A film-coated tablet of jujube seed and Ganoderma lucidum and its preparation method

Abstract

This application discloses a jujube seed and Ganoderma lucidum film-coated tablet and its preparation method. The film-coated tablet uses jujube seed and Ganoderma lucidum in a weight ratio of (2.9–3.1):2 as active raw materials, employs a microcrystalline cellulose and erythritol compound as fillers, and combines them with silica, magnesium stearate, and a specific composite film-coating agent. The preparation method includes raw material pretreatment, water extraction, vacuum concentration, vacuum drying, fluidized bed granulation, total mixing and tableting, and film coating, optimizing each process parameter. This application solves the technical problems of existing traditional Chinese medicine extracts, such as high hygroscopicity, poor compressibility, poor stability, and unclear synergistic effects. The prepared product has high active ingredient content, good stability, rapid disintegration, and good patient compliance, making it suitable for large-scale industrial production and possessing good market application prospects.

Description

Technical Field

[0001] This application belongs to the field of health food preparation technology, specifically relating to a jujube seed and Ganoderma lucidum film-coated tablet and its preparation method. Background Technology

[0002] Sleep disorders are a common health problem plaguing modern populations. Chronic insomnia can lead to weakened immunity, memory loss, endocrine disorders, and an increased risk of cardiovascular disease, severely impacting quality of life and physical health. While commonly used chemically synthesized sedative-hypnotic drugs have a rapid onset of action, they carry potential risks such as dependence, tolerance, residual effects the following day, and liver and kidney damage, making them unsuitable for long-term use. Health foods made from traditional Chinese medicinal herbs, which are considered both food and medicine, are gradually becoming the mainstream choice in the sleep improvement market due to their high safety, fewer side effects, and suitability for long-term conditioning.

[0003] Sour jujube seed, the dried, mature seed of the sour jujube plant (Rhamnaceae family), is a classic traditional Chinese medicine for nourishing the heart and calming the mind. Its main active ingredients are jujube seed saponins A / B, spinosin, and total flavonoids, which exert a sedative and hypnotic effect by regulating the level of central neurotransmitters. Reishi mushroom, the dried fruiting body of the fungus Ganoderma lucidum (Polyporaceae family), has the effects of tonifying qi, calming the mind, relieving cough, and alleviating asthma. Its main active ingredients are reishi polysaccharides and triterpenoids, which can improve sleep quality and enhance the body's immunity. The combination of these two ingredients has a synergistic calming effect in traditional Chinese medicine and is widely used in health foods that improve sleep.

[0004] However, existing compound preparations of jujube seed and Ganoderma lucidum still face the following technical challenges: Existing products are mostly based on traditional experience or arbitrary combinations of raw material ratios, without clearly defining the critical range of synergistic effects between jujube seed and Ganoderma lucidum. Most formulations can only produce a simple additive effect and cannot maximize the efficacy.

[0005] Jujube seed and Ganoderma lucidum water-extracted dry extract powders are rich in polar components such as polysaccharides and saponins, which are extremely prone to absorbing moisture and clumping, leading to difficulties in granulation, tablet sticking during compression, and an imbalance between tablet hardness and disintegration properties. Conventional fillers such as lactose, mannitol, and starch, used alone or in simple combinations, cannot fundamentally solve this problem, and the resulting products are prone to cracking and mold growth during storage.

[0006] Jujube seed saponin A is a heat-sensitive component. While extending the extraction time or increasing the number of extractions can improve the yield of the extract, it will lead to significant degradation of the active ingredients. Conversely, shortening the extraction time will result in insufficient extraction of the effective ingredients, failing to achieve the expected efficacy. Current processes struggle to achieve the optimal balance between these two factors.

[0007] Uncoated Chinese herbal extract tablets have problems such as bitter taste and fishy smell, resulting in low patient willingness to take them; moreover, uncoated tablets are prone to moisture absorption and deterioration when directly exposed to the environment, resulting in a short shelf life and making it difficult to meet the requirements of industrial production and market circulation.

[0008] Therefore, developing a film-coated tablet with high active ingredient extraction rate, good formulation stability, rapid disintegration, good patient compliance, and a clear synergistic effect between jujube seed and Ganoderma lucidum has significant practical importance and market value. Summary of the Invention

[0009] The purpose of this application is to overcome the above-mentioned defects of the prior art and provide a jujube seed and Ganoderma lucidum film-coated tablet and its preparation method.

[0010] To achieve the above objectives, this application adopts the following technical solution: A jujube seed and Ganoderma lucidum film-coated tablet is made from active raw materials and pharmaceutical excipients; the active raw materials are composed of jujube seed and Ganoderma lucidum in a weight ratio of (2.9-3.1):2; the pharmaceutical excipients include fillers, flow aids, lubricants and compound film coating agents; the filler is a compound of microcrystalline cellulose and erythritol, the flow aid is silicon dioxide, and the lubricant is magnesium stearate.

[0011] Furthermore, based on 1000 tablets, the amounts of each raw material are as follows: 970-1030g of jujube seed, 647-687g of Ganoderma lucidum; 85-95g of microcrystalline cellulose, 5.8-6.6g of silicon dioxide, 3.0-3.6g of magnesium stearate, 22-26g of compound film coating agent, and the amount of erythritol used is to make the total weight of the tablets reach 570-590g.

[0012] Furthermore, based on 1000 tablets, the amounts of each ingredient are as follows: 1000g of jujube seed, 667g of Ganoderma lucidum; 90.0g of microcrystalline cellulose, 6.2g of silicon dioxide, 3.3g of magnesium stearate, 24g of compound film coating agent, and erythritol added to the total weight of the tablets 580g.

[0013] Furthermore, the compound film coating agent is composed of the following components in weight percentage: 52%–58% hydroxypropyl methylcellulose, 6%–10% polyethylene glycol, 10%–14% titanium dioxide, 16%–20% talc, 3%–5% triethyl glycerol, 2%–3% polyoxyethylene sorbitan monooleate, and 0.4%–0.6% colorant.

[0014] Furthermore, the compound film coating agent is composed of the following components in weight percentage: 55% hydroxypropyl methylcellulose, 8% polyethylene glycol, 12% titanium dioxide, 18% talc, 4% triethyl glycerol, 2.5% polyoxyethylene sorbitan monooleate, 0.4% tartrazine aluminum lake, and 0.1% brilliant blue aluminum lake.

[0015] This application also provides a method for preparing the above-mentioned jujube seed and Ganoderma lucidum film-coated tablets, including the following steps: (1) Raw material pretreatment: Jujube seeds are crushed into coarse powder, and Ganoderma lucidum is cleaned and set aside; (2) Water extraction: Jujube seed coarse powder and Ganoderma lucidum are mixed, and water is added for reflux extraction 2 to 3 times, with 8 to 12 times the amount of water added each time, and the extraction time is 1.2 to 1.8 hours each time. The extract is filtered through a 180 to 220 mesh sieve, and the filtrates are combined; (3) Vacuum concentration: The filtrate is concentrated to a thick paste with a relative density of 1.18 to 1.28 (measured at 60℃) under the conditions of -0.06 to -0.09 MPa and 60 to 70℃. (4) Reduced pressure drying: Dry the viscous paste to constant weight under conditions of -0.07 to -0.10 MPa and 55 to 70°C, pulverize it through a 70 to 90 mesh sieve to obtain dry extract powder; (5) Boiling granulation: Mix the dry extract powder with the filler, spray it with purified water to granulate, dry it until the moisture content of the particles is ≤5.5%, and granulate it to obtain dry granules; (6) Total mixing and tableting: Add the glidant and lubricant and mix for 12 to 18 minutes, and compress it into plain tablets; (7) Film coating: Prepare a 10% to 14% (w / v) coating solution with the compound film coating agent, and coat the plain tablets until the weight gain is 2.5% to 3.5%.

[0016] Further, the water extraction in step (2) is as follows: reflux extraction is performed 3 times. 9 to 11 times the amount of water is added in the first extraction, and 7 to 9 times the amount of water is added in the second and third extractions. Each extraction lasts for 1.4 to 1.6 hours, and the extract is filtered through a 200-mesh sieve.

[0017] Further, in step (3), the concentration is increased to a relative density of 1.20 to 1.25 (measured at 60°C); in step (4), the material is pulverized through an 80-mesh sieve.

[0018] Furthermore, in step (5), the amount of purified water used is the same as the weight of the substrate, and the air inlet temperature is 72-78℃.

[0019] Furthermore, in step (7), the concentration of the coating solution is 11% to 13% (w / v), the air inlet temperature is 65 to 70°C, and the boiler rotation speed is 4 to 8 Hz. Beneficial effects

[0020] Compared with the prior art, this application has the following significant advantages: This application demonstrates a significant synergistic effect and clear efficacy. Through formulation analysis, it was confirmed that jujube seed and Ganoderma lucidum in a weight ratio range of (2.9–3.1):2 exhibit a significant synergistic effect in improving sleep, with a synergistic index Q=1.99 (>1.15). Compared to using jujube seed or Ganoderma lucidum alone, the product of this invention significantly increases the extension of sodium pentobarbital sleep time in mice; compared to conventional ratios such as 1:1, 2:1, and 3:1, the extension of sleep time is significantly increased. This synergistic effect is unpredictable by those skilled in the art based on existing knowledge, breaking through the limitations of traditional empirical formulations.

[0021] This application demonstrates excellent moisture-proof performance, solving a common problem in traditional Chinese medicine preparations. It utilizes a compound of microcrystalline cellulose and erythritol as a filler, sealing the moisture-absorbing sites of the extract powder through physical adsorption and steric hindrance. Experiments show that the tablets of this application, after being stored at 40℃ and 75% relative humidity for 10 days, exhibited only a 1.8% increase in weight due to moisture absorption, with no significant changes in appearance or disintegration properties. In contrast, the control products using conventional fillers such as lactose, mannitol, and starch showed increases in weight exceeding 3.5% during the same period, reaching a maximum of 6.8%, and exhibited problems such as tablet cracking and sticking to the packaging.

[0022] This application optimizes the extraction process, balancing efficiency and activity retention. Through orthogonal experiments, the interaction between the number of extractions and extraction time was optimized, determining the optimal process of three extractions, each lasting 1.5 hours. This process maintains an average extract yield of 13.85%, while increasing the retention rate of jujube seed saponin A by more than 22% compared to the conventional two-extraction process, thus overcoming the bottleneck of existing processes where "high extract yield and high activity retention cannot be simultaneously achieved."

[0023] The formulation of this application exhibits outstanding stability and a long shelf life. The results of accelerated stability testing (40℃, 75% relative humidity, 6 months) show that the appearance and color of the film-coated tablets of this application do not change significantly, the disintegration time remains at 25-28 minutes, the retention rate of jujube seed saponin A and Ganoderma lucidum polysaccharide are both above 95%, and there is no cracking or mold growth. The product quality is stable and reliable.

[0024] This formulation offers excellent patient compliance and a superior user experience. The film coating technology effectively masks the bitterness and fishy taste of the herbal extracts, improving palatability. The tablet disintegration time meets pharmacopoeia requirements, facilitating rapid release and absorption of the active ingredients. The convenient and quick administration of three tablets twice daily increases patients' willingness to use it long-term.

[0025] The process parameters in this application are reasonable and suitable for industrial production. All process parameters are limited to a reasonable range, covering equipment differences and normal operational fluctuations in industrial production. This ensures both the uniformity of product quality and avoids the problem of overly narrow protection scope caused by limiting precise point values. The process in this application requires no special equipment and can be directly scaled up on existing traditional Chinese medicine preparation production lines, demonstrating good industrial applicability. Detailed Implementation

[0026] The present application will be further described in detail below with reference to specific embodiments, but the scope of protection of the present application is not limited thereto.

[0027] All raw materials used in all embodiments of this application are commercially available qualified products: Ziziphus jujuba seed is the dried mature seed of Ziziphus jujuba, a plant of the Rhamnaceae family, which meets the standards of Part I of the 2025 edition of the Chinese Pharmacopoeia; Ganoderma lucidum is the dried fruiting body of Ganoderma lucidum, a fungus of the Polyporaceae family, which meets the standards of Part I of the 2025 edition of the Chinese Pharmacopoeia; all pharmaceutical excipients meet the standards of Part IV of the 2025 edition of the Chinese Pharmacopoeia; the experimental animals are SPF-grade Kunming mice.

[0028] General preparation method The preparation method of the jujube seed and Ganoderma lucidum film-coated tablets described in this application includes the following steps: (1) Raw material pretreatment Put the prescribed amount of jujube seeds into a jaw crusher and crush them into coarse powder that can pass through a 10-mesh sieve. Remove the fine powder and coarse residue by sieving, and collect the intermediate-sized particles for later use. Select Ganoderma lucidum slices to remove impurities, moldy products and non-medicinal parts, rinse them quickly with clean water and drain them. Cut them into small pieces of 2-3 cm and weigh them for later use.

[0029] (2) Water extraction Mix the coarse jujube seed powder and Ganoderma lucidum segments evenly, and put them into a multi-functional extraction tank. Add purified water according to the prescription, turn on steam to heat to boiling, and maintain a gentle boil for reflux extraction. During the extraction process, control the pressure inside the tank to ≤0.1MPa, and turn on the circulation pump every 30 minutes to ensure the liquid is mixed evenly. After extraction, immediately filter the extract while hot through a 180-220 mesh stainless steel sieve and collect the filtrate. Repeat the extraction process on the residue, and combine the filtrates from multiple extractions to obtain the total extract.

[0030] (3) Reduced pressure concentration The combined extracts were transferred to a double-effect vacuum concentrator. The vacuum pump and heating system were turned on, and the vacuum level of the first effect was controlled at -0.03 to -0.05 MPa and the temperature at 70 to 80°C, while the vacuum level of the second effect was controlled at -0.06 to -0.09 MPa and the temperature at 60 to 70°C for vacuum concentration. During the concentration process, a sample was taken every 30 minutes to measure the relative density. Concentration was stopped when the relative density of the thick paste reached 1.18 to 1.28 (measured at 60°C), and the thick paste was released for later use.

[0031] (4) Reduced pressure drying Transfer the above-mentioned thick paste into the stainless steel tray of the vacuum drying oven, spreading it evenly with a layer thickness controlled at 1-2 cm. Close the oven door, turn on the vacuum pump and heating system, and control the vacuum degree to -0.07 to -0.10 MPa and the temperature to 55-70℃ for reduced pressure drying. Turn the material over every 4 hours during the drying process to ensure uniform drying. After drying to constant weight (the difference between two consecutive weighings ≤ 0.5%), turn off the heating system and wait for the temperature inside the oven to drop to room temperature before breaking the vacuum and discharging the material. Take out the dry extract, pulverize it with a universal pulverizer, and pass it through a 70-90 mesh sieve to obtain dry extract powder. Seal it in a double-layer polyethylene bag and store it in a cool, dry place.

[0032] (5) Fluidized bed granulation The dry extract powder, along with the prescribed amounts of microcrystalline cellulose and erythritol, are sequentially added to a fluidized bed granulator. The induced draft system and heating system are turned on, and the inlet air temperature is controlled at 70–80°C to ensure good fluidization of the materials within the fluidized bed. Preheating and mixing are performed for 10 minutes. Then, a peristaltic pump is turned on to spray purified water as a binder for granulation, controlling the spraying speed at 5–15 mL / min and the atomization pressure at 0.2–0.4 MPa. During granulation, the granulation process is monitored through an observation window to observe the granule formation state, adjusting the spraying speed and inlet air temperature to prevent clumping or over-drying. After granulation, hot air is continued to be introduced for drying until the granule moisture content is ≤5.5% (detected by a rapid moisture analyzer). Heating is then stopped, and the granules are discharged after cooling to below 40°C. The granules are then granulated using a gyratory granulator through a 1.5 mm sieve to remove large particles and fine powder, yielding dry granules. The granule yield is calculated by weighing.

[0033] (6) Total mixed tablets The above-mentioned dry granules were transferred to a three-dimensional motion mixer, and the prescribed amounts of silica and magnesium stearate were added. The speed was set to 15 rpm, and the mixture was mixed for 12–18 minutes to obtain the final mixture. Samples were taken to determine the uniformity of the mixture content, angle of repose, and moisture content. After confirming that the requirements were met, the final mixture was fed into a rotary tablet press for tableting. A shallow arc-shaped die with a diameter of 11 mm was selected. The filling amount, pressure, and speed of the tablet press were adjusted to control the average weight of the unprocessed tablets to 0.57–0.59 g / tablet, the hardness to 110–140 N, and the disintegration time to ≤25 minutes. During the tableting process, the tablet weight difference was checked every 15 minutes and controlled within ±5%. Unqualified tablets were promptly removed.

[0034] (7) Film coating Preparation of compound film coating agents Weigh out hydroxypropyl methylcellulose, polyethylene glycol, titanium dioxide, talc, triethyl glycerol, polyoxyethylene sorbitan monooleate, tartrazine aluminum lake, and brilliant blue aluminum lake according to the formula ratio. Add titanium dioxide, talc, and colorant to 30% of the total amount of purified water, and grind with a colloid mill for 10 minutes until the particle size is ≤5μm to obtain a uniform suspension. Slowly add hydroxypropyl methylcellulose to 50% of the total amount of purified water at 80-90℃ while stirring at high speed (800rpm). After uniform dispersion, cool to below 40℃ and continue stirring for 30 minutes until completely dissolved. Add polyethylene glycol, triethyl glycerol, and polyoxyethylene sorbitan monooleate to the hydroxypropyl methylcellulose solution in sequence and stir until completely dissolved. Finally, add the above suspension, and make up to the specified volume with the remaining purified water. Continue stirring for 30 minutes and pass through an 80-mesh sieve to obtain a 10%-14% (w / v) coating solution.

[0035] Coating operation The raw tablets are placed into a high-efficiency coating machine. The exhaust and heating systems are turned on to preheat the tablet bed to 40–45°C. The inlet air temperature is controlled at 60–75°C, the rotation speed of the coating chamber at 4–8 Hz, and the spray pressure at 0.3–0.5 MPa. The peristaltic pump is turned on to spray the coating solution evenly onto the surface of the raw tablets, controlling the spraying speed at 5–10 mL / min to ensure the coating solution spreads evenly on the tablet bed surface. During the coating process, samples are taken every 15 minutes to check the tablet weight and calculate the coating weight gain. Spraying is stopped when the coating weight gain reaches 2.5%–3.5%. The coating chamber is rotated and hot air is introduced for drying for 5 minutes. Then the heating system is turned off, and the tablets are removed from the chamber after the tablet bed temperature drops to room temperature. They are then air-dried in a clean environment for 24 hours to obtain the finished product: jujube seed and Ganoderma lucidum film-coated tablets.

[0036] Example 1 This embodiment prepares 1000 jujube seed and Ganoderma lucidum film-coated tablets, with the following formula composition. Active ingredients: 1000g of jujube seed, 667g of Ganoderma lucidum Excipients: Microcrystalline cellulose 90.0g, silicon dioxide 6.2g, magnesium stearate 3.3g, compound film coating agent 24g, erythritol added to the total weight of the tablets 580g. The compound coating agent composition (by weight percentage) is as follows: hydroxypropyl methylcellulose 55%, polyethylene glycol 8%, titanium dioxide 12%, talc 18%, triethyl glycerol 4%, polyoxyethylene sorbitan monooleate 2.5%, tartrazine aluminum lake 0.4%, and brilliant blue aluminum lake 0.1%. The preparation process is as follows: Raw material pretreatment: Crush 1000g of jujube seeds into 10-mesh coarse powder, with a yield of 95%; clean and select 667g of Ganoderma lucidum and cut it into 2cm pieces for later use.

[0037] Water extraction: The raw materials were mixed and placed into an extraction tank, and water was added and refluxed for extraction three times. For the first extraction, 10 times the volume of purified water (16670 mL) was added, and extraction was carried out for 1.5 hours. For the second and third extractions, 8 times the volume of purified water (13336 mL) was added, and extraction was carried out for 1.5 hours each time. The extract was filtered through a 200-mesh sieve, and the combined filtrates amounted to approximately 44000 mL.

[0038] Concentration under reduced pressure: The filtrate was concentrated to a relative density of 1.23 (60℃) at -0.07MPa and 65℃ to obtain a thick paste of about 950g.

[0039] Reduced pressure drying: The thick paste was laid in a 1.5 cm thick layer and dried at -0.09 MPa and 65°C for 18 hours until constant weight. After pulverizing and passing through an 80-mesh sieve, 231.2 g of dry extract powder was obtained, with a yield of 13.87%.

[0040] Fluidized bed granulation: Dry extract powder, 90.0g microcrystalline cellulose, and 258.8g erythritol were added to a fluidized bed granulator and preheated for 10 minutes. 580g purified water was sprayed in for granulation, with an inlet air temperature of 75℃ and a spraying speed of 8mL / min. The granules were dried until the moisture content was 4.8%, yielding 576g of dry granules, with a granule yield of 99.3%.

[0041] Total granulation and tableting: Add 6.2g of silica and 3.3g of magnesium stearate to the dry granules and mix for 15 minutes. The angle of repose of the total mixture is 37.6°, and the moisture content is 4.7%. The average weight of the tablets is controlled at 0.58g / tablet, the hardness is 125N (range 118~132N), the disintegration time is 19 minutes, and the tablet weight difference is within ±3%.

[0042] Film coating: Prepare a 12% (w / v) coating solution using 24g of the compound coating agent. The coating inlet air temperature is 68℃, the reactor rotation speed is 6Hz, the spray pressure is 0.35MPa, and the spray rate is 6mL / min. Coat until a weight gain of 3.0% is achieved, then remove from the reactor and air dry.

[0043] Finished product test results: This product is a light green film-coated tablet, which turns brownish-brown after removing the coating; it has a slightly fragrant odor and a slightly bitter taste. The average tablet weight is 0.60g / tablet, and the weight variation meets the requirements of the pharmacopoeia; the disintegration time is 26 minutes; the hardness is 135N; the content of jujube seed saponin A is 0.35mg / tablet, and the content of Ganoderma lucidum polysaccharide is 13.2mg / tablet; the microbial limits meet the regulations.

[0044] Example 2 This embodiment prepares 1000 jujube seed and Ganoderma lucidum film-coated tablets, with the following formula: Active ingredients: 970g of jujube seed and 647g of Ganoderma lucidum (weight ratio 2.9:2) Excipients: 85g microcrystalline cellulose, 5.8g silicon dioxide, 3.0g magnesium stearate, 22g compound film coating agent, erythritol added to the total weight of the tablets 570g. The composition of the compound coating agent is the same as in Example 1. The preparation process is basically the same as in Example 1, except that the process parameters are adjusted as follows: Water extraction: reflux extraction 3 times. For the first extraction, add 9 times the amount of water (based on the total weight of jujube seed and Ganoderma lucidum). For the second and third extractions, add 7 times the amount of water each time. Each extraction lasts 1.4 hours. The extract is filtered through a 200-mesh sieve. Concentration under reduced pressure: -0.06 MPa, 60℃, to a relative density of 1.20 (60℃). Reduced pressure drying: -0.07MPa, 55℃, drying for 20 hours, then pulverized and passed through a 70-mesh sieve; Fluidized bed granulation: inlet air temperature 72℃, spraying speed 5mL / min, drying to granule moisture content 5.2%; General mixing: Mix for 12 minutes; Coating: Coating solution concentration 11% (w / v), inlet air temperature 65℃, pot rotation speed 4Hz, coating until weight gain 2.5%.

[0045] Finished product test results: 223.3g of dry extract powder, yield 13.79%; 565g of dry granules, yield 99.1%; angle of repose of total mixture 38.2°; average weight of uncoated tablets 0.57g / tablet, hardness 118N, disintegration time 20 minutes; average weight of coated tablets 0.584g / tablet, disintegration time 27 minutes; jujube seed saponin A content 0.34mg / tablet, Ganoderma lucidum polysaccharide content 12.9mg / tablet; all indicators meet the requirements.

[0046] Example 3 This embodiment prepares 1000 jujube seed and Ganoderma lucidum film-coated tablets, with the following formula: Active ingredients: 1030g of jujube seed and 687g of Ganoderma lucidum (weight ratio 3.1:2) Excipients: 95g microcrystalline cellulose, 6.6g silicon dioxide, 3.6g magnesium stearate, 26g compound film coating agent, erythritol added to the total weight of the tablets 590g. The composition of the compound coating agent is the same as in Example 1. The preparation process is basically the same as in Example 1, except that the process parameters are adjusted as follows: Water extraction: reflux extraction 3 times, adding 11 times the amount of water for the first time, and 9 times the amount of water for the second and third times, each extraction lasting 1.6 hours, and the extract is filtered through a 200-mesh sieve; Concentration under reduced pressure: -0.09 MPa, 70℃, concentrated to a relative density of 1.25 (60℃). Reduced pressure drying: -0.10MPa, 70℃, drying for 16 hours, then pulverized and passed through a 90-mesh sieve; Fluidized bed granulation: inlet air temperature 78℃, spray rate 12mL / min, drying to granule moisture content 4.5%; Total mixing: Mix for 18 minutes; Coating: Coating solution concentration 13% (w / v), inlet air temperature 70℃, pot rotation speed 8Hz, coating until weight gain 3.5%.

[0047] Finished product test results: 239.6g of dry extract powder, yield 13.92%; 585g of dry granules, yield 99.2%; angle of repose of total mixture 37.1°; average weight of uncoated tablets 0.59g / tablet, hardness 132N, disintegration time 18 minutes; average weight of coated tablets 0.611g / tablet, disintegration time 25 minutes; jujube seed saponin A content 0.36mg / tablet, Ganoderma lucidum polysaccharide content 13.5mg / tablet; all indicators meet the requirements.

[0048] Example 4 This embodiment prepares 1000 jujube seed and Ganoderma lucidum film-coated tablets, with the same formula as in Example 1.

[0049] The water extraction process was adjusted as follows: water was added and refluxed twice, with 12 times the amount of water added each time, and the extraction time was 1.8 hours each time. The extract was then filtered through a 180-mesh sieve. The remaining steps were the same as in Example 1.

[0050] Finished product test results: 227.5g of dry extract powder, yield 13.65%; 572g of dry granules, yield 98.6%; angle of repose of total mixture 37.9°; average weight of unprocessed tablets 0.58g / tablet, hardness 122N, disintegration time 21 minutes; disintegration time of coated tablets 28 minutes; jujube seed saponin A content 0.33mg / tablet, Ganoderma lucidum polysaccharide content 12.7mg / tablet; all indicators meet the requirements.

[0051] Example 5 This embodiment prepares 1000 jujube seed and Ganoderma lucidum film-coated tablets, with the same formula as in Example 1.

[0052] The pretreatment to total mixing and tableting steps in the preparation process are the same as in Example 1. The film coating step is adjusted as follows: the compound coating agent is prepared into a 14% (w / v) coating solution, the inlet air temperature is 60°C, the pot rotation speed is 4Hz, the spray pressure is 0.3MPa, the spraying speed is 5mL / min, and the coating is carried out until the weight gain is 2.8%.

[0053] Finished product test results: The coated tablets have a smooth appearance and uniform color, with an average tablet weight of 0.596g / tablet, a disintegration time of 27 minutes, and the weight variation meets the requirements; the content of jujube seed saponin A is 0.35mg / tablet, and the content of Ganoderma lucidum polysaccharide is 13.1mg / tablet; all indicators meet the requirements.

[0054] Comparative Example 1 This comparative example prepared 1000 film-coated tablets, with the active ingredient ratio adjusted to 1:1: 833g of jujube seed and 833g of Ganoderma lucidum. The types and amounts of excipients were the same as in Example 1 (the amount of erythritol was adjusted to a total tablet weight of 580g based on the weight of the dry extract). The preparation process was the same as in Example 1.

[0055] Test results: 253.5g of dry extract powder, yield 15.21%; during fluidized bed granulation, the material severely adhered to the fluidized bed air filter and filter bag, resulting in poor granule formability; the fine powder rate passing through a 100-mesh sieve reached 28%; the dry granule yield was only 85% (based on a theoretical total weight of 580g); the angle of repose of the total mixture was 43.5°, indicating poor flowability; during tableting, the material was stuck and punched 12-15 times per hour; the uncoated tablets had a rough surface with obvious spots, an average hardness of 95N, and a disintegration time of 35 minutes; after coating, the tablet weight varied significantly, with a disintegration time of 42 minutes; these results did not meet the quality requirements.

[0056] Comparative Example 2 This comparative example prepared 1000 film-coated tablets. The active ingredient formulation was the same as in Example 1, and the filler was entirely 348.8g of microcrystalline cellulose (replacing the microcrystalline cellulose and erythritol compound in Example 1). The remaining excipients and their amounts were the same as in Example 1. The preparation process was the same as in Example 1.

[0057] Test results: The granules are highly hygroscopic, the angle of repose of the total mixture is 45.2°, and the flowability is extremely poor; frequent sticking and punching during tableting makes continuous production impossible; the hardness of the uncoated tablets is 92N, and the disintegration time is 42 minutes; after coating, a large number of pits appear on the surface of the tablets, and the disintegration time limit is 50 minutes; it does not meet the quality requirements.

[0058] Comparative Example 3 This comparative example prepared 1000 film-coated tablets using the same formulation as in Example 1. The water extraction step was adjusted as follows: reflux extraction once, adding 10 times the amount of water, and extraction for 1.0 hour. The remaining steps were the same as in Example 1.

[0059] Test results: 145.4g of dry extract powder, with an extract yield of only 8.72%; the content of jujube seed saponin A was 0.21mg / tablet, only 60% of that in Example 1; the content of Ganoderma lucidum polysaccharide was 7.8mg / tablet, only 59% of that in Example 1; the content of effective ingredients could not meet the expected health care efficacy requirements.

[0060] Comparative Example 4 This comparative example prepared 1000 tablets of jujube seed and Ganoderma lucidum extract, with the same formula as in Example 1, but without the film coating step.

[0061] Test results: When the tablets were left open at 40℃ and 75% relative humidity for 10 days, they absorbed moisture and increased in weight by 8.5%. Obvious moisture absorption marks appeared on the surface of the tablets, the edges softened, and some tablets showed cracks and mold spots. The disintegration time was extended to 65 minutes. All 10 subjects reported that the tablets tasted bitter, had a strong fishy smell of Chinese medicine, and were difficult to swallow.

[0062] Effect verification experiment Experiment 1: Verification of the synergistic sleep-improving effects of different ratios of jujube seed and Ganoderma lucidum The experiment was conducted in accordance with the Technical Specifications for Inspection and Evaluation of Health Foods (2020 Edition). Seventy SPF-grade Kunming mice, half male and half female, weighing 18-22g, were randomly divided into 7 groups of 10 mice each. They were housed in a barrier environment with a temperature of 22±2℃ and a relative humidity of 50±10%, with free access to food and water.

[0063] The dosing regimens for each group are as follows (the recommended human dose is 3 tablets twice daily, equivalent to 3.6g daily; the animal dose is 10 times the recommended human dose, i.e., 0.70g / kg body weight): Blank control group: administered an equal volume of purified water by gavage. Ziziphus jujuba seed monotherapy group: oral administration of 0.42 g / kg of Ziziphus jujuba seed dry extract powder suspension. Ganoderma lucidum monotherapy group: Ganoderma lucidum dry extract powder suspension (0.28g / kg) administered by gavage. Formula A (1:1): 1:1 ratio of extract suspension (0.70 g / kg) administered by gavage Formula B (2:1): 0.70 g / kg of extract suspension prepared by gavage in a 2:1 ratio. Formula C (3:1): 0.70 g / kg of extract suspension prepared by gavage in a 3:1 ratio. Experimental group 1 (3:2): Oral administration of finely ground powder suspension of the tablets from Example 1 (0.70 g / kg) Mice were administered the medication once daily by gavage for 30 consecutive days. Thirty minutes after the last administration, each group of mice was intraperitoneally injected with 50 mg / kg sodium pentobarbital (prepared with physiological saline before use). The disappearance of the righting reflex was used as the indicator of sleep onset. Sleep latency (time from injection to the disappearance of the righting reflex) and sleep duration (time from the disappearance of the righting reflex to its recovery) were recorded. The synergistic index Q was calculated using the King's Law formula: Q = E(a+b) / (Ea+Eb-Ea×Eb), where Ea and Eb are the sleep duration prolongation rates in the single-drug groups, and E(a+b) is the prolongation rate in the combined-drug group. Q > 1.15 indicates a synergistic effect, 0.85–1.15 indicates an additive effect, and Q < 0.85 indicates an antagonistic effect.

[0064] The experimental results are shown in Table 1.

[0065] Table 1. Experimental results of the sleep-improving effects of different formulations (x±s, n=10)

[0066] The results showed that experimental group 1 significantly shortened the sleep latency and prolonged the sleep time in mice, with a synergistic index Q=1.42>1.15, indicating a significant synergistic effect; while other groups only showed an additive effect.

[0067] Experiment 2: Comparison of moisture-proof performance of different filler solutions Take 20 tablets each from the unprocessed tablets of Example 1 and Comparative Example 2, as well as tablets prepared using lactose + microcrystalline cellulose (1:1), mannitol + microcrystalline cellulose (1:1), and pregelatinized starch + microcrystalline cellulose (1:1) as fillers. After accurately measuring the initial weight, place them open in a constant temperature and humidity chamber at 40°C and 75% relative humidity. Remove them on days 0, 1, 3, 5, 7, and 10, weigh them quickly using an analytical balance, calculate the percentage increase in weight due to moisture absorption, observe changes in appearance, and determine the disintegration time.

[0068] The experimental results are shown in Table 2.

[0069] Table 2 Comparison of moisture-proof performance of different filler formulations

[0070] The results show that the microcrystalline cellulose and erythritol compound filler used in this application has the best moisture-proof performance.

[0071] Experiment 3: Comparison of Extraction Processes Take 1000g of jujube seed and 667g of Ganoderma lucidum, and extract them using the following three processes respectively: The process described in this application is: 3 times × 1.5 hours, with a water addition of 10 / 8 / 8 times the normal volume. Conventional process: 1:2 times × 2.0 hours, water addition 10 / 10 times. Conventional process 2: 4 times × 1.0 hour, water addition 8 / 8 / 8 / 8 times. After extraction, the extract was concentrated and dried under the same conditions as in Example 1, and the yield and content of jujube seed saponin A were determined.

[0072] The experimental results are shown in Table 3.

[0073] Table 3 Comparison of different extraction processes

[0074] The results show that the process described in this application retains the heat-sensitive active ingredient jujube seed saponin A to the maximum extent while ensuring a high yield of extract.

[0075] Experiment 4: Accelerated Stability Test Three batches of film-coated tablets prepared in Example 1 were placed at 40℃±2℃ and 75%±5% relative humidity for 6 months, according to the stability test guidelines of the 2025 edition of the Chinese Pharmacopoeia, Part IV. Samples were taken at 0, 1, 2, 3, and 6 months to test various indicators.

[0076] The experimental results are shown in Table 4.

[0077] Table 4 Results of Accelerated Stability Test

[0078] The results show that the product of this application met all the requirements and had good stability after being placed under accelerated testing conditions for 6 months.

[0079] Experiment 5: Content Determination Method Determination of jujube seed saponin A (HPLC method) Chromatographic conditions: Octadecylsilane-bonded silica gel (250 mm × 4.6 mm, 5 μm) as the stationary phase; acetonitrile-water (32:68) as the mobile phase; detection wavelength 203 nm; column temperature 30 ℃; flow rate 1.0 mL / min. The theoretical plate number, calculated based on the jujube seed saponin A peak, should be no less than 3000.

[0080] Preparation of reference solution: Take an appropriate amount of jujube seed saponin A reference standard, accurately weigh it, and add methanol to prepare a solution containing 0.1 mg per 1 mL.

[0081] Preparation of test solution: Take 20 tablets of this product, remove the coating, weigh accurately, grind finely, take about 1.0g, weigh accurately, place in a stoppered conical flask, accurately add 50mL of methanol, weigh, sonicate (power 250W, frequency 40kHz) for 30 minutes, cool, weigh again, replenish the lost weight with methanol, shake well, filter, and take the filtrate to obtain the test solution.

[0082] Determination method: Accurately pipette 10 μL each of the reference solution and the test solution into the liquid chromatograph and determine the result.

[0083] Determination of Ganoderma lucidum polysaccharides (ultraviolet-visible spectrophotometry)

[0084] Preparation of reference solution: Take an appropriate amount of anhydrous glucose reference standard, accurately weigh it, add water to prepare a solution containing 0.1 mg per 1 mL.

[0085] Preparation of standard curve: Accurately measure 0.2, 0.4, 0.6, 0.8, and 1.0 mL of the reference solution and place them in 10 mL stoppered test tubes respectively. Add water to 2.0 mL, accurately add 1 mL of 5% phenol solution, shake well, quickly add 5 mL of concentrated sulfuric acid, shake well, heat in a boiling water bath for 15 minutes, remove, and cool in an ice bath for 5 minutes. Using the corresponding reagent as a blank, measure the absorbance at a wavelength of 490 nm and plot the standard curve.

[0086] Preparation of the test solution: Accurately weigh approximately 0.5 g of the fine powder of this product, place it in a round-bottom flask, add 100 mL of water, heat under reflux for 2 hours, filter, transfer the filtrate to a 250 mL volumetric flask, add water to the mark, and shake well. Accurately measure 10 mL of the solution, add 150 mL of ethanol, shake well, incubate at 4°C for 12 hours, centrifuge (3000 rpm, 10 minutes), discard the supernatant, dissolve the precipitate in water and transfer it to a 50 mL volumetric flask, add water to the mark, and shake well to obtain the test solution.

[0087] Assay: Accurately measure 2 mL of the test solution, determine the absorbance according to the method under the preparation of the standard curve, and calculate the content.

[0088] The above description is only a preferred embodiment of this application and is not intended to limit this application. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of this application should be included within the protection scope of this application.

Claims

1. A spina date seed and ganoderma lucidum film-coated tablet, which is made of an active material and pharmaceutical excipients, characterized in that, The active raw material is composed of jujube seed and Ganoderma lucidum in a weight ratio of (2.9-3.1):2; the pharmaceutical excipients include fillers, flow aids, lubricants and compound film coating agents; the filler is a compound of microcrystalline cellulose and erythritol, the flow aid is silicon dioxide, and the lubricant is magnesium stearate.

2. The Suanzaoren Lingzhi film-coated tablet according to claim 1, characterized in that, Based on 1000 tablets, the following amounts of raw materials are used: 970-1030g of jujube seed, 647-687g of Ganoderma lucidum; 85-95g of microcrystalline cellulose, 5.8-6.6g of silicon dioxide, 3.0-3.6g of magnesium stearate, 22-26g of compound film coating agent, and erythritol to make the total weight of the tablets reach 570-590g.

3. The jujube seed and Ganoderma lucidum film-coated tablets according to claim 2, characterized in that, Based on 1000 tablets, the following amounts of raw materials are used: 1000g of jujube seed, 667g of Ganoderma lucidum; 90.0g of microcrystalline cellulose, 6.2g of silicon dioxide, 3.3g of magnesium stearate, 24g of compound film coating agent, and erythritol added to the total weight of the tablets 580g.

4. The jujube seed and Ganoderma lucidum film-coated tablets according to claim 1, characterized in that, The compound film coating agent is composed of the following components by weight percentage: 52%–58% hydroxypropyl methylcellulose, 6%–10% polyethylene glycol, 10%–14% titanium dioxide, 16%–20% talc, 3%–5% triethyl glycerol, 2%–3% polyoxyethylene sorbitan monooleate, and 0.4%–0.6% colorant, with the sum of the weight percentages of each component being 100%.

5. The jujube seed and Ganoderma lucidum film-coated tablets according to claim 4, characterized in that, The compound film coating agent is composed of the following components by weight percentage: 55% hydroxypropyl methylcellulose, 8% polyethylene glycol, 12% titanium dioxide, 18% talc, 4% triethyl glycerol, 2.5% polyoxyethylene sorbitan monooleate, 0.4% tartrazine aluminum lake, and 0.1% brilliant blue aluminum lake.

6. A method for preparing jujube seed and Ganoderma lucidum film-coated tablets as described in any one of claims 1-5, characterized in that, Includes the following steps: Raw material pretreatment: Crush the jujube seeds into coarse powder, and clean and select the Ganoderma lucidum for later use; Water extraction: Mix the coarse powder of jujube seed with Ganoderma lucidum, add water and reflux to extract 2-3 times, adding 8-12 times the amount of water each time, and extracting for 1.2-1.8 hours each time. Filter the extract through a 180-220 mesh sieve and combine the filtrates. Concentration under reduced pressure: The filtrate is concentrated to a thick paste with a relative density of 1.18 to 1.28 (measured at 60℃) under conditions of -0.06 to -0.09 MPa and 60 to 70℃; Reduced pressure drying: The thick paste is dried to constant weight under conditions of -0.07 to -0.10 MPa and 55 to 70°C, and then pulverized through a 70 to 90 mesh sieve to obtain dry extract powder; Fluidized bed granulation: Mix dry extract powder with filler, spray with purified water to granulate, dry until the moisture content of the particles is ≤5.5%, and granulate to obtain dry granules; Total mixing and tableting: Add glidin and lubricant, mix for 12-18 minutes, and compress into plain tablets; Film coating: Prepare a 10% to 14% (w / v) coating solution with the compound film coating agent, and coat the uncoated tablets until the weight gain is 2.5% to 3.5%.

7. The preparation method according to claim 6, characterized in that, The water extraction in step (2) is as follows: reflux extraction is performed 3 times. 9 to 11 times the amount of water is added for the first extraction, and 7 to 9 times the amount of water is added for the second and third extractions. Each extraction lasts for 1.4 to 1.6 hours, and the extract is filtered through a 200-mesh sieve.

8. The preparation method according to claim 6, characterized in that, In step (3), the concentration is increased to a relative density of 1.20 to 1.25 (measured at 60°C); in step (4), the powder is pulverized through an 80-mesh sieve.

9. The preparation method according to claim 6, characterized in that, In step (5), the amount of purified water used is the same as the weight of the substrate, and the air inlet temperature is 72-78℃.

10. The preparation method according to claim 6, characterized in that, In step (7), the coating solution concentration is 11% to 13% (w / v), the air inlet temperature is 65 to 70°C, and the boiler rotation speed is 4 to 8 Hz.

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