifugation, the precipitate was washed with anhydrous ethanol to obtain hydrophobic MSNs. S23. Add the Chinese herbal extract TCME to anhydrous ethanol and disperse it by ultrasonication. Add hydrophobic MSNs in portions and slowly at 50-60℃ with stirring. After the addition is complete, continue stirring for 2-5 h. Then, remove the ethanol by rotary evaporation and vacuum dry overnight to obtain TCME-MSNs nanoparticles.

4. The preparation method according to claim 1, characterized in that: In step S2, the mass-to-volume ratio of TCME-MSNs nanoparticles to FAC-PVP-VA coating solution is 1~2:15~40.

5. The preparation method according to claim 1, characterized in that: In step S3, the mass ratio of gallic acid to resistant starch is 1~2:1.2~2.

5.

6. The preparation method according to claim 1, characterized in that: In step S4, the mass-to-volume ratio of FAC layer microspheres to gallic acid-resistant starch composite coating solution is 1:15~25; the remaining amount of gallic acid-resistant starch composite coating solution before spraying is 10~15%; and the light intensity is 10~30 mW / cm². 2 .

7. The preparation method according to claim 1, characterized in that, The weight percentages of the components in the ultrafine powder tablet formulation in step S5 are: MOG microspheres 10-25%, filler 20-55%, disintegrant 3-15%, and glidant 1-5%.

8. The preparation method according to claim 1, characterized in that: In step S5, the filler is any one or more of lactose, microcrystalline cellulose, mannitol, and starch; the disintegrant is any one or more of povidone, croscarmellose sodium, carboxymethyl starch sodium, and hydroxypropyl methylcellulose; and the flow aid is any one or more of magnesium stearate, calcium stearate, and talc.

9. The ultrafine powder tablet preparation prepared by any one of claims 1 to 8.

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