Phyllanthus emblica and spina date seed tablets for improving sleep and tranquilizing mind by nourishing heart and preparation method thereof

Abstract

The invention relates to the technical field of traditional Chinese medicine preparations, and discloses an emblic leafflower fruit and spina date seed tablet for improving sleep and tranquilizing mind by nourishing the heart and a preparation method thereof, and the tablet is prepared from spina date seed powder, lily powder, longan aril powder, lucid ganoderma powder, maltodextrin, sorbitol, emblic leafflower fruit powder, magnesium stearate and a compound coating agent. The preparation method comprises the following steps: forming a granulation matrix solution from reserved polyethylene glycol and sorbitol, spraying the granulation matrix solution on the surface of a polysaccharide base material, spraying the emblic leafflower fruit powder at high pressure in a high-viscosity critical period of a fluidized bed for crosslinking, then carrying out instant cold air quenching to generate phase change, tabletting and then carrying out aqueous film coating. According to the preparation method disclosed by the invention, an amorphous glassy network structure formed by crosslinking a polyethylene glycol macromolecular chain segment and tannin polyphenol in the emblic leafflower fruit powder is utilized, so that the mechanical thermal softening resistance of the polysaccharide powder in a continuous tabletting process is improved, and the water absorption swelling risk in a damp and hot operation environment is reduced; the retention rate of effective components of the tablet core and the integrity of a coating film are guaranteed.

Description

Technical Field

[0001] This invention relates to the field of traditional Chinese medicine preparation technology, and in particular to a tablet made from Phyllanthus emblica and Ziziphus jujuba seeds that improves sleep, nourishes the heart and calms the mind, and its preparation method. Background Technology

[0002] Sleep disorders such as insomnia and palpitations are becoming increasingly common. Using traditional Chinese medicine ingredients that are both food and medicine, such as jujube seed, lily bulb, and Ganoderma lucidum, in compound prescriptions is a common intervention method. These compound prescriptions typically contain abundant plant polysaccharides in their raw materials or extracts.

[0003] In the actual production of solid dosage forms, materials rich in polysaccharides are inherently hygroscopic and have low glass transition temperatures. To improve taste or formability, polyol excipients are often introduced into the formulation, which further exacerbates the material's heat sensitivity and hygroscopic tendency. In continuous tableting processes, the mechanical frictional heat generated by equipment operation can easily cause the polysaccharide and polyol matrix to cross the glass transition temperature, resulting in phase softening and viscous rheology, causing significant sticking and impaction, affecting the continuity of dosage form production and the quality of tableting.

[0004] Furthermore, in subsequent film coating processes, especially in the humid and hot environment of aqueous film coating, the polysaccharide tablet core readily absorbs moisture from the coating solution, leading to localized swelling. This internal expansion not only ruptures the newly formed film, causing surface cracking, but also promotes the penetration of external moisture into the tablet core, triggering microenvironmental hydration reactions. This moisture intrusion causes degradation and loss of easily hydrolyzed or heat-sensitive active ingredients such as jujube seed saponins, resulting in a decreased retention rate of active ingredients and making it difficult to guarantee the batch-to-batch quality stability of the final product. Conventional physical mixing or traditional granulation processes struggle to construct a microscopic physical structure within the tablet core with sufficient mechanical rigidity and moisture-retaining capacity, thus failing to effectively address the aforementioned processing adaptability issues. Summary of the Invention

[0005] The technical problem solved by this invention is that Chinese herbal polysaccharide powder and polyol excipients are prone to softening and sticking due to mechanical heating during the formulation process, and are also prone to moisture absorption and swelling in humid and hot environments, which leads to degradation of active ingredients and cracking of coating.

[0006] To address the above problems, the present invention provides the following technical solution:

[0007] In a first aspect, the present invention provides a jujube seed and amla seed tablet for improving sleep and calming the mind, which is prepared from the following components in parts by weight: 20.0-35.0 parts of jujube seed powder; 10.0-20.0 parts of lily powder; 10.0-20.0 parts of longan pulp powder; 5.0-15.0 parts of Ganoderma lucidum powder; 5.0-15.0 parts of maltodextrin; 10.0-25.0 parts of sorbitol; 3.0-8.0 parts of amla powder; 0.5-1.5 parts of magnesium stearate; and 2.0-6.0 parts of compound coating agent.

[0008] By employing the above technical solution, this invention utilizes the specific interactions of each component at the microscopic phase to construct an amorphous solid dispersion network with a high glass transition temperature, thereby improving the thermodynamic stability of the formulation powder during machining and in humid and hot environments. The specific mechanism of action is as follows:

[0009] 1) Provides a hydrogen bond donor-acceptor basis; polysaccharide extracts and sorbitol are introduced into the system as a matrix, and structural intervention is achieved by adding a specific ratio of compound coating agent and amla powder. The compound coating agent contains polyethylene glycol macromolecular segments, and amla powder contains tannins and polyphenols.

[0010] 2) Multi-point non-covalent cross-linking reaction: The surface of tannin molecules has a high density of phenolic hydroxyl groups. These phenolic hydroxyl groups act as strong hydrogen bond donors, undergoing extensive non-covalent cross-linking with the aliphatic hydroxyl groups of sorbitol and the ether oxygen atoms on the polyethylene glycol backbone. The ether oxygen atoms of polyethylene glycol provide lone pairs of electrons, participating extensively in the construction of external hydrogen bonds.

[0011] 3) Spatial hindrance and network formation: The multi-point anchoring effect at the molecular level effectively restricts the free twisting of the surrounding polymer chain segments, thereby constructing a rigid polymer network with strong steric hindrance inside the system. This causes the stretching vibration peak to shift to the low-frequency direction and the peak shape to broaden, weakening the original chemical bond force field.

[0012] 4) Macroscopic phase locking: Changes in the microstructure significantly increase the glass transition temperature of the system, exceeding the mechanical heating temperature range of the tableting process. The glassy network structure, under continuous heating and pressure, resists the phase transition to a more elastic state, maintaining the brittle fracture characteristics of the particles and blocking the viscous rheological behavior of low-melting-point sorbitol. Simultaneously, the amorphous network formed by this cross-linking has an extremely low free volume, forming a tight coating on the particle surface, cutting off the microscopic capillary channels through which external moisture permeates into the internal polysaccharide core, reducing the risk of water absorption and swelling, and ensuring the structural integrity and chemical component retention of the formulation under aqueous coating and high-humidity environments.

[0013] Preferably, it is prepared from the following components in parts by weight: 27.5 parts of jujube seed powder; 15.0 parts of lily powder; 15.0 parts of longan pulp powder; 10.0 parts of Ganoderma lucidum powder; 10.0 parts of maltodextrin; 17.5 parts of sorbitol; 5.5 parts of amla powder; 1.0 part of magnesium stearate; and 4.0 parts of compound coating agent.

[0014] By adopting the above technical solution, the above ratio achieves a relative balance between the number of hydrogen bond donors of tannin polyphenols and the number of hydrogen bond acceptors of polyethylene glycol and sorbitol, forming a cross-linked network with better density, thus ensuring the content of active ingredients while achieving better anti-plasticization and water retention effects.

[0015] Preferably, the compound coating agent is a pre-compounded composition of hydroxypropyl methylcellulose and polyethylene glycol; the number average molecular weight of the polyethylene glycol is 4000 or 6000.

[0016] By employing the above technical solution, the combination of hydroxypropyl methylcellulose and polyethylene glycol (PEG) achieves a balance between film-forming properties and molecular crosslinking capabilities. PEG with a number-average molecular weight of 4000 or 6000 is selected, as its long-chain structure provides sufficient spatial span to entangle surrounding tannin and sorbitol molecules, and possesses a suitable ether bond density as crosslinking sites. Furthermore, PEG in this molecular weight range exhibits suitable solubility and rheological properties in the granulation matrix solvent of subsequent processes, contributing to stable structural shaping during matrix solvent evaporation.

[0017] Preferably, 30.0% to 40.0% of the total mass of the compound coating agent is polyethylene glycol, and this portion of polyethylene glycol is distributed in the core of the jujube seed tablet as a granulation auxiliary matrix to provide a crosslinking network, and the remaining portion of the compound coating agent is distributed on the outside of the uncoated tablet as a film coating layer.

[0018] By employing the above technical solution, the compound coating agent is spatially distributed and broken down in a specific ratio, achieving dual functionality of a single excipient. The polyethylene glycol macromolecular segments distributed inside the tablet core serve as the key framework of the cross-linking network, establishing a microscopic physical defense against mechanical and thermal softening and moisture penetration. The remaining hydroxypropyl methylcellulose and the remaining polyethylene glycol composition are distributed on the outside of the tablet, forming a smooth coating layer and providing a macroscopic external isolation barrier. The synergistic layout of the internal and external spatial structures further enhances the overall formulation's adaptability to processing in humid and hot environments.

[0019] Secondly, the present invention provides a method for preparing Phyllanthus emblica and Ziziphus jujuba seed tablets that improve sleep and nourish the heart and calm the mind, comprising the following steps:

[0020] (1) Material weighing and pretreatment: Weigh each raw material component according to the weight parts, extract and retain the polyethylene glycol in the compound coating agent for use in the subsequent granulation step, and use the remaining part of the compound coating agent as coating powder for later use.

[0021] (2) Dry powder premixing: The jujube seed powder, lily powder, longan pulp powder, Ganoderma powder and maltodextrin are dry mixed to obtain the granulation base material;

[0022] (3) Preparation of granulation matrix solution: Sorbitol and polyethylene glycol retained in step (1) are added to an aqueous ethanol solution and heated and kept warm to dissolve and form a uniform dispersion.

[0023] (4) Primary encapsulation and critical cross-linking: In the fluidized bed, the granulation matrix solution is sprayed onto the granulation substrate, and then the inlet air temperature is increased for constant temperature fluidized drying. When the exhaust air temperature reaches the preset value, under the condition of not stopping the machine and not cooling down, the amla powder is quickly sprayed into the boiling material bed of the fluidized bed through high pressure airflow to maintain the hot air temperature and continue strong fluidized mixing.

[0024] (5) Quenching and freezing phase change: After mixing, the heating source is cut off instantly and the system is switched to cold air system for fluidized bed cold air quenching until the overall temperature of the material bed drops below the target temperature, and the fluidization is stopped to obtain dry particles.

[0025] (6) Tableting and coating: After the dry granules and magnesium stearate are mixed evenly, they are continuously compressed to obtain the tablet core; the remaining coating powder in step (1) is prepared into a coating solution, and the tablet core is coated with water spray and dried to obtain the finished product.

[0026] By adopting the above technical solution, this process alters the natural thermodynamic defects of the highly hygroscopic polysaccharide system through spatiotemporal coupling control of the temperature field and the timing of material addition. The specific mechanism and reaction process are as follows:

[0027] The first stage involves substrate coating and solvent evaporation. Spraying the granulation matrix solution coats the polysaccharide powder surface with sorbitol and polyethylene glycol. Increasing the inlet air temperature accelerates ethanol solvent evaporation. As the solvent concentration decreases, the surface polymer matrix gradually concentrates, increasing the friction between molecular chains, and the system transitions from a solution state to a high-viscosity rubber state.

[0028] The second stage is the critical state crosslinking reaction. When the exhaust temperature reaches the preset value, the granulation matrix is ​​exactly in the critical window period of a high-viscosity rubber state. At this time, amla powder is injected under high pressure, and the following multi-point hydrogen bond crosslinking occurs:

[0029] Tannin-OH + polyethylene glycol-O- + sorbitol-OH → spatially cross-linked polymer network;

[0030] The large tannin polyphenols carried by Phyllanthus emblica powder enter the system. The dense phenolic hydroxyl groups on its surface act as hydrogen bond donors, crosslinking with the ether bonds of polyethylene glycol and the hydroxyl groups of sorbitol. The rubber-like matrix allows tannin molecules to embed within the polymer network, forming spatial interference and hindering the phase separation and rearrangement crystallization tendency of sorbitol.

[0031] The third stage involves freezing the phase transition and locking the structure. Immediately after crosslinking, the material is quenched with cold air, causing the temperature to rapidly cross the glass transition temperature range. This rapid temperature drop deprives the molecules of the free volume required for thermal motion, preventing the relaxation of the previously established non-covalent intermolecular interactions during slow cooling. This forces the crosslinked polymer network structure to freeze in a metastable glassy state, macroscopically endowing the particles with a high glass transition temperature and excellent resistance to damp heat and mechanical strength.

[0032] Preferably, in step (2), the mixture is dry-mixed at room temperature for 15-20 min at a speed of 15-25 rpm; in step (3), the volume fraction of the ethanol aqueous solution is 85%, the solvent temperature is stabilized at 55-65℃ by heating, and the solution is kept warm and dissolved for 30-45 min at a speed of 100-200 rpm.

[0033] By adopting the above technical solution, the above dry mixing parameters can ensure the uniformity of mixing; the 85% volume fraction of ethanol aqueous solution takes into account the solubility of polyethylene glycol and sorbitol, and can provide a suitable evaporation rate in the fluidized bed; the dissolution temperature of 55-65℃ helps the polymer chain segments to fully expand in the solvent, providing a uniform structural basis for subsequent spray film formation and crosslinking.

[0034] Preferably, in step (4), the initial air inlet temperature of the fluidized bed is set to 45-55℃, the spraying flow rate of the granulation matrix solution is 15-30mL / min, and the atomizing pressure is set to 0.15-0.25MPa; after spraying, the air inlet temperature of the fluidized bed is immediately increased and kept constant at 60-65℃ to continue fluidized drying.

[0035] By adopting the above technical solution, the initial air inlet temperature, spray flow rate and atomization pressure are set in coordination to control the droplet size and drying rate, prevent the droplets from drying into powder before contacting the powder, and ensure that the matrix solution forms a continuous liquid film on the substrate surface. After spraying, the temperature is raised to 60-65°C, which forcibly increases the enthalpy of the system, accelerates the escape of the remaining solvent, and causes the liquid film layer to shrink rapidly and enter the high viscosity range that is conducive to the cross-linking reaction.

[0036] Preferably, in step (4), when the exhaust temperature reaches 48-52℃, the high-pressure airflow powder feeding device is turned on, and the amla powder is rapidly sprayed into the fluidized bed within 1-2 minutes under a conveying air pressure of 0.2-0.4MPa. After the spraying is completed, the hot air temperature of 60-65℃ is maintained to continue strong fluidization and mixing for 3-6 minutes.

[0037] By adopting the above technical solution, the exhaust temperature is an objective indicator reflecting the true thermodynamic state of the material bed and the solvent residue rate. An exhaust temperature of 48–52℃ accurately pinpoints the time point at which the granulation matrix reaches the critical high-viscosity rubber state. A conveying air pressure of 0.2–0.4 MPa provides the amla powder with the kinetic energy to overcome the fluid resistance of the bed, enabling it to penetrate deeply and distribute evenly within the boiling particle group in a short time; the subsequent isothermal mixing time provides the necessary thermodynamic collision probability and reaction window for the hydrogen bond network assembly between phenolic hydroxyl groups and ether bonds.

[0038] Preferably, in step (5), the inlet air temperature is rapidly reduced to 15-20°C within 2-4 minutes for fluidized bed cold air quenching until the overall temperature of the material bed drops below 25°C.

[0039] By employing the above technical solution, a high-intensity temperature gradient is formed within a short period of 2–4 minutes, resulting in rapid cooling and hardening of the material surface. This quenching rate limits the free time for polymer chain segments to restore lattice order, interrupting the path for sorbitol to form a crystalline phase, thereby effectively maintaining the rigid steric hindrance of the amorphous solid dispersion.

[0040] Preferably, in step (6), continuous tableting is performed under parameters of main pressure 10-20kN and rotation speed 20-40rpm; the coating powder is prepared into a coating purification aqueous solution with a mass fraction of 6.0%-10.0%, and spray coating is performed under conditions of tablet bed temperature 38-42℃ and atomization pressure 0.20-0.30MPa. When the coating weight gain reaches 2.0%-2.5%, the spraying is stopped and the original machine is dried.

[0041] By adopting the above technical solution, under these tableting parameters, the modified particles with high glass transition temperature achieve a balance between plastic deformation and brittle fracture, avoiding sticking caused by mechanical and thermal softening; the specific coating parameters enable the water vapor evaporation rate and the liquid spraying rate to reach a dynamic balance on the tablet bed surface, which, together with the water penetration resistance provided by the polyethylene glycol cross-linked network on the tablet core surface, avoids tablet core swelling and degradation of effective ingredients caused by water retention.

[0042] Based on the above technical solutions, the formulation components of this invention achieve the functions of improving sleep and calming the mind through multiple synergistic pathways at the pharmacological level. The specific pharmacological mechanism is achieved through the following pathways:

[0043] First, neurotransmitter regulation. Jujube seed powder contains active ingredients such as jujube seed saponins, which can act on the central nervous system, participating in the regulation of the release and receptor binding of inhibitory neurotransmitters such as γ-aminobutyric acid (GABA) in the synaptic cleft. This effect can reduce the overall excitability of neurons in the cerebral cortex, shorten the sleep latency, and prolong slow-wave sleep time, thus providing the basic substances for sedation and hypnosis.

[0044] Secondly, it nourishes the mind and blood. Lily powder contains lily polysaccharides and trace amounts of alkaloids, which have a calming and soothing effect; longan pulp powder contains amino acids and trace elements, which can replenish blood and qi. The combination of the two can improve palpitations, anxiety, insomnia, and excessive dreaming caused by deficiency of both heart and spleen or neurasthenia, and provide basic nutritional and metabolic support for the normal functioning of the nervous system.

[0045] Third, neuroendocrine network regulation. The polysaccharides and triterpenoids in Ganoderma lucidum powder can participate in regulating the dynamic balance of the autonomic nervous system and the immune system, improve neuroendocrine dysfunction caused by long-term sleep deprivation or mental stress, and reduce the body's fatigue.

[0046] Fourth, antioxidant and central nervous system protection. Besides providing tannins and polyphenols as physical cross-linking agents during the formulation process, amla powder is rich in natural antioxidants that, once in the body, can cross the blood-brain barrier or scavenge excess oxygen free radicals in the peripheral microcirculation. This antioxidant process reduces the risk of oxidative stress damage to nerve cells and, synergistically with jujube seed and lily bulb, maintains the normal physiological rhythm of the central nervous system.

[0047] Through the above-mentioned combination of multiple components, the active substances within the system exert synergistic effects in regulating neurotransmitter transmission, improving microcirculation and nutrient supply, and reducing neuronal oxidative damage, thus comprehensively achieving the formulation functions of nourishing the heart and calming the mind, and improving sleep.

[0048] In summary, the present invention has at least one of the following beneficial technical effects:

[0049] 1. This invention effectively restricts the relative movement of low molecular weight excipients and polysaccharide segments by constructing an amorphous cross-linked network with a high glass transition temperature. Under the condition of continuous tableting operation generating mechanical frictional heat, the material can resist the phase transition softening to a highly elastic state and maintain brittle fracture characteristics, thereby solving the engineering processing problems of traditional polysaccharide formulations being prone to sticking and impact, and having a large amount of adhesion to equipment.

[0050] 2. This invention utilizes a dense, rigid network formed by the crosslinking of polyethylene glycol and tannin polyphenols, significantly reducing the free volume of the system. This structure creates spatial physical isolation on the particle surface, cutting off the microscopic channels through which external moisture permeates into the polysaccharide core, effectively reducing the water absorption and swelling rate of the tablets in high-humidity environments and during the water-based film coating process, and preventing the coating film from cracking.

[0051] 3. This invention utilizes the low-molecular-weight mobility barrier established by the aforementioned spatiotemporal coupling process to block the microenvironment hydration reaction caused by external moisture intrusion into the tablet core. During moist heat coating operations or long-term storage, it effectively reduces the degradation and loss of heat-sensitive and water-sensitive active ingredients such as jujube seed saponins, ensuring the uniformity of the final product's quality.

[0052] 4. This invention rationally combines raw materials such as jujube seed, lily bulb, longan pulp, Ganoderma lucidum and amla, and utilizes the synergistic effects of each component on multiple targets such as regulating central neurotransmitters, improving microcirculation nutrient supply, balancing neuroendocrine rhythms and reducing neuronal oxidative stress damage, to comprehensively achieve the pharmacological functions of nourishing the heart and calming the mind and improving sleep. Attached Figure Description

[0053] Figure 1 The differential scanning calorimetry (DSC) heat flow curves of the dry particles prepared in Example 1 and Comparative Examples 1-4 of this invention are shown.

[0054] Figure 2 The Fourier transform infrared (FT-IR) spectra of Example 1 and each control sample of the present invention are shown below.

[0055] Figure 3 This is a scatter plot showing the number of forced shutdowns for cleaning during the pressing of 100,000 wafers in Examples 1 to 4 and Comparative Examples 1 to 4 of the present invention.

[0056] Figure 4 This is a graph showing the relationship between the moisture absorption weight gain rate of the unflake cores in Examples 1-4 and Comparative Examples 1-4 of the present invention and time under constant temperature and humidity conditions.

[0057] Figure 5 The following are comparative charts evaluating the water-based coating tolerance and retention rate of effective ingredients in Examples 1-4 and Comparative Examples 1-4 of the present invention; wherein (a) is a line graph showing the distribution of appearance defect rate of each group after water-based coating, and (b) is a trend graph showing the retention rate of jujube seed saponin A before and after coating based on high performance liquid chromatography detection. Detailed Implementation

[0058] To make the objectives, technical solutions, and advantages of this invention clearer, the technical solutions of this invention will be clearly and completely described below in conjunction with the embodiments of this invention. Obviously, the described embodiments are merely some embodiments of this invention, and not all embodiments. Based on the embodiments of this invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of this invention.

[0059] The main raw materials and reagents used in the following examples and comparative examples have the following sources and specifications. Reagents not specifically mentioned are all commercially available analytical grade or higher grade products.

[0060] Jujube seed powder is made by spray-drying a concentrated aqueous extract of jujube seeds with maltodextrin, wherein the maltodextrin content is 30.0% by mass and the jujube seed saponin A content is greater than or equal to 0.5% by mass. Lily powder is made by extracting dried fleshy scales of lily bulbs with pure water and then spray-drying. Longan pulp powder is made by extracting longan aril with pure water and then spray-drying. Ganoderma lucidum (red Ganoderma) powder is made by extracting dried fruiting bodies of red Ganoderma lucidum with pure water and then spray-drying, with a crude polysaccharide content greater than or equal to 10.0% by mass. Maltodextrin CAS number is 9050-36-6, and its glucose equivalent is 10-15. Sorbitol CAS number is 50-70-4, and its purity is greater than or equal to 98.0%. Phyllanthus emblica powder is an extract powder made by extracting Phyllanthus emblica fruit with pure water and then vacuum-drying, with a total polyphenol content greater than or equal to 30.0% and a moisture content less than or equal to 5.0% by mass. Magnesium stearate CAS number is 557-04-0. Polyethylene glycol (PEG) has CAS number 25322-68-3 and a number-average molecular weight range of 4000–6000. Hydroxypropyl methylcellulose (HMC) has CAS number 9004-65-3, a methoxy group mass fraction of 28.0%–30.0%, a hydroxypropoxy group mass fraction of 7.0%–12.0%, and a kinetic viscosity of its 2% aqueous solution at 20°C of 3 mPa·s–15 mPa·s. In this invention, the compound coating agent is a coating composition formed by pre-componenting hydroxypropyl methylcellulose and polyethylene glycol, wherein polyethylene glycol serves as a plasticizer and hydroxypropyl methylcellulose serves as a film-forming component. The compound coating agent can be prepared by pre-mixing the components in a predetermined ratio. In the examples, the extracted and retained polyethylene glycol refers to the portion of polyethylene glycol that is pre-measured and retained during the preparation of the compound coating agent for use in subsequent granulation steps, rather than the physical disintegration or chemical separation of the already formed commercial coating powder. The 85% ethanol aqueous solution used in this embodiment of the invention is prepared from purified water and analytical grade ethanol.

[0061] Example 1:

[0062] This embodiment provides a method for preparing Phyllanthus emblica and Ziziphus jujuba seed tablets, including the following steps:

[0063] (1) Material weighing and pretreatment: Weigh 27.5g of jujube seed powder, 15.0g of lily powder, 15.0g of longan pulp powder, 10.0g of Ganoderma lucidum powder, 10.0g of maltodextrin, 17.5g of sorbitol, 5.5g of amla powder, 1.0g of magnesium stearate, and 4.0g of compound coating agent. The compound coating agent is a pre-compounded hydroxypropyl methylcellulose / polyethylene glycol composition, of which 1.4g of polyethylene glycol with a number average molecular weight of 4000, accounting for 35.0% of the total mass of the compound coating agent, is pre-measured and reserved for subsequent granulation steps, and the remainder is reserved as coating powder.

[0064] (2) Dry powder premixing: The above-weighed jujube seed powder, lily powder, longan pulp powder, Ganoderma powder and maltodextrin are put into a three-dimensional motion mixer and dry-mixed at room temperature for 18 minutes at a speed of 20 rpm. The resulting mixture is then transferred to a fluidized bed silo as the granulation base material.

[0065] (3) Preparation of granulation matrix solution: Add 85% ethanol aqueous solution to a jacketed heating tank and start heating to stabilize the solvent temperature at 60℃. Add the prescribed amount of sorbitol and 1.4g of polyethylene glycol extracted in step (1) to hot ethanol, and keep it at a stirring rate of 150rpm for 35min to form a uniform dispersion, and keep it at 60℃.

[0066] (4) Primary encapsulation and critical crosslinking: Start the bottom spray fluidized bed, set the inlet air temperature to 50℃, turn on the atomization system, and spray the granulation liquid, which is kept at 60℃, onto the bottom material at a flow rate of 22mL / min. The atomization pressure is set to 0.20MPa. After the granulation liquid is sprayed, immediately raise the inlet air temperature of the fluidized bed and keep it constant at 62℃ to continue fluidization and drying. When the exhaust air temperature reaches 50℃, turn on the high-pressure airflow powder feeding device without stopping the machine or lowering the temperature. Under the conveying air pressure of 0.3MPa, the formulated amount of amla powder is rapidly sprayed into the boiling material bed of the fluidized bed within 1.5min. After the spraying is completed, maintain the hot air temperature of 62℃ and continue strong fluidization and mixing for 4.5min.

[0067] (5) Quenching and freezing phase change: After the above strong mixing is completed, the heating source is cut off instantly and the cold air system is switched to make the air inlet temperature drop sharply to 18°C ​​within 3 minutes for fluidized bed cold air quenching until the overall temperature of the material bed drops below 25°C, and the fluidization is stopped to obtain dry particles.

[0068] (6) Tableting and Coating: The obtained dry granules and magnesium stearate were mixed in a mixer for 8 minutes, and then transferred to a rotary tablet press. The tablets were continuously compressed at a main pressure of 15 kN and a rotation speed of 30 rpm to obtain the tablet cores. The tablet cores were placed in a high-efficiency film coating machine. The remaining coating powder from step (1) was dissolved in purified water to prepare a coating solution with a mass fraction of 8.0%. Spray coating was carried out at a tablet bed temperature of 40°C and an atomization pressure of 0.25 MPa. The spraying was stopped when the coating weight gain reached 2.5%. The product was then dried.

[0069] Example 2:

[0070] This embodiment provides a method for preparing Phyllanthus emblica and Ziziphus jujuba seed tablets, including the following steps:

[0071] (1) Material weighing and pretreatment: Weigh 20.0g of jujube seed powder, 10.0g of lily powder, 10.0g of longan pulp powder, 5.0g of Ganoderma lucidum powder, 5.0g of maltodextrin, 10.0g of sorbitol, 3.0g of amla powder, 0.5g of magnesium stearate, and 2.0g of compound coating agent. The compound coating agent is a pre-compounded hydroxypropyl methylcellulose / polyethylene glycol composition, of which 0.6g of polyethylene glycol with a number average molecular weight of 4000, accounting for 30.0% of the total mass of the compound coating agent, is pre-measured and reserved for subsequent granulation steps, and the remainder is reserved as coating powder.

[0072] (2) Dry powder premixing: Jujube seed powder, lily powder, longan pulp powder, Ganoderma powder and maltodextrin are put into a three-dimensional motion mixer and dry-mixed at room temperature for 15 minutes at a speed of 15 rpm. The mixture is then transferred to a fluidized bed silo as a granulation base material.

[0073] (3) Preparation of granulation matrix solution: Add an 85% ethanol aqueous solution to the mixing tank and heat it to stabilize the solvent temperature at 55℃. Add sorbitol and the extracted polyethylene glycol to the hot ethanol and keep it at 100 rpm for 30 min to form a uniform dispersion. Then raise the temperature to 60℃ and keep it at that temperature for later use.

[0074] (4) Primary encapsulation and critical crosslinking: Start the fluidized bed, set the inlet air temperature to 45℃, and spray the heat-insulating granulation liquid onto the substrate at a flow rate of 15mL / min, with an atomizing air pressure of 0.15MPa. After spraying, immediately raise the inlet air temperature to 60℃ for constant-temperature fluidized drying. When the exhaust air temperature reaches 48℃, without stopping the machine or lowering the temperature, spray the amla powder into the fluidized bed within 1 minute at a conveying air pressure of 0.2MPa, and maintain strong fluidized mixing with 60℃ hot air for 3 minutes.

[0075] (5) Quenching and freezing phase change: Instantly cut off the heat source and switch to cold air, so that the air inlet temperature drops to 20°C within 2 minutes for fluidized bed cold air quenching until the material bed temperature drops below 25°C, and dry granules are discharged.

[0076] (6) Tableting and Coating: Mix the dry granules with magnesium stearate for 5 minutes, then transfer the mixture to a tablet press and compress it into tablets at a main pressure of 10 kN and a rotation speed of 20 rpm to obtain uncoated tablet cores. Dissolve the remaining coating powder in purified water to prepare a coating solution with a mass fraction of 6.0%, and spray-coat the solution at a tablet bed temperature of 38℃ and an atomization pressure of 0.20 MPa. Stop the coating when the weight gain reaches 2.0% and dry the product to obtain the finished product.

[0077] Example 3:

[0078] This embodiment provides a method for preparing Phyllanthus emblica and Ziziphus jujuba seed tablets, including the following steps:

[0079] (1) Material weighing and pretreatment: Weigh 35.0g of jujube seed powder, 20.0g of lily powder, 20.0g of longan pulp powder, 15.0g of Ganoderma lucidum powder, 15.0g of maltodextrin, 25.0g of sorbitol, 8.0g of amla powder, 1.5g of magnesium stearate, and 6.0g of compound coating agent. The compound coating agent is a pre-compounded hydroxypropyl methylcellulose / polyethylene glycol composition, of which 2.4g of polyethylene glycol with a number average molecular weight of 4000, accounting for 40.0% of the total mass of the compound coating agent, is pre-measured and reserved for subsequent granulation steps, and the remainder is reserved as coating powder.

[0080] (2) Dry powder premixing: Add jujube seed powder, lily powder, longan pulp powder, Ganoderma lucidum powder and maltodextrin into a mixer and dry mix at room temperature for 20 minutes at 25 rpm, then transfer to a fluidized bed silo.

[0081] (3) Preparation of granulation matrix solution: Add an 85% ethanol aqueous solution to the mixing tank and heat to stabilize the solvent temperature at 65℃. Add sorbitol and polyethylene glycol to the hot ethanol and keep it at 200 rpm for 45 min to form a dispersion. Then cool it down to 60℃ and keep it at that temperature for later use.

[0082] (4) Primary encapsulation and critical crosslinking: Start the fluidized bed, set the inlet air temperature to 55℃, and spray the granulation liquid onto the substrate at a flow rate of 30mL / min with an atomizing pressure of 0.25MPa. After spraying, raise the inlet air temperature to 65℃ for constant-temperature fluidized drying. When the exhaust air temperature reaches 52℃, without stopping the machine or lowering the temperature, spray the amla powder into the material bed within 2 minutes at a pressure of 0.4MPa, and maintain strong fluidized mixing with hot air at 65℃ for 6 minutes.

[0083] (5) Quenching and freezing phase change: Cut off the heat source and switch to cold air, so that the air inlet temperature drops sharply to 15°C within 4 minutes for quenching until the material bed temperature drops below 25°C, and dry granules are discharged.

[0084] (6) Tableting and Coating: Mix the dry granules with magnesium stearate for 10 min, transfer to a tablet press and compress under a main pressure of 20 kN and a rotation speed of 40 rpm to obtain a tablet core. Prepare a coating solution with a mass fraction of 10.0% by spray coating at a tablet bed temperature of 42℃ and an atomization pressure of 0.30 MPa. Stop coating when the weight gain reaches 2.5% and dry to obtain the finished product.

[0085] Example 4:

[0086] This embodiment provides a method for preparing Phyllanthus emblica and Ziziphus jujuba seed tablets, including the following steps:

[0087] (1) Material weighing and pretreatment: Weigh 27.5g of jujube seed powder, 15.0g of lily powder, 15.0g of longan pulp powder, 10.0g of Ganoderma lucidum powder, 10.0g of maltodextrin, 17.5g of sorbitol, 5.5g of amla powder, 1.0g of magnesium stearate, and 4.0g of compound coating agent. The compound coating agent is a pre-compounded hydroxypropyl methylcellulose / polyethylene glycol composition, of which 1.4g of polyethylene glycol with a number average molecular weight of 6000, accounting for 35.0% of the total mass of the compound coating agent, is pre-measured and reserved for subsequent granulation steps, and the remainder is reserved as coating powder.

[0088] (2) Dry powder premixing: Jujube seed powder, lily powder, longan pulp powder, Ganoderma powder and maltodextrin are put into a three-dimensional motion mixer and dry-mixed at room temperature for 18 minutes at a speed of 20 rpm, and then transferred to a fluidized bed silo.

[0089] (3) Preparation of granulation matrix solution: Add 85% ethanol aqueous solution to the mixing tank and heat to stabilize the temperature at 60℃. Add sorbitol and polyethylene glycol with a number average molecular weight of 6000 to the hot ethanol, keep warm at 150 rpm for 35 min, and then keep warm at 60℃.

[0090] (4) Primary encapsulation and critical crosslinking: Start the fluidized bed, set the inlet air temperature to 50℃, and spray the heat-preserving granulation solution onto the substrate at a flow rate of 22mL / min and an air pressure of 0.20MPa. After spraying, raise the inlet air temperature to 62℃ and continue drying. When the exhaust air temperature reaches 50℃, spray Phyllanthus emblica powder into the fluidized bed at an air pressure of 0.3MPa within 1.5min without stopping the machine or lowering the temperature, and maintain the 62℃ hot air mixing for 4.5min.

[0091] (5) Quenching and freezing phase change: Instantly cut off the heat source and switch the cold air system to make the air inlet temperature drop to 18°C ​​within 3 minutes for cold air quenching until the overall temperature of the material drops below 25°C and dry granules are discharged.

[0092] (6) Tableting and Coating: Mix the dry granules with magnesium stearate for 8 min, and continuously compress the mixture at a main pressure of 15 kN and a rotation speed of 30 rpm to obtain uncoated tablet cores. Prepare a coating solution with a mass fraction of 8.0% by spray coating at a tablet bed temperature of 40℃ and an air pressure of 0.25 MPa. Stop spraying when the weight gain reaches 2.5% and dry to obtain the finished product.

[0093] Comparative Example 1:

[0094] Compared with Example 1, the difference is that the timing of adding amla powder was changed. The amla powder of the formula was added together with the base materials such as jujube seed powder in step (2) and premixed at room temperature in a three-dimensional motion mixer; in step (4), after the granulation liquid was sprayed, it was only kept at 62°C for hot air drying for 4.5 minutes, and the high-pressure airflow powder feeding operation was not performed, and the rest were the same.

[0095] Comparative Example 2:

[0096] Compared with Example 1, the difference is that the dynamic quenching drop feature is missing. In step (5), after the strong mixing is completed, the cold air system is not switched to quenching. Instead, the heating source is cut off and the fluidized bed is kept running at a very low air volume so that the material can be naturally and slowly cooled to below 25°C at room temperature. The rest are the same.

[0097] Comparative Example 3:

[0098] Compared with Example 1, the difference is that the macromolecular antiplasticizer feature is missing. In step (4), the powder injected by the high-pressure airflow is replaced by an equal mass of maltodextrin instead of amla powder, and the formula no longer contains amla powder, while the rest are the same.

[0099] Comparative Example 4:

[0100] Compared with Example 1, the difference is that the powder was not fed when the material was in a high-viscosity rubber state. After the granulation liquid was sprayed in step (4), the heating source was directly cut off to cool down. After the exhaust temperature dropped to room temperature (25°C), the high-pressure airflow powder feeding device was turned on at room temperature to spray in Phyllanthus emblica powder and mix for 4.5 minutes. After the mixing was completed, the cold air quenching described in step (5) was not performed. Dry granules were directly discharged. The rest were the same.

[0101] Test Example 1:

[0102] The experimental steps are as follows:

[0103] (1) Take the dry granules prepared in Example 1 and Comparative Examples 1 to 4 as test samples, place them in a desiccator at room temperature for 24 hours to balance the moisture, and then weigh 3.15 mg to 3.62 mg of each group of samples using an analytical balance.

[0104] (2) The weighed samples are placed into standard aluminum crucibles and sealed with perforated caps using a special capping device. At the same time, an empty aluminum crucible of the same specification is prepared as a reference.

[0105] (3) Turn on the main unit and cooling accessories of the differential scanning calorimeter, set high-purity nitrogen as the purge gas, and control the gas flow rate at 50 mL / min. Place the crucible containing the sample and reference material on the corresponding sensor tray of the heating furnace.

[0106] (4) Set the heating program in the instrument control software. Set the initial temperature to 0℃ and keep it constant for 5 minutes to eliminate the thermal history of the sample. Then heat linearly to 150℃ at a heating rate of 10℃ / min. During this process, the system automatically records the curve of heat flow changing with temperature.

[0107] (5) After the test, export the heat flow curve data of each group of samples. Select the transition zone where the baseline changes abruptly using data analysis software, calculate the extrapolated onset temperature as the glass transition temperature Tg of the sample; at the same time, record the endothermic peak temperature that appears in the curve as the crystallization melting peak Tm, and calculate the enthalpy of fusion ΔH of the sample by integrating the area of ​​the endothermic peak.

[0108] The experimental results are shown in Table 1.

[0109] Table 1. Thermodynamic phase characteristics of Example 1 and each comparative sample:

[0110] Group Glass transition temperature Tg (°C) Crystallization melting peak Tm (°C) Enthalpy of fusion ΔH (J / g) Example 1 58.34 Not detected 0 Comparative Example 1 28.71 92.43 45.26 Comparative Example 2 31.22 93.15 38.74 Comparative Example 3 34.56 91.82 22.41 Comparative Example 4 29.45 94.27 51.63

[0111] According to Table 1 and Figure 1 According to the data, the glass transition temperature of Example 1 increased to 58.34℃, which is higher than the mechanical heating temperature range in the conventional tableting process. No obvious sorbitol crystallization melting peak was observed in the corresponding heat flow curve, indicating that the internal components of the system mainly exist in an amorphous phase. This reflects that the process parameters set in this scheme help maintain this metastable structure at the thermodynamic level. In contrast, when the order of material addition was adjusted, for example, in Comparative Example 1 where amla powder was introduced during the premixing stage, the Tg of the system dropped to 28.71℃, and an obvious crystallization melting peak appeared near 92.43℃. This change in data indicates that if the macromolecular antiplasticizer is not introduced during the window period when the granulation matrix has a specific viscosity, tannin polyphenols may have difficulty fully embedding into the polymer network to form effective steric hindrance, thus making the sorbitol in the system prone to phase separation and rearrangement crystallization.

[0112] Further observation of the effect of temperature field control conditions on phase state revealed that in Comparative Example 2, which did not employ a rapid cooling process, the initially established intermolecular interactions may have loosened during the slow cooling process. This data showed that the Tg remained at 31.22℃, suggesting that a prolonged cooling process may allow polyethylene glycol and sorbitol segments to gain some free volume to restore some lattice order, thus affecting the stability of the amorphous solid dispersion. In Comparative Example 3, conventional maltodextrin was used to replace amla powder. Although the macromolecular polysaccharide exhibited a certain volume effect, the lack of high-density phenolic hydroxyl groups and other structures as hydrogen bond crosslinking sites resulted in relatively limited steric hindrance, with the Tg only rising to 34.56℃. Combined with the data from Comparative Example 4, which showed a melting enthalpy of 51.63 J / g generated by feeding powder at room temperature, it can be concluded that once the acceptor surface cools and returns to a glassy state, externally added macromolecules have difficulty effectively penetrating the network, and the components exhibit more of a physical mixing or surface adhesion state. The above-mentioned spectral features and data comparisons indicate that process intervention at specific temperature nodes and material states has certain application significance for improving the thermodynamic phase characteristics of polysaccharide suspension systems.

[0113] Test Example 2:

[0114] (1) The dry granules prepared in Example 1 were selected as test samples. At the same time, pure powders of each raw material that had not been granulated by fluidized bed were accurately weighed according to the formulation ratio of Example 1 and mixed evenly in an agate mortar at room temperature as a physical mixture control sample. In addition, pure sorbitol, pure polyethylene glycol, and pure amla powder were taken as pure component control samples. All samples were dried in a vacuum desiccator containing phosphorus pentoxide for 48 hours before testing to remove interference from free moisture.

[0115] (2) Test target sheets were prepared using the potassium bromide (KBr) compression method. Under a dry environment with infrared lamp baking, approximately 2.0 mg of each group of dried samples and approximately 200.0 mg of spectrally pure KBr powder were weighed and placed in a mortar, and ground thoroughly in the same direction until the powder particle size was fine and uniformly distributed. The ground mixture was transferred into a compression mold and pressed into a transparent or translucent circular sheet under a pressure of approximately 10 MPa for 2 minutes. A pure KBr sheet without the sample was also pressed using the same method as a background reference.

[0116] (3) Turn on the Fourier transform infrared spectrometer and preheat until the system is stable. Place the pure KBr thin film in the sample optical path and scan to acquire the background spectrum, then place each sample thin film in sequence for measurement. The test parameters are set to a spectral resolution of 4 cm⁻¹. -1 The scanning wavenumber range is 4000 cm⁻¹ -1 Up to 400cm -1A single spectrum is obtained by 32 cumulative scans to improve the signal-to-noise ratio.

[0117] (4) After spectral acquisition, baseline calibration and smoothing were performed on all raw spectra using spectral processing software. The baseline of each sample at approximately 3300 cm⁻¹ was extracted and recorded. -1 The central wavenumber and half-maximum width of the hydroxyl (-OH) stretching vibration absorption peak in the vicinity were recorded, along with the wavenumber positions of the characteristic ether bond (COC) asymmetric stretching vibration peak in the polyethylene glycol component.

[0118] The experimental results are shown in Table 2.

[0119] Table 2. Characteristic infrared absorption peak parameters of Example 1 and each control sample:

[0120] Group <![CDATA[Wavenumber of the hydroxyl (-OH) stretching vibration peak (cm -1 )]]> <![CDATA[Full width at half maximum (cm) of the hydroxyl (-OH) absorption peak -1 )]]> <![CDATA[Wavenumber of the stretching vibration peak of the ether bond (C-O-C) (cm -1 )]]> Sorbitol (pure) 3385.24 82.35 No characteristic peaks detected Pure polyethylene glycol 3450.11 65.18 1112.45 Pure Phyllanthus emblica powder 3362.79 115.32 1045.18 (Ester / Glycoside Interference) physical mixtures 3375.63 120.54 1111.82 Example 1: Dry Granules 3314.26 168.71 1098.53

[0121] According to Table 2 and Figure 2 The data shows that under physical mixing, the components of each raw material basically maintain their original spectral characteristics. The absorption peak positions of this mixture mainly exhibit the superposition of characteristic peaks of the pure components, with the peak at 3375.63 cm⁻¹ being the most prominent. -1 The hydroxyl peak at 1111.82 cm⁻¹ -1 No significant wavenumber shift was observed in the ether bond peak. In the dry particulate sample of Example 1, the peak was located at 3300 cm⁻¹. -1 The nearby absorption bands show a trend towards lower frequencies, with the characteristic wavenumber decreasing to 3314.26 cm⁻¹. -1 Meanwhile, the half-maximum width increased from 120.54 cm⁻¹ for the physically mixed sample. -1 Width extended to 168.71cm -1 The redshift and broadening of such stretching vibration peaks in infrared spectroscopy usually indicate that extensive intermolecular hydrogen bonding may have formed within the system, thereby affecting the original chemical bond force field.

[0122] Further observation of the absorption peak of the ether bond (COC) of polyethylene glycol revealed that its position changed from 1112.45 cm⁻¹ in the pure product. -1 Offset to 1098.53cm -1This frequency shift may indicate that oxygen atoms on the polymer backbone participate in the construction of the hydrogen bond network. Analysis of the preparation process conditions reveals that adding amla powder when the granulation matrix is ​​at a high viscosity during a specific solvent evaporation stage allows polyphenolic structures such as tannins to enter the system. The polyphenolic hydroxyl groups in amla may act as hydrogen bond donors, generating certain non-covalent interactions with the hydroxyl groups of sorbitol and the ether bonds of polyethylene glycol. This intermolecular force helps restrict the relative movement of surrounding polymer chain segments, thereby increasing the local steric hindrance of the system to some extent. The aforementioned changes in spectral characteristics provide a corresponding microstructural analysis reference for the increase in the glass transition temperature of the system.

[0123] Test Example 3:

[0124] The experimental steps are as follows:

[0125] (1) The tablets prepared by the total mixing process in Examples 1-4 and Comparative Examples 1-4 were selected as test samples. Before the test, the punch and die assembly of the high-speed rotary tablet press was completely disassembled, and the tablets were wiped and washed alternately with purified water and anhydrous ethanol. The tablets were then placed in a drying oven and baked to constant weight to ensure that there was no organic residue or moisture interference on the working surface of the punch.

[0126] (2) Pour the samples from each group into the sealed hopper of the tableting chamber. Install a circular flat die with a diameter of 10mm. On the control panel, adjust the main pressure parameter to a constant 15kN and fix the turntable speed to 30rpm. Start the equipment for continuous operation. Set the compression target for each group of tests to 100,000 tablets. Set an infrared thermal imaging thermometer on the side of the tableting chamber to monitor the highest temperature rise of the tableting working area and the die surface throughout the process.

[0127] (3) During the long pressing cycle, closely monitor the appearance integrity of the finished product in the tablet slot and the changes in the motor load of the tablet pressing spindle. When visible peeling pits are found on the surface of the tablet core, or when the working surface of the punch is affected by material adhesion and accumulation, causing a surge in equipment operating resistance, abnormal vibration, or even alarm shutdown, manual intervention is carried out. Use a special copper scraper to clean the punch surface and record in detail the number of forced shutdowns required for each group to complete 100,000 tablets of production.

[0128] (4) After the single test task is completed, the five upper punches used in the tableting process of that group are randomly disassembled. The removed punches are immersed in a custom elution tank containing 50 mL of 60% methanol aqueous solution and ultrasonic cleaner is turned on for 15 minutes to fully dissolve and peel off the residual matrix that is tightly attached to the metal surface.

[0129] (5) Transfer all the methanol-water solution containing the eluent to a pre-weighed petri dish, place it in a constant temperature water bath to slowly evaporate the volatile solvent, and then transfer it to a 105°C oven to continue drying until the mass no longer changes. Use an analytical balance with a sensitivity of 0.01 mg to measure the final mass of the petri dish, and calculate the average dry basis weight of the material adhering to each group of punches after subtraction. This will serve as the quantitative basis for the amount of material adhering to the punch.

[0130] The experimental results are shown in Table 3.

[0131] Table 3. Test data on anti-sticking performance of continuous tableting and evaluation data on die adhesion amount:

[0132] Group Maximum surface temperature of the die (°C) Number of times production was forced to stop when 100,000 units were produced. Average adhesion amount of the upper punch (mg / punch) Example 1 42.8 0 0.73 Example 2 41.3 0 1.05 Example 3 43.5 0 0.58 Example 4 42.1 0 0.82 Comparative Example 1 43.2 5 17.84 Comparative Example 2 44.1 6 21.36 Comparative Example 3 42.9 8 28.15 Comparative Example 4 41.8 4 14.62

[0133] According to Table 3 and Figure 3 The data showed that, under the condition of continuous operation of the tablet press generating mechanical heat, each test group exhibited different processing adaptability in a local temperature environment of 41℃ to 44℃. The materials in Examples 1-4 showed relatively stable flow and demolding states within a 100,000-tablet pressing cycle, with no overload shutdowns during equipment operation, and the amount of material adhering to the upper punch remained below 1.1 mg. This phenomenon may be related to the coating effect of the network structure with a high glass transition temperature inside the material on the low molecular weight polyol. Solid dispersions with glassy characteristics tend to maintain the brittle fracture characteristics of particles under heated and pressurized conditions, thereby mitigating the tendency of the system to transition to a highly elastic state or undergo viscous rheology to a certain extent.

[0134] In contrast, due to differences in their internal microstructure, the comparative groups exhibited varying degrees of softening and adhesion to the die surface after heating. In Comparative Examples 1 and 2, which did not employ the specific high-viscosity feeding period of a fluidized bed or lacked a quenching step, the amount of material eluted from the die exceeded 17 mg. This data suggests that if sorbitol and polyethylene glycol fail to form an effective spatial network cross-linking structure, the system may more readily exhibit the original low melting point and heat-induced softening characteristics of the excipients.

[0135] In the material substitution test, Comparative Example 3, which used maltodextrin to replace amla powder, experienced more machine interruptions during tableting. This may indicate that relying solely on the volume effect of the large-molecule polysaccharide, without providing hydrogen bonding crosslinking sites such as polyphenolic hydroxyl groups, has a relatively limited effect on restricting the movement of polymer molecules within the system. Furthermore, Comparative Example 4, which was mixed and fed at room temperature, showed an adhesion amount of 14.62 mg to the upper punch. This suggests that room-temperature mixing tends to form physical adhesion around the particles, making it more susceptible to peeling under the mechanical shear force of tableting, thus failing to provide sustained anti-plasticization protection in the phase structure. Combining temperature rise monitoring and adhesion data evaluation, the aforementioned structural reshaping operations at specific process nodes and environments provide a certain process control reference for improving the softening and adhesion behavior of related polysaccharide powders under mechanical heating conditions.

[0136] Test Example 4:

[0137] The experimental steps are as follows:

[0138] (1) Uncoated tablet cores of Examples 1-4 and Comparative Examples 1-4 were selected as test samples. Before the test, all surface dust of the samples were gently brushed off with a soft brush to eliminate the interference of external adhering substances on the initial quality.

[0139] (2) Prepare three dried and constant-weight glass weighing dishes for each group of samples. Place 10 uncut slices flat in each weighing dish, ensuring that there are gaps between the slice cores and that they do not overlap. Use an analytical balance with an accuracy of 0.1 mg to accurately weigh the initial total mass of each weighing dish and the sample inside.

[0140] (3) Place the weighing dish containing the sample open and unobstructed into a pre-set and stably operating constant temperature and humidity test chamber. The operating parameters of the test chamber are set to a temperature of 40℃ and a relative humidity of 75% to simulate accelerated destructive environmental conditions.

[0141] (4) When the set placement time reaches the four key time nodes of 24 hours, 48 ​​hours, 72 hours and 168 hours, quickly remove the weighing dish from the test chamber. To avoid moisture condensation caused by a sudden drop in ambient temperature, immediately cover it after removal and let it stand under ambient conditions for 5 minutes, then weigh it. After weighing, quickly open the dish and put it back into the constant temperature and humidity chamber to continue the test.

[0142] (5) Based on the weighing data at different time points, calculate the average moisture absorption weight gain rate of a single sample at each stage after deducting the mass of the empty dish. The formula for calculating the moisture absorption weight gain rate is: (mass of sample at a specific time point - initial sample mass) / initial sample mass × 100%.

[0143] The experimental results are shown in Table 4.

[0144] Table 4. Moisture absorption and weight gain rate (%) of each group of untreated tablet cores under constant temperature and humidity conditions:

[0145] Group 24h 48h 72h 168h Example 1 0.81 1.45 1.92 2.34 Example 2 0.95 1.62 2.15 2.87 Example 3 0.72 1.28 1.76 2.11 Example 4 0.88 1.51 1.98 2.53 Comparative Example 1 3.12 6.45 9.87 14.21 Comparative Example 2 3.56 7.12 10.54 15.68 Comparative Example 3 4.21 8.35 12.41 18.05 Comparative Example 4 2.89 5.76 8.92 12.84

[0146] According to Table 4 and Figure 4 The data shows that, under the established high humidity and high heat test environment, the unprocessed tablets of Examples 1-4 exhibited relatively stable moisture retention. After 168 hours of storage, their mass increase remained within 3.0%. Combined with the trend of the data curves, it can be observed that the moisture absorption rate of each example slowed down and gradually stabilized after 72 hours. This difference in apparent moisture absorption behavior may be related to the amorphous network structure formed by the crosslinking of polyethylene glycol segments and tannin polyphenols. This type of network structure typically has a low free volume, and its coating on the particle surface may have a certain spatial restriction effect on the relaxation of molecular chains, thereby reducing the microscopic channels for external moisture to penetrate into the polysaccharide core within the tablet core skeleton.

[0147] In the comparative test data, the moisture absorption rate curves generally showed different upward trends. Taking Comparative Example 3, which replaced amla powder with maltodextrin, as an example, due to the failure to introduce macromolecular components with specific cross-linking effects, its moisture absorption rate reached 18.05% at the end of the 168-hour test, and it exhibited surface deliquescence during the observation process. Comparative Example 2, which did not use the cold air quenching process, and Comparative Example 1, which adjusted the powder feeding sequence, recorded moisture absorption rates of 15.68% and 14.21%, respectively. The above data suggest that if sorbitol and highly hygroscopic plant polysaccharides exist mainly in a physically mixed or partially recrystallized state, the exposed hydroxyl groups on their surfaces are more likely to combine with moisture in the environment and cause water absorption and swelling.

[0148] Observations in Comparative Example 4, which involved powdering at room temperature, revealed that although the outer layer of the granules was coated with tannin-containing components, the physical adhesion structure during tableting may have developed some pores due to mechanical stress, making it difficult to form a relatively continuous coating interface. This allowed external moisture to still penetrate into the tablet core through these gaps. Based on the moisture absorption data of each group of samples, intervening in the phase structure of the material under specific process conditions provides a reference for improving the physical stability and moisture-proof performance of polysaccharide formulations under humid and hot environments.

[0149] Test Example 5:

[0150] The experimental steps are as follows:

[0151] (1) The uncoated tablets of Examples 1-4 and Comparative Examples 1-4 were selected as the subjects of the coating experiment. A purified aqueous solution of commercially available gastric-soluble aqueous coating powder with a solid content of 10% was prepared. During the preparation process, the solution was continuously stirred with a magnetic stirrer for 45 minutes. Then, it was passed through an 80-mesh sieve to remove undissolved lumps and air bubbles, and then left to stand for later use.

[0152] (2) Feed the set number of uncoated tablets for each group into the rollers of the high-efficiency intelligent coating machine. Turn on the air inlet heating system and adjust the parameters to keep the tablet bed temperature stable within the critical operating range of 40℃ to 42℃. Set the roller speed to 15 rpm, the peristaltic pump spray rate to 8 g / min, and the atomization pressure to 0.2 MPa.

[0153] (3) Perform continuous aqueous spray coating under the above-mentioned uniform process parameters until the average coating weight gain of each group of cores reaches about 3.0% of the indicated amount. After coating is completed, cut off the liquid supply system and continue drying in the original machine with a gentle airflow for 20 minutes. Then discharge the material and seal it for cooling at room temperature.

[0154] (4) Randomly select 1000 pieces from each group of coated finished products as appearance evaluation samples. Lay the samples flat on a white inspection table and observe them one by one under a standard D65 light source. Count the number of pieces with cracks, pitting, obvious swelling and deformation or peeling of the coating film on the surface, and calculate the appearance defect rate of the water-based coating for this batch.

[0155] (5) In the active ingredient detection stage, accurately weigh an appropriate amount of sample (approximately equivalent to the average weight of 10 tablets) from each group of uncoated tablets and corresponding coated finished products, and grind them into fine powder. Add methanol as the extraction solvent, and ultrasonically extract at room temperature for 30 minutes. Filter the extract through a 0.45μm microporous membrane to obtain the test solution.

[0156] (6) A high-performance liquid chromatograph (HPLC) equipped with an ultraviolet detector was used, with octadecylsilane-bonded silica gel as the chromatographic column packing material and an acetonitrile-water gradient elution program. The chromatographic peak area of ​​the labeled easily degradable component (jujube seed saponin A) was detected at a wavelength of 204 nm. The actual content in the uncoated tablets and the finished product was calculated by the external standard method, and the retention rate of the effective component after being tested in a water-based coating heat and humidity environment at 40℃ was calculated after deducting the weight gain of the coating layer.

[0157] The experimental results are shown in Table 5.

[0158] Table 5. Results of determination of water-based coating defect rate and jujube seed saponin A retention rate in Examples 1 to 4 and each comparative example:

[0159] Group Appearance defect rate (%) Content of saponin A in the tablets (mg / g) Conversion content of saponin A in coated finished product (mg / g) Retention rate of saponin A (%) Example 1 0.8 4.12 4.05 98.3 Example 2 1.1 4.08 3.97 97.3 Example 3 0.5 4.15 4.1 98.79 Example 4 1.3 4.06 3.94 97.04 Comparative Example 1 14.5 4.1 3.49 85.12 Comparative Example 2 18.2 4.14 3.37 81.4 Comparative Example 3 24.7 4.09 3.12 76.28 Comparative Example 4 15.6 4.11 3.45 83.94

[0160] According to Table 5 and Figure 5Data shows that, in the humid and hot operating environment involved in aqueous film coating, the core skeletons rich in plant polysaccharides in each group exhibited different physical adaptability. Observation of appearance defect statistics revealed that the defect rate of Examples 1-4 was generally controlled below 1.5%, and the overall coating interface was relatively smooth, with no obvious water absorption and swelling characteristics observed. Combined with the operation records during the coating process, the uncoated sheets corresponding to the examples maintained good flowability in the roller, without obvious surface stickiness or clumping. This apparent stability suggests that the amorphous network structure formed by the crosslinking of amla tannin and polymers during a specific high viscosity period may have maintained a certain spatial skeleton support under aqueous spray conditions at around 40°C. This crosslinked structure helps increase the physical resistance to the inward penetration of external moisture, thereby limiting, to some extent, the tendency of excipients such as low molecular weight sorbitol to transform into a highly elastic state.

[0161] In the comparative tests, the coating defect rate increased significantly due to the lack of specific cross-linking steps or corresponding macromolecular anti-plasticizing components. Taking Comparative Example 3, which replaced amla powder with maltodextrin, as an example, its coating defect rate reached 24.7%. Some tablet cores showed local swelling after contact with the aqueous coating solution, which affected the integrity of the coating film and caused surface cracking.

[0162] Analysis of the retention rate data of the active ingredient jujuboside A showed that the retention rate of the example group remained above 97% after aqueous coating, while the retention rates of the comparative examples ranged from 76% to 85%. Considering that jujuboside A has a certain tendency to degrade under heating and water conditions, the change in its content indirectly reflects that water may have penetrated the surface barrier of some samples and caused corresponding microenvironmental hydration reactions inside the tablet core. Further data suggests that conventional room-temperature physical mixing (such as in Comparative Example 4) or slow cooling without quenching (such as in Comparative Example 2) makes it difficult to form an effective isolation structure with low molecular mobility. This may lead to easier penetration of external moisture into the tablet core, not only causing softening of the internal excipients but also affecting the stability of heat-sensitive or water-sensitive active ingredients. Based on the evaluation results of appearance defect rate and active ingredient retention rate, constructing a phase structure with a high glass transition temperature through a specific process provides a feasible process control reference for mitigating the interference of moisture and heat on the internal formulation materials during aqueous coating.

[0163] Although embodiments of the invention have been shown and described, it will be understood by those skilled in the art that various changes, modifications, substitutions and alterations can be made to these embodiments without departing from the principles and spirit of the invention, the scope of which is defined by the appended claims and their equivalents.

Claims

1. A type of amla and jujube seed tablet for improving sleep, nourishing the heart and calming the mind, characterized in that, It is prepared from the following components in parts by weight: 20.0–35.0 parts of jujube seed powder; 10.0–20.0 parts of lily powder; 10.0–20.0 parts of longan pulp powder; 5.0–15.0 parts of Ganoderma lucidum powder; 5.0–15.0 parts of maltodextrin; 10.0–25.0 parts of sorbitol; 3.0–8.0 parts of amla powder; 0.5–1.5 parts of magnesium stearate; and 2.0–6.0 parts of compound coating agent.

2. The Phyllanthus emblica and Ziziphus jujuba seed tablets for improving sleep and calming the mind according to claim 1, characterized in that, It is prepared from the following components in parts by weight: 27.5 parts of jujube seed powder; 15.0 parts of lily powder; 15.0 parts of longan pulp powder; 10.0 parts of Ganoderma lucidum powder; 10.0 parts of maltodextrin; 17.5 parts of sorbitol; 5.5 parts of amla powder; 1.0 part of magnesium stearate; and 4.0 parts of compound coating agent.

3. The Phyllanthus emblica and Ziziphus jujuba seed tablets for improving sleep and calming the mind according to claim 1, characterized in that, The compound coating agent is a pre-compounded composition of hydroxypropyl methylcellulose and polyethylene glycol; the number average molecular weight of the polyethylene glycol is 4000 or 6000.

4. The Phyllanthus emblica and Ziziphus jujuba seed tablets for improving sleep, nourishing the heart, and calming the mind according to claim 1, characterized in that, 30.0% to 40.0% of the total mass of the compound coating agent is polyethylene glycol. This portion of polyethylene glycol is distributed in the core of the jujube seed tablet as a granulation auxiliary matrix to provide a crosslinking network. The remaining portion of the compound coating agent is distributed on the outside of the uncoated tablet as a thin film coating layer.

5. A method for preparing Phyllanthus emblica and Ziziphus jujuba seed tablets as described in any one of claims 1-4, characterized in that, Includes the following steps: (1) Material weighing and pretreatment: Weigh each raw material component according to the weight parts, extract and retain the polyethylene glycol in the compound coating agent for use in the subsequent granulation step, and use the remaining part of the compound coating agent as coating powder for later use. (2) Dry powder premixing: The jujube seed powder, lily powder, longan pulp powder, Ganoderma powder and maltodextrin are dry mixed to obtain the granulation base material; (3) Preparation of granulation matrix solution: Sorbitol and polyethylene glycol retained in step (1) are added to an aqueous ethanol solution and heated and kept warm to dissolve and form a uniform dispersion. (4) Primary encapsulation and critical cross-linking: In the fluidized bed, the granulation matrix solution is sprayed onto the granulation substrate, and then the inlet air temperature is increased for constant temperature fluidized drying. When the exhaust air temperature reaches the preset value, under the condition of not stopping the machine and not cooling down, the amla powder is quickly sprayed into the boiling material bed of the fluidized bed through high pressure airflow to maintain the hot air temperature and continue strong fluidized mixing. (5) Quenching and freezing phase change: After mixing, the heating source is cut off instantly and the system is switched to cold air system for fluidized bed cold air quenching until the overall temperature of the material bed drops below the target temperature, and the fluidization is stopped to obtain dry particles. (6) Tableting and coating: The dry granules are mixed evenly with magnesium stearate and then continuously compressed to obtain the tablet core; the remaining coating powder in step (1) is prepared into a coating solution, and the tablet core is coated with water spray and dried to obtain the finished product.

6. The preparation method according to claim 5, characterized in that, In step (2), the mixture is dry-mixed at room temperature for 15-20 min at a speed of 15-25 rpm; in step (3), the volume fraction of the ethanol aqueous solution is 85%, the solvent temperature is stabilized at 55-65℃ by heating, and the solution is kept warm and dissolved for 30-45 min at a speed of 100-200 rpm.

7. The preparation method according to claim 5, characterized in that, In step (4), the initial air inlet temperature of the fluidized bed is set to 45-55℃, the spraying flow rate of the granulation matrix solution is 15-30mL / min, and the atomizing pressure is set to 0.15-0.25MPa. After spraying, immediately increase and maintain the fluidized bed inlet air temperature at 60-65℃ to continue fluidized drying.

8. The preparation method according to claim 5, characterized in that, In step (4), when the exhaust temperature reaches 48-52℃, the high-pressure airflow powder feeding device is turned on, and the amla powder is rapidly sprayed into the fluidized bed within 1-2 minutes under a conveying air pressure of 0.2-0.4MPa. After the spraying is completed, the hot air temperature of 60-65℃ is maintained to continue strong fluidization and mixing for 3-6 minutes.

9. The preparation method according to claim 5, characterized in that, In step (5), the inlet air temperature is rapidly reduced to 15-20°C within 2-4 minutes for fluidized bed cold air quenching until the overall temperature of the material bed drops below 25°C.

10. The preparation method according to claim 5, characterized in that, In step (6), continuous tableting is performed under parameters of 10-20 kN main pressure and 20-40 rpm rotation speed; The coating powder was prepared into a coating purification aqueous solution with a mass fraction of 6.0% to 10.0%. Spray coating was carried out under the conditions of tablet bed temperature of 38 to 42℃ and atomization pressure of 0.20 to 0.30 MPa. When the coating weight gain reached 2.0% to 2.5%, the spraying was stopped and the product was dried in its original state.

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