Tablet for assisting in protecting liver injury and improving liver fat metabolism and preparation method thereof

Abstract

The invention provides a tablet for assisting in protecting liver injury and improving liver fat metabolism and a preparation method of the tablet, and belongs to the technical field of biological pharmacy. The tablet for assisting in protecting liver injury and improving liver fat metabolism comprises a yeast extract, dihydroquercetin, curcumin composite powder, a filling agent and a lubricant, and the curcumin composite powder is prepared by the following steps: dissolving curcumin in a 95% ethanol solution, adding croscarmellose sodium, uniformly mixing, and performing freeze drying to obtain the curcumin composite powder. The preparation method comprises the following steps: adding water under a high-speed stirring condition, carrying out reduced pressure distillation, carrying out vacuum drying to obtain a curcumin-croscarmellose sodium compound, adding silicon dioxide and crushed ice, mixing, and carrying out low-temperature ball milling to obtain the curcumin-croscarmellose sodium compound. According to the invention, the problems of tabletting and forming of the curcumin and the yeast extract are solved, the prepared tablet is high in hardness, low in friability and smooth in surface, and the water solubility and bioavailability of the curcumin are improved.

Description

Technical Field

[0001] This invention belongs to the field of biopharmaceuticals, and in particular relates to tablets for adjuvant protection against liver damage and improvement of liver lipid metabolism, and methods for their preparation. Background Technology

[0004] Curcumin is a polyphenolic compound extracted from the rhizomes of Curcuma longa L., Curcuma wenyujin, and Curcuma kwangsiensis, all plants in the genus Curcuma. It possesses various pharmacological activities, including antioxidant, anti-inflammatory, free radical scavenging, bile excretion promotion, lipid-lowering, antiviral, and antitumor effects. Numerous in vitro and in vivo experiments have demonstrated that curcumin can exert good preventative and therapeutic effects on various experimental liver injuries, including those caused by chemicals, alcohol, and drugs, by regulating oxidative stress, inhibiting the release of inflammatory factors, and modulating hepatocyte apoptosis.

[0005] Dihydroquercetin, also known as Taxifolin, is a natural dihydroflavonol compound primarily extracted from the roots of larch trees in high-altitude regions. It belongs to the bioflavonoid class and possesses various biological activities, including antioxidant, antiviral, anti-allergic, anti-atherosclerotic, antiarrhythmic, and blood pressure-regulating effects. Dihydroquercetin exhibits excellent antioxidant capacity, inhibiting stem cell apoptosis, promoting regeneration, and slowing the progression of liver fibrosis.

[0006] Yeast extract is a product obtained by enzymatic hydrolysis and autolysis (which can be further separated and extracted) of food-grade yeast as the main raw material, under the combined action of the yeast's own enzymes or added food-grade enzymes. It is rich in soluble components from yeast cells, such as amino acids, peptides, and polypeptides. Glutathione in yeast extract can protect the activity of sulfhydryl groups in proteins, thus maintaining normal protein activity. It also acts as a coenzyme and prosthetic group for many enzymes, possessing various biological functions. These include scavenging free radicals in the body, protecting liver cell membranes, promoting liver membrane activity, anti-oxidation, detoxification, and maintaining the integrity of red blood cell membranes.

[0007] Patent application number: CN202510171231.7, publication date: 2025.04.11, discloses a hangover relief composition and its preparation method, which obtains a complex by co-precipitating yeast extract and curcumin, thereby improving the solubility and bioavailability of curcumin.

[0008] In existing technologies, the preparation of tablets by combining hydrophobic active ingredients such as curcumin and dihydroquercetin with yeast extracts faces a dual dilemma of mutual constraints between "formation" and "dissolution." Firstly, there are problems with difficult formation and poor tablet mechanical properties. Yeast extracts have a tendency to rebound elastically, disrupting the interfacial contact and tight packing between particles, making it difficult to achieve a strong bond even with increased compression pressure. Simultaneously, the hydrophobicity of curcumin and dihydroquercetin further hinders the formation of hydrogen bonds and other binding forces between particles. This results in weak internal binding forces in the tablets, easily leading to defects such as edge breakage, surface powdering, and even tablet cracking, resulting in poor uniformity of tablet quality within a batch. Secondly, conventional processes often rely on increasing the amount of binder to overcome the formation problem. While this method can improve tablet hardness to some extent, it can cause sticking and impaction, affecting production efficiency. Excessive binder can also lead to slow tablet disintegration, directly hindering the dissolution and release of hydrophobic components such as curcumin, ultimately preventing the effective improvement of their bioavailability with formulation and affecting the final efficacy of the product. Summary of the Invention

[0009] This invention systematically solves the core problems in the prior art, such as difficulty in compressing yeast extracts and curcumin into tablets, poor tablet quality, and low curcumin dissolution and bioavailability. It provides a tablet for adjuvant protection against liver damage and improvement of liver lipid metabolism, which simultaneously optimizes material compressibility, ensures tablet mechanical strength, and promotes efficient curcumin dissolution. The prepared tablet has high hardness, low brittleness, smooth surface, good disintegration performance, and high curcumin bioavailability.

[0010] The technical solution of the present invention is: a tablet for assisting in the protection of liver damage and improving liver fat metabolism, characterized in that: it is composed of 250 parts by weight of yeast extract, 5 parts by weight of dihydroquercetin, 47.2-50.4 parts by weight of curcumin composite powder, 243 parts by weight of filler and 5.5 parts by weight of lubricant, wherein the curcumin composite powder is prepared by the following method: (1) 30 parts by weight of curcumin is dissolved in 3000 parts by weight of 95% ethanol solution, stirred at 60°C until completely dissolved, and 10 parts by weight of curcumin is added. -12 parts by weight of cross-linked carboxymethyl cellulose sodium were stirred evenly, and 3000 parts by weight of water at 0-4℃ were quickly added under high-speed stirring. After stirring for 3-5 minutes, the mixture was vacuum distilled and then dried to obtain curcumin-cross-linked carboxymethyl cellulose sodium complex; (2) 5-6 parts by weight of silica, 2.2-2.4 parts by weight of crushed ice and curcumin-cross-linked carboxymethyl cellulose sodium complex were mixed and added to a low-temperature ball mill. The mixture was ground for 20-30 minutes at -5-0℃ and a speed of 300-400 r / min.

[0011] This invention employs solid dispersion technology and a "low-temperature ball milling in crushed ice media" process to integrate the hydrophobic active ingredient curcumin with cross-linked carboxymethyl cellulose sodium and silica carriers, successfully constructing a highly drug-loaded and highly stable curcumin composite powder. Curcumin is dissolved in an ethanol solution, and after adding water, amorphous powder precipitates under high-speed stirring and is loaded onto the surface and interior of cross-linked carboxymethyl cellulose sodium. Cross-linked carboxymethyl cellulose sodium is insoluble in water; water causes its surface to swell, expanding the three-dimensional mesh structure. The precipitated curcumin amorphous powder is confined within this three-dimensional mesh, achieving loading and embedding of the curcumin amorphous powder. The three-dimensional spatial structure of cross-linked carboxymethyl cellulose sodium prevents recrystallization of the curcumin amorphous powder. The curcumin-cross-linked carboxymethyl cellulose sodium composite obtained after vacuum distillation and vacuum drying is a yellow, brittle, thin sheet.

[0012] During the low-temperature ball milling process, the trace amounts of moisture released during the slow melting of crushed ice, combined with the sustained low-temperature environment, allow the carrier (crosslinked sodium carboxymethyl cellulose and silica) to fully expose hydroxyl, carboxyl, and silanol functional groups. Under the synergistic effect of mechanical force, stable hydrogen bonds form between the amorphous curcumin powder and the crosslinked sodium carboxymethyl cellulose. Silica disrupts the adsorption and aggregation phenomena between the curcumin-crosslinked sodium carboxymethyl cellulose complex, preventing agglomeration, improving grinding efficiency and uniformity, and resulting in a uniform particle size distribution of the composite powder. The gradual solid-liquid transition of the crushed ice precisely controls the effect of moisture, avoiding local agglomeration and excessive swelling of the crosslinked sodium carboxymethyl cellulose caused by direct water addition. Furthermore, the phase change endothermic process maintains the low temperature, suppressing the viscosity of the material caused by frictional heating, ensuring efficient and uniform grinding. This not only unexpectedly achieves efficient loading of curcumin and excellent powder flowability simultaneously, but also provides an ideal raw material with both good formability and rapid dissolution for subsequent tableting processes, fundamentally solving the problem of difficult tableting of compound materials.

[0013] Preferably, the curcumin composite powder is prepared by the following method: (1) Dissolve 30 parts by weight of curcumin in 3000 parts by weight of 95% ethanol solution, stir at 60°C until completely dissolved, add 10-12 parts by weight of cross-linked carboxymethyl cellulose sodium, stir at 300 r / min for 50 min, and then quickly add 3000 parts by weight of water at 0-4°C at a stirring speed of 1500 r / min. Continue stirring at 1500 r / min for 3-5 min. The solvent was removed by vacuum distillation at 50℃ and vacuum degree -0.09MPa with stirring speed of 600r / min, and the mixture was dried under vacuum at 40℃ for 8-10h to obtain curcumin-crosslinked carboxymethyl cellulose sodium complex; (2) 5-6 parts by weight of silica, 2.2-2.4 parts by weight of crushed ice and curcumin-crosslinked carboxymethyl cellulose sodium complex were mixed and added to a low-temperature ball mill, and ground for 20-30min at -5-0℃ and speed of 300-400r / min to obtain the final product.

[0014] During tablet compression, the curcumin complex powder effectively counteracts the adverse effects of yeast extract and curcumin on the interparticle hydrogen bond network. The curcumin complex powder forms additional, stable hydrogen bond connections with the yeast extract and povidone K30, significantly enhancing the overall cohesiveness of the tablets and ultimately reducing tablet brittleness and improving mechanical stability.

[0015] The curcumin composite powder was prepared by the following method: (1) 30 parts by weight of curcumin were dissolved in 3000 parts by weight of ethanol solution with a volume concentration of 95%, and stirred at 60°C until completely dissolved. 11 parts by weight of cross-linked carboxymethyl cellulose sodium were added and stirred at 300 r / min for 50 min. At a stirring speed of 1500 r / min, 3000 parts by weight of water at 0-4°C were quickly added and stirred at 1500 r / min for 3-5 min. The solvent was removed by vacuum distillation at 50°C, vacuum degree of -0.09 MPa and stirring speed of 600 r / min. The mixture was then vacuum dried at 40°C for 8-10 h to obtain the curcumin-cross-linked carboxymethyl cellulose sodium complex. (2) 5.5 parts by weight of silica, 2.2 parts by weight of crushed ice and the curcumin-cross-linked carboxymethyl cellulose sodium complex were mixed and added to a low-temperature ball mill. The mixture was ground at -5-0°C and a speed of 360 r / min for 20 min to obtain the curcumin-cross-linked carboxymethyl cellulose sodium complex.

[0016] As a micro-grinding medium, crushed ice, when melted, produces deionized water that does not participate in chemical reactions but reduces the friction coefficient between particles through liquid bridging. The amount of crushed ice used is precisely targeted to achieve a "wet grinding" effect. Furthermore, the ice-like addition allows the deionized water to melt slowly, preventing excessive water from causing recrystallization of curcumin or over-hydration of cross-linked carboxymethyl cellulose sodium, which would negatively impact the grinding effect. Additionally, the endothermic melting of crushed ice prevents localized overheating within the ball mill caused by grinding, thus avoiding thermal decomposition of curcumin.

[0017] The crushed ice has a particle size of 1-2 mm and is stored at -18°C.

[0018] Ice fragments pass through a 10-mesh sieve at temperatures below -18°C and remain on an 18-mesh sieve.

[0019] To improve the heat absorption capacity of crushed ice and avoid excessive local hydration and swelling of cross-linked sodium carboxymethyl cellulose, crushed ice that has been "frozen" at -18°C is required to improve the uniformity of the system and prevent the material from condensing into clumps.

[0020] The tablets have a friability of 0.15-0.23%, and the curcumin in the tablets has a saturated solubility of 317.53-321.70 μg / mL in artificial gastric fluid.

[0021] The filler is 231 parts by weight of microcrystalline cellulose and 12 parts by weight of povidone K30, and the lubricant is 5.5 parts by weight of magnesium stearate.

[0022] A method for preparing a tablet for assisting in the protection of liver damage and improving liver lipid metabolism, characterized by: (S1) mixing 250 parts by weight of yeast extract, 231 parts by weight of microcrystalline cellulose and 5 parts by weight of dihydroquercetin through a 60-mesh sieve for 20 minutes to obtain a mixed powder; (S2) preparing curcumin composite powder; (S3) dissolving 12 parts by weight of povidone K30 in 150 mL of 95% ethanol solution to obtain a povidone ethanol solution; (S4) mixing the mixed powder and curcumin composite powder evenly, spraying the povidone ethanol solution during the stirring process, forming a soft mass, granulating it through a 14-mesh sieve to obtain wet granules; (S5) drying the wet granules at 50°C to a moisture content of 3-5%, granulating them through a 14-mesh sieve to obtain dry granules; (S6) mixing the dry granules with 5.5 parts by weight of magnesium stearate for 10 minutes, compressing them into tablets to obtain a tablet for assisting in the protection of liver damage and improving liver lipid metabolism.

[0023] Due to the hygroscopic and viscous characteristics of yeast extract, the selection of wetting agents needs to consider viscosity adjustment, particle uniformity, and granulation effect. Insufficient humidity leads to low viscosity of the yeast extract, insufficient interparticle binding force for tableting, resulting in unsatisfactory tablet hardness and brittleness, causing significant quality variations between tablets. Excessive humidity causes the yeast extract to clump together, resulting in uneven particle size, poor flowability, and inability to pass through sieves. This invention uses high-concentration ethanol to prevent the excessive dissolution of water-soluble viscous substances in the yeast extract, which would affect particle flowability and tablet uniformity, thus improving particle uniformity and granulation effect. During the drying process of wet granules, the evaporating alcohol allows the composite powder to form "bridging points" with the yeast extract, enhancing interparticle binding force and compensating for the loss of elastic rebound in the yeast extract.

[0024] The preparation method of this invention comprehensively utilizes a variety of materials and processes to achieve effective loading of curcumin, improve particle quality, and control stability during tableting.

[0025] (S4) Use an atomizing nozzle to spray the povidone ethanol solution and control the spraying time to 8-10 minutes.

[0026] Because curcumin is soluble in ethanol, the ethanol spraying time needs to be shortened, and the processes of preparing the soft material and granulation need to be accelerated. This prevents curcumin from having time to move freely, aggregate, and rearrange into crystals in the ethanol before being encapsulated in the framework of the wet particles. Ethanol acts as a wetting agent to wet the solid powder and make it sticky. Even if a small amount of ethanol is dissolved, it will be rapidly absorbed and distributed by a large amount of microcrystalline cellulose and yeast extract, resulting in a localized decrease in curcumin concentration and preventing the formation of a supersaturated solution. This keeps curcumin in its most stable amorphous composite powder state. However, if the spraying time is too short, the soft material will be uneven, so the spraying time needs to be controlled at 8-10 minutes.

[0027] (S4) requires maintaining an air humidity of 60-70%.

[0028] When using atomizing nozzles to spray 95% ethanol solution, the operating procedures must be strictly controlled and attention must be paid to production safety.

[0029] The tablet described herein is intended for use in the preparation of drugs or health foods that assist in protecting against liver damage and improving liver fat metabolism.

[0030] The tablets prepared from yeast extract, curcumin, and dihydroquercetin of this invention not only provide auxiliary protection against liver damage but also improve hepatic lipid metabolism. In mouse experiments, the tablets of this invention significantly increased the content of reduced GSH in mouse liver homogenate, significantly reduced the content of MDA and TG in mouse liver homogenate, and significantly alleviated the degree of hepatocyte steatosis in mouse liver histopathology.

[0031] A curcumin composite powder is prepared by the following method: (1) Dissolve 30 parts by weight of curcumin in 3000 parts by weight of ethanol solution with a volume concentration of 95%, stir at 60°C until completely dissolved, add 10-12 parts by weight of cross-linked carboxymethyl cellulose sodium and stir at 300 r / min for 50 min, add 3000 parts by weight of water at 0-4°C at a stirring speed of 1500 r / min, stir continuously at 1500 r / min for 3-5 min, remove the solvent by vacuum distillation at 50°C and vacuum degree of -0.09 MPa at a stirring speed of 600 r / min, and vacuum dry at 40°C for 8-10 h to obtain curcumin-cross-linked carboxymethyl cellulose sodium complex; (2) Mix 5-6 parts by weight of silica, 2.2-2.4 parts by weight of crushed ice with curcumin-cross-linked carboxymethyl cellulose sodium complex and add to a low temperature ball mill, grind at -5-0°C and a speed of 300-400 r / min for 20-30 min to obtain the curcumin-cross-linked carboxymethyl cellulose sodium complex.

[0032] The advantages and positive effects of this invention are as follows: 1. The tablets prepared by this invention remain intact after being rotated 100 times in a tablet fragility tester, without any breakage or cracking, with a fragility of 0.15-0.23%, meeting the requirement of less than 1% tablet weight loss. 2. The tablets prepared by this invention have a curcumin saturated solubility of 317.53-321.70 μg / mL in artificial gastric juice, which is 8 times higher than that of Comparative Example 1, achieving a qualitative leap in the dissolution performance of hydrophobic curcumin and improving the bioavailability of curcumin. 3. The tablets prepared by this invention for assisting in the protection of liver injury and improving liver lipid metabolism significantly increased the content of reduced GSH in mouse liver homogenate in mouse animal experiments; decreased the content of MDA and TG in mouse liver homogenate; and significantly reduced the degree of hepatocyte steatosis in liver histopathology. 4. No toxic pathological changes were observed in rats after oral administration of the tablets of this invention for 28 days. Attached Figure Description

[0033] Figure 1 This is a histopathological section of the liver of a mouse in the blank control group of Experiment 3 of the present invention (Oil Red O staining ×400).

[0034] Figure 2 This is a histopathological section of the liver of the control group mouse in Experiment Example 3 of this invention (Oil Red O staining ×400).

[0035] Figure 3 This is a histopathological section of the liver of mice in the low-dose group of Experiment 3 of the present invention (Oil Red O staining ×400).

[0036] Figure 4 This is a histopathological section of the liver of mice in the medium-dose group of Experiment 3 of the present invention (Oil Red O staining ×400).

[0037] Figure 5 This is a histopathological section of the liver of mice in the high-dose group of Experiment 3 of the present invention (Oil Red O staining ×400).

[0038] Figure 6 This is a histopathological section (HE 10×10) of the liver of ♀9 rats, the negative control group in Experiment 4 of this invention.

[0039] Figure 7 This is a histopathological section of the liver of rat ♂56 in the high-dose group of Experiment 4 of the present invention (HE 10×10).

[0040] Figure 8 This is a histopathological section (HE 10×10) of the liver of rat ♀8 in the high-dose group of Experiment 4 of this invention.

[0041] Figure 9 This is a histopathological section of the kidney of a ♂55 rat in the high-dose group of Experiment 4 of this invention (HE 10×10).

[0042] Figure 10 This is an X-ray powder diffraction pattern of the curcumin composite powder in Example 1 of the present invention. Detailed Implementation Example 1

[0043] (S1) Mix 250 parts by weight of yeast extract, 231 parts by weight of microcrystalline cellulose and 5 parts by weight of dihydroquercetin through a 60-mesh sieve for 20 minutes to obtain a mixed powder. (S2) (1) Dissolve 30 parts by weight of curcumin in 3000 parts by weight of 95% ethanol solution, stir at 60°C until completely dissolved, add 11 parts by weight of cross-linked carboxymethyl cellulose sodium and stir at 300 r / min for 50 min, add 3000 parts by weight of 4°C water at 1500 r / min and stir at 1500 r / min for 3-5 min, then remove the solvent by vacuum distillation at 50°C, vacuum degree -0.09 MPa and stirring speed of 600 r / min, and vacuum dry at 40°C for 8-10 h to obtain curcumin-cross-linked carboxymethyl cellulose sodium complex; (2) Mix 5.5 parts by weight of silica, 2.2 parts by weight of crushed ice and curcumin-cross-linked carboxymethyl cellulose sodium complex and add to a low temperature ball mill, grind at -5-0°C and speed of 360 r / min for 20 min to obtain curcumin composite powder, the crushed ice particle size is 1-2 mm, and it is stored at -18°C; (S3) Dissolve 12 parts by weight of povidone K30 in 150 mL of 95% ethanol solution to obtain povidone ethanol solution; (S4) Mix the mixed powder and curcumin composite powder evenly, spray povidone ethanol solution during the mixing process, make soft material, granulate through a 14-mesh sieve to obtain wet granules. (S5) The wet granules are dried at 50°C to a moisture content of 5%, and then sieved through a 14-mesh sieve to obtain dry granules; (S6) Mix the dry granules with 5.5 parts by weight of magnesium stearate for 10 minutes, compress into tablets, and obtain tablets for adjuvant protection against liver damage and improvement of liver fat metabolism, with a specification of 0.55g / tablet.

[0044] The tablets are yellow, with the characteristic taste and odor of this product, no off-odor, and the tablet surface is intact and smooth; there are no foreign objects visible to normal vision. According to product quality testing, the ash content is 7.3%, the disintegration time is 13 minutes, the glutathione content is 7.20g / 100g, the curcumin content is 4.84g / 100g, and the weight variation is ±1.19%, which meets the requirements of the Chinese Pharmacopoeia for the limit of tablet weight variation.

[0045] The X-ray powder diffraction pattern of the curcumin composite powder prepared by (S2) after vacuum drying was measured using Cu-Kα rays, as shown in the figure. Figure 10 As shown, the X-ray powder diffraction pattern of the curcumin solid dispersion has no characteristic peaks, indicating that the curcumin in the curcumin solid dispersion is an amorphous powder. Example 2

[0046] (S1) Mix 250 parts by weight of yeast extract, 231 parts by weight of microcrystalline cellulose and 5 parts by weight of dihydroquercetin through a 60-mesh sieve for 20 minutes to obtain a mixed powder. (S2) (1) Dissolve 30 parts by weight of curcumin in 3000 parts by weight of 95% ethanol solution, stir at 60°C until completely dissolved, add 12 parts by weight of cross-linked carboxymethyl cellulose sodium and stir at 300 r / min for 50 min, add 3000 parts by weight of 2°C water at 1500 r / min and stir continuously at 1500 r / min for 3-5 min, remove the solvent by vacuum distillation at 50°C and vacuum degree -0.09 MPa at 600 r / min, and vacuum dry at 40°C for 8-10 h to obtain curcumin-cross-linked carboxymethyl cellulose sodium complex; (2) Mix 5 parts by weight of silica, 2.4 parts by weight of crushed ice and curcumin-cross-linked carboxymethyl cellulose sodium complex and add to a low temperature ball mill, grind at -5-0°C and 300 r / min for 30 min to obtain curcumin composite powder, the crushed ice particle size is 1-2 mm, and it is stored at -18°C; (S3) Dissolve 12 parts by weight of povidone K30 in 150 mL of 95% ethanol solution to obtain povidone ethanol solution; (S4) Mix the mixed powder and curcumin composite powder evenly, spray povidone ethanol solution during the mixing process, make soft material, granulate through a 14-mesh sieve to obtain wet granules. (S5) The wet granules are dried at 50°C to a moisture content of 3%, and then sieved through a 14-mesh sieve to obtain dry granules; (S6) Mix the dry granules with 5.5 parts by weight of magnesium stearate for 10 minutes, compress into tablets, and obtain tablets for adjuvant protection against liver damage and improvement of liver fat metabolism, with a specification of 0.55g / tablet.

[0047] The tablets are yellow in color, with the characteristic taste and odor of this product, and no off-odor. The tablets are intact and smooth. There are no foreign objects visible to normal vision. According to product quality testing, the ash content is 7.3%, the disintegration time is 14 minutes, the glutathione content is 7.30 g / 100 g, the curcumin content is 4.86 g / 100 g, and the weight variation is ±1.53%, which meets the requirements of the Chinese Pharmacopoeia for the limit of tablet weight variation. Example 3

[0048] (S1) Mix 250 parts by weight of yeast extract, 231 parts by weight of microcrystalline cellulose and 5 parts by weight of dihydroquercetin through a 60-mesh sieve for 20 minutes to obtain a mixed powder. (S2) (1) Dissolve 30 parts by weight of curcumin in 3000 parts by weight of 95% ethanol solution, stir at 60°C until completely dissolved, add 10 parts by weight of cross-linked carboxymethyl cellulose sodium and stir at 300r / min for 50min, add 3000 parts by weight of 0°C water at 1500r / min and stir continuously at 1500r / min for 3-5min, remove the solvent by vacuum distillation at 50°C and vacuum degree -0.09MPa and stirring speed of 600r / min, and vacuum dry at 40°C for 8-10h to obtain curcumin-cross-linked carboxymethyl cellulose sodium complex; (2) Mix 6 parts by weight of silica, 2.2 parts by weight of crushed ice and curcumin-cross-linked carboxymethyl cellulose sodium complex and add to a low temperature ball mill, grind at -5-0°C and speed of 400r / min for 25min to obtain curcumin composite powder, the crushed ice particle size is 1-2mm, and it is stored at -18°C; (S3) Dissolve 12 parts by weight of povidone K30 in 150 mL of 95% ethanol solution to obtain povidone ethanol solution; (S4) Mix the mixed powder and curcumin composite powder evenly, spray povidone ethanol solution during the mixing process, make soft material, granulate through a 14-mesh sieve to obtain wet granules. (S5) The wet granules are dried at 50°C to a moisture content of 5%, and then sieved through a 14-mesh sieve to obtain dry granules; (S6) Mix the dry granules with 5.5 parts by weight of magnesium stearate for 10 minutes, compress into tablets, and obtain tablets for adjuvant protection against liver damage and improvement of liver fat metabolism, with a specification of 0.55g / tablet.

[0049] The tablets are yellow, with the characteristic taste and odor of this product, no off-odor, and the tablet surface is intact and smooth; there are no foreign objects visible to normal vision. According to product quality testing, the ash content is 7.3%, the disintegration time is 12 minutes, the glutathione content is 7.40g / 100g, the curcumin content is 4.85g / 100g, and the weight variation is ±1.32%, which meets the requirements of the Chinese Pharmacopoeia for the limit of tablet weight variation. Comparative Example 1

[0050] (S1) 250 parts by weight of yeast extract, 231 parts by weight of microcrystalline cellulose, 5 parts by weight of dihydroquercetin, 30 parts by weight of curcumin, 5.5 parts by weight of silica and 11 parts by weight of cross-linked sodium carboxymethyl cellulose were passed through a 60-mesh sieve and mixed for 20 minutes to obtain a mixed powder. (S2) Dissolve 12 parts by weight of povidone K30 in 150 mL of 95% ethanol solution and spray it into the mixed powder to make a soft material. Granulate it through a 14-mesh sieve to obtain wet granules. (S3) The wet granules are dried at 50°C to a moisture content of 5%, and then sieved through a 14-mesh sieve to obtain dry granules; (S4) Mix the dry granules and 5.5 parts by weight of magnesium stearate for 10 min, compress into tablets to obtain Comparative Example 1 tablets with a specification of 0.55g / tablet.

[0051] The tablets are yellow, with the characteristic taste and odor of this product, and no off-odor. There is yellow powder on the surface of the tablets. There are no foreign objects visible to normal vision. According to product quality testing, the ash content is 7.2%, the disintegration time is 6 minutes, the glutathione content is 7.20g / 100g, the curcumin content is 4.85g / 100g, and the weight variation is ±8.66%, which does not meet the requirements of the Chinese Pharmacopoeia for the limit of tablet weight variation.

[0052] Table 1 shows the product quality testing results for Examples 1-3 and Comparative Example 1.

[0053] Group Ash content (%) Disintegration timeout (min) Glutathione content (g / 100g) Curcumin content (g / 100g) Weight variation (%) Example 1 7.3 13 7.20 4.84 1.19 Example 2 7.3 14 7.30 4.86 1.53 Example 3 7.3 12 7.40 4.85 1.32 Comparative Example 1 7.2 6 7.20 4.85 8.66 The disintegration time of Examples 1-3 of this invention is 12-14 minutes, which is lower than the upper limit of 15 minutes specified in the pharmacopoeia and fully meets the quality standards. Experimental Example 1: Tablet Friability Test

[0054] Referring to the tablet friability test method (General Rule 0923), 12 tablets each of those prepared in Examples 1-3 and Comparative Example 1 of this invention were taken. The powder detached from the tablets was blown away with a blower, and the tablets were accurately weighed to obtain the initial tablet weight W1. The tablets were then placed in the cylinder of a tablet friability tester and rotated 100 times. Afterward, the tablets were removed, the powder was removed using the same method, and the tablets were accurately weighed to obtain the final weight W2. The friability was calculated as follows: Friability = (W1 - W2) / W1. The results are shown in Table 2.

[0055] Table 2. Data on friability inspection.

[0056] Group <![CDATA[Initial weight W1 (g)]]> <![CDATA[Weight W2 (g) after detection]]> Friability % Example 1 6.6008 6.5909 0.15 Example 2 6.6025 6.5912 0.17 Example 3 6.6012 6.5860 0.23 Comparative Example 1 6.5924 6.5101 1.25 As shown in the table above, the tablets prepared by the process of this invention maintain a stable friability level of 0.15-0.23%, which is far below the pharmacopoeia's quality standard requirement of less than 1%, indicating that the tablets of this invention have excellent physical strength and abrasion resistance. In contrast, the tablets prepared by the process of Comparative Example 1 have a friability as high as 1.25%, which not only fails to meet the pharmacopoeia standard but also exhibits severe powdering, partial tablet breakage, or cracking during testing. This directly proves that the process of this invention fundamentally solves the molding problem of mixed compression tablets of yeast extract and curcumin by constructing a stable curcumin solid dispersion and hydrogen bond network. Example 2: In vitro dissolution experiment of curcumin

[0057] Two tablets each from Examples 1-3 and Comparative Example 1 were placed in Erlenmeyer flasks, and 100 mL of hydrochloric acid solution containing 0.5% Tween-80 (pH 1.2) was added to each flask. The flasks were heated in a water bath at 37±0.5℃ with a stirring speed of 50 r / min for 24 h. After stirring, the mixture was allowed to stand for equilibrium. Two mL of the supernatant was collected and filtered. The filtrate was filtered through a 0.22 μm microporous membrane, and the filtrate was analyzed by HPLC. Chromatographic conditions: Water BEH C18 column (100 mm × 2.1 mm, 1.7 μm), mobile phase: acetonitrile-4% acetic acid solution (50:50), flow rate: 0.2 mL / min, detection wavelength: 425 nm, column temperature: 30℃, injection volume: 5 μL. The results are shown in Table 3.

[0058] Table 3. Saturated solubility of curcumin tablets in simulated gastric juice in Examples 1-3 and Comparative Example 1.

[0059] Group Saturated solubility (μg / mL) Example 1 321.70 Example 2 319.48 Example 3 317.53 Comparative Example 1 36.94 As shown in the table above, the saturated solubility of curcumin in artificial gastric fluid in the tablets prepared by the method of this invention is significantly improved compared with Comparative Example 1. The saturated solubility of the tablets in Examples 1-3 is 8 times that of the tablets in Comparative Example 1. During the preparation of the curcumin solid dispersion in this invention, the crystal structure of curcumin is disrupted, allowing some curcumin to be embedded in the cross-linked carboxymethyl cellulose in the form of amorphous powder, achieving a qualitative leap in the dissolution performance of curcumin (solubility increased from 37 μg / mL to 320 μg / mL). This invention solves the two major problems of tablet "inability to be compressed into a solid form" and "low solubility of the active ingredient," providing a practical and feasible key technical solution for developing high-quality, highly effective tablets for adjuvant protection against liver damage and improvement of liver lipid metabolism. Experiment Example 3: Mouse Alcoholic Liver Injury Experiment

[0060] Experimental Groups: Sixty male SPF-grade KM mice, aged 4-6 weeks and weighing 18-22g, were used. During the experiment, all mice had free access to food and water and were housed in an SPF-grade animal laboratory at a temperature of 20-26℃, humidity of 30-70%, with 12 hours of light / 12 hours of darkness and good ventilation. Before administration of the test substance, all animals underwent a 3-day acclimatization period, with quarantine and acclimatization feeding conducted simultaneously. They were randomly divided into 5 groups of 12 mice each: three dosage groups, one blank control group, and one model group.

[0061] Dosage design: The recommended daily intake for humans is 2.2 g / person / day, or 0.037 g / kg BW (calculated based on the average adult weight of 60 kg). The low, medium, and high dose groups are 10, 20, and 30 times the recommended daily intake, respectively, i.e., 0.37 g / kg BW, 0.74 g / kg BW, and 1.11 g / kg BW. The tablets prepared in Example 1 of this invention were used as the test substance. After grinding the test substance into powder using a mortar and pestle, 0.925 g, 1.850 g, and 2.775 g of the tablet powder were accurately weighed, and an appropriate amount of distilled water was added and thoroughly stirred until the volume was adjusted to 50 mL, serving as the low, medium, and high dose groups. 50 mL of distilled water was used as the blank control group and the model control group, respectively. The tablets were thoroughly shaken before preparation and use. The gavage volume was 20 mL / kg BW. The tablets were thoroughly shaken before preparation and use. Mice were weighed twice a week, and the gavage volume was adjusted according to changes in body weight.

[0062] On day 30 after drug administration, the model group and each experimental group were administered 14 mL / kg BW of 50% ethanol by gavage, while the blank control group was given an equal volume of distilled water. After fasting for 16 hours, the animals were weighed and euthanized by cervical dislocation. 0.5 g of liver was accurately weighed and added to 9 times its volume of physiological saline at a weight (g):volume (mL) ratio of 1:9. The mixture was mechanically homogenized under low temperature to prepare 10% and 5% homogenates. The levels of malondialdehyde (MDA), reduced glutathione (GSH), and triglycerides (TG) in the liver tissue were measured, and the histopathological changes in the liver were examined.

[0063] 3.1 Body weight: Mice were weighed twice a week, and their body weight was measured before and after the experiment. The weight gain of each group of mice was calculated. The results are shown in Table 4.

[0064] Table 4 Effect on mouse body weight (mean ± standard deviation).

[0065] Group Dosage (g / kg BW) Number of animals (individuals) Pre-experiment body weight (g) Post-experiment body weight (g) Weight gain (g) Blank control group 0.00 12 20.43±1.31 44.28±3.58 23.85±2.90 Model control group 0.00 12 20.59±1.57 44.68±3.96 24.10±4.33 low-dose group 0.37 12 20.43±1.37 41.95±3.65 21.52±3.90 medium dose group 0.74 12 20.61±1.52 42.08±3.48 21.47±4.17 High-dose group 1.11 12 20.73±1.24 42.37±2.71 21.64±3.12 Note: Comparisons between each dosage group and the model control group and the blank control group are all... P >0.05.

[0066] The test substance had no significant effect on the body weight of mice in each dose group, and there was no significant difference compared with the model control group and the blank control group (P>0.05).

[0067] Detection of MDA, TG, and reduced GSH in liver homogenate: The detection and calculation methods for MDA and reduced GSH were based on the kit instructions from Nanjing Jiancheng Bioengineering Institute. TP and TG were detected using a Beckman Coulter AU680 fully automated biochemical analyzer. The results are shown in Table 5.

[0068] Table 5 Effects of MDA, reduced GSH, and TG on liver homogenate (mean ± standard deviation).

[0069] Group Dosage (g / kg BW) Number of animals (individuals) MDA (nmol / 100mg prot) Reduced GSH (μmol / g liver tissue) TG (μmol / g liver tissue) Blank control group 0.00 12 <![CDATA[66.58±29.97 * ]]> <![CDATA[0.41±0.15 * ]]> <![CDATA[27.0±7.5 * ]]> Model control group 0.00 12 220.74±170.54 0.26±0.08 35.1±6.3 low-dose group 0.37 12 145.42±107.60 <![CDATA[0.33±0.09 * ]]> 32.3±8.5 medium dose group 0.74 12 <![CDATA[80.34±63.02 * ]]> <![CDATA[0.35±0.11 * ]]> <![CDATA[29.4±6.1 * ]]> High-dose group 1.11 12 <![CDATA[86.70±88.56 * ]]> <![CDATA[0.35±0.10 * ]]> <![CDATA[28.8±3.8 * ]]> Note: Compared with the model control group: * P <0.05.

[0070] After administration of 50% anhydrous ethanol at a dose of 14 mL / kg BW for 16 hours, compared with the blank control group, the model group showed significantly increased MDA and TG levels and decreased reduced GSH levels (all values ​​were negative). P <0.05), which is consistent with the changes in biochemical indicators in the alcoholic liver injury model.

[0071] Compared with the model control group, the levels of reduced GSH in the liver homogenate of mice in the low, medium, and high dose groups were significantly increased. P<0.05); The levels of MDA and TG in the liver homogenate of mice in the medium and high dose groups were decreased, with significant differences (both <0.05). P <0.05). The significantly reduced TG content indicates that the tablets in this application have the effect of improving hepatic lipid metabolism.

[0072] 3.3 Liver pathological and histological examination.

[0073] Pathological observation materials: Liver samples were taken from the middle of the left lobe of each group of animals, cross-sections were prepared, frozen sections were prepared, and Oil Red O staining was performed. For example... Figure 1-5 As shown. He staining, as... Figure 6-9 As shown.

[0074] Pathological diagnostic criteria: The degree of hepatocyte damage was observed under a light microscope. The main focus was on observing the distribution, extent, and area of ​​lipid droplets in the liver, and the total score for the lesions in the observed fields of view was calculated. The scoring criteria are shown in Table 6, and the impact on mouse liver histopathology is shown in Table 7.

[0075] Table 6. Scoring criteria for liver lesions.

[0076] Lipid droplets are scattered and sparse within hepatocytes. 0 points No more than 1 / 4 of the hepatocytes contained lipid droplets. 1 point The number of hepatocytes containing lipid droplets does not exceed 1 / 2. 2 points No more than 3 / 4 of the hepatocytes contained lipid droplets. 3 points The liver tissue was almost entirely replaced by lipid droplets. 4 points Table 7 Effects on mouse liver histopathology (mean ± standard deviation).

[0077] Group Dosage (g / kg BW) Number of animals (individuals) Hepatocellular steatosis score Blank control group 0.00 12 <![CDATA[0.33±0.49 * ]]> Model control group 0.00 12 3.18±0.81 low-dose group 0.37 12 2.80±0.54 medium dose group 0.74 12 <![CDATA[2.57±0.42 * ]]> High-dose group 1.11 12 <![CDATA[1.88±0.59 * ]]> Note: Compared with the model control group: * P <0.05.

[0078] Compared with the blank control group ( Figure 1 Compared with the model control group () Figure 2 The score of hepatic fat cell degeneration in mice was significantly increased, and the difference was statistically significant. P The result was <0.05, which, combined with the biochemical results of liver homogenate, indicates that the alcoholic liver injury model is valid.

[0079] Compared with the model control group ( Figure 2 Compared to the medium- and high-dose groups, Figure 4 , Figure 5 The degree of steatosis in the liver of mice was significantly reduced, with a statistically significant difference. P <0.05).

[0080] Conclusion: Animal experiments were conducted using an alcoholic liver injury model to investigate the adjuvant protective effect of the tablets of this invention on liver injury and improvement of hepatic lipid metabolism. The recommended human intake of the test substance is 2.2 g / person / day, or 0.037 g / kg BW. SPF-grade Kunming mice were used, and three dosage groups were designed: 0.37 g / kg BW, 0.74 g / kg BW, and 1.11 g / kg BW (equivalent to 10, 20, and 30 times the recommended human intake, respectively). A model control group and a blank control group were also included. The animals were administered the medication by gavage for 30 consecutive days before testing began. An alcoholic liver injury model was induced in mice using 50% ethanol, and various indicators were measured 16 hours later. The experimental results are presented as follows: P A value <0.05 is considered a significant difference.

[0081] The results showed that: 1) There was no significant difference in body weight gain between the mice in each dose group and the model control group and the blank control group; 2) Compared with the blank control group, the model control group showed significantly increased MDA and TG levels and decreased reduced GSH levels in liver homogenate, as well as significantly increased hepatic fat cell degeneration (lipid droplets), indicating that the alcoholic liver injury model was established; 3) Compared with the model control group, the reduced GSH content in the liver homogenate of mice in the low, medium, and high dose groups was significantly increased; the MDA and TG content in the liver homogenate of mice in the medium and high dose groups was significantly decreased; 4) Compared with the model control group, the degree of hepatocyte steatosis in the liver histopathology of the medium and high dose groups was significantly reduced.

[0082] In summary, the animal experiment results showed that the liver MDA, reduced GSH and TG levels, as well as the pathological histological examination results, were all positive. Based on the judgment criteria in the "Methods for Functional Testing and Evaluation of Health Foods" (2023 edition), the test substance was determined to have an auxiliary protective effect on the alcoholic liver injury model and to improve liver lipid metabolism.

[0083] Experimental Groups: Eighty 4-5 week old SPF-grade Wistar rats were included, 40 males and 40 females. At the time of grouping, female rats weighed 67.5-96.6 g, and male rats weighed 68.3-96.6 g. Before administration of the test substance, the rats underwent 3 days of quarantine and acclimatization (quarantine and acclimatization were conducted simultaneously). Housing Conditions: Animals were housed in barrier-controlled cages (IVC), with two rats of the same sex per cage. Environmental Conditions: Laboratory temperature 20-26℃, relative humidity 30-70%. The IVC cages had at least 15 air changes per hour, with alternating 12-hour light / 12-hour dark cycles. The conditions met the national standard GB 14925-2023 for laboratory animal environments and facilities. Feed and Water: Animal feed consisted of rodent pellets with nutritional components meeting the requirements of GB 14924.3-2010. Drinking water was autoclaved. Animals had free access to food and water throughout the experiment (except for the fasting specified in the experimental protocol). Animals were randomly divided into low-dose, medium-dose, and high-dose groups and a negative control group according to sex and weight, with 20 animals in each group (10 males and 10 females). Each group of animals was individually numbered (1-10).

[0084] Dosage design: The recommended daily dose for the general population is 0.037 g / kg BW. The recommended daily dose was increased by 25, 50, and 100 times to create three dose groups: low, medium, and high, respectively, corresponding to 0.925 g / kg BW, 1.850 g / kg BW, and 3.700 g / kg BW. The test substance was administered orally for 28 consecutive days. A negative control group was also included, receiving distilled water. No toxicity reports were found in the literature; therefore, a satellite group was not included.

[0085] The tablets prepared in Example 1 of this invention were used as test substances. After grinding and crushing the test substances in a mortar, 3.7 g, 7.4 g, and 14.8 g of the test substances were accurately weighed, and an appropriate amount of distilled water was added. The mixture was stirred thoroughly and the volume was adjusted to 40 mL, resulting in concentrations of 0.0925 g / mL, 0.1850 g / mL, and 0.3700 g / mL, respectively. The tablets were prepared and used immediately upon application. The volume of the prepared sample was adjusted according to the animal's weight.

[0086] Table 8. Dosage design for the 28-day oral toxicity test in rats.

[0087] Group Number of animals (individuals) Dosage (g / kg BW) Test substance concentration (g / mL) Gavage volume (mL / kg BW) negative control group 20 0.000 0.0000 10.0 low-dose group 20 0.925 0.0925 10.0 medium dose group 20 1.850 0.1850 10.0 High-dose group 20 3.700 0.3700 10.0 4.1 Clinical Symptom Observation: Throughout the experiment, the animals' general clinical manifestations were observed once a day, and the signs, severity, duration, and mortality of poisoning were recorded. Observations included coat, skin, eyes, mucous membranes, secretions, excretions, respiratory system, nervous system, spontaneous activities (such as tearing, piloerection, pupil size, and abnormal breathing), and behavioral patterns.

[0088] Throughout the experiment, all groups of animals were in good general condition, with no unexpected deaths and no obvious abnormalities observed in clinical observation.

[0089] 4.2 Body weight, food intake, and food utilization: All surviving animals were weighed weekly, with body weight measured twice a week. The gavage volume was adjusted based on the animal's weight each time. Weekly food intake and food utilization were calculated for each animal. At the end of the experiment, body weight gain, total food intake, and total food utilization were calculated.

[0090] Table 9 Body weight of female mice during the experiment (g, mean ± standard deviation, n=10).

[0091] Weeks negative control group low-dose group medium dose group High-dose group 0 82.0±6.9 82.5±7.4 82.4±5.6 82.6±6.3 1 130.3±8.5 130.7±6.8 128.9±6.4 132.5±12.8 2 168.7±10.3 170.2±6.6 170.5±13.2 173.7±16.0 3 198.7±11.7 201.9±10.2 203.4±15.0 210.3±21.2 4 215.1±9.6 222.4±12.3 217.7±12.5 228.6±23.4 0-4（G） 133.1±8.4 139.9±13.1 135.4±14.7 146.0±21.4 Note: 0-4 (G): represents the total weight gain over 0-4 weeks; all dosage groups were compared with the negative control group. P >0.05.

[0092] Table 10. Changes in body weight in male rats during the experiment (g, mean ± standard deviation, n=10).

[0093] Weeks negative control group low-dose group medium dose group High-dose group 0 83.3±6.9 82.9±8.4 83.9±7.0 83.4±7.4 1 143.8±9.8 141.1±10.3 140.1±10.4 143.2±11.2 2 212.8±12.9 205.1±14.1 201.5±12.2 206.8±17.0 3 277.4±13.4 268.0±17.2 265.1±13.7 270.7±22.2 4 329.7±20.9 318.1±21.0 312.5±17.3 321.6±25.9 0-4（G） 246.3±22.4 235.2±16.8 228.6±15.0 238.2±26.1 Note: 0-4 (G): represents the total weight gain over 0-4 weeks; all dosage groups were compared with the negative control group. P >0.05.

[0094] As shown in Tables 9 and 10, there were no significant differences in body weight and total weight gain at each week between the male and female rat dose groups and the negative control group. P >0.05).

[0095] Table 11. Changes in food intake in female mice during the experiment (g / week / rat, mean ± standard deviation, n=10).

[0096] Weeks negative control group low-dose group medium dose group High-dose group 1 108.9±8.8 109.8±6.2 106.9±6.3 116.5±11.5 2 129.3±8.6 129.3±6.1 134.7±14.9 138.5±17.6 3 149.9±7.3 144.8±11.1 149.4±15.3 158.6±18.3 4 154.7±12.0 153.5±9.2 153.0±13.9 162.7±19.5 0-4（T） 542.7±28.6 537.3±28.3 544.0±45.0 576.3±64.6 Note: 0-4 (T): represents the total food intake during weeks 0-4; all dosage groups were compared with the negative control group. P >0.05.

[0097] Table 12. Changes in food intake during the male rat experiment (g / week / rat, mean ± standard deviation, n=10).

[0098] Weeks negative control group low-dose group medium dose group High-dose group 1 123.6±11.8 124.8±10.7 121.4±9.2 126.5±8.1 2 173.3±11.3 171.1±10.8 165.4±9.9 167.3±12.3 3 190.4±13.6 182.3±11.2 183.8±10.2 191.5±18.5 4 208.5±11.6 215.8±30.3 196.3±10.9 193.0±19.2 0-4（T） 695.8±27.9 693.8±45.8 666.9±35.8 678.3±47.1 Note: 0-4 (T): represents the total food intake during weeks 0-4; all dosage groups were compared with the negative control group. P >0.05.

[0099] As shown in Tables 11 and 12, there were no significant differences in food intake and total food intake at each week between the male and female rat dose groups and the negative control group.P >0.05).

[0100] Table 13 Food utilization rate results during the female rat experiment (%, mean ± standard deviation, n=10).

[0101] Weeks negative control group low-dose group medium dose group High-dose group 1 44.5±5.5 44.0±4.2 43.6±4.8 42.6±3.4 2 29.8±3.1 30.5±4.7 30.5±5.5 29.8±2.3 3 20.0±4.0 21.8±2.8 22.1±2.4 23.0±2.6 4 10.6±3.3 13.3±2.6 9.5±3.1 11.1±2.9 0-4（T） 24.6±1.4 26.0±2.0 24.9±1.7 25.3±0.9 Note: 0-4 (T): represents the total utilization rate during weeks 0-4; all dose groups were compared with the negative control group. P >0.05.

[0102] Table 14 Food utilization rate during the male rat experiment (%, mean ± standard deviation, n=10).

[0103] Weeks negative control group low-dose group medium dose group High-dose group 1 49.1±4.5 46.8±3.8 46.3±3.5 47.2±4.3 2 39.7±6.0 37.4±2.5 37.1±3.0 37.8±4.5 3 33.9±4.3 34.5±2.8 34.6±1.9 33.4±1.5 4 25.0±5.7 23.4±3.3 24.1±3.6 26.2±3.5 0-4（T） 35.4±2.7 34.0±2.3 34.3±1.6 35.0±2.0 Note: 0-4 (T): represents the total utilization rate during weeks 0-4; all dose groups were compared with the negative control group. P >0.05.

[0104] As shown in Tables 13 and 14, there were no significant differences in food intake and total food intake in each dose group of female and male rats compared with the negative control group (P>0.05).

[0105] 4.3 Eye examination: Before and at the end of the experiment, the eyes (cornea, lens, bulbar conjunctiva, iris) of rats in the negative control group and the high-dose group were examined.

[0106] Before and at the end of the experiment, ocular examinations (cornea, lens, bulbar conjunctiva, iris) were performed on rats in the negative control group and the high-dose group, and no obvious abnormalities were found.

[0107] 4.4 Clinical Examination: At the end of the experiment, animals underwent hematological, blood biochemistry, coagulation, and urinary parameter tests before final necropsy. Animals were fasted overnight before blood collection, and a dose of 20 mg / kg of sulfadiazine was administered. ® After intramuscular anesthesia with 50% injection solution (0.2 mL / 100g, concentration 10 mg / mL), blood was collected via the abdominal aorta. Approximately 1 mL was collected using an EDTA-K2 tube, approximately 1.8 mL using a sodium citrate anticoagulant vacuum tube, and 3-5 mL using a non-anticoagulant vacuum tube. These were then used for hematological, coagulation, and blood biochemistry tests. Urine was collected using a metabolic cage and sent for testing.

[0108] Table 15 Results of hematological parameters in female mice (mean ± standard deviation, n=10).

[0109] project negative control group low-dose group medium dose group High-dose group <![CDATA[WBC (×10 9 / L)]]> 3.9±1.2 3.6±0.8 4.1±1.1 4.1±1.2 <![CDATA[RBC (x10 12 / L)]]> 7.19±0.44 7.01±0.36 7.00±0.44 7.07±0.35 HGB (g / L) 143±7 144±6 142±5 144±5 HCT (%) 41.5±1.9 41.7±1.7 41.3±1.6 41.9±1.5 <![CDATA[PLT (x10 9 / L)]]> 1111±218 963±161 1022±115 1072±124 NEUT (%) 25.5±5.3 25.7±4.9 24.0±4.9 25.5±4.5 LY (%) 72.6±5.7 72.4±5.4 74.3±5.2 72.9±4.7 MO (%) 1.0±0.5 1.2±0.9 0.9±0.3 0.9±0.4 EO (%) 0.9±0.5 0.7±0.5 0.9±0.5 0.8±0.3 BASO (%) 0.0±0.0 0.0±0.0 0.0±0.0 0.0±0.0 APTT (S) 19.0±2.1 19.0±1.6 18.6±2.7 18.1±2.2 PT (S) 12.6±0.8 12.9±0.8 12.4±0.9 12.4±0.8 Compared with the negative control group, all dosage groups showed [significant improvement]. P >0.05.

[0110] Table 16 Results of hematological parameters in male rats (mean ± standard deviation, n=10).

[0111] project negative control group low-dose group medium dose group High-dose group <![CDATA[WBC (×10 9 / L)]]> 6.5±1.6 5.8±1.9 5.4±2.1 7.3±1.8 <![CDATA[RBC (x10 12 / L)]]> 7.13±0.46 7.23±0.30 7.14±0.36 7.09±0.29 HGB (g / L) 146±7 147±6 147±8 145±6 HCT (%) 43.0±1.6 43.2±1.8 43.7±1.8 42.7±1.6 <![CDATA[PLT (x10 9 / L)]]> 1246±152 1176±160 1059±149 1204±236 NEUT (%) 22.6±3.9 20.9±2.5 23.4±4.9 20.7±3.9 LY (%) 75.9±4.1 77.8±2.6 74.7±5.0 77.9±4.1 MO (%) 1.0±0.6 0.9±0.3 1.5±0.8 1.0±0.5 EO (%) 0.5±0.3 0.5±0.2 0.5±0.2 0.5±0.2 BASO (%) 0.0±0.0 0.0±0.0 0.0±0.0 0.0±0.0 APTT (S) 20.0±1.5 20.9±1.5 21.2±0.9 19.9±3.1 PT (S) 13.7±0.7 13.9±1.0 13.6±1.0 13.8±1.2 Compared with the negative control group, all were P >0.05.

[0112] As shown in Table 15, in female rats, there were no significant differences in any of the indicators among the different dosage groups compared to the negative control group. P >0.05).

[0113] As shown in Table 16, in male rats, there were no significant differences in any of the indicators among the different dosage groups compared to the negative control group. P >0.05).

[0114] Table 17 Results of biochemical indicators in female mice (mean ± standard deviation, n=10).

[0115] project negative control group low-dose group medium dose group High-dose group ALT (U / L) 38±9 44±12 37±4 36±6 AST (U / L) 146±50 143±16 126±15 128±28 TP (g / L) 56.3±4.1 57.2±3.4 58.2±2.9 58.1±3.2 ALB (g / L) 33.6±1.7 34.0±1.9 34.4±1.5 34.8±1.9 <![CDATA[AK P (IU / L)]]> 128±44 159±43 144±50 132±42 GLU (mmol / L) 6.28±0.44 6.11±0.37 6.16±0.75 6.42±0.66 Urea (mmol / L) 4.12±0.79 3.86±0.53 3.69±0.44 3.90±0.59 Crea (μmol / L) 39.2±3.1 38.1±2.2 38.4±2.3 38.1±2.3 TC (mmol / L) 1.79±0.49 2.11±0.38 1.81±0.30 2.16±0.39 TG (mmol / L) 0.64±0.08 0.67±0.11 0.64±0.09 0.72±0.07 <![CDATA[K + (mmol / L)]]> 4.43±0.34 4.28±0.19 4.24±0.30 4.45±0.35 <![CDATA[Na + (mmol / L)]]> 138.5±1.4 139.2±1.0 138.4±0.9 139.2±1.2 <![CDATA[Cl - (mmol / L)]]> 101.9±1.3 102.7±1.3 102.6±1.0 102.6±1.5 GGT (ng / mL) 38.3±1.5 35.9±2.5 <![CDATA[34.8±2.8 * ]]> 33.7±4.4 Compared with the negative control group, *: P <0.05.

[0116] Table 18 Results of biochemical indicators in male rats (mean ± standard deviation, n=10).

[0117] project negative control group low-dose group medium dose group High-dose group ALT (U / L) 42±6 46±7 40±8 41±9 AST (U / L) 120±20 131±23 123±21 118±26 TP (g / L) 55.3±2.5 54.9±2.7 57.4±3.1 56.3±2.1 ALB (g / L) 32.3±1.4 31.7±1.3 32.7±1.3 32.9±0.6 <![CDATA[AK P (IU / L)]]> 194±61 191±63 195±40 202±64 GLU (mmol / L) 5.89±0.53 5.94±0.90 6.36±1.08 6.46±1.04 Urea (mmol / L) 3.24±0.68 3.11±0.62 3.31±0.68 3.28±0.25 Crea (μmol / L) 35.2±2.3 35.1±2.6 34.2±2.6 34.3±1.5 TC (mmol / L) 1.82±0.47 1.77±0.41 1.79±0.36 2.01±0.38 TG (mmol / L) 0.73±0.26 0.71±0.37 0.75±0.27 0.85±0.28 <![CDATA[K + (mmol / L)]]> 4.52±0.21 4.61±0.16 4.49±0.18 4.61±0.25 <![CDATA[Na + (mmol / L)]]> 141.0±1.0 140.4±1.0 140.7±0.9 140.1±0.8 <![CDATA[Cl - (mmol / L)]]> 102.5±1.8 102.9±1.5 103.0±0.6 101.8±1.0 GGT (ng / mL) 31.8±2.3 28.3±3.3 31.7±2.2 34.4±3.9 Compared with the negative control group, all were P >0.05.

[0118] As shown in Tables 17 and 18, in female rats, compared with the negative control group, the GGT value of the medium-dose group decreased significantly. P＜ 0.05); however, the decrease in GGT levels was not clinically significant, therefore it had no toxicological significance. There were no significant differences in any of the other indicators among the dosage groups. P >0.05). Male rats: Compared with the negative control group, there were no significant differences in any indicators among the different dosage groups ( P >0.05).

[0119] Table 19 Results of urine analysis in female mice (n=10).

[0120]

[0121] Compared with the negative control group, all were P >0.05.

[0122] Table 20 Results of urine analysis in male rats (n=10).

[0123]

[0124] Compared with the negative control group, *: P <0.05.

[0125] As shown in Tables 19 and 20, in female rats, there were no significant differences in any of the indicators among the different dosage groups compared to the negative control group. P >0.05). Male rats: Compared with the negative control group, the pH value of rats in the high-dose group increased significantly. P＜ The pH value was 0.05, but the pH value was within the normal range of our laboratory (pH: 5.5~8.5), therefore it had no toxicological significance. There were no significant differences in any of the other indicators among the dosage groups. P >0.05).

[0126] 4.5 Pathological examination and organ weighing: At the end of the experiment, all surviving animals were anesthetized, blood was collected, and they were euthanized for gross anatomical examination, organ weighing, and histological examination. The animal carcasses were frozen and centrally processed.

[0127] 4.5.1 Systemic Dissection: For the dissected animal, perform a complete systemic dissection and a detailed gross examination, including the body surface, skull, thorax, abdominal cavity and its organs, and record the findings. Collect the tissues listed in Table 21 and fix them in 10% formalin solution.

[0128] Table 21 Organs sampled for pathological examination.

[0129] Animal identification liver Stomach Adrenal glands (bilateral) Lymph nodes (mesenteric) Testes (bilateral) brain Ovaries (bilateral) thymus spleen pancreas Thyroid and parathyroid glands heart pituitary bladder Kidneys (bilateral) Large intestine (colon) Small intestine (duodenum) lump 4.5.2 Weigh the organs: Weigh the organs listed in Table 21 and calculate the organ / body ratio.

[0130] Organ / body weight ratio (%) = [wet weight of organs (g) / body weight after fasting (g)] × 100%. The results are shown in Tables 22 and 23.

[0131] Table 22 Organ weights of female mice (absolute weight and relative weight) (mean ± standard deviation, n=10).

[0132] organs negative control group low-dose group medium dose group High-dose group Dissection weight (g) 205.2±11.0 213.0±12.4 208.5±11.8 216.2±23.5 Heavy heart (g) 0.80±0.08 0.83±0.07 0.86±0.13 0.85±0.07 Heart weight / body weight ratio (%) 0.39±0.03 0.39±0.04 0.41±0.04 0.39±0.03 Liver weight (g) 6.64±0.71 6.92±0.63 7.05±1.00 7.25±0.75 Liver weight / body weight ratio (%) 3.23±0.26 3.25±0.24 3.37±0.33 3.35±0.07 Spleen weight (g) 0.607±0.148 0.673±0.096 0.663±0.097 0.656±0.085 Spleen weight / body weight ratio (%) 0.296±0.073 0.316±0.040 0.318±0.042 0.305±0.040 Kidney weight (g) 1.62±0.22 1.63±0.10 1.70±0.15 1.70±0.20 Kidney weight / body weight ratio (%) 0.79±0.09 0.77±0.07 0.81±0.04 0.79±0.06 Thymus weight (g) 0.552±0.159 0.519±0.138 0.499±0.117 0.511±0.080 Thymus weight / body weight ratio (%) 0.268±0.075 0.245±0.064 0.238±0.048 0.238±0.042 Adrenal gland weight (g) 0.069±0.015 0.067±0.011 0.071±0.016 0.066±0.011 Adrenal weight / body weight ratio 0.033±0.006 0.032±0.005 0.034±0.008 0.031±0.006 Compared with the negative control group, all dosage groups showed [significant improvement]. P >0.05.

[0133] Table 23 Organ weights of male rats (absolute weight and relative weight) (mean ± standard deviation, n=10).

[0134] organs negative control group low-dose group medium dose group High-dose group Dissection weight (g) 307.9±18.8 296.1±19.0 290.2±18.9 300.2±25.5 Heavy heart (g) 1.10±0.11 1.08±0.14 1.09±0.08 1.14±0.15 Heart weight / body weight ratio (%) 0.36±0.02 0.36±0.03 0.38±0.04 0.38±0.03 Liver weight (g) 9.52±1.05 9.00±1.12 9.42±0.51 9.91±1.40 Liver weight / body weight ratio (%) 3.09±0.18 3.03±0.25 3.26±0.26 3.29±0.32 Spleen weight (g) 0.916±0.092 0.890±0.180 0.846±0.104 1.016±0.261 Spleen weight / body weight ratio (%) 0.297±0.022 0.298±0.043 0.291±0.025 0.336±0.072 Kidney weight (g) 2.47±0.31 2.38±0.22 2.37±0.14 2.49±0.21 Kidney weight / body weight ratio (%) 0.80±0.09 0.80±0.05 0.82±0.05 0.83±0.04 Testicular weight (g) 3.00±0.25 2.96±0.22 2.99±0.27 2.85±0.32 Testicular weight / body weight ratio (%) 0.98±0.10 1.00±0.08 1.03±0.11 0.95±0.12 Thymus weight (g) 0.700±0.132 0.700±0.060 0.701±0.168 0.698±0.133 Thymus weight / body weight ratio (%) 0.227±0.045 0.237±0.020 0.241±0.054 0.233±0.043 Adrenal gland weight (g) 0.067±0.013 0.061±0.008 0.067±0.012 0.067±0.017 Adrenal weight / body weight ratio 0.022±0.004 0.021±0.002 0.023±0.004 0.022±0.005 Compared with the negative control group, all dosage groups showed [significant improvement]. P >0.05.

[0135] As shown in Tables 22 and 23, there were no significant differences in organ weight and organ coefficient between the female and male dosage groups and the negative control group (P>0.05).

[0136] 4.5.3 Histological changes: No histopathological changes related to the test substance were found in the high-dose group at the end of the experiment.

[0137] Liver: In the negative control group, one animal (1 / 20, ♀9) showed a small amount of inflammatory cell infiltration in the liver; in the high-dose group, one animal (1 / 20, ♂56) showed a small amount of inflammatory cell infiltration in the liver; in the high-dose group, two animals (2 / 20, ♀8, ♀40) showed a small amount of hepatocyte vacuolar degeneration; in other animals in the high-dose group and the negative control group, the liver lobules and portal areas were clearly defined, and hepatocytes were clearly visible, with no obvious abnormalities observed. Figures 6-8 ) Kidneys: In the high-dose group, one animal (1 / 20, male 55) showed a small amount of inflammatory cell infiltration in the renal interstitium; the renal capsules of other animals in the high-dose group and the negative control group were intact, and the glomeruli and proximal and distal convoluted tubules were clearly structured without obvious abnormalities. Figure 9 ) For details on lesion types and the number of cases, please refer to Table 24: Table 24 Summary of lesion types and number of cases.

[0138] gender lesion name negative control group High-dose group p-value ♀ n=10 n=10 A small amount of inflammatory cell infiltration in the liver 1 0 1.000 A small number of hepatocytes showed vacuolar degeneration. 0 2 0.474 ♂ n=10 n=10 A small amount of inflammatory cell infiltration in the liver 0 1 1.000 A small amount of inflammatory cell infiltration in the renal interstitium 0 1 1.000 total 1 4 The above results indicate that the pathological changes in the high-dose group and the negative control group were mainly manifested as a small amount of inflammatory cell infiltration in the liver, a small amount of hepatocyte vacuolar degeneration, and a small amount of inflammatory cell infiltration in the renal interstitium. These pathological changes are common spontaneous lesions in rats and should be unrelated to the test substance and have no toxicological significance.

[0139] Pathological histological examination data were analyzed using SPSS 20.0 statistical software, with Fisher's exact test (n≤40) as the statistical method. Statistical results showed no statistically significant difference between the high-dose group and the control group.

[0140] Histopathological examination results showed that no toxic pathological changes caused by the test substance were observed in rats after oral administration of the tablets of this invention for 28 days.

[0141] 4.6 Results and Discussion: Throughout the administration period of the test substance, the animals in all groups were in good general condition with no unexpected deaths. Compared with the negative control group, each dose of the test substance had no significant effect on clinical observation, ophthalmic examination, body weight, food intake, food utilization rate, or hematological indicators in rats. Compared with the negative control group, some indicators in routine urine tests and blood biochemical indicators showed statistically significant differences, but these were not clinically significant or were within the normal range of our laboratory. At the end of the experiment, there were no significant differences in the weight of each organ and the organ ratio in each dose group compared with the negative control group; no abnormalities were observed in the ophthalmic examination of any organ in each group, and no toxic pathological changes caused by the test substance were found in histopathological examination. These results indicate that continuous administration of low, medium, and high doses of the test substance to rats for 28 days did not induce significant toxic reactions.

[0142] Under the conditions of this experiment, the no adverse effect (NOAEL) observed in the oral toxicity test of the tablets of the present invention in rats over 28 days was 3.700 g / kg BW.

[0143] The embodiments of the present invention have been described in detail above, but the content described is only a preferred embodiment of the present invention and should not be considered as limiting the scope of the present invention. All equivalent changes and improvements made within the scope of the present invention should still fall within the patent coverage of the present invention.

Claims

1. A tablet for adjuvant protection against liver damage and improvement of hepatic lipid metabolism, characterized in that: The product comprises 250 parts by weight of yeast extract, 5 parts by weight of dihydroquercetin, 47.2-50.4 parts by weight of curcumin composite powder, 243 parts by weight of filler and 5.5 parts by weight of lubricant. The curcumin composite powder is prepared by the following method: (1) Dissolve 30 parts by weight of curcumin in 3000 parts by weight of 95% ethanol solution and stir at 60°C until completely dissolved. Add 10-12 parts by weight of cross-linked carboxymethyl cellulose sodium and stir evenly. Add 3000 parts by weight of 0-4°C water under high-speed stirring and continue stirring for 3-5 min. After vacuum distillation, dry under vacuum to obtain curcumin-cross-linked carboxymethyl cellulose sodium complex; (2) Mix 5-6 parts by weight of silica, 2.2-2.4 parts by weight of crushed ice with curcumin-cross-linked carboxymethyl cellulose sodium complex and add to a low-temperature ball mill. Grind at -5-0°C and 300-400 r / min for 20-30 min to obtain the product.

2. The tablet for assisting in the protection of liver damage and improving liver lipid metabolism according to claim 1, characterized in that: The curcumin composite powder was prepared by the following method: (1) 30 parts by weight of curcumin were dissolved in 3000 parts by weight of ethanol solution with a volume concentration of 95%, and stirred at 60°C until completely dissolved. 11 parts by weight of cross-linked carboxymethyl cellulose sodium were added and stirred at 300 r / min for 50 min. At a stirring speed of 1500 r / min, 3000 parts by weight of water at 0-4°C were quickly added and stirred at 1500 r / min for 3-5 min. The solvent was removed by vacuum distillation at 50°C, vacuum degree of -0.09 MPa and stirring speed of 600 r / min. The mixture was then vacuum dried at 40°C for 8-10 h to obtain the curcumin-cross-linked carboxymethyl cellulose sodium complex. (2) 5.5 parts by weight of silica, 2.2 parts by weight of crushed ice and the curcumin-cross-linked carboxymethyl cellulose sodium complex were mixed and added to a low-temperature ball mill. The mixture was ground at -5-0°C and a speed of 360 r / min for 20 min to obtain the curcumin-cross-linked carboxymethyl cellulose sodium complex.

3. The tablet for assisting in the protection of liver damage and improving liver lipid metabolism according to claim 2, characterized in that: The crushed ice has a particle size of 1-2 mm and is stored at -18°C.

4. The tablet for assisting in the protection of liver damage and improving liver lipid metabolism according to claim 3, characterized in that: The tablets have a friability of 0.15-0.23%, and the curcumin in the tablets has a saturated solubility of 317.53-321.70 μg / mL in artificial gastric fluid.

5. The tablet for assisting in the protection of liver damage and improving liver lipid metabolism according to any one of claims 1-4, characterized in that: The filler is 231 parts by weight of microcrystalline cellulose and 12 parts by weight of povidone K30, and the lubricant is 5.5 parts by weight of magnesium stearate.

6. A method for preparing a tablet according to claim 5 for assisting in the protection of liver injury and improving liver lipid metabolism, characterized in that: (S1) Mix 250 parts by weight of yeast extract, 231 parts by weight of microcrystalline cellulose and 5 parts by weight of dihydroquercetin through a 60-mesh sieve for 20 min to obtain a mixed powder; (S2) Prepare curcumin complex powder; (S3) Dissolve 12 parts by weight of povidone K30 in 150 mL of 95% ethanol solution to obtain a povidone ethanol solution; (S4) Mix the mixed powder and curcumin complex powder evenly, spray the povidone ethanol solution during the stirring process, form a soft mass, granulate through a 14-mesh sieve to obtain wet granules; (S5) Dry the wet granules at 50℃ to a moisture content of 3-5%, granulate through a 14-mesh sieve to obtain dry granules; (S6) Mix the dry granules with 5.5 parts by weight of magnesium stearate for 10 min, compress into tablets to obtain tablets for adjuvant protection against liver damage and improvement of liver lipid metabolism.

7. The method for preparing tablets for adjuvant protection against liver damage and improvement of hepatic lipid metabolism according to claim 6, characterized in that: (S4) uses an atomizing nozzle to spray povidone ethanol solution, and controls the spraying time to 8-10 minutes.

8. The use of the tablet according to claim 7 for assisting in the protection of liver damage and improving liver fat metabolism in the preparation of a drug or health food for assisting in the protection of liver damage and improving liver fat metabolism.

9. A curcumin composite powder, characterized in that: The preparation method is as follows: (1) Dissolve 30 parts by weight of curcumin in 3000 parts by weight of ethanol solution with a volume concentration of 95%, stir at 60°C until completely dissolved, add 10-12 parts by weight of cross-linked carboxymethyl cellulose sodium and stir at 300r / min for 50min, add 3000 parts by weight of 0-4°C water at a stirring speed of 1500 / min, stir continuously at 1500 / min for 3-5min, remove the solvent by vacuum distillation at 50°C and vacuum degree of -0.09MPa with a stirring speed of 600r / min, and vacuum dry at 40°C for 8-10h to obtain curcumin-cross-linked carboxymethyl cellulose sodium complex; (2) Mix 5-6 parts by weight of silica, 2.2-2.4 parts by weight of crushed ice with curcumin-cross-linked carboxymethyl cellulose sodium complex and add to a low temperature ball mill, grind at -5-0°C and a speed of 300-400r / min for 20-30min to obtain the curcumin-cross-linked carboxymethyl cellulose sodium complex.

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