A synergistic lycium polysaccharide-glycoside compound nutritional supplement and a preparation method thereof

Abstract

The application discloses a kind of synergistic lycium barbarum polysaccharide-glycoside composite nutritional supplement and preparation method thereof, belong to food nutritional supplement preparation technical field.New fresh Ningxia wolfberry is used as raw material, high-activity lycium barbarum polysaccharide is obtained by enzyme hydrolysis-ultrasonic synergistic extraction, fractional ultrafiltration purification, and target group and crosslinking site are introduced by "click chemistry" strategy;Ginkgo biloba flavonoid glycoside, astragalus saponin and gardenia jasminoides glycoside with specific active conformation are selected, and after being directionally modified by enzyme method, site-specific coupling is carried out with modified lycium barbarum polysaccharide, forming "polysaccharide-glycoside" target coupling compound;After compounding intestinal adhesion type adjuvant and antioxidant protective agent, the finished product is prepared after low-temperature vacuum spray granulation and target modification.The application realizes the double breakthrough of targeted delivery and synergistic effect, the intestinal target enrichment rate is increased by more than 60%, the bioavailability of active ingredient is 90%, the activity retention rate is more than 98% after 6 months of storage, and the antioxidant and immunomodulatory functions are increased by about 2 times compared with traditional products.

Description

Technical Field

[0001] This invention belongs to the field of food nutritional supplement preparation technology, specifically a synergistic wolfberry polysaccharide-glycoside compound nutritional supplement and its preparation method. Background Technology

[0002] With the popularization of the concept of precision nutrition, targeted nutritional supplements have become a new market hotspot, and consumers are demanding higher standards for targeted delivery, synergistic effects, and precise efficacy. Market data shows that the global precision nutritional supplement market will reach approximately $1.5 billion by 2025, with compound products targeting intestinal absorption experiencing an annual growth rate exceeding 10%. Compound products containing goji berry polysaccharides and glycosides have become mainstream due to their antioxidant and immunomodulatory functions; however, current technologies still have many key shortcomings that make it difficult to meet the needs of precision nutrition.

[0003] In the prior art, CN120788218A discloses a plant-derived nutritional supplement based on glycosides, which uses a physical mixing method to compound wolfberry polysaccharides and glycosides, but fails to solve the problems of component compatibility and absorption efficiency, with bioavailability generally below 50%; CN118546270A focuses on the optimization of the extraction process of wolfberry polysaccharides, without involving targeted modification and synergistic coupling, resulting in a single function and lack of targeting; CN115005430A achieves nutritional supplementation through compounding of commercial products, without core technological innovation, and has poor efficacy stability; CN113133522A uses seaweed as raw material to prepare a supplement through fermentation, which is not suitable for the wolfberry polysaccharide-glycoside system and lacks targeted design. In addition, the core limitations of CN120788218A and CN118546270A are: they only focus on physical mixing or single-component optimization, without achieving molecular-level coupling and targeted delivery; they lack site-specific modification, and the synergistic effect relies on simple superposition; the stability design is crude, the active ingredients are easily oxidized and inactivated, and the activity retention rate after 6 months is mostly less than 70%.

[0004] Current technological gaps are concentrated in the following areas: First, the lack of targeted delivery; existing products lack intestinal targeting function, and active ingredients are easily degraded in the stomach, resulting in an intestinal enrichment rate of less than 30%. Second, inefficient synergistic mechanisms; physical mixing or simple chemical combination cannot maximize functional synergy, limiting efficacy enhancement. Third, outdated conjugation technology; a lack of efficient and specific conjugation methods, resulting in low conjugation efficiency and numerous byproducts. Fourth, insufficient stability; no specific protection scheme designed for targeted conjugated complexes. This invention addresses these technological pain points by introducing innovative technologies such as click chemistry, enzymatic targeted modification, and intestinal targeted design, breaking through the traditional technical framework of compound nutritional supplements to create a precision nutritional supplement with strong targeting, significant synergistic effects, and excellent stability, filling a market gap. Summary of the Invention

[0005] (1) The purpose of this invention.

[0006] The purpose of this invention is to overcome the technical shortcomings of existing Lycium barbarum polysaccharide-glycoside compound nutritional supplements, such as lack of targeting, limited synergistic effects, low coupling efficiency, and insufficient stability, and to provide a synergistic Lycium barbarum polysaccharide-glycoside compound nutritional supplement and its preparation method. A click chemistry strategy is used to achieve site-specific coupling between Lycium barbarum polysaccharides and glycosides, introducing intestinal targeting groups (galactose residues) to enhance intestinal accumulation. Enzymatic modification of glycoside compounds is employed to optimize their active conformation and lipid solubility. Intestinal adhesion excipients and antioxidants are compounded to prolong the residence time of active ingredients in the intestine and prevent oxidative inactivation. Low-temperature vacuum spray granulation and targeted enhancement treatment ensure the product's targeting and stability, ultimately achieving a dual breakthrough in targeted delivery and synergistic effect, meeting the market demand for precision nutritional supplementation.

[0007] (2) The technical solution of the present invention.

[0008] The technical solution of this invention runs through the entire process of "targeted modification - enzymatic modification - site coupling - targeted molding": First, fresh Ningxia wolfberry is used as raw material. High-activity wolfberry polysaccharide is obtained through enzymatic hydrolysis-ultrasound synergistic extraction and fractional ultrafiltration purification. By azidation and propargylation modification, galactose targeting groups and alkyne cross-linking sites are introduced to obtain targeted modified wolfberry polysaccharide. Second, ginkgo leaf flavonoid glycosides, astragaloside, and geniposide are selected and modified by immobilized lipase directional acylation modification to optimize their lipid solubility and active conformation, thus obtaining an enzymatically modified glycoside complex. Subsequently, site-specific coupling between the targeted modified wolfberry polysaccharide and the enzymatically modified glycoside complex is achieved through click chemistry to form a "polysaccharide-glycoside" targeted coupling complex, ensuring molecular-level synergy. Chitosan-sodium alginate intestinal adhesion excipient and glutathione-vitamin C antioxidant protectant are compounded and molded by low-temperature vacuum spray drying. Finally, the targeting is enhanced by galactose modifier to obtain the finished product. The entire process employs multiple quality controls, with key parameters being precisely controllable and nitrogen protection throughout, ensuring the product's targeting, synergy, and stability.

[0009] A synergistic Lycium barbarum polysaccharide-glycoside complex nutritional supplement comprises, by weight: 10-18 parts of targeted modified Lycium barbarum polysaccharide, 50-65 parts of enzymatically modified glycoside complex, 6-12 parts of intestinal adhesion excipient, and 2-4 parts of antioxidant protectant.

[0010] Preferably, the targeted modified wolfberry polysaccharide is a water-soluble polysaccharide that has been modified by azide to introduce a target group (galactose residue) and an alkyne crosslinking site, with a molecular weight of 10,000-18,000 Daltons, a target group substitution degree of 0.4-0.6, and an alkyne grafting rate of 30%-45%.

[0011] Preferably, the intestinal adhesion excipient is a chitosan-based composite microsphere intestinal adhesion material, more preferably a chitosan-sodium alginate composite microsphere; preferably, the antioxidant is an antioxidant composition of reducing peptides and water-soluble vitamins, more preferably a compound of glutathione and vitamin C. The degree of substitution of the galactose targeting group was calculated as follows: Degree of substitution = number of moles of grafted galactose residues / number of moles of total sugar residues in Lycium barbarum polysaccharide, determined by high performance liquid chromatography (HPLC) to measure the molar amounts of galactose residues and total sugar residues after polysaccharide hydrolysis; the alkynyl grafting rate was calculated as follows: Grafting rate = number of moles of grafted alkynyl groups / number of moles of repeating units in Lycium barbarum polysaccharide, determined by 1H NMR spectroscopy (1H NMR spectroscopy). 1 The glycoside partition coefficient logP of the enzymatically modified glycoside complex was determined by ¹H-NMR, with the characteristic peak at 4.6-4.8 ppm. The determination conditions were 25℃, n-octanol-water two-phase system, equilibration time 24 h, and the concentration of the glycoside complex in the two phases was determined by high performance liquid chromatography and the logP value was calculated.

[0012] Preferably, the enzymatically modified glycoside complex is a complex formed by the directional acylation modification of ginkgo biloba flavonoids, astragaloside, and geniposide by lipase, followed by coupling with targeted modified Lycium barbarum polysaccharide via click chemistry, with a mass ratio of 4~6:2~4:1~3 and a coupling efficiency ≥90%; preferably, the intestinal adhesion excipient is chitosan-sodium alginate composite microspheres (particle size 5~10μm); preferably, the antioxidant is a compound of glutathione and vitamin C in a mass ratio of 0.5~2:1~3.

[0013] The preparation method of the chitosan-sodium alginate composite microspheres includes the following steps: dissolving chitosan (degree of deacetylation ≥85%, viscosity 50-200 mPa·s) and sodium alginate (viscosity 200-500 mPa·s) in a 0.8%-1.2% (w / v) glacial acetic acid solution at a mass ratio of 1-3:2-4 to prepare a mixed solution with a total concentration of 1.5%-2.5% (w / v), stirring at room temperature for 2-4 hours until completely dissolved, and allowing to stand to remove bubbles; and then, under stirring conditions (speed 300-600 rpm), mixing... The solution was sprayed into a 0.4%~0.6% (w / v) calcium chloride crosslinking solution through a microporous atomizer (pore size 0.2-0.5 mm), with an atomization pressure of 0.1-0.2 MPa and a receiving distance of 10-20 cm. The crosslinking was cured at room temperature for 1-2 h. The obtained microspheres were washed with deionized water 2-3 times to remove free calcium ions, and then placed in a freeze dryer for pre-freezing at -40℃ to -50℃ for 3-5 h. They were then sublimated and dried under a vacuum of 5-10 Pa for 20-30 h to obtain chitosan-sodium alginate composite microspheres with a particle size of 5-10 μm.

[0014] Preferably, the galactose residues of the targeted modified Lycium barbarum polysaccharide specifically bind to the galactose receptor on the surface of intestinal epithelial cells; preferably, the degree of acylation of the enzymatically modified glycoside complex is 0.3~0.5, and the lipid-water partition coefficient logP is 1.8~2.5; preferably, the in vitro intestinal targeted enrichment rate of the coupled complex is ≥75%.

[0015] This invention also discloses a method for preparing a synergistic Lycium barbarum polysaccharide-glycoside complex nutritional supplement, comprising the following steps: S1. Preparation of targeted modified Lycium barbarum polysaccharides: S11. Take 10-20 kg of fresh Ningxia wolfberries, rinse 3-5 times with clean water and drain. Add 2-4 L of deionized water and put them into a colloid mill (3000-4000 r / min, stator-rotor gap 0.05-0.10 mm) to homogenize for 15-20 min. Add a compound enzymatic hydrolysate (cellulase: pectinase: β-glucosidase = 4-6:2-4:1-3), with 10000 U / g cellulase and pectinase... Enzyme 30000 U / g, β-glucosidase 100 U / g, total enzyme activity of compound enzyme powder 18010~34030 U / g, mass concentration of compound enzyme hydrolysate 2.0%~3.0%, final total enzyme activity of enzymatic hydrolysis system 3602~10209 U / g, enzymatic hydrolysis temperature 45~55℃, pH 4.5~5.5, material-liquid ratio 1:12~1:18, stirring speed 150~200 r / min, enzymatic hydrolysis 2~3 h; S12. The enzymatic hydrolysate was extracted with ultrasonic assistance (power 400~600W, temperature 50~60℃, time 1.5~2.5h), and then centrifuged in a disc centrifuge (3000~4000r / min, separation factor 3000~4000×g) for 15~25min. The supernatant was collected, filtered through a 0.40~0.50μm microporous membrane, and then passed through a staged ultrafiltration system, passing through a 15000-20000Da and 4000-6000Da polyethersulfone membrane for ultrafiltration in sequence, and the 10000-18000Da retentate was collected. S13. Add ≥95% food-grade ethanol to the retentate to achieve an alcohol content of 80%~90%, refrigerate at 10~15℃ and stand for 24~36h, collect the precipitate by suction filtration using a Buchner funnel, wash 2~4 times with 70%~80% ethanol, and freeze-dry (pre-freeze at -40~-50℃ for 3~5h, sublimation drying at -20~-30℃ under vacuum of 5~10Pa, and desorption drying at 25~30℃ under vacuum of 3~6Pa) to obtain highly active Lycium barbarum polysaccharide (purity ≥95%). S14. Weigh 5-7g of highly active Lycium barbarum polysaccharide, dissolve it in 50-70mL of pH 7.2-7.6 phosphate buffer (0.12-0.18mol / L), add 1.0-1.4 times the molar ratio of succinimide azidoacetate, and stir under nitrogen protection at 35-45℃ and 120-180r / min for 2.5-3.5h to introduce azido groups; then add 0.6-1.0 times the molar ratio of propargyl bromide, and stir at 45-55℃ and 180-220r / min for 2-3h to introduce alkynyl crosslinking sites; dialyze the reaction solution through a dialysis bag (molecular weight cutoff 10000Da) for 30-40h (changing the solution every 5-7h), and freeze-dry to obtain targeted modified Lycium barbarum polysaccharide; S2. Preparation of enzymatically modified glycoside complexes: S21. Weigh out ginkgo flavonoids (purity ≥95%), astragaloside (purity ≥90%), and geniposide (purity ≥90%) in a mass ratio of 4~6:2~4:1~3, mix them, add 10~14 times the mass of ethanol-water mixture (volume ratio 6:4~8:2), stir at 30~40℃ and 180~220r / min to dissolve them, and obtain a glycoside mixture. S22. Add immobilized lipase (enzyme activity 5000~7000U / g, amount is 6%~10% of the total mass of glycosides) to the glycoside mixture, add acylation reagent at a molar ratio of 0.4~0.8, stir the reaction at 40~50℃ and 160~200r / min for 3~5h, and perform enzymatic targeted acylation modification; after the reaction is completed, filter and recover the immobilized lipase, purify the filtrate by silica gel column chromatography (eluent: dichloromethane-methanol = 8:1~10:1), concentrate and dry to obtain the enzymatically modified glycoside complex; S3. Site-specific coupling reaction: S31. Targeted modified Lycium barbarum polysaccharide was dissolved in phosphate buffer (pH 7.2-7.6, concentration 12-18 mg / mL), and an enzymatically modified glycoside complex (mass ratio 1:3-1:5) was added. 4-6 mol% CuSO4·5H2O and 8-12 mol% sodium ascorbate were added. The mixture was stirred at 30-40℃ and 220-280 r / min for 5-7 h under nitrogen protection. Azide-alkynyl site-specific coupling was achieved through click chemistry. S32. The coupling reaction solution was purified by gel filtration chromatography, the target component was collected, and freeze-dried to obtain the "polysaccharide-glycoside" targeted coupling complex (coupling efficiency ≥90%). S4. Targeted molding and stabilization treatment: S41. Take the targeted coupling complex, add intestinal adhesion excipient (chitosan-sodium alginate composite microspheres, mass ratio 1~3:2~4) and antioxidant protectant (glutathione-vitamin C=0.5~2:1~3), add deionized water to make a mixture with a solid content of 20%~30%, and filter it through a 0.20~0.25μm microporous membrane; S42. Pump the mixture into a low-temperature vacuum spray dryer, control the feed rate at 10~15mL / min, the inlet air temperature at 120~140℃, the outlet air temperature at 45~55℃, the vacuum degree inside the tower at -0.07~-0.09MPa, the atomization pressure at 0.4~0.5MPa, and provide nitrogen protection throughout the process (oxygen content ≤3%). S43. The dried powder is sieved through a 180-220 mesh vibrating screen, and the sieve material is collected. 0.3%-0.7% of galactose modifier is sprayed in a sterile environment, and the powder is aged for 2-4 hours at 25-35℃ and 35%-45% relative humidity to enhance its targeting. Subsequently, it is vacuum packaged (vacuum degree ≤ -0.095MPa), and nano-level desiccant (2%-4% of the product weight) is placed inside the packaging bag to obtain the finished product of targeted synergistic wolfberry polysaccharide-glycoside coupled nutritional supplement.

[0016] Preferably, in step S11, the mass concentration of the compound enzymatic hydrolysate is 2.0%~3.0%, and ultrasonic assistance (power 180~220W, time 4~6min) is used every 25~35min during enzymatic hydrolysis to promote enzymatic hydrolysis efficiency; in step S12, the ultrasonic frequency of ultrasonic extraction is 35~45kHz, the operating pressure of fractional ultrafiltration is 0.3~0.4MPa, and the temperature is controlled at 23~27℃.

[0017] Preferably, in step S14, the purity of succinimide azidoacetate is ≥99%, the dropping rate of propargyl bromide is 0.2~0.4 mL / min, and the temperature is controlled by an ice bath (≤45℃) during the reaction; the dialysis bag is soaked in 0.08~0.12 mol / L EDTA solution for 0.8~1.2 h before use to remove metal impurities.

[0018] Preferably, in step S22, the immobilized lipase is one or more of immobilized Candida antarcticis lipase B, immobilized Pseudomonas fluorescens lipase, immobilized Rhizopus miheyne lipase, and immobilized Candida pleurisy lipase; the pH of the acylation reaction system is controlled at 6.0~6.5; the elution flow rate of silica gel column chromatography is 1.2~1.8 BV / h, and the main peak component at a wavelength of 270~290 nm is collected.

[0019] Preferably, in step S22, the acylation reagent is selected from one or more of vinyl octanoate, vinyl decanoate, vinyl laurate, and vinyl palmitate, and more preferably vinyl octanoate.

[0020] Preferably, in step S31, the concentration of CuSO4·5H2O solution is 0.08~0.12mol / L, and the concentration of sodium ascorbate solution is 0.18~0.22mol / L. Both are prepared and used immediately. The reaction progress is monitored in real time during the coupling reaction, and the reaction is stopped when the ultraviolet absorption peak (270~290nm) of the reaction solution no longer changes.

[0021] Preferably, in step S42, the atomizer speed of the low-temperature vacuum spray dryer is 22000~28000 r / min, the purity of nitrogen is ≥99.995%, and the introduction rate is 0.6~1.0 m. 3 / h; In step S43, the galactose modifier is a galactose-bovine serum albumin conjugate, and the spraying method is atomized spraying (droplet size 5~10μm).

[0022] Preferably, the supplement has an intestinal targeted enrichment rate of ≥75%, a DPPH free radical scavenging rate of ≥98%, a macrophage phagocytosis rate of 35.2%-37.8%, and a shelf life of 24 months, making it suitable for the precise nutritional supplementation scenarios of middle-aged and elderly people and sub-healthy individuals.

[0023] Preparation method of compound enzymatic hydrolysate: Weigh cellulase (10000U / g), pectinase (30000U / g), and β-glucosidase (100U / g) in a mass ratio of 4~6:2~4:1~3, and mix them evenly to obtain compound enzyme powder; dissolve the compound enzyme powder in deionized water and stir until completely dissolved to prepare an aqueous solution with a mass concentration of 2.0%~3.0%, which is the compound enzymatic hydrolysate. Prepare and use immediately.

[0024] (3) The core innovation of this invention is explained.

[0025] Targeted conjugation technology innovation: Click chemistry is introduced into the Lycium barbarum polysaccharide-glycoside complex system. Through specific conjugation at the "azido-alkynyl" site, precise molecular-level binding of the two is achieved, with a conjugation efficiency of ≥90%, which is more than 40% higher than that of traditional chemical conjugation. At the same time, a galactose targeting group is introduced, which specifically binds to the galactose receptor on the surface of intestinal epithelial cells. The intestinal targeted enrichment rate is increased from less than 30% in traditional products to more than 75%, solving the technical pain point of low delivery efficiency of active ingredients.

[0026] Innovative Enzymatic Directed Modification and Synergistic Design: Immobilized lipases are used to perform targeted acylation modification of glycosides, precisely controlling the degree of acylation substitution (0.3~0.5), optimizing their lipid solubility and active conformation, making it easier for glycosides to couple with Lycium barbarum polysaccharides and exert synergistic effects. By screening the optimal ratio (flavonoid glycosides: saponins: geniposides = 4~6:2~4:1~3), the synergistic enhancement of antioxidant and immunomodulatory functions is achieved, with efficacy approximately twice that of single-component or physical mixture systems.

[0027] Innovative dual delivery system combining intestinal adhesion and targeting: The combination of chitosan and sodium alginate microspheres as an intestinal adhesion excipient exhibits excellent biocompatibility and intestinal adhesion, extending the product's residence time in the intestine (from 2 hours to over 8 hours). Combined with the specific recognition of galactose targeting groups, a dual delivery system of "adhesion + targeting" is formed, further improving the intestinal absorption efficiency and enrichment rate of active ingredients, with a bioavailability of approximately 90%, far exceeding that of traditional products.

[0028] Innovation in end-to-end stabilization technology: Constructing a multi-dimensional stabilization system of "antioxidant + low-temperature vacuum drying + nitrogen protection + nano desiccant". Antioxidant (glutathione-vitamin C) inhibits the oxidation of active ingredients; low-temperature vacuum spray drying (air inlet 120~140℃) avoids the breakage of coupling bonds and loss of activity caused by high temperature; end-to-end nitrogen protection (oxygen content ≤3%) and nano desiccant work synergistically to prevent oxidation and moisture absorption during product storage, with an activity retention rate of over 98% after 6 months and a shelf life extended to 24 months.

[0029] (4) Related mechanisms The core mechanisms of this invention include a targeted recognition mechanism, a coupling synergistic mechanism, and a stabilization mechanism. Regarding the targeted recognition mechanism, the galactose residues on the surface of the modified Lycium barbarum polysaccharide specifically bind to the galactose lectin receptor on the surface of intestinal epithelial cells. Simultaneously, the chitosan-sodium alginate composite microspheres adhere to the intestinal mucosa through electrostatic interactions, forming a dual "recognition-adhesion" targeting mechanism. This allows for precise enrichment of the active ingredient in the intestine and prolongs its residence time. Regarding the coupling synergistic mechanism, click chemistry enables site-specific coupling between Lycium barbarum polysaccharide and glycosides, forming stable triazole bonds to prevent component separation. Lycium barbarum polysaccharide activates immune cell activity, and the acylated glycosides enhance antioxidant activity. Both synergistically activate antioxidant and immunomodulatory pathways in vivo, resulting in a multiplied effect. Regarding the stabilization mechanism, the glutathione-vitamin C composite protectant scavenge free radicals in the system, inhibiting the oxidation of active ingredients. Low-temperature vacuum drying reduces residual moisture and thermal damage. Nitrogen protection lowers the oxygen content of the system, and nano-desiccants adsorb residual moisture within the packaging. These multiple safeguards ensure the long-term storage stability of the product.

[0030] (5) Beneficial technical effects Significantly improved targeted delivery efficiency: Through the dual design of "targeted recognition + intestinal adhesion", the intestinal targeted enrichment rate reaches more than 75%, which is 60% higher than that of traditional products; the degradation rate of active ingredients in the stomach is reduced from 40% to less than 10%, and the intestinal absorption rate reaches 90%, achieving precise delivery and efficient absorption, solving the problem of "wide distribution and inefficient absorption" of traditional products.

[0031] The synergistic effect is outstanding: the click chemistry achieves molecular-level coupling of wolfberry polysaccharides and glycosides, and the enzymatic modification optimizes the active conformation. The two work together to achieve a DPPH free radical scavenging rate of over 98% and a macrophage phagocytosis rate of 35.2-37.8%, which is about twice as effective as traditional physical mixed products. The antioxidant and immune regulation functions are dually enhanced, which is suitable for precise nutritional supplementation needs.

[0032] Excellent storage stability and industrial adaptability: The multi-dimensional stabilization system design allows the product to be stored at 15~25℃ and relative humidity ≤60% for about 6 months with an activity retention rate of over 98% and a shelf life extended to about 24 months. The preparation process adopts standardized parameters and multiple quality controls, with key indicators such as coupling efficiency and targeting fluctuating by ≤2%, making it suitable for continuous industrial production. The product yield reaches over 88%, and the production cost is reduced by 15% compared to traditional processes, resulting in outstanding market competitiveness. Attached Figure Description

[0033] Figure 1 This is a schematic diagram of the entire process of the preparation method in Example 1 of the present invention.

[0034] Figure 2 This is a diagram illustrating the click chemical coupling mechanism of targeted modified Lycium barbarum polysaccharides and glycosides in Example 1 of the present invention.

[0035] Figure 3 This is a schematic diagram of the "targeted recognition-intestinal adhesion" dual delivery mechanism in Embodiment 1 of the present invention.

[0036] Figure 4 This is a comparison chart of the intestinal targeted enrichment rates of embodiments and comparative examples of the present invention.

[0037] Figure 5 This is a graph showing the change in the activity retention rate of the embodiments and comparative examples of the present invention after 6 months of storage.

[0038] The names of the components shown in the diagram are as follows: Figure 3 In the microspheres, 301 represents galactose residues, 302 represents electrostatic adhesion, 303 represents recognition and binding, 304 represents galactose receptors, 305 represents complex particles, and 306 represents adhesive microspheres. The dual delivery mechanism of "targeted recognition-intestinal adhesion" involves the specific binding of galactose residues to galactose receptors; and the electrostatic adhesion of adhesive microspheres, achieving dual targeting. Detailed Implementation

[0039] Before further describing specific embodiments of the present invention, it should be understood that the scope of protection of the present invention is not limited to the specific embodiments described below; it should also be understood that the terminology used in the embodiments of the present invention is for describing specific embodiments and not for limiting the scope of protection of the present invention. Test methods in the following embodiments that do not specify specific conditions are generally performed under conventional conditions or as recommended by the respective manufacturers.

[0040] When numerical ranges are given in the embodiments, it should be understood that, unless otherwise stated in this invention, both endpoints of each numerical range and any value between the two endpoints may be selected. Unless otherwise defined, all technical and scientific terms used in this invention have the same meaning as commonly understood by those skilled in the art. In addition to the specific methods, apparatus, and materials used in the embodiments, based on the knowledge of those skilled in the art and the description of this invention, any prior art methods, apparatus, and materials similar to or identical to those described in the embodiments of this invention may be used to implement this invention.

[0041] Unless otherwise stated, the test methods, detection methods and preparation methods disclosed in this invention all adopt conventional techniques in this technical field.

[0042] (a) Explanation of the function of reagents and chemical substances Fresh Ningxia wolfberries: As a natural raw material for wolfberry polysaccharides, wolfberries from the Zhongning production area of ​​Ningxia have a polysaccharide content of ≥5%, rich in active polysaccharides and amino acids, providing a high-quality raw material basis for targeted modification. Compound enzymatic hydrolysate (cellulase: pectinase: β-glucosidase = 4~6:2~4:1~3): Synergistically breaks down wolfberry cell walls, promotes polysaccharide dissolution, and improves extraction rate and polysaccharide activity; enzyme activity of 200,000 U / g ensures efficient hydrolysis. Azide-based succinimide ester: Used for azidation modification of wolfberry polysaccharides, introducing azido groups to provide reaction sites for click chemical coupling; purity ≥99% avoids impurities affecting coupling specificity. Propylene bromide: Introduces alkynyl crosslinking sites, undergoing click chemical reactions with azido groups to achieve site-specific linkage between polysaccharides and glycosides. Immobilized Candida antarcticis lipase B: Directional acylation modification of glycosides, precisely controlling acylation sites and degree of substitution, optimizing glycoside lipid solubility and active conformation, with an enzyme activity of 6000 U / g ensuring modification efficiency. Chitosan-sodium alginate composite microspheres: Intestinal-adhesive excipients that adhere to the intestinal mucosa via electrostatic interactions, prolonging product residence time; particle size of 5-10 μm is suitable for the intestinal absorption environment. Glutathione-vitamin C complex protectant: Synergistically scavenging free radicals and inhibiting the oxidation of active ingredients; glutathione provides a reducing environment, and vitamin C enhances antioxidant effects. Galactose-bovine serum albumin conjugate: A targeted enhancer that supplements galactose targeting groups, improving intestinal receptor recognition efficiency.

[0043] (ii) Source and model of reagents and equipment In the following embodiments of the present invention, fresh Ningxia wolfberries were purchased from Ningxia Zhongning Wolfberry Industry Group Co., Ltd. (Grade A); cellulase, 10000 U / g, was from Ningxia Xiasheng Industrial Group Co., Ltd.; pectinase, 30000 U / g, was from Shanghai Coleman Reagent; β-glucosidase, 100 U / g, was from Beijing Bio-Lab Technology Co., Ltd., product number: Y14643. The succinimide azidoacetate (99% purity) was purchased from Shanghai Aladdin Biochemical Technology Co., Ltd.; the immobilized Candida antarcticis lipase B (enzyme activity 6000U / g) was purchased from Beijing Lingbao Technology Co., Ltd.; the ginkgo flavonoid glycosides (95% purity), astragaloside (90% purity), and geniposide (90% purity) were purchased from Xi'an Xiaocao Plant Technology Co., Ltd.; chitosan, sodium alginate, glutathione, and vitamin C were purchased from Sinopharm Chemical Reagent Co., Ltd. (food grade); the galactose-bovine serum albumin conjugate was purchased from Xi'an Qiyue Biotechnology Co., Ltd., item number: Q-0024218; the nano-desiccant, colloid mill, disc centrifuge, fractionated ultrafiltration system, freeze dryer, low-temperature vacuum spray dryer, gel filtration chromatography column, constant temperature and humidity chamber, and vacuum packaging machine are all conventional equipment in this technical field.

[0044] Example 1 A method for preparing a synergistic Lycium barbarum polysaccharide-glycoside compound nutritional supplement includes the following steps: Take 10 kg of fresh Ningxia Lycium barbarum, wash it, add 2 L of deionized water, and homogenize it in a colloid mill for 15 min. Adjust the material-liquid ratio to 1:12, add a 2.0% (w / w) compound enzymatic hydrolysate (cellulase: pectinase: β-glucosidase = 4:2:1, cellulase 10000 U / g, pectinase 30000 U / g, β-glucosidase 100 U / g, total enzyme activity of compound enzyme powder 18010 U / g, final total enzyme activity of the enzymatic hydrolysate system 3602 U / g), and enzymatically hydrolyze at 45℃ and pH 4.5 for 2 h, supplemented by ultrasonic treatment at 200W for 5 min every 30 min. Heat the enzymatic hydrolysate to 50℃ and ultrasonically extract it at 400W for 2 h, then centrifuge it in a disc centrifuge for 15 min, and filter the supernatant through a 0.45 μm microporous membrane. The filtrate was fed into a fractional ultrafiltration system, passing sequentially through 18000 Da and 5000 Da polyethersulfone membranes at 0.35 MPa and 25 °C, collecting the 10000-18000 Da cutoff. 95% ethanol was added to the cutoff until the alcohol content reached 80%, and the mixture was allowed to stand at 10 °C for 24 h. The precipitate was collected by suction filtration, washed three times with 75% ethanol, and freeze-dried to obtain highly active Lycium barbarum polysaccharide. 5 g of the highly active Lycium barbarum polysaccharide was weighed and dissolved in 50 mL of pH 7.4 phosphate buffer. A 1.0 molar ratio of succinimide azidoacetate was added, and the mixture was stirred at 40 °C for 3 h under nitrogen protection to introduce azido groups. Then, 0.6 molar ratio of propargyl bromide was added dropwise at a rate of 0.3 mL / min, and the mixture was reacted at 50 °C for 2 h to introduce alkynyl groups. The reaction solution was dialyzed through a dialysis bag with a molecular weight cutoff of 10000 Da for 36 h, and then freeze-dried to obtain targeted modified Lycium barbarum polysaccharide. Weigh out 50g of ginkgo flavonoids, astragaloside, and geniposide (mass ratio 4:2:1) and dissolve them in 12 times their mass of an ethanol-water mixture (volume ratio 7:3). Add 6% of immobilized Candida antarctica lipase B and 0.4 molar ratio of vinyl octanoate, and react at 42℃ and 180 r / min for 4 h for targeted acylation modification. Filter the reaction solution to recover the enzyme, and purify the filtrate by silica gel column chromatography (eluent: dichloromethane:methanol = 9:1). Collect the main peak fraction at 280 nm, concentrate and dry to obtain the enzymatically modified glycoside complex. Dissolve 10 parts of targeted modified Lycium barbarum polysaccharide in pH 7.4 buffer to prepare a 15 mg / mL solution, mix it with 50 parts of the enzymatically modified glycoside complex, add 5 mol% CuSO4·5H2O and 10 mol% sodium ascorbate, and react at 35℃ and 250 r / min for 6 h under nitrogen protection for click chemical coupling. The reaction solution was purified by gel filtration chromatography and freeze-dried to obtain the "polysaccharide-glycoside" targeted coupling complex.The complex was mixed with 6 parts chitosan-sodium alginate composite microspheres (prepared by cross-linking chitosan and sodium alginate at a mass ratio of 1:2, with a particle size of 8 μm) and 2 parts glutathione-vitamin C (mass ratio of 1:1) antioxidant protectant. Deionized water was added to prepare a mixture with a solid content of 25%, which was then filtered through a 0.22 μm filter membrane. The mixture was pumped into a low-temperature vacuum spray dryer at a rate of 10 mL / min. The inlet air temperature was set to 120℃, the outlet air temperature to 45℃, the vacuum degree inside the tower to -0.08 MPa, the atomization pressure to 0.45 MPa, and the atomizer speed to 25000 r / min. High-purity nitrogen gas was used for protection throughout the process. After drying, the powder is passed through a 200-mesh sieve and sprayed with 0.3% galactose-bovine serum albumin conjugate in a sterile environment. It is then aged for 3 hours at 30°C and 40% relative humidity. Finally, it is packaged under a vacuum of ≤-0.095MPa and 3% nano-desiccant is added to obtain the finished product.

[0045] Preparation of chitosan-sodium alginate composite microspheres: Chitosan with a degree of deacetylation of 85% and a viscosity of 100 mPa·s and sodium alginate with a viscosity of 300 mPa·s were dissolved in 1.0% (w / v) glacial acetic acid solution at a mass ratio of 1:2 to prepare a mixed solution with a total concentration of 2.0% (w / v). The solution was stirred at 25°C for 3 h until completely dissolved and allowed to stand to remove bubbles. The mixed solution was sprayed into a 0.5% (w / v) calcium chloride crosslinking solution through a microporous atomizer (pore size 0.3 mm) under stirring at 500 rpm. The atomization pressure was 0.15 MPa and the receiving distance was 15 cm. The solution was crosslinked and cured at 25°C for 1.5 h. The obtained microspheres were washed three times with deionized water to remove free calcium ions. Then, they were placed in a freeze dryer and pre-frozen at -45°C for 4 h. They were then sublimated and dried under a vacuum of 8 Pa for 25 h. The microspheres with a particle size of 8 μm were obtained by sieving.

[0046] Example 2 A method for preparing a synergistic Lycium barbarum polysaccharide-glycoside compound nutritional supplement includes the following steps: Take 15 kg of fresh Ningxia Lycium barbarum, wash it, and add 3 L of deionized water to homogenize for 18 min. Adjust the material-to-liquid ratio to 1:15, add a 2.5% (w / w) compound enzymatic hydrolysate (cellulase:pectinase:β-glucosidase = 5:3:2, cellulase 10000 U / g, pectinase 30000 U / g, β-glucosidase 100 U / g, total enzyme activity of the compound enzyme powder 25020 U / g, final total enzyme activity of the enzymatic hydrolysate system 6255 U / g), and enzymatically hydrolyze for 2.5 h at 50℃ and pH 5.0, supplemented by ultrasonic treatment. Extract the enzymatic hydrolysate with ultrasound at 550 W for 2 h, centrifuge and filter, and collect the 10000-18000 Da cutoff liquid by fractional ultrafiltration. Ethanol precipitation and freeze-drying yield highly active Lycium barbarum polysaccharides. 6g of the polysaccharide was weighed and dissolved in 60mL of buffer solution. A 1.2 molar ratio of succinimide azidoacetate was added, and the mixture was reacted for 3 hours. Then, it was reacted with 0.8 molar ratio of propargyl bromide at 52℃ for 2.5 hours. The resulting product was dialyzed and lyophilized to obtain targeted modified Lycium barbarum polysaccharide. 58g of ginkgo biloba flavonoids, astragaloside, and geniposide (mass ratio 5:3:2) were weighed, dissolved, and then 8% of the total mass of immobilized lipase and 0.6 molar ratio of vinyl octanoate were added. The mixture was reacted at 45℃ for 4.5 hours, and the resulting product was purified to obtain an enzymatically modified glycoside complex. 14 parts of the targeted modified Lycium barbarum polysaccharide were mixed with 58 parts of the enzymatically modified glycoside complex (mass ratio 1:4), and a catalyst was added for click chemical coupling. The purified product was then purified to obtain a targeted coupling complex. The complex was mixed with 9 parts chitosan-sodium alginate composite microspheres (mass ratio 2:3) and 3 parts antioxidant (glutathione:vitamin C = 1:2) to prepare a mixture with a solid content of 28%. The spray drying parameters were adjusted to a feed rate of 12 mL / min, an inlet air temperature of 130℃, and an outlet air temperature of 50℃, with other conditions the same as in Example 1. After sieving the dried powder, 0.5% galactose modifier was sprayed on, and the mixture was aged and vacuum-packed to obtain the finished product.

[0047] Preparation of chitosan-sodium alginate composite microspheres: Chitosan with a degree of deacetylation of 85% and a viscosity of 120 mPa·s and sodium alginate with a viscosity of 350 mPa·s were dissolved in 1.0% (w / v) glacial acetic acid solution at a mass ratio of 2:3 to prepare a mixed solution with a total concentration of 2.0% (w / v). The solution was stirred at 25°C for 3 h until completely dissolved and allowed to stand to remove bubbles. The mixed solution was sprayed into a 0.5% (w / v) calcium chloride crosslinking solution through a microporous atomizer (pore size 0.3 mm) under stirring at 500 rpm. The atomization pressure was 0.15 MPa and the receiving distance was 15 cm. The solution was crosslinked and cured at 25°C for 1.5 h. The resulting microspheres were washed three times with deionized water, pre-frozen at -45°C for 4 h, and sublimated and dried under vacuum of 8 Pa for 25 h. The microspheres with a particle size of 7 μm were obtained by sieving.

[0048] Example 3 A method for preparing a synergistic Lycium barbarum polysaccharide-glycoside compound nutritional supplement includes the following steps: Take 20 kg of fresh Ningxia Lycium barbarum, wash it, and add 4 L of deionized water to homogenize for 20 min. Adjust the material-liquid ratio to 1:18, and add a 3.0% (w / w) compound enzymatic hydrolysate (cellulase:pectinase:β-glucosidase = 6:4:3, cellulase 10000 U / g, pectinase 30000 U / g, β-glucosidase 100 U / g, total enzyme activity of compound enzyme powder 34030 U / g, final total enzyme activity of the enzymatic hydrolysate system 10209 U / g). Enzymatic hydrolysis is carried out at 55℃ and pH 5.5 for 3 h, supplemented by ultrasonic treatment. The enzymatic hydrolysate is ultrasonically extracted at 600 W for 2.5 h, centrifuged and filtered, and the 10000-18000 Da cutoff liquid is collected by fractional ultrafiltration. High-activity Lycium barbarum polysaccharide is obtained by alcohol precipitation and freeze-drying. 7g of the polysaccharide was weighed and dissolved in 70mL of buffer solution. A 1.4 molar ratio of succinimide azidoacetate was added, and the mixture was reacted for 3.5h. Then, it was reacted with 1.0 molar ratio of propargyl bromide at 55℃ for 3h. The resulting product was dialyzed and lyophilized to obtain targeted modified Lycium barbarum polysaccharide. 65g of ginkgo biloba flavonoids, astragaloside, and geniposide (mass ratio 6:4:3) were weighed, dissolved, and then 10% of the total mass of immobilized lipase and 0.8 molar ratio of vinyl octanoate were added. The mixture was reacted at 48℃ for 5h, and the resulting product was purified to obtain an enzymatically modified glycoside complex. 18 parts of the targeted modified Lycium barbarum polysaccharide were mixed with 65 parts of the enzymatically modified glycoside complex (mass ratio approximately 1:3.6), and a catalyst was added for click chemical coupling. The purified product was then purified to obtain a targeted coupling complex. The complex was mixed with 12 parts chitosan-sodium alginate composite microspheres (mass ratio 3:4) and 4 parts antioxidant (glutathione:vitamin C = 2:3) to prepare a mixture with a solid content of 30%. The spray drying parameters were adjusted to a feed rate of 15 mL / min, an inlet air temperature of 140℃, and an outlet air temperature of 55℃, with other conditions the same as in Example 1. After sieving the dried powder, 0.7% galactose modifier was sprayed on, and the mixture was aged and vacuum-packed to obtain the finished product.

[0049] Preparation of chitosan-sodium alginate composite microspheres: Chitosan with a degree of deacetylation of 85% and a viscosity of 150 mPa·s and sodium alginate with a viscosity of 400 mPa·s were dissolved in 1.0% (w / v) glacial acetic acid solution at a mass ratio of 3:4 to prepare a mixed solution with a total concentration of 2.0% (w / v). The solution was stirred at 25°C for 3 h until completely dissolved and allowed to stand to remove bubbles. The mixed solution was sprayed into a 0.5% (w / v) calcium chloride crosslinking solution through a microporous atomizer (pore size 0.3 mm) under stirring at 500 rpm. The atomization pressure was 0.15 MPa and the receiving distance was 15 cm. The solution was crosslinked and cured at 25°C for 1.5 h. The obtained microspheres were washed three times with deionized water, pre-frozen at -45°C for 4 h, and sublimated and dried under vacuum of 8 Pa for 25 h. The microspheres with a particle size of 9 μm were obtained by sieving.

[0050] Comparative Example 1 Using the invention patent technology disclosed in Chinese Invention Patent Publication No. CN120788218A, 14 parts of unmodified wolfberry polysaccharide, 58 parts of unmodified glycoside mixture, 9 parts of yam starch, and 3 parts of vitamin E were physically mixed to obtain a mixture with a solid content of 25%, which was then filtered through a 0.22μm filter membrane. A conventional spray drying process was adopted, with the feed rate set at 10mL / min, atomization pressure at 0.45MPa, atomizer speed at 25000r / min, inlet air temperature at 190℃, outlet air temperature at 85℃, and no nitrogen protection. After drying, the powder was passed through a 200-mesh sieve, without targeted modification, enzymatic modification, or click coupling steps. The finished product was packaged in ordinary sealed packaging without adding desiccant or vacuum protection, and stored at 25℃ and 60% relative humidity.

[0051] Comparative Example 2 The non-targeted modification step (step S14 omitted) and the remaining raw material ratios and preparation steps are the same as in Example 2; in the click chemical coupling stage, a 0.10 mol / L CuSO4·5H2O solution and a 0.20 mol / L sodium ascorbate solution are prepared and used immediately, and the catalyst addition amount is the same as in Example 2; the preparation method of chitosan-sodium alginate composite microspheres and the finished product packaging method (vacuum packaging + 3% nano silica gel desiccant) are completely the same as in Example 2.

[0052] Comparative Example 3 Traditional chemical coupling (glutaraldehyde crosslinking) was used instead of click chemistry, and the remaining raw material ratios and preparation steps were the same as in Example 2. The specific coupling steps were as follows: 14 parts of unmodified wolfberry polysaccharide and 58 parts of enzymatically modified glycoside complex were mixed, and 25% glutaraldehyde solution was added. The amount of glutaraldehyde was 3% of the total mass of polysaccharide and glycoside. The mixture was stirred at 25°C and 200 r / min for 8 hours. The composite was achieved by crosslinking with glutaraldehyde. No CuSO4·5H2O or sodium ascorbate was added. The preparation method of chitosan-sodium alginate composite microspheres and the finished product packaging method (vacuum packaging + 3% nano silica gel desiccant) were completely consistent with Example 2.

[0053] Comparative Example 4 The enzyme-free modification step (step S22 omitted) and the remaining raw material ratios and preparation steps are the same as in Example 2; in the click chemical coupling stage, a 0.10 mol / L CuSO4·5H2O solution and a 0.20 mol / L sodium ascorbate solution are prepared and used immediately, and the catalyst addition amount is the same as in Example 2; the preparation method of chitosan-sodium alginate composite microspheres and the finished product packaging method (vacuum packaging + 3% nano silica gel desiccant) are completely the same as in Example 2.

[0054] Comparative Example 5 The process employed was physical mixing followed by conventional spray drying, with the remaining raw material ratios and preparation steps identical to those in Example 2. No click-chemical coupling step was used; the targeted modified Lycium barbarum polysaccharide was directly and physically mixed with the enzymatically modified glycoside complex. The spray drying process used conventional methods, with a feed rate of 12 mL / min, atomization pressure of 0.45 MPa, atomizer speed of 25000 r / min, inlet air temperature of 190°C, outlet air temperature of 85°C, and no nitrogen protection. The finished product was packaged in ordinary sealed packaging without added desiccant or vacuum protection and stored at 25°C and 60% relative humidity.

[0055] Performance testing (I) Testing Standards and Methods Intestinal targeted enrichment rate: Using a rat in situ intestinal perfusion model, the sample was coupled with a fluorescent label (FITC). Intestinal tissue and contents were collected at different time points after perfusion, and the fluorescence intensity was measured by a fluorescence spectrophotometer to calculate the intestinal enrichment rate.

[0056] Bioavailability: SD rats were administered the drug by gavage, and plasma was collected at different time points. The concentration of the active ingredient was determined by HPLC-MS / MS, and the area under the curve (AUC) was calculated to compare bioavailability.

[0057] DPPH free radical scavenging rate: The free radical scavenging rate of the compound nutritional supplement was determined using the DPPH free radical scavenging method. 0.1 g of each example and comparative sample was dissolved in distilled water and diluted to 1000 mL. 1 mL of the sample solution was mixed with 1 mL of 0.2 mmol / L DPPH ethanol solution, and the mixture was reacted in the dark for 30 min. The absorbance was then measured at 517 nm. The free radical scavenging rate was calculated. This method is based on the principle of spectrophotometry. The sample solution was mixed with a certain concentration of DPPH ethanol (or methanol) solution, and the mixture was reacted in the dark for a certain time (usually 30 minutes). DPPH free radicals have a characteristic absorption peak at 517 nm. When the antioxidant components in the sample provide hydrogen atoms to combine with DPPH free radicals, their absorbance decreases. The DPPH free radical scavenging rate of the sample was calculated by measuring the change in absorbance of the solution before and after the reaction.

[0058] Macrophage phagocytosis rate: Mouse peritoneal macrophage culture method, sample concentration 0.5 mg / mL, counted under a microscope after neutral red staining.

[0059] Storage stability: Samples were placed in a constant temperature and humidity chamber at 25℃ and 60% relative humidity, and samples were taken at 1, 3, 6, 12 and 24 months to determine the retention rate of active ingredients and appearance.

[0060] Intestinal transit time: Fluorescence imaging technology was used to track the distribution and metabolism of samples in rats and record the intestinal transit time.

[0061] (II) Test Results Table 1. Performance test results of the examples and comparative examples.

[0062] Examples 1-3 exhibit excellent performance, primarily due to the complete adoption of the targeted coupling and synergistic design technology of this invention: click chemistry achieves site-specific coupling between polysaccharides and glycosides, resulting in high coupling efficiency and structural stability, preventing component separation; the galactose targeting group specifically binds to intestinal receptors, significantly improving intestinal accumulation rate and residence time when combined with intestinal adhesive excipients; enzymatic modification optimizes the active conformation of glycosides, enhancing synergistic effects; and the multidimensional stabilizing system effectively inhibits oxidative inactivation, extending shelf life. Example 2, with the optimal parameter combination, demonstrates the best performance across all indicators, achieving an intestinal targeted accumulation rate of 82.6%, bioavailability of 90.3%, and a 24-month activity retention rate of 98.2%.

[0063] Comparative Example 1 performed the worst. Due to its traditional physical mixing and high-temperature spray drying method, lacking targeted, coupling, and enzymatic modification design, it exhibited poor component compatibility, low intestinal accumulation, and easy degradation and oxidation of active ingredients, failing to meet the needs of precision nutrition. Comparative Example 2 lacked a targeted modification step, relying solely on intestinal adhesion excipients, resulting in insufficient targeting and significantly lower intestinal accumulation and bioavailability compared to the examples. Comparative Example 3 used traditional glutaraldehyde crosslinking instead of click chemistry, leading to poor coupling specificity, numerous byproducts, impaired targeting and synergistic effects, and glutaraldehyde residue affecting product safety. Comparative Example 4 lacked an enzymatic modification step, resulting in unoptimized glycoside active conformations, insufficient lipophilicity and coupling compatibility, and lower synergistic effects and bioavailability than the examples. Comparative Example 5, limited by traditional processes and lacking core innovative technologies, lagged behind the examples of this invention in all aspects of performance, making it difficult to meet the market demands for precision nutrition.

[0064] Finally, it should be noted that the above embodiments are used to illustrate the technical solutions of the present invention and not to limit the scope of protection of the present invention. Although the present invention has been described in detail with reference to preferred embodiments, those skilled in the art should understand that modifications or equivalent substitutions can be made to the technical solutions of the present invention without departing from the essence and scope of the technical solutions of the present invention.

Claims

1. A synergistic Lycium barbarum polysaccharide-glycoside compound nutritional supplement, characterized in that, By weight, it includes the following components: Targeted modified wolfberry polysaccharide 10-18 parts, enzymatically modified glycoside complex 50-65 parts, intestinal adhesion excipient 6-12 parts, antioxidant protectant 2-4 parts; The targeted modified Lycium barbarum polysaccharide is a Lycium barbarum polysaccharide that has been modified by azide to introduce a galactose targeting group and an alkyne cross-linking site; the enzymatically modified glycoside complex is a mixture of ginkgo flavonoid glycosides, astragaloside and geniposide after being modified by immobilized lipase for directional acylation; the targeted modified Lycium barbarum polysaccharide and the enzymatically modified glycoside complex are site-specifically coupled through click chemistry to form a "polysaccharide-glycoside" targeted coupling complex.

2. The synergistic Lycium barbarum polysaccharide-glycoside compound nutritional supplement according to claim 1, characterized in that: The targeted modified Lycium barbarum polysaccharide has a molecular weight of 10,000-18,000 Daltons, a degree of substitution of the galactose targeting group of 0.4-0.6, and an alkyne grafting rate of 30%-45%.

3. The synergistic Lycium barbarum polysaccharide-glycoside compound nutritional supplement according to claim 1, characterized in that: In the enzymatically modified glycoside complex, the mass ratio of ginkgo flavonoid glycoside, astragaloside and geniposide is 4-6:2-4:1-3; the degree of acylation modification is 0.3-0.5, and the lipid-water partition coefficient logP is 1.8-2.

5.

4. The synergistic Lycium barbarum polysaccharide-glycoside compound nutritional supplement according to claim 1, characterized in that: The intestinal adhesion excipient is a chitosan-sodium alginate composite microsphere with a particle size of 5-10 μm, a chitosan degree of deacetylation ≥85%, a viscosity of 50-200 mPa·s, and a sodium alginate viscosity of 200-500 mPa·s; the antioxidant is a compound of glutathione and vitamin C with a mass ratio of 0.5-2:1-3.

5. A method for preparing the synergistic Lycium barbarum polysaccharide-glycoside complex nutritional supplement as described in any one of claims 1-4, characterized in that, Includes the following steps: S1. Preparation of targeted modified Lycium barbarum polysaccharide: Using Lycium barbarum as raw material, highly active Lycium barbarum polysaccharide was obtained by enzymatic hydrolysis-ultrasound synergistic extraction and fractional ultrafiltration purification; then, through azidation and propargylation reactions, it was modified by azidation and propargylation to introduce galactose targeting groups and alkynyl crosslinking sites, thus obtaining targeted modified Lycium barbarum polysaccharide. S2. Preparation of enzymatically modified glycoside complex: Ginkgo biloba flavonoids, astragaloside and geniposide were mixed and directionally acylated under the action of immobilized lipase and acylation reagent. After purification, the enzymatically modified glycoside complex was obtained. S3. Site-specific coupling reaction: The targeted modified Lycium barbarum polysaccharide from step S1 is mixed with the enzymatically modified glycoside complex from step S2, and coupled by click chemistry under the action of a catalyst. After purification, a "polysaccharide-glycoside" targeted coupling complex is obtained. S4. Targeted molding and stabilization treatment: The "polysaccharide-glycoside" targeted coupling complex prepared in step S3 is mixed with intestinal adhesion excipients and antioxidants, dried under low temperature vacuum spray, and then targeted strengthening treatment with galactose modifier to obtain the finished product.

6. The preparation method according to claim 5, characterized in that: In step S1, the compound enzyme used in the enzymatic hydrolysis-ultrasound synergistic extraction is a mixture of cellulase, pectinase, and β-glucosidase in a mass ratio of 4-6:2-4:1-3. The enzyme activities of each individual enzyme are 10,000 U / g for cellulase, 30,000 U / g for pectinase, and 100 U / g for β-glucosidase. The total enzyme activity of the compound enzyme powder is 18,010~34,030 U / g, the mass concentration of the compound enzyme hydrolysate is 2.0%~3.0%, and the final total enzyme activity of the enzymatic hydrolysis system is 3,602~10,209 U / g. The fractional ultrafiltration involves first passing the extract through an ultrafiltration membrane with a molecular weight cutoff of 15,000-20,000 Da and collecting the permeate; then, the permeate is concentrated through an ultrafiltration membrane with a molecular weight cutoff of 4,000-6,000 Da and the retentate is collected, thus obtaining the Lycium barbarum polysaccharide component with a molecular weight range of 10,000-18,000 Da.

7. The preparation method according to claim 5, characterized in that: In step S2, the immobilized lipase is one or more of immobilized Candida antarcticis lipase B, immobilized Pseudomonas fluorescens lipase, immobilized Mucor milch lipase, and immobilized Candida pleuropsis lipase; the acylation reagent is one or more of vinyl octanoate, vinyl decanoate, vinyl laurate, and vinyl palmitate.

8. The preparation method according to claim 5, characterized in that: In step S3, the catalyst is CuSO4·5H2O and sodium ascorbate. The amount of CuSO4·5H2O used is 4-6 mol of the total molar amount of the targeted modified wolfberry polysaccharide and the enzymatically modified glycoside complex, and the amount of sodium ascorbate used is 8-12 mol of the total molar amount of the targeted modified wolfberry polysaccharide and the enzymatically modified glycoside complex; the mass ratio of the targeted modified wolfberry polysaccharide to the enzymatically modified glycoside complex is 1:3-1:

5.

9. The preparation method according to claim 5, characterized in that: In step S4, the inlet air temperature of the low-temperature vacuum spray dryer is 120-140℃, the outlet air temperature is 45-55℃, the vacuum degree inside the tower is -0.07--0.09MPa, and nitrogen protection is applied throughout the process; the galactose modifier is a galactose-bovine serum albumin conjugate.

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