Sugar-free granules for nourishing blood and tranquilizing mind and preparation method of sugar-free granules

Abstract

The invention relates to the technical field of nerve calming granules, and discloses sugar-free blood nourishing and nerve calming granules and a preparation method thereof.The sugar-free blood nourishing and nerve calming granules are composed of hairyvein agrimony, prepared rehmannia roots, vine of multiflower knotweed, yerbadetajo herbs, rehmannia roots, suberect spatholobus stems, cortex albiziae and sugar-free auxiliary materials; comprising microcrystalline cellulose, isomaltitol, mannitol, nano silicon dioxide, Arabic gum, hydroxypropyl methyl cellulose and polyvinylpyrrolidone. By optimizing the proportion and process conditions of the auxiliary materials and the synergistic effect of the medicinal material extract and the auxiliary materials, the humidity of the wet granules is controlled to be 30-35%, the granulation pressure is 3-6 MPa, the drying temperature is 50-55 DEG C, and finally the granules with the particle size of 200-400 microns are prepared. According to the invention, the problems of poor particle formability and insufficient disintegration performance caused by removal of sugar are overcome, rapid disintegration, good formability and stability of sugar-free particles are realized, the solubility and taste of the particles are improved, and the sugar-free granules are suitable for long-term administration by diabetics and sugar-sensitive people.

Description

Technical Field

[0001] The invention relates to the technical field of tranquilizing granules, in particular to sugar-free blood-nourishing and tranquilizing granules and a preparation method thereof. Background Art

[0002] As people pay more and more attention to health management, Chinese medicine preparations are widely used in the treatment of insomnia, neurasthenia and other symptoms. As a common Chinese medicine preparation, blood-nourishing and tranquilizing granules have a wide range of applications due to their effects of nourishing blood, nourishing yin, and calming the mind. However, in the production of traditional Chinese medicine granules, more carbohydrate fillers are usually added to improve the taste and enhance the molding properties of the granules. Although these sugars can improve the patient's taking experience, they limit the application of granules in specific populations (such as diabetics and sugar-sensitive people).

[0003] In the prior art, some low-sugar or sugar-free granule products have been launched. These products mainly replace traditional sucrose with artificial sweeteners or other sugar-free fillers to reduce the sugar content of the granules. However, such solutions usually have problems such as uneven ratio of auxiliary materials, poor granule formability, and insufficient disintegration performance. In addition, some sweeteners are too strong or uneven in sweetness, resulting in a hard or irritating taste after the granules are dissolved, affecting the taking experience. In terms of granule preparation technology, insufficient control of parameters such as humidity and granulation pressure of wet granules further exacerbates the volatility of the physical properties of the granules.

[0004] However, in the prior art, how to solve the contradiction between particle formability and disintegration performance by optimizing the auxiliary material formula and process conditions under the premise of removing sugar has not been effectively solved. Especially in the sugar-free filling system, the selection and proportion of auxiliary materials have a significant impact on the overall performance of the particles. If a scientific design is not achieved, the particles are prone to defects such as decreased formability and prolonged disintegration time. Therefore, how to design a sugar-free blood-nourishing and tranquilizing granule that has good formability, disintegration and a suitable taste has become a technical problem that needs to be solved urgently. Summary of the invention

[0005] In view of the deficiencies in the prior art, the present invention provides a sugar-free Yangxue Anshen granule and a preparation method thereof, which solves the problem of poor formability and disintegration performance of the sugar-free Yangxue Anshen granule after removing sugar.

[0006] To achieve the above object, the present invention is implemented by the following technical scheme: the particles are composed of the following components by weight: Drug ingredients: 150-180 parts of Herba Agrimoniae, 90-120 parts of Rehmannia glutinosa, 90-120 parts of Polygonum multiflorum, 90-120 parts of Eclipta prostrata, 90-120 parts of Rehmannia glutinosa, 90-120 parts of Millettia reticulata, 90-120 parts of Albizzia julibrissin; Auxiliary ingredients: 150-160 parts of microcrystalline cellulose, 60-70 parts of gum arabic, 120-150 parts of isomalt, 20-40 parts of nano silicon dioxide, 30-50 parts of hydroxypropyl methylcellulose, 70-90 parts of mannitol, and 15-25 parts of polyvinyl pyrrolidone.

[0007] A method for preparing sugar-free blood-nourishing and nerve-calming granules comprises the following steps: Step 1, mix Agrimoniae, Rehmanniae Preparata, Polygonum Multiflorum, Eclipta Prostrata, Rehmannia Glutinosa, Millettia Spatholobi and Albizzia Julibrissin according to weight ratio, add 10-15 times of water by weight and soak for 2-3 hours; Step 2, decocting three times: the first decocting is 1.5 hours, the second decocting is 1 hour, and the third decocting is 0.5 hours, the filtrate is combined and concentrated under reduced pressure to a relative density of 1.18-1.22; Step 3, mixing microcrystalline cellulose, gum arabic, nano silicon dioxide and hydroxypropyl methylcellulose evenly; Step 4, dissolving isomalt and mannitol in purified water, adding polyvinyl pyrrolidone to form an auxiliary material liquid phase solution; Step 5: Mix the drug extract paste and the auxiliary material dry mixture in proportion, gradually add the auxiliary material liquid solution, adjust the humidity to 32%-35%, and prepare wet granules; Step 6: granulate the wet granules through a rotary extrusion granulator at a granulation pressure of 3-6 MPa; Step 7: Place the wet granules in a fluidized bed drying device at a drying temperature of 50-55°C for 40-60 minutes, and sieve to obtain granules with a particle size of 250-350 microns.

[0008] Preferably, in step 1, the weight ratio of medicinal materials to water is preferably 1:12.

[0009] Preferably, in step 2, the amount of water added in the three decoctions is 10 times, 8 times and 6 times the weight of the medicinal materials respectively.

[0010] Preferably, in the seventh step of drying, the fluidized bed drying temperature is preferably 50-52°C.

[0011] The present invention provides a sugar-free blood-nourishing and nerve-calming granule and a preparation method thereof, which has the following beneficial effects: 1. The present invention adopts a combination formula of drugs and excipients based on molecular complementarity theory and interface thermodynamic optimization, and ensures that the particles still have excellent formability and disintegration performance after removing sugar by adjusting the intermolecular forces and interface wettability of drug extracts and excipients. Compared with the existing solution of simply adding artificial sugar substitutes or traditional fillers to solve the problem of sugar-free particles, it avoids the defects of poor particle formability or prolonged disintegration time due to insufficient compatibility between excipients.

[0012] 2. The present invention adopts a process design combining medicinal material extraction and concentration with low-temperature drying, which optimizes the mixing uniformity between the drug and the excipients and the mechanical strength of the particles after drying while maintaining the concentration and activity of the active ingredients. Compared with the prior art solution that causes partial ineffectiveness of the active ingredients of the drug or fragile particles due to high-temperature drying, the present invention effectively solves the problems of component loss and insufficient particle stability.

[0013] 3. The present invention achieves good taste, suitable particle strength and fast disintegration speed of sugar-free granules by compounding isomalt, mannitol and a variety of functional excipients. Compared with the traditional technical path of using sucrose or single sugar substitutes to improve the taste, the present invention avoids the problem of single sweetness or poor disintegration, and at the same time broadens the applicable population of the granules, especially diabetic patients and sugar-sensitive people.

[0014] 4. The present invention aims at the fluidity and storage stability of the particles. By introducing the synergistic effect of nano-silicon dioxide and hydroxypropyl methylcellulose into the formula, the fluidity of the particles during granulation and packaging is significantly improved, and the hygroscopicity is effectively reduced. Compared with the problem of easy agglomeration of sugar-free particles in the prior art due to high hygroscopicity, the present invention successfully solves the technical problem of insufficient storage stability of the particles and significantly extends the shelf life of the product. BRIEF DESCRIPTION OF THE DRAWINGS

[0015] Figure 1 It is a schematic diagram of the method flow of the present invention. DETAILED DESCRIPTION

[0016] The following will be combined with the drawings in the specification of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0017] Please see attached Figure 1 The embodiment of the present invention provides a sugar-free blood-nourishing and tranquilizing granule and a preparation method thereof, including.

[0018] 1. Components and ratios of the composition 1.1 Drug ingredients and proportions This sugar-free Yangxue Anshen granule is composed of the following drug ingredients, by weight (per 1000g of granules): Agrimony: 150-180 parts; Rehmannia root: 90-120 parts; Polygonum multiflorum: 90-120 parts; Eclipta prostrata: 90-120 parts; Rehmannia root: 90-120 parts; Millettia reticulata: 90-120 parts; Albizzia julibrissin: 90-120 parts Analysis of drug ingredient mechanism: Herba Agrimoniae has the effects of cooling blood, stopping bleeding and astringing, and can balance the blood heat caused by excessive liver fire in insomnia; Rehmannia glutinosa and Radix Rehmanniae glutinosae are the main drugs for nourishing yin and blood, which can supplement the symptoms caused by yin and blood deficiency in patients with insomnia and neurasthenia; Polygonum multiflorum and Millettia reticulata have the function of nourishing blood and unblocking meridians, and can improve the irritability and insomnia caused by blood deficiency; Eclipta prostrata is a product for nourishing the liver and kidneys, and can be used with Radix Rehmanniae Preparata and Radix Rehmanniae to enhance the efficacy of nourishing blood and yin; Albizia Julibrissin bark is mainly used to calm the mind and relieve depression, and to relieve patients' insomnia caused by bad emotions.

[0019] Through the synergistic effect of the above-mentioned medicinal ingredients, the granules can comprehensively improve the symptoms of insomnia and neurasthenia from multiple aspects such as nourishing blood, nourishing yin, unblocking meridians, and calming the mind.

[0020] 1.2 Excipient ingredients and ratio The selection and proportion optimization of excipients are based on the molecular complementarity theory and interface thermodynamics principles, and specifically include the following components (by weight): Microcrystalline cellulose (MCC): 140-160 parts; Arabic gum: 50-70 parts; Isomalt: 100-150 parts; Nano silicon dioxide: 20-40 parts; Hydroxypropyl methylcellulose (HPMC): 30-50 parts; Mannitol: 70-90 parts; Polyvinyl pyrrolidone (PVP-K30): 15-25 parts Microcrystalline cellulose (MCC): As a particle skeleton material, it provides physical support through its porous structure, enhances the formability of the particles, and ensures the uniformity and fluidity of the particles; Gum Arabic: forms weak intermolecular interactions with drug extract paste, enhances the molding strength of wet granules, and improves the mechanical strength of dried granules; Isomalt: provides a slightly sweet taste and optimizes the dissolution properties of the particles, while improving the patient's taking experience; Nano-silicon dioxide: As a flow aid, it reduces friction between particles, improves fluidity, and helps achieve uniformity during granulation; Hydroxypropyl methylcellulose (HPMC): provides rapid disintegration during particle dissolution, adjusts the hydrophilicity of particles, and promotes rapid release of active ingredients; Mannitol: increases the palatability of the granules, reduces their hygroscopicity, and improves their storage stability; Polyvinyl pyrrolidone (PVP-K30): As a binder, it works synergistically with gum arabic to enhance the compression resistance and formability of the particles.

[0021] Through the optimized ratio of the above excipients, the particles can achieve excellent formability, rapid disintegration and stable storage performance.

[0022] 2. Preparation method and mechanism analysis 2.1 Process steps Step 1: Extraction of medicinal materials Mix Agrimoniae, Rehmanniae Preparata, Polygonum Multiflorum, Eclipta Prostrata, Rehmannia Glutinosa, Millettia Spatholobi, and Albizzia Julibrissin according to weight ratio, add 10-15 times of water by weight and soak for 2-3 hours; Decoction three times: add 10 times the weight of the medicinal materials in water for the first time and decoct for 1.5 hours; add 8 times the weight of the medicinal materials in water for the second time and decoct for 1 hour; add 6 times the weight of the medicinal materials in water for the third time and decoct for 0.5 hours; Combine the three decoctions, filter, and concentrate under reduced pressure to a clear paste with a relative density of 1.18-1.22 (60°C) for later use.

[0023] Through multiple decoctions and reduced pressure concentration, the water-soluble active ingredients in the medicinal materials (such as total flavonoids, alkaloids and polysaccharides) can be effectively extracted, and the destruction of heat-sensitive components by high temperature can be avoided. At the same time, the effective concentration of the extract can be guaranteed by controlling the density of the concentrated liquid.

[0024] Step 2: Pretreatment of auxiliary materials Mix microcrystalline cellulose, gum arabic, nano silicon dioxide and hydroxypropyl methylcellulose in proportion and stir evenly; Isomalt and mannitol are dissolved in purified water, heated to 50-60°C to completely dissolve, and then PVP-K30 is added and stirred evenly to form a liquid auxiliary material solution.

[0025] Uniform mixing of solid excipients can ensure the consistency of the physical properties of the particles; The heating and dissolution of the liquid excipients ensures uniform distribution, while the molecular bonding effect of PVP-K30 improves the molding properties of the particles during the wetting stage.

[0026] Step 3: Wet Granule Preparation Gradually add the drug extract paste into the dry excipient mixture and stir evenly (stirring speed is 30-50rpm); Slowly add the auxiliary material liquid solution and adjust the humidity to 30%-35% to make wet granules.

[0027] When the drug extract paste is mixed with the excipients, weak intermolecular bonding is formed through molecular complementarity to ensure the uniformity of the wet particles; Controlling the humidity at 30%-35% can optimize the plasticity of wet granules and avoid the decrease in formability due to granules being too wet or too dry.

[0028] Step 4: Granulation and Drying The wet granules are granulated by a rotary extrusion granulator with a granulation pressure of 3-6 MPa and a controlled particle size of 200-400 μm; The wet granules are placed in a fluidized bed drying device at a drying temperature of 50-55°C for 40-60 minutes until the moisture content of the granules is less than 5%.

[0029] During the granulation process, the physical strength and particle size distribution of the particles are optimized by controlling the pressure and particle size; Low temperature drying avoids heat-sensitive degradation of drug ingredients and improves particle stability by controlling the final moisture content.

[0030] Step 5: Screening and packaging The dried particles are screened through a screening machine to remove particles that are too large or too small and retain particles with a particle size of 200-400 microns; Depending on the requirements, the granules can be coated or packaged directly.

[0031] The sieving step ensures the uniformity of particle size and helps stabilize the dissolution and disintegration properties; Packaging design can enhance the moisture resistance of granules and extend shelf life.

[0032] Embodiment 1: Pretreatment of medicinal materials Weigh 160g of Herba Agrimoniae, 100g of Radix Rehmanniae Preparata, 100g of Radix Polygoni Multiflori, 100g of Ecliptae, 100g of Radix Rehmanniae, 100g of Caulis Spatholobi, and 100g of Cortex Albizziae, mix well, add 12 times the weight of purified water, soak for 2 hours, and allow the medicinal materials to fully absorb water and swell.

[0033] Extraction and concentration The soaked herbs were boiled three times: the first time, 10 times the weight of water was added and boiled for 1.5 hours; the second time, 8 times the weight of water was added and boiled for 1 hour; the third time, 6 times the weight of water was added and boiled for 0.5 hours. The three extracts were combined, filtered, and concentrated under reduced pressure to a relative density of 1.20 (60°C).

[0034] Premixing of excipients Weigh 150 g of microcrystalline cellulose, 60 g of gum arabic, 30 g of nano silicon dioxide and 40 g of hydroxypropyl methylcellulose, mix them evenly, and stir for 5 minutes to ensure that the powders are evenly dispersed.

[0035] Excipient solution preparation Take 120 g of isomalt and 80 g of mannitol and dissolve them in purified water heated to 55° C., add 20 g of polyvinyl pyrrolidone, and stir thoroughly to obtain a uniform auxiliary material liquid.

[0036] Particle preparation During the stirring process, the drug concentrate was slowly added to the dry mixture of excipients, stirred evenly, and then the excipient liquid was gradually added to adjust the humidity to 34%. The wet mixture was granulated by a rotary extrusion granulator, and the granulation pressure was set to 4 MPa.

[0037] Drying and sieving The wet granules were placed in a fluidized bed dryer, the drying temperature was set to 50°C, and the drying time was controlled to 50 minutes, until the moisture content of the granules was less than 5%. The granules were sieved to obtain granules with a particle size of 250-350 microns.

[0038] In this embodiment, the wet granules are adjusted to 34% in humidity, and the granules have good formability and are not easy to break. Fluidized bed drying is used to ensure the stability of the active ingredients of the drug, and the granule disintegration time is controlled within 3 minutes, with excellent solubility.

[0039] Embodiment 2: Pretreatment of medicinal materials Weigh 170g of Herba Agrimoniae, 110g of Rehmannia Glutinosa, 95g of Caulis Polygoni Multiflori, 95g of Ecliptae, 95g of Rehmannia Glutinosa, 110g of Caulis Spatholobi, and 95g of Albizzia Julibrissin, add 13 times the weight of water, and soak for 3 hours to allow the medicinal materials to fully absorb water.

[0040] Extraction and concentration The medicinal material was decocted three times, with 10 times the weight of the medicinal material added for the first time and decocted for 1.5 hours, 8 times the weight of the medicinal material added for the second time and 6 times the weight of the medicinal material added for the third time and decocted for 0.5 hours. After combining the three extracts, filter and concentrate under reduced pressure to a relative density of 1.18 (60°C).

[0041] Excipient mixing 160 g of microcrystalline cellulose and 70 g of gum arabic were mixed and stirred for 8 minutes, and 30 g of nano silicon dioxide was added separately and mixed again to make the mixture evenly distributed.

[0042] Preparation of auxiliary liquid Dissolve 140 g of isomalt and 85 g of mannitol in water at 60° C., add 25 g of polyvinyl pyrrolidone, and continue stirring until completely dissolved to obtain a viscous liquid.

[0043] Granulation The drug concentrate was mixed with the dry mixture of excipients, and the excipient solution was gradually added and stirred until the humidity reached 32%. The wet granules were granulated by a twin-screw extruder and the pressure was adjusted to 5 MPa.

[0044] Drying and granulation The wet granules are placed in a hot air drying device, the temperature is controlled at 52°C, the drying time is 40 minutes, and the final moisture content is less than 4%. The granules are screened by a sieving machine and the granules with a particle size of 200-400 microns are selected.

[0045] The optimized humidity control and twin-screw granulator greatly improve the strength and pressure resistance of the granules. The drying temperature is increased to 52°C to avoid the agglomeration problem caused by excessive moisture content in the granules, and the storage stability is significantly improved.

[0046] Embodiment 3: Medicinal Extraction Take 160g of Herba Agrimoniae, 100g of Radix Rehmanniae Preparata, 100g of Radix Polygoni Multiflori, 100g of Ecliptae, 100g of Radix Rehmanniae, 90g of Caulis Spatholobi, and 110g of Cortex Albizziae, mix them in proportion, add 14 times of water by weight of the medicinal materials, and soak for 2.5 hours. Decoction three times, the first time for 1.5 hours, the second time for 1 hour, and the third time for 0.5 hours, and combine the extracts. Concentrate under reduced pressure to a relative density of 1.22 (60°C).

[0047] Preparation of auxiliary materials Weigh 140g of microcrystalline cellulose, 50g of gum arabic, 50g of hydroxypropyl methylcellulose, and 40g of nano silicon dioxide, and mix them evenly. Dissolve 150g of isomalt and 90g of mannitol in 55°C water, add 15g of polyvinyl pyrrolidone, and stir until completely dissolved.

[0048] Wet granulation preparation The drug concentrate and the dry mixture of excipients are mixed evenly, and the excipient solution is added in batches, and the humidity is controlled at 35%. The wet mixture is granulated by a rotary extrusion granulator with a granulation pressure of 4.5 MPa.

[0049] Drying and sieving The wet granules were placed in a fluidized bed dryer at 55°C for 45 minutes with a moisture content of 4.5%. The dried granules were sieved to obtain granules with a particle size of 300-350 microns.

[0050] By increasing the proportion of isomalt, the sweetness of the granules becomes softer and the taste is significantly improved. The increase in the proportion of hydroxypropyl methylcellulose speeds up the disintegration of the granules, and the complete disintegration time is 2.5 minutes, meeting the demand for rapid dissolution.

[0051] Embodiment 4: Medicinal material processing and extraction Mix 180g of Agrimoniae Herba, 110g of Rehmannia Glutinosa, 110g of Polygonum Multiflorum, 90g of Ecliptae, 90g of Rehmannia Glutinosa, 100g of Millettia Spatholobi, and 100g of Albizzia Julibrissin, add 15 times the weight of water and soak for 2 hours. After three decoctions, combine the filtrate and concentrate under reduced pressure to a relative density of 1.18 (60°C).

[0052] Excipient mixing 150g of microcrystalline cellulose, 60g of gum arabic, and 40g of nano-silicon dioxide were stirred evenly. 130g of isomalt and 85g of mannitol were dissolved in purified water, heated to 60°C, and 20g of PVP-K30 was added, and stirred until transparent.

[0053] Granulation and drying Mix the concentrated paste with the auxiliary materials and adjust the moisture content to 33%. Set the granulation pressure to 5.5 MPa and control the particle size to 250-300 μm. Drying temperature is 50°C and drying time is 50 minutes.

[0054] Screening and packaging After screening, particles with a size of 200-350 microns are selected and bagged and sealed.

[0055] The nano-silicon dioxide content is increased to 40g, which greatly reduces the friction between particles and significantly improves fluidity. The packaging process is simple, the particles do not agglomerate, and the storage performance is greatly optimized.

[0056] Comparative Example 1: Medicinal Extraction Take 160g of Herba Agrimoniae, 100g of Radix Rehmanniae Preparata, 100g of Radix Polygoni Multiflori, 100g of Ecliptae, 100g of Radix Rehmanniae, 100g of Caulis Spatholobi, 100g of Cortex Albizziae, add 12 times the weight of water, and soak for 2 hours. Decoction is performed three times according to the extraction method in Example 1, and the extracts are combined and concentrated under reduced pressure to a relative density of 1.20 (60°C).

[0057] Preparation of auxiliary materials Traditional sucrose is used as a filler, and the auxiliary material ratio is: sucrose 200g, microcrystalline cellulose 100g, gum arabic 40g, hydroxypropyl methylcellulose 20g. Nano silicon dioxide and mannitol are not added.

[0058] Granulation and drying Granulate according to the method in Example 1, and adjust the humidity to 35%. Rotate and squeeze granulate, and the granulation pressure is 4 MPa. The wet granules are placed in a fluidized bed dryer, the temperature is set to 55°C, and the drying time is 45 minutes. After screening, select granules with a particle size of 200-400 microns.

[0059] Traditional sucrose was used instead of isomalt and mannitol, nano silicon dioxide and mannitol were not added, and the proportion of auxiliary materials changed significantly.

[0060] Comparative Example 2: Medicinal Extraction Take 170g of Herba Agrimoniae, 110g of Rehmannia Glutinosa, 95g of Caulis Polygoni Multiflori, 95g of Ecliptae, 95g of Rehmannia Glutinosa, 110g of Caulis Spatholobi, and 95g of Albizzia Julibrissin, and extract and concentrate according to the method of Example 2. The relative density of the concentrate is 1.18 (60°C).

[0061] Preparation of auxiliary materials The auxiliary material ratio is: 160 g microcrystalline cellulose, 70 g gum arabic, 140 g isomalt, 30 g nano silicon dioxide, 85 g mannitol, 25 g polyvinyl pyrrolidone, and 50 g hydroxypropyl methylcellulose. The auxiliary material preparation is consistent with Example 2.

[0062] Granulation and drying After the drug concentrate was mixed with the excipients, the humidity of the wet granules was adjusted to 28% (not reaching the 32% humidity recommended in the embodiment). Granulation was performed by a twin-screw granulator with a granulation pressure of 4 MPa. The drying temperature was set to 50°C and the drying time was 50 minutes. After sieving, particles with a particle size of 200-400 microns were retained.

[0063] Difference: The humidity of the wet granules did not reach the optimal range (28% vs. 32%), and the granulation pressure was low (4MPavs. 5MPa).

[0064] Comparative Example 3: Medicinal Extraction Take 160g of Herba Agrimoniae, 100g of Rehmannia Glutinosa, 100g of Caulis Polygoni Multiflori, 100g of Ecliptae, 100g of Rehmannia Glutinosa, 90g of Millettia Spatholobi, and 110g of Albizzia Julibrissin, and extract and concentrate according to the method of Example 3. The relative density is 1.22 (60°C).

[0065] Preparation of auxiliary materials The proportion of auxiliary materials was adjusted to: 150 g microcrystalline cellulose, 50 g gum arabic, 150 g isomalt, 90 g mannitol, 15 g polyvinyl pyrrolidone, and 50 g hydroxypropyl methylcellulose. No nano silicon dioxide was added as a flow aid.

[0066] Granulation and drying After the drug concentrate is mixed with the excipients, the humidity is controlled at 35%. The rotary extrusion granulator is used to granulate the particles at a granulation pressure of 4.5 MPa. The drying temperature is 50°C and the drying time is 45 minutes. After sieving, particles with a particle size of 300-350 microns are retained.

[0067] Difference: No nano-silicon dioxide flow aid was added, and other excipients and preparation parameters remained consistent.

[0068] Comparative Example 4: Medicinal Extraction Take 180g of Herba Agrimoniae, 110g of Rehmannia Glutinosa, 110g of Caulis Polygoni Multiflori, 90g of Ecliptae, 90g of Rehmannia Glutinosa, 100g of Millettia Spatholobi, and 100g of Albizzia Julibrissin, treat them according to the extraction method in Example 4, and concentrate under reduced pressure to a relative density of 1.18 (60°C).

[0069] Preparation of auxiliary materials The auxiliary material ratio is: 150g microcrystalline cellulose, 60g gum arabic, 130g isomalt, 85g mannitol, 20g polyvinyl pyrrolidone, 40g hydroxypropyl methylcellulose. No nano silicon dioxide is added. The auxiliary material liquid preparation method is the same as that of Example 4.

[0070] Granulation and drying After the drug concentrate is mixed with the excipients, the humidity is adjusted to 33%. The wet granules are granulated by a rotary extrusion granulator, and the granulation pressure is set to 5 MPa. The drying temperature is set to 50°C and the drying time is 50 minutes. After sieving, particles with a particle size of 200-350 microns are retained.

[0071] Difference: No nano-silica is added, the friction between particles is not optimized, and the fluidity may be insufficient.

[0072] Comparative Example 5 (corresponding to Example 2): Drying conditions were not optimized Medicinal Extraction Take 170g of Herba Agrimoniae, 110g of Rehmannia Glutinosa, 95g of Caulis Polygoni Multiflori, 95g of Ecliptae, 95g of Rehmannia Glutinosa, 110g of Caulis Spatholobi, and 95g of Albizzia Julibrissin, and extract and concentrate according to the method in Example 2. The relative density is 1.18 (60°C).

[0073] Preparation of auxiliary materials The proportion of auxiliary materials is consistent with that in Example 2: 160 g of microcrystalline cellulose, 70 g of gum arabic, 140 g of isomalt, 30 g of nano silicon dioxide, 85 g of mannitol, 25 g of polyvinyl pyrrolidone, and 50 g of hydroxypropyl methylcellulose.

[0074] Granulation and drying After the drug concentrate is mixed with the excipients, the humidity of the wet granules is adjusted to 32%. The wet granules are granulated by a twin-screw granulator with a granulation pressure of 5 MPa. The drying temperature is set at 60°C and the drying time is 40 minutes. After sieving, particles with a particle size of 200-400 microns are retained.

[0075] Difference: Increasing the drying temperature to 60°C and shortening the drying time to 40 minutes may result in the loss of heat-sensitive components of the drug or reduced particle strength.

[0076] Experiment 1: Comparative test of particle formability and mechanical strength Experimental Description Experimental objectives By testing the formability and mechanical strength of the granules of the embodiments and comparative examples, the effects of the wet granule humidity, auxiliary material ratio and granulation process on the physical properties of the granules were verified, and the advantages of the present invention were evaluated.

[0077] Experimental procedures Sample preparation: Take 10 g of particle samples from Example 1, Example 2, Comparative Example 1 and Comparative Example 2 respectively, and ensure that the samples are dry and the particle size is uniform (screening range is 200-400 microns).

[0078] Hardness test: Use a particle hardness tester to place individual particles on the platform one by one, apply gradually increasing pressure, and record the pressure value when the particles break. Repeat the test 10 times for each group of samples, take the average value, and record it in N.

[0079] Integrity observation: Randomly sample the particles to see whether they have regular appearance and cracks on the surface, and record the particle appearance integrity score (full score 100, evaluating smoothness, uniformity, and crack ratio).

[0080] Experimental conditions: room temperature 25℃, relative humidity 50%. Experimental instruments were calibrated uniformly, and the test time intervals were the same.

[0081] Table 1: Experimental data on particle formability and mechanical strength comparison sample Hardness value (N) Appearance integrity score Example 1 8.2 95 Example 2 9.1 97 Comparative Example 1 5.4 85 Comparative Example 2 6.2 88 Example 1 8.5 94 Example 2 8.9 96 Comparative Example 1 5.7 83 Comparative Example 2 6.4 87 Example 1 8.3 93 Example 2 9.2 96 Comparative Example 1 5.8 84 Comparative Example 2 6.1 86 The formability of the particles depends largely on the humidity control of the wet particles and the skeleton support of the auxiliary materials. The humidity of Example 1 and Example 2 is controlled within the optimal range (32%-34%), and microcrystalline cellulose is introduced as a skeleton material to provide sufficient mechanical strength for the particles. This strength not only ensures the stability of the particles during the granulation process, but also significantly reduces the breakage rate of the particles after drying. However, the humidity of Comparative Examples 1 and 2 is insufficient or uneven, resulting in a loose particle structure and a significantly reduced hardness.

[0082] From the perspective of appearance integrity, Example 2, which added gum arabic and nano-silicon dioxide, performed best, with a smooth, uniform surface and no obvious cracks. Nano-silicon dioxide plays a role in flow and friction resistance during the granulation process, reducing the adhesion and pulling between particles, so the finished particles are more regular. However, due to the lack of nano-silicon dioxide, the particle surface of Comparative Example 1 is rough, with many cracks, and the integrity score is the lowest.

[0083] Microcrystalline cellulose and drug extracts form a stable weak intermolecular interaction, generating a uniform particle matrix structure under the condition of optimized humidity. However, sucrose, as a traditional filler in Comparative Example 1, cannot form a similar molecular network structure due to its single molecular characteristics, which ultimately leads to poor particle strength and appearance integrity.

[0084] Experiment 2: Particle disintegration and dissolution performance test Experimental Description Experimental objectives By testing the disintegration time of the granules and the dissolution ratio of the active ingredients, the effect of the optimized auxiliary material ratio and process conditions of the present invention on improving the rapid disintegration and dissolution performance of the granules was evaluated.

[0085] Experimental procedures Sample preparation 6 g of particle samples were taken from Example 3, Example 4, Comparative Example 3 and Comparative Example 4 respectively, ensuring that the particle size range was 200-400 μm, and the samples were stored in a dry environment.

[0086] Disintegration time test Take 2 g of each sample, put it into the test basket of the disintegrator, and immerse it in simulated gastric fluid (900 mL, pH = 1.2) at 37 ± 0.5 °C.

[0087] Start the equipment and record the time from immersion to complete disintegration of the particles (unit: minutes).

[0088] Each group of samples was tested 3 times and the average value was recorded.

[0089] Dissolution performance test After the granules were completely disintegrated (within 15 minutes), 10 mL of simulated gastric fluid was taken, filtered and diluted to 50 mL, and the dissolution concentration of the active ingredient was detected using an ultraviolet spectrophotometer at 254 nm.

[0090] The release ratio of the active ingredient within 15 minutes (unit: %) was calculated based on the standard curve.

[0091] Each group of samples was tested 3 times and the average value was recorded.

[0092] Experimental conditions The disintegration apparatus was set to move the immersion basket up and down at a frequency of 30 times / min; The UV spectrophotometer calibration error for dissolution testing was less than ±0.5%.

[0093] Table 2: Particle disintegration and dissolution performance test data sample Disintegration time (min) Dissolution ratio of active ingredients (%) Example 3 2.8 88.3 Example 4 2.5 90.1 Comparative Example 3 5.1 74.8 Comparative Example 4 4.7 78.6 Example 3 3 87.6 Example 4 2.6 91.3 Comparative Example 3 4.9 76.1 Comparative Example 4 4.6 79.4 Example 3 2.9 89.1 Example 4 2.7 90.7 Comparative Example 3 5.2 73.5 Comparative Example 4 4.8 78.9 The disintegration rate of the particles is essentially determined by the hydrophilicity of the excipients and the particle matrix structure. In both Example 3 and Example 4, hydroxypropyl methylcellulose is used as a disintegration promoter in the excipient formula, and the ratio is further optimized to ensure that the particles can quickly absorb water and swell after contacting the liquid and disperse into fine particles. This design makes the disintegration time of the embodiments less than 3 minutes, while the disintegration process of Comparative Examples 3 and 4 is significantly slow because no key excipients are added or reduced. The state of the particles in the liquid is visibly different, and the surface smoothness directly corresponds to the rate of water absorption and swelling.

[0094] In the solubility test, Example 4 performed best, with a dissolution ratio of nearly 90%. This result is mainly due to the synergistic effect of nano-silicon dioxide and mannitol, which optimizes the dispersion performance of the particles and reduces the problem of particle agglomeration in the solution. However, due to the imbalance of the proportion of excipients in Comparative Example 3, the surface hydration of the particles is uneven, resulting in some active ingredients being retained in the matrix that is not completely dissolved. In contrast, the particles of the embodiment decompose rapidly in the solution, and the release process is uniform and efficient.

[0095] The Example precisely controls the wet granule humidity (35%), and the excipients form a stable intermolecular complementary structure, making the pore distribution of the granule matrix more uniform. The hydrophilic matching between the excipients accelerates water penetration and diffusion of the active ingredients. The Comparative Example fails to achieve this synergy between the formula and the process, and the granule structure is too dense or the water absorption is insufficient, which ultimately shows a significant gap in disintegration and dissolution.

[0096] Experiment 3: Granule fluidity and granulation efficiency test Experimental Description Experimental objectives The fluidity and granulation efficiency of the granules during the granulation and drying process were tested to verify the effects of nano-silicon dioxide in the excipients and humidity control of the wet granules on the granule formability and fluidity.

[0097] Experimental procedures Sample preparation Take 50g of granule samples from Example 2, Example 4, Comparative Example 2 and Comparative Example 4 respectively, and ensure that the sample particle size range is 200-400 microns. Record the humidity of the wet granules and indicate the corresponding example or comparative example number.

[0098] Liquidity test Use a particle flow funnel to place the sample at the top of the funnel and measure the time (in seconds) for the sample to completely pass through the funnel.

[0099] Each test was repeated 3 times and the average value was recorded.

[0100] Granulation efficiency test After the wet granules were prepared, the total mass of the wet granules (including unformed granules and waste) was measured.

[0101] The wet granules were dried and sieved after drying. The mass of granules within the particle size range (200-400 microns) was weighed and the granulation efficiency was calculated.

[0102] Experimental conditions Specifications of flow funnel: lower diameter 8mm; Room temperature 25℃, humidity 50%; The granulation pressure, humidity and drying temperature are consistent with those of the corresponding embodiments and comparative examples.

[0103] Table 3: Granule flowability and granulation efficiency test data.

[0104] sample Liquidity (funnel time, s) Granulation efficiency (%) Example 2 5.1 92.3 Example 4 4.6 94.7 Comparative Example 2 8.3 78.5 Comparative Example 4 7.9 81.2 Example 2 5.3 91.5 Example 4 4.8 93.6 Comparative Example 2 8.5 76.9 Comparative Example 4 7.7 79.8 Example 2 5 92 Example 4 4.7 94.3 Comparative Example 2 8.1 80.4 Comparative Example 4 7.8 80.9 The fluidity of particles depends largely on the friction between the particle surfaces and the uniformity of the internal pores. In Example 2 and Example 4, by adding nano-silicon dioxide as a flow aid, the friction between the particles is significantly reduced, allowing the particles to pass through the funnel smoothly, which is clearly reflected in the data. In contrast, Comparative Examples 2 and 4 lack nano-silicon dioxide, and the particles are prone to blockage in the funnel, and the fluidity test time is significantly increased. This shows that the use of flow aids plays an irreplaceable role in improving the fluidity of particles.

[0105] Granulation efficiency is also affected by particle formability and matrix structure. The humidity of the wet granules in Example 4 is controlled within the range of 33%-35%, and the ratio of microcrystalline cellulose to gum arabic is optimized, so that the wet granules are formed more uniformly, the particle disintegration rate is low after drying, and the yield of the finished granules after screening is greatly improved. However, the humidity of Comparative Example 2 is low (28%), and the wet granules are not sufficiently cohesive during the forming stage, resulting in an increase in waste and a significant reduction in the final granulation efficiency. This also indirectly verifies the non-negligible influence of the humidity of the wet granules in the granulation process.

[0106] From a mechanistic point of view, the core of this difference lies in the physical effect of nano-silicon dioxide. As a flow aid for particles, it forms a "lubricating layer" on the surface of the particles, reducing the contact area and friction coefficient between particles, while preventing excessive adhesion of the particle surface. The stable skeleton structure formed by the molecular complementarity of microcrystalline cellulose and gum arabic ensures the internal strength of the particles, further improving the stability of the formed particles.

[0107] Experiment 4: Granule storage stability test Experimental Description Experimental objectives The hygroscopicity and storage stability of the particles under different storage conditions were evaluated, and the effect of the optimized ratio of mannitol and nano-silicon dioxide in the excipients on the moisture resistance and storage performance of the particles was verified.

[0108] Experimental procedures Sample preparation Take the particle samples of Example 2, Example 4, Comparative Example 2 and Comparative Example 4 respectively, pack each group into 4 samples, each sample weighs 20g, and put them into the same type of aluminum foil bags and seal them.

[0109] Storage condition settings The samples were placed in two storage environments: a) Constant temperature and humidity environment 1: 25℃, humidity 60%; b) Constant temperature and humidity environment 2: 40℃, humidity 75%.

[0110] Each group of samples was stored under the above conditions for 90 days, and one sample was taken out every 30 days for testing.

[0111] Moisture absorption and weight gain test Take out the sample from the storage environment, weigh the total mass of the sample with a precision balance, and calculate the moisture absorption weight gain rate: Particle agglomeration observation Observe whether the particles are clumped, record with the naked eye whether the particles appear to be clumped or deformed, and record changes in fluidity.

[0112] Fluidity change test: Use a particle fluidity funnel to test the time (unit: s) required for particles to pass through the funnel and record the data.

[0113] Experimental conditions Storage environment control error range: temperature ±1°C, humidity ±5%; When sampling, avoid prolonged exposure to room temperature.

[0114] Table 4: Granule storage stability test data sample Storage days Moisture absorption weight gain rate (%) Whether it is agglomerated Liquidity (funnel time, s) Example 2 30 0.8 no 5.3 Example 4 30 0.5 no 4.7 Comparative Example 2 30 2.3 yes 8.1 Comparative Example 4 30 2.1 yes 7.8 Example 2 60 1.2 no 5.8 Example 4 60 0.7 no 4.9 Comparative Example 2 60 3.5 yes 9.2 Comparative Example 4 60 3.1 yes 8.6 Example 2 90 1.6 no 6.1 Example 4 90 0.9 no 5.1 Comparative Example 2 90 4.7 yes 10.3 Comparative Example 4 90 4.2 yes 9.8 Experiment 5: Particle palatability and sweetness acceptance test Experimental objectives The palatability and sweetness acceptance of the granules were evaluated, and the effect of optimizing the ratio of isomalt and mannitol on improving the taste was verified.

[0115] Experimental procedures Sample preparation Take 10 g of each of the particle samples of Example 1, Example 3, Comparative Example 1 and Comparative Example 3, dissolve them in 200 mL of warm water (50° C.), stir evenly, and prepare a particle solution. Ensure that the appearance of each group of samples is consistent to avoid affecting the subjective judgment of the volunteers.

[0116] Volunteer Recruitment Recruit 20 healthy volunteers without diabetes or taste abnormalities, with an even gender distribution and an age range of 20-50 years old. Do not eat sweet foods for 1 hour before the test and drink water to clean your mouth.

[0117] Sweet taste acceptance test The volunteers tasted the four samples in turn, with an interval of 2 minutes, and rinsed their mouths with water after each tasting. They scored the following three indicators: sweetness uniformity, sweetness moderation, and mouthfeel smoothness. The scoring standard was 1-5 points (1 point for poor, 5 points for excellent).

[0118] Palatability evaluation The volunteers gave a comprehensive score on the overall palatability of each sample (taste of the dissolved particles, sweetness coordination, and oral feeling), with a full score of 10.

[0119] Experimental conditions The order of sample testing was randomly assigned; Volunteers were not informed of the sample number to ensure the blind fairness of the test.

[0120] Table 5: Particle palatability and sweetness acceptance test data sample Sweetness uniformity (1-5 points) Moderate sweetness (1-5 points) Mouth smoothness (1-5 points) Overall palatability score (1-10 points) Example 1 4.2 4.5 4.3 8.7 Example 3 4.6 4.8 4.7 9.2 Comparative Example 1 3.1 3.5 3 6.5 Comparative Example 3 3.4 3.8 3.2 6.8 Example 1 4.3 4.6 4.2 8.8 Example 3 4.5 4.7 4.6 9 Comparative Example 1 3.2 3.6 3.1 6.6 Comparative Example 3 3.5 3.9 3.3 6.9 The sweetness acceptance of the granules is highly correlated with the uniformity of the compounding of the auxiliary materials. In Examples 1 and 3, isomalt and mannitol are compounded in a specific ratio to provide a softer sweetness, and the problem of abrupt or sweet sweetness in traditional sucrose samples (such as Comparative Example 1) will not occur. In particular, the ratio of isomalt is further increased in Example 3, making the sweetness more uniform and refreshing. The samples of Comparative Examples 1 and 3 have low sweetness uniformity scores due to the unoptimized compounding ratio, and the taste is monotonous, which is obviously inferior to the examples.

[0121] In terms of palatability, Example 3 has the best overall performance. The combination of mannitol and isomalt not only optimizes the sweetness of the particles, but also provides a delicate and smooth feeling after dissolution. This smooth feeling comes from the solubility of mannitol in liquid, which can form a soft coating in the mouth, thereby improving the taste. However, the design of the comparative example lacks mannitol, and the texture of the particles after dissolution is slightly rough, and some volunteers even report that they have a slight powdery feeling.

[0122] The improvement in sweetness acceptance in the example is due to the synergistic effect between the two excipients. The sweetness of isomalt is pure but not strong, and mannitol, as a flavoring ingredient, reduces the irritation after the particles are dissolved and improves the overall sweetness uniformity and dissolution smoothness during the hydration process. However, the single filler design in the comparative example cannot form such an advantage in taste coordination, the sweetness is too single or even strong, and the oral experience is poor when the particles are dissolved.

[0123] Although embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that various changes, modifications, substitutions and variations may be made to the embodiments without departing from the principles and spirit of the present invention, and that the scope of the present invention is defined by the appended claims and their equivalents.

Claims

1. A sugar-free blood-nourishing and mind-calming granule, characterized in that: The granules consist of the following components by weight: Drug ingredients: 150-180 parts of Herba Agrimoniae, 90-120 parts of Rehmannia glutinosa, 90-120 parts of Polygonum multiflorum, 90-120 parts of Eclipta prostrata, 90-120 parts of Rehmannia glutinosa, 90-120 parts of Millettia reticulata, 90-120 parts of Albizzia julibrissin; Auxiliary ingredients: 150-160 parts of microcrystalline cellulose, 60-70 parts of gum arabic, 120-150 parts of isomalt, 20-40 parts of nano silicon dioxide, 30-50 parts of hydroxypropyl methylcellulose, 70-90 parts of mannitol, and 15-25 parts of polyvinyl pyrrolidone.

2. A method for preparing sugar-free Yangxue Anshen granules, according to the sugar-free Yangxue Anshen granules according to claim 1, characterized in that: The following steps are involved: Step 1: Mix Agrimoniae, Rehmanniae Preparata, Polygonum Multiflorum, Eclipta Prostrata, Rehmannia Glutinosa, Millettia Spatholobi and Albizzia Julibrissin according to weight ratio, add 10-15 times of water by weight and soak for 2-3 hours; Step 2, decocting three times: the first decocting is 1.5 hours, the second decocting is 1 hour, and the third decocting is 0.5 hours, the filtrate is combined and concentrated under reduced pressure to a relative density of 1.18-1.22; Step 3, mixing microcrystalline cellulose, gum arabic, nano silicon dioxide and hydroxypropyl methylcellulose evenly; Step 4, dissolving isomalt and mannitol in purified water, adding polyvinyl pyrrolidone to form an auxiliary material liquid phase solution; Step 5: Mix the drug extract paste and the auxiliary material dry mixture in proportion, gradually add the auxiliary material liquid solution, adjust the humidity to 32%-35%, and prepare wet granules; Step 6: granulate the wet granules through a rotary extrusion granulator at a granulation pressure of 3-6 MPa; Step 7: Place the wet granules in a fluidized bed drying device at a drying temperature of 50-55°C for 40-60 minutes, and sieve to obtain granules with a particle size of 250-350 microns.

3. The method for preparing the sugar-free Yangxue Anshen granules according to claim 2, characterized in that: In the step 1, the weight ratio of the medicinal material to water is preferably 1:

12.

4. The method for preparing the sugar-free Yangxue Anshen granules according to claim 2, characterized in that: In the step 2, the amount of water added in the three decoctions is 10 times, 8 times and 6 times the weight of the medicinal material respectively.

5. The method for preparing the sugar-free Yangxue Anshen granules according to claim 2, characterized in that: In the seventh step of drying, the fluidized bed drying temperature is preferably 50-52°C.

Images